CANCER AND LEUKEMIA GROUP B CALGB 30801 A

Transcription

Activation Date: February 15, 2010
Includes Update #5
CANCER AND LEUKEMIA GROUP B
CALGB 30801
A RANDOMIZED PHASE III DOUBLE BLIND TRIAL EVALUATING SELECTIVE COX-2 INHIBITION IN COX-2
EXPRESSING ADVANCED NON-SMALL CELL LUNG CANCER
Celecoxib/Placebo (NSC #719627, CALGB IND #107051) will be supplied by the NCI PMB
Study Chair
Martin J. Edelman, M.D.
University of Maryland Greenebaum Cancer Center
22 South Greene Street
Baltimore, Maryland 21201
Tel: 410-328-2703
Fax: 410-328-1975
medelman@umm.edu
Respiratory Committee Chair
Everett Vokes, MD
Tel: 773-702-9306
Fax: 773-702-3002
evokes@medicine.bsd.uchicago.edu
Respiratory Pathology Cadre Leader
Richard Cheney
Tel: 716-845-7700
Fax: 716-845-3427
richard.cheney@roswellpark.org
Respiratory Correlative Sciences Chair
Robert Kratzke, MD
Tel: 612-626-3794
Fax: 612-625-6919
kratz003@umn.edu
Respiratory Correlative Sciences Co-chair
Ginger Milne
Tel: 615-936-5611
Fax: 615-322-3669
ginger.milne@vanderbilt.edu
PET Committee Chair
Mark Ratain, MD
Tel: 773-702-4400
Fax: 773-702-3969
mratain@medicine.bsd.uchicago.edu
PET Committee Co-chair
Michael Maitland, M.D., Ph.D.
Tel: 773-834-8981
Fax: 773-834-0188
mmaitlan@medicine.bsd.uchicago.edu
Respiratory Faculty Statistician
Xiaofei Wang, Ph.D.
Tel: 919-681-5406
Fax: 919-681-8028
xiaofei.wang@duke.edu
PET Faculty Statistician
Kouros Owzar, Ph.D.
Tel: 919-681-1829
Fax: 919-668-8028
owzar001@mc.duke.edu
Staff Statistician
Lydia Hodgson, M.S.
Tel: 919-681-1632
Fax: 919-681-8028
lydia.hodgson@duke.edu
Data Coordinator
Edythe Parker
Tel: 919-668-9365
Fax: 919-668-9348
edy.parker@duke.edu
Protocol Coordinator
Colleen RB Watt
Tel: 773-702-4670
Fax: 312-345-0117
cboyle@uchicago.edu
For NCI Use Only
Version Date: 11/04/11
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CALGB 30801
CALGB Central Office
230 West Monroe Street, Suite 2050
Chicago, IL 60606
Tel: 773-702-9171
Fax: 312-345-0117
www.calgb.org
Adverse Event Reporting
http://ctep.cancer.gov/reporting/adeers.html
CALGB Pathology Coordinating Office
The Ohio State University
Innovation Centre
2001 Polaris Parkway
Columbus, OH 43240
Tel: 614-293-7073 Fax: 614-293-7967
path.calgb@osumc.edu
CALGB Statistical Center
Hock Plaza
2424 Erwin Road, Suite 802
Durham, NC 27705
Tel: 919-668-9350
Data Operations Fax: 919-668-9348
Biostatistics Fax: 919-681-8028
CALGB Patient Registration
Tel: 919-668-9396
Fax: 919-668-9397
CALGB 30801 Pharmacy Contact
Carol Hubbard, RPh
Tel: 315-342-6215
hubbardc@upstate.edu
CALGB 30801 Nursing Contact
Michelle Bedor-Turner
Tel: 410-328-3929
mbedor@umm.edu
This study is supported by the NCI Cancer Trials Support Unit (CTSU).
Institutions not aligned with CALGB will participate through the CTSU mechanism as outlined
below and detailed in the CTSU logistical appendix.
This trial is open only to US and Canadian sites for both CALGB and the CTSU.
• The study protocol and all related forms and documents must be downloaded from the
protocol-specific Web page of the CTSU Web site located at http://www.ctsu.org
•
Send completed site registration documents to the CTSU Regulatory Office. Refer to the CTSU
logistical appendix for specific instructions and documents to be submitted.
•
Patient enrollments will be conducted by the CTSU. Refer to the CTSU logistical appendix for
specific instructions and forms to be submitted.
•
Data management will be performed by the CALGB. Case report forms (with the exception of
patient enrollment forms), clinical reports, and transmittals must be sent to CALGB unless
otherwise directed by the protocol. Do not send study data or case report forms to the CTSU
Data Operations.
•
Data query and delinquency reports will be sent directly to the enrolling site by CALGB
(generally via e-mail but may be sent via fax or postal mail). Please send query responses and
delinquent data to CALGB and do not copy the CTSU Data Operations. Query responses should
be sent to CALGB via postal mail (no transmittal form needs to accompany response). Each site
should have a designated CTSU Administrator and Data Administrator and must keep their
CTEP IAM account contact information current. This will ensure timely communication between
the clinical site and the CALGB Statistical Center.
Lead Group – Investigators from this Group should enroll patients through CALGB. CALGB
Ordering Group(s) – Investigators must have a current affiliation with one of these Groups
to receive investigational agent and / or an Investigator’s Brochure for this protocol.
CALGB and CTSU
Endorsing Groups–Investigators from these Groups must enroll patients via the CTSU.
SWOG
Karen L. Reckamp, M.D.
626-256-4673
kreckamp@coh.org
The pharmacogenomic component of this study is conducted as part of the NIH
Pharmacogenomics Research Network, which is funded through a separate U01 mechanism (see
http://www.nigms.nih.gov/pharmacogenomics/research_net.html) for details
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A RANDOMIZED PHASE III DOUBLE BLIND TRIAL EVALUATING SELECTIVE COX-2 INHIBITION IN COX-2
EXPRESSING ADVANCED NON-SMALL CELL LUNG CANCER
Required Initial Laboratory Values
(Pre-reg and Reg)
Granulocytes
≥1,500/µl
Platelets
≥100,000/µl
Calculated
Creatinine Clear.
≥ 45 ml/min
Bilirubin
≤1.5 mg/dl
AST and ALT
≤2.0 x ULN (up to
5 x ULN if liver
Reg only:
mets)
Serum albumin
≥ 2.5 g/dl
Patient Pre-registration Eligibility Criteria
Histologically or cytologically documented NSCLC
Stage IV and selected stage IIIB (Section 4.1.2)
Tissue specimen required
No untreated CNS metastases (Section 4.1.2)
Measurable or non-measurable disease (Section.4.1.3).
No prior chemotherapy, immunotherapy or systemic
treatments for NSCLC including adjuvant therapy.
≥2 weeks since prior surgery and recovered
ECOG PS 0-2
Age ≥18 years.
No concurrent malignancy (Section 4.1.6).
No known hypersensitivity to aspirin, NSAIDs or sulfonamides
No active ulcer disease.
No treatment with other investigational therapy.
No chronic therapy w/ non-steroidal anti-inflammatory drugs (Section 4.1.10).
No cardiac disease (Section 4.1.11)
Patients must be able to swallow capsules.
Non-pregnant and non-nursing
Patient Registration Eligibility Criteria
COX-2 index ≥ 2
Prior radiotherapy must be completed 2 weeks before protocol therapy begins.
Schema: 1 cycle = 21 days
COX-2 <2
P
R
ER
E
G
I
S
T
E
R
Tissue
submission for
COX-2 testing
by IHC
COX-2 ≥2
Not registered; treat at physician’s discretion
R
E
G
I
S
T
E
R
/
R
A
N
D
O
M
I
Z
E
ARM A
For Squamous Carcinoma:
Gemcitabine 1000 mg/m2 IV d 1,8
Carboplatin AUC = 5.5* IV d 1
Celecoxib 400 mg (1 capsule) po bid
OR
For Non-squamous Carcinoma:
Pemetrexed 500 mg/m2 IV d 1 w/ pre-meds
Carboplatin AUC = 6 IV d 1
Celecoxib 400 mg (1 capsule) po bid
ARM B
Gemcitabine 1000 mg/m2 d 1,8
Carboplatin AUC = 5.5* IV d 1
Placebo (1 capsule) po bid
OR
For Non-squamous Carcinoma:
Pemetrexed 500 mg/m2 IV d 1 w/ pre-meds
Carboplatin AUC = 6 IV d 1
Placebo (1 capsule) po bid
*
Patients treated with prior chest radiotherapy should receive carboplatin at an AUC=5.0 when
combined with gemcitabine.
Treat patients for a maximum of 6 cycles. For responding or stable disease after 6 cycles, continue
treatment with celecoxib/placebo beyond 6 cycles until tumor progression or unacceptable toxicity.
Discontinue all protocol therapy for disease progression or unacceptable toxicity.
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TABLE OF CONTENTS
SECTION
PAGE
1.0
INTRODUCTION ...........................................................................................................5
2.0
OBJECTIVES..............................................................................................................11
3.0
ON-STUDY GUIDELINES ............................................................................................12
4.0
ELIGIBILITY CRITERIA ...............................................................................................12
5.0
PRE-REGISTRATION, REGISTRATION/RANDOMIZATION AND STRATIFICATION .......14
6.0
DATA AND SAMPLE SUBMISSION ..............................................................................17
7.0
REQUIRED DATA .......................................................................................................21
8.0
TREATMENT PLAN .....................................................................................................22
9.0
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITIES ....................................24
10.0
DRUG FORMULATION, AVAILABILITY AND PREPARATION.........................................27
11.0
ANCILLARY THERAPY.................................................................................................34
12.0
CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE ......................................35
13.0
REMOVAL OF PATIENTS FROM PROTOCOL THERAPY ...............................................40
14.0
STATISTICAL CONSIDERATIONS................................................................................40
15.0
CORRELATIVE SCIENCES METHODOLOGY ...............................................................45
16.0
ADVERSE EVENT (AER) REPORTING .........................................................................50
17.0
REFERENCES ............................................................................................................52
18.0
MODEL CONSENT FORM ...........................................................................................56
APPENDIX I CTSU LOGISTICS ...............................................................................................69
APPENDIX II CRADA LANGUAGE ...........................................................................................73
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1.0
INTRODUCTION
Of 150,000 patients who will develop non-small cell lung cancer (NSCLC) in the United
States in the next year, at least 40% will present with metastatic disease, and the vast
majority of the remainder will eventually develop metastases. Recent advances in
chemotherapy have improved the outlook for patients with Stage IV disease. Studies
employing “best supportive care” result in a 4-6 month median survival with only 10% of
patients alive at one year. By comparison, median survival of about 6-8 months and one
year survival of 20% are achieved with “older” platinum (cisplatin or carboplatin) based
regimens (e.g., single-agent platinum, cisplatin/etoposide, cisplatin/vindesine). Most
recent studies evaluating combinations of platinums with “newer agents”
(carboplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/vinorelbine) have reported
improved median survivals to 8-10 months with one year survival of 30-35%, and/or
reduced toxicity relative to older combinations (1-3)
The recently reported results of the Eastern Cooperative Oncology Group trial (ECOG
1594) compared four platinum-based “new drug regimens”: cisplatin/paclitaxel,
cisplatin/gemcitabine, cisplatin/docetaxel and carboplatin/paclitaxel and found all to be
roughly equivalent in terms of response and survival. The regimen of
cisplatin/gemcitabine was significantly superior in terms of time-to-progression while the
regimen of carboplatin/paclitaxel was superior in terms of toxicity (4). Supporting the
conclusion of the equivalence of these regimens were the results of SWOG 9509 which
demonstrated
similar
response
and
survival
for
cisplatin/vinorelbine
and
carboplatin/paclitaxel (5). Though these results represent a therapeutic advance, only 1015% of patients will survive two years, and there are few long-term survivors.
Recently ECOG presented data (ECOG 4599) demonstrating that bevacizumab (Avastin)
was beneficial in selected patients with advanced NSCLC. This study compared
carboplatin/paclitaxel (AUC =6 and 200 mg/m2, respectively) vs. the same doses of
chemotherapy with bevacizumab (15 mg/kg), all drugs administered q21 days. A
significant advantage was found for patients on the experimental arm in terms of
response, median and one-year survival. However, this study involved a highly selected
population, excluding individuals with squamous cell carcinoma, CNS metastases,
bleeding or thrombotic disorder or a history of hemoptysis.
1.1
COX-2 inhibition (Celecoxib)
Cyclooxygenase-2 (COX-2), the enzyme that converts arachidonic acid to
prostaglandins is overexpressed in a variety of malignancies. Khuri and colleagues
demonstrated that overexpression of COX-2 is common in non-small cell lung cancer
and associated with poor prognosis (5). Nearly 80% of NSCLC express the COX-2
enzyme (6,7). COX-2 has been shown to be expressed not only in the tumor cells but
also in the tumor vasculature (8,9). Inhibition of COX-2 has resulted in reduced
proliferation of cancer cells in vitro (10). Celecoxib, a selective inhibitor of COX-2,
inhibits tumor growth of Lewis lung carcinoma implanted in mice in a dosedependent manner. The extent of inhibition ranges from 48% to 85% with increasing
doses of celecoxib (9). A selective COX-2 inhibitor, ns-398, enhanced the effects of
radiation in COX-2 overexpressing cells (11). In addition, it has recently been shown
that expression of COX-2 could be associated with overexpression of p-glycoprotein
(12). Inhibition of COX -2 could potentially reverse drug resistance. Several selective
COX-2 inhibitors are now commercially available. Selective COX -2 inhibitors, such
as celecoxib, have the potential to inhibit tumor angiogenesis and metasases and
might serve as ideal agents for long term maintenance therapy. Celecoxib is generally
well tolerated and has no overlapping toxicities with standard chemotherapy agents
(carboplatin, gemcitabine, paclitaxel and docetaxel). Celecoxib is a proven and
approved agent for the reduction of adenomatous polyps (a premalignant lesion) in
patients with familial adencomatous polyposis (13).
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Several trials have evaluated cyclooxygenase inhibition in general, and COX-2
inhibition specifically, in lung cancer. Of note, there is considerable epidemiological
evidence that inhibition of cyclooxygenase is effective for the prevention of lung
cancer (14). Csiki et al evaluated the combination of celecoxib and docetaxel for
second-line treatment of metastatic NSCLC (15). There was no overall survival
benefit; however, patients who had evidence of inhibition of urinary PGE-M levels (a
metabolite of PGE-2, the product of COX-2) had prolonged survival compared to
other patients. Part of this benefit may come from inhibition of COX-2 expression
induced by chemotherapy. Altorki et al evaluated COX-2 expression after
neoadjuvant chemotherapy (carboplatin/paclitaxel) in localized lung cancer and
found that intratumoral levels were 3-fold higher than patients who did not receive
chemotherapy. However, this effect was abrogated when celecoxib was administered
concurrently with chemotherapy (16).
1.2
CALGB 30203
CALGB 30203 tested the concept of eicosanoid inhibition in advanced lung cancer
(17). The hypothesis was that eicosanoid inhibition in addition to standard
chemotherapy would potentially increase progression free survival. Furthermore, the
concept of single vs. double pathway inhibition was tested with inhibitors of COX-2
and 5-LOX as both single agents and in combination. A pilot trial at the University of
Maryland demonstrated that the combination of celecoxib and zileuton was well
tolerated
when
combined
with
either
carboplatin/gemcitabine
or
carboplatin/paclitaxel. CALGB 30203 enrolled 140 patients in under one year.
Neither the population as a whole nor any of the three arms achieved the
predetermined criterion for a successful outcome. However, the study required the
submission
of
tissue
specimens.
We
had
also
hypothesized
that
immunohistochemistry (IHC) for COX-2 and/or 5-LOX might identify a population of
patients who would be particularly benefited by this strategy. Of 107 specimens
submitted, 80 were of adequate quality for analysis. This analysis demonstrated the
following:
1. Analysis of arm A (chemotherapy + zileuton, the 5-LOX inhibitor) demonstrated
that patients with overexpression of COX-2 had a worse overall survival than
those who did not have overexpression (HR for moderate overexpression = 2.68 ,
p = 0.018 ). For those with high levels of overexpression the result was even more
dramatic, with a HR of 4.16, p=0.009. This is the first prospective confirmation
that COX-2 overexpression is a negative prognostic factor.
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Endpoint
Cut point of HR (95% CI)
COX-2 index
(n)
Pvalue
MST (low
expression)
(mo)
MST (high
expression)
(mo)
Survival
>1 (17)
1.459
(0.602,3.540)
.403
13.3
(7.3, )
7.1
(3.4,16.7)
Survival
>4 (11)
2.683
(1.195,6.856)
.018
14.7
(9.4,22.3)
3.8
(0.9,10.5)
Survival
>9 (6)
4.155
.009
(1.437,12.014)
14.7
(7.3,22.3)
4.0
(3.4,6.5)
FFS
>1 (17)
0.600
(.237,1.315)
.202
3.9(3.1,5.2)
4.2
(2.9,7.7)
FFS
>4 (11)
2.00
(.883,4.530)
.097
4.7 (3.2,6.7) 3.4
(0.8,6.4)
FFS
>9 (6)
1.680
(.641,4.403)
.292
4.3 (3.1,6.7) 3.8
(3.3,4.2)
2. Patients receiving celecoxib (with or without zileuton) who had overexpression of
COX-2 had a superior outcome compared with patients with overexpression who
did not receive celecoxib.
Endpoint
Cut point of
HR (95% CI)
COX-2 index
(n for A vs
B/C)
P-value
Did not
receive
celecoxib
(mo)
Did receive
celecoxib
(mo)
Survival
<1 (12,18)
1.843
(.757,4.485)
.178
13.3
(7.3, )
8.1
(4.9,14.9)
Survival
>4 (11,21)
.420
(0.184,.9555)
.039
3.8
(0.9,10.5)
10.6
(8.3,17.6)
Survival
>9 (6,14)
.194
(.060..629)
.006
4.0
(3.4,6.5)
11.3
(8.0, )
FFS
<1 (12,18)
.866 (.408,1.835)
.707
3.9
(3.1,5.2)
3.9
(2.8,4.6)
FFS
>4 (11,21)
.312
(0.135,0.718)
.006
3.4
(0.8,6.4)
6.5
(4.8,8.4)
FFS
>9 (6,14)
.218 (0.070,.681)
.009
3.8
(3.3,4.2)
6.5
(5.5,10.5)
3. The higher the degree of COX-2 overexpression the greater the degree of benefit
from celecoxib. Those with moderate to high expression (i.e. >4) had a HR of
0.420, p=0.039, while those with high levels of expression (i.e. >9) had a HR of
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0.194, p=0.006. There appeared to be a steadily increasing level of benefit with
increased COX-2 expression. The overall population for COX-2 ≥ 2 had a HR of
0.879 (p = ns). However, the number of patients with COX-2 index of 2-3 was
very small.
4. Patients who did not demonstrate overexpression of COX-2 (i.e., COX-2 index = 0)
and received celecoxib appeared to have an inferior outcome, HR = 1.84, p=0.178.
For patients with COX-2 index <2, the HR was 1.455.
5. Multivariate analysis considering potentially confounding factors of stage (IIIb vs.
IV), sex and performance status, confirmed the independent predictive value of
COX-2 expression and response to celecoxib (with a HR = 0.17 (0.06, 0.49),
P=0.0011).
6. 5-LOX expression was neither prognostic nor predictive.
These findings lead to the current hypothesis: inhibition of COX-2 with celecoxib can
improve outcome in patients with a moderate or higher degree of tumor COX-2
expression, defined as a COX-2 index of ≥ 4. Given the small numbers of patients, it
is possible that those with lower levels of COX-2 expression, i.e., ≥2, may also
benefit. The finding that a negative prognostic marker is a positive predictive marker
for a therapy targeting that marker is reminiscent of HER-2-neu and trastuzumab.
Interestingly, a similar finding for COX-2 has been reported in renal cell carcinoma in
which a small study of interferon alpha + celecoxib demonstrated the best results for
the COX-2 overexpressing patients despite the fact that these patients demonstrated
several other negative prognostic variables in addition to COX-2 overexpression (18).
This small (n=25) study evaluated interferon alpha + celecoxib. Only patients who
overexpressed COX-2 demonstrated measurable response and increased time to
progression. Importantly, there are supporting data from other lung cancer studies.
A multicenter trial of gefitinib + celecoxib in second-line NSCLC has recently been
reported with negative overall results. However, tissue was obtained from 21
patients, evenly divided between COX-2 non-expressing and overexpressing patients.
COX-2 overexpressing patients had substantially superior survival (p=0.03) (19). A
study in metastatic breast cancer combining capecitabine with celecoxib also noted
significantly improved progression-free and overall survival for patients with
moderate-to-high levels of COX-2 expression (20). Further supporting the concept of
a selective effect of COX-2 inhibition on COX-2 expressing malignancy is a recent
report from a large retrospective study (n=130,274) that demonstrated that aspirin, a
nonselective COX inhibitor, only suppressed COX-2 expressing colorectal cancers
(21). An industry sponsored phase III study adding celecoxib to chemotherapy in
advanced NSCLC has been completed and did not demonstrate a survival advantage.
However, as this study was done in an unselected population of patients, it is not
relevant to the current study.
1.3
Justification for a Phase III trial
A phase III trial represents an enormous expenditure of time and resources. The
many recent negative Phase III trials with a diverse group of promising agents (e.g.
erlotinib, gefitinib, bexarotene, etc) indicate that a phase III trial should be
undertaken only after considerable thought. There should be clear pre-clinical and
clinical evidence to justify a phase III study. The current evidence for COX-2
inhibition meets these criteria.
1. COX-2 inhibition (celecoxib) has unequivocal effect in the prevention of colorectal
cancer. There is no question that celecoxib is an effective chemopreventive agent.
2. The population most likely to benefit can be clearly identified.
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3. Strong preliminary evidence from a multicenter, cooperative group trial, i.e.,
CALGB 30203 exists. Obtaining tissue was feasible and accrual rapid despite the
3-arm design.
4. The results of CALGB 30203 are biologically plausible and supported by other
studies.
5. Celecoxib is well tolerated. The side-effect profile of this agent is superior to that
of virtually any other anticancer drug. Adverse cardiovascular effects are
relatively uncommon and, while not acceptable in the management of minor
ailments, would be acceptable for life-prolonging therapy in advanced NSCLC.
1.4
Toxicity Issues
There has been significant concern regarding the safety of selective COX-2 inhibitors.
Significant cardiovascular complications (stroke, myocardial infarction) led to
withdrawal of rofecoxib from the market. In December 2004, the Adenoma Prevention
with Celecoxib trial was halted prematurely due to increased risk of cardiovascular
death from the drug (22). As noted above, though this trial was halted due to toxicity
concerns, it was unequivocally positive in demonstrating a marked decrease in
colorectal adenomas and carcinoma, confirming the chemopreventive benefit of
celecoxib. While it appears that this benefit is not obtained at an acceptable degree
of risk in the prevention of cancer, the treatment of established disease is a
completely different matter and must be viewed in the context of other active
anticancer agents. The cardiotoxicity of celecoxib is relatively infrequent and far less
than that of accepted cancer treatments, including anthracyclines and trastuzumab.
Several recent trials, including CALGB 30203, did not demonstrate any significant
number of cardiovascular deaths. Therefore, in this scenario, the potential benefits
outweigh the small risk involved.
1.5
Current Trial Design
The primary endpoint for this trial will be progression free survival for those patients
with COX-2 index ≥ 4. This is based upon the findings that this group demonstrated
significantly improved PFS and OS on CALGB 30203. However, as there were too few
patients with COX-2 index of 2-3 to exclude a potential benefit, those patients will
also be eligible for this trial, but will be analyzed separately.
In CALGB 30203 the “core regimen” employed was carboplatin/gemcitabine. Since
that study there have been several developments in the chemotherapy of advanced
NSCLC. Specifically, the approvals of bevacizumab and pemetrexed for first line use
in non-squamous carcinoma. Bevacizumab was approved in combination with
carboplatin/paclitaxel based upon ECOG 4599 (42) This trial randomized patients
between carboplatin/paclitaxel with or without bevacizumab 15 mg/kg and
demonstrated an improved overall and median survival favoring the bevacizumab
containing regimen. There was a significantly greater degree of neutropenic fever in
the bevacizumab arm. A similar trial (AVAIL) has been reported with a randomization
between cisplatin/gemcitabine and two bevacizumab containing arms (7.5 mg/kg
and 15 mg/kg). This study demonstrated improved median but not overall survival.
In general, studies utilizing bevacizumab have demonstrated a greater degree of both
arterial and venous thromboembolic disease. Given the potential overlapping toxicity
with celecoxib, the use of bevacizumab will not be permitted on this trial.
An industry sponsored trial compared pemetrexed 500 mg/m2 plus cisplatin 75
mg/m2 on Day 1 of a 21-day cycle (PC) versus gemcitabine 1250 mg/m2 on Day 1
and Day 8 plus cisplatin 75 mg/m2 on Day 1 of a 21-day cycle (GC), met its primary
endpoint and demonstrated that OS with PC was noninferior to GC, with significantly
fewer side effects (43). In the intent-to-treat (ITT) population (all histologies), the 2
arms of the study were equivalent in terms of OS (unadjusted HR 0.93; 95% CI: 0.83
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to 1.04; median 10.3 months for both arms), PFS (unadjusted HR 1.04; 95% CI: (0.95
to 1.15); median PFS 4.8 and 5.1 months for the pemetrexed and gemcitabine arms,
respectively), and RR (30.6% versus 28.2% for the pemetrexed versus the
gemcitabine arm).
Preplanned analyses evaluating the differences in OS with respect to baseline patient
and disease characteristics identified a differential effect on survival according to
NSCLC histologic subgroups. Overall survival time with PC was statistically superior
to GC in patients with nonsquamous histology (adjusted HR 0.844; 95% CI: 0.74 to
0.96; p = 0.01 ). For patients with squamous histology, overall survival time with PC
was shorter than with GC (adjusted HR 1.229; 95% CI: 1.00 to 1.51; p = 0.050).
As a result of the above data both the U.S. Food and Drug Administration and the
European Medicines Agency issued an approval for use of pemetrexed with cisplatin
in the initial treatment of NSCLC other than predominantly squamous histology.
Retrospectively, two other controlled trials comparing pemetrexed to other treatments
in non-small cell lung cancer were evaluated for the influence of histology on
outcomes. In the second line treatment of NSCLC after progression from first line
platinum based chemotherapy comparing pemetrexed to docetaxel (44). It is
hypothesized that the selective benefit of pemetrexed in non-squamous lung cancer
relates to the relatively low levels of thymidylate synthase present in those
histologies.
The combination of pemetrexed and carboplatin has been extensively evaluated. A
Phase 1 mesothelioma study verified the safety of the combination (45). A 32% RR
was noted, with acceptable toxicity. The industry sponsored Phase 2 studies
examined pemetrexed with carboplatin and vitamin supplementation to determine
whether the combination would maintain the efficacy achieved with pemetrexed plus
cisplatin in advanced NSCLC. Scagliotti et al reported a study of 83 chemonaive
patients with Stage IIIB or IV NSCLC who were randomized to receive pemetrexed
500 mg/m2 plus either carboplatin area under the curve (AUC) 6 (41 patients) or
oxaliplatin 120 mg/m2 (42 patients) on Day 1 of a 21-day cycle, for up to 6 cycles of
therapy (46). In the pemetrexed-carboplatin arm, 12 of the 38 evaluable patients
(31.6%) had best overall response of PR and 17 (44.7%) had best overall response of
SD. Median TTP was 5.7 months, the 1-year survival rate was 43.9%, and median OS
was 10.5 months. Grade 3/4 neutropenia was observed in 10 (25.6%) of 39 patients
evaluable for safety. Grade 3/4 thrombocytopenia was reported in 7 (17.9%) patients.
Grade 3 events also included anemia and fatigue, each reported in 3 (7.7%) patients,
and stomatitis and febrile neutropenia, each reported in 1 (2.6%) patient. One (2.6%)
patient experienced Grade 4 infection without neutropenia. Zinner reported a trial of
50 chemonaive patients with Stage IIIB (with effusion) or IV NSCLC who received
pemetrexed 500 mg/m2 and carboplatin AUC 6 on Day 1 every 3 weeks for 6 cycles
(47). Twelve patients (24%) had PRs, and 25 (50%) had SD. Median TTP was 5.4
months, the 1-year survival rate was 56%, and median OS was 13.5 months. Grade
3/4 neutropenia was observed in 13 (26%) patients. One (2%) patient had Grade 3
thrombocytopenia, and 1 (2%) patient had Grade 4 anemia. Three (6%) patients
experienced Grade 3 nonhematologic side effects (nausea, fatigue, diarrhea, and
vomiting). These Phase 2 trials demonstrated that the combination of pemetrexed
with carboplatin is tolerable and that its activity in first-line treatment of advancedstage NSCLC is comparable to other standard platinum doublets. The toxicity with
the pemetrexed and carboplatin combination appears to be less than that seen with
other standard regimens in first-line NSCLC.
Given the emerging data regarding the selective efficacy of pemetrexed regimens for
nonsquamous
carcinoma,
this
study
will
utilize
the
regimen
of
carboplatin/pemetrexed for those histologies. Patients with NSCLC with histologies
of adenocarcinoma, large cell carcinoma, undifferentiated or not otherwise specified
will be treated with carboplatin/pemetrexed. Patients with mixed histologies will be
treated based upon the predominant histology.
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CALGB 30801
The approval for pemetrexed specifies that the agent should not be utilized
concurrently with NSAIDs (48). This restriction was based upon prior experience with
altered clearance with methotrexate, most likely due to competition for renal tubular
secretion resulting in increased systemic exposure. However, more recent data
demonstrates that patients with preserved renal function can receive pemetrexed
simultaneously with NSAIDs with only mild increases in exposure (49). Therefore, in
CALGB 30801, patients will receive celecoxib/placebo concurrently with the
carboplatin/pemetrexed regimen.
1.6
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this study
without alteration in eligibility criteria. There is currently no evidence to suggest that
differences in response to treatment exist between groups on the basis of gender or
race. Exploratory analyses will be conducted using Cox's proportional hazards model
to determine whether treatment differences in survival are consistent across men and
women, and are also consistent among races.
2.0
OBJECTIVES
2.1
Primary Objective
To confirm the beneficial effect of COX-2 inhibition in patients who have NSCLC that
expresses COX-2. The primary endpoint is to demonstrate improvement in
progression-free survival in patients with a COX-2 index ≥4 with an estimated hazard
ratio of 0.6.
2.2
Secondary Objectives
2.2.1 To describe the response rate, as well as the distribution of progression free
survival and overall survival.
2.2.2 To compare progression free survival between treatment arms for patients with
COX-2 ≥2. The comparison will also be made adjusting for CYP2C9 genotype and
celecoxib trough concentrations as covariates.
2.2.3 To correlate urinary PGE-M level with COX-2 expression, COX-2 inhibition and
outcome.
2.2.4 To evaluate the association between the -765G/C polymorphism in PTGS2 and
COX-2 expression in non-small cell lung cancer specimens.
2.2.5 To characterize a trough plasma celecoxib concentration which will be used as a
measure of patient adherence to protocol treatment and which may be used in
the future in correlations with genotype and pharmacodynamic outcomes of the
study.
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CALGB 30801
3.0
ON-STUDY GUIDELINES
The following guidelines are to assist physicians in selecting patients for whom protocol
therapy is safe and appropriate. Physicians should recognize that the following may
seriously increase the risk to the patient entering this protocol:
4.0
•
Psychiatric illness, which could prevent the patient from giving informed consent or
compliance with treatment.
•
Medical conditions such as uncontrolled infection (including HIV), interstitial
pneumonia, fibroid lung, uncontrolled diabetes mellitus, inability to take oral
medications, malabsorption or cardiac disease which, in the opinion of the treating
physician, would make this protocol unreasonably hazardous for the patient.
•
Women and men of reproductive potential should agree to use an appropriate method
of birth control throughout their participation in this study due to the teratogenic
potential of the chemotherapy utilized in this trial. Appropriate methods of birth
control include abstinence, oral contraceptives, implantable hormonal contraceptives
(Norplant), or double-barrier method (diaphragm plus condom).
•
Life expectancy ≥3 months.
ELIGIBILITY CRITERIA
4.1
Pre-registration Eligibility Criteria
4.1.1 Histologic documentation: All patients must have histologically- or cytologicallydocumented, non-small cell carcinoma of the lung (adenocarcinoma, large cell,
squamous, or mixtures of these types). A tissue block must be available at the
time of registration.
4.1.2 Extent of Disease (AJCC v. 6)
•
Patients with Stage IIIB because of a malignant pleural effusion are eligible.
Patients with supraclavicular node involvement or contralateral hilar nodes
are eligible providing they are not candidates for potentially curative
chemoradiotherapy.
•
Patients with Stage IV disease are eligible. Patients with recurrent disease,
not amenable to (or refusing) a potentially “curative therapy,” are eligible.
•
Patients with CNS metastases that are symptomatic must have received
therapy (surgery, XRT, gamma knife) and be neurologically stable and off of
steroids. The patient should be off steroids at least 14 days before
registration. Asymptomatic CNS metastatic disease without associated edema,
shift, requirement for steroids or antiseizure medications are eligible after
discussion with the Study Chair. Patients with leptomeningeal disease or
carcinomatous meningitis are NOT eligible.
4.1.3 Patients must have Measurable or Non-measurable Disease
Measurable Disease
Lesions that can be accurately measured in at least one dimension (longest
diameter to be recorded) as ≥ 2 cm with conventional techniques or as ≥ 1 cm
with spiral CT scan.
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CALGB 30801
Non-measurable Disease
All other lesions, including small lesions (longest diameter < 20 mm with
conventional techniques or < 10 mm with spiral CT scan) and truly nonmeasurable lesions.
Lesions that are considered non-measurable include the following:
•
Bone lesions
•
Leptomeningeal disease
•
Ascites
•
Pleural/pericardial effusion
•
Inflammatory breast disease
•
Lymphangitis cutis/pulmonis
•
Abdominal masses that are not confirmed and followed by imaging techniques
•
Cystic lesions
4.1.4 Prior Treatment:
No prior chemotherapy, immunotherapy or systemic treatments for NSCLC,
including adjuvant therapy;
≥ 2 weeks since prior surgery and completely recovered
4.1.5 ECOG Performance Status: 0-2
Age ≥18 years
4.1.6 No “currently active” second malignancy other than non-melanoma skin cancers.
Patients are not considered to have a “currently active” malignancy if they have
completed therapy and are considered by their physician to be at less than 30%
risk of relapse.
4.1.7 No known hypersensitivity to aspirin, non-steroidal anti-inflammatory agents, or
sulfonamides.
4.1.8 No active ulcer disease. No history of GI bleeding within the past three years.
4.1.9 No treatment with other investigational therapy.
4.1.10 Patients who are chronically (i.e., > 4 weeks of daily use) utilizing a regimen of
another NSAID are not eligible. Such medications include: aspirin (≤325 mg
daily is allowed), celecoxib, choline Mg, trisalicylate (Trilisate), or other nonsteroidal anti-inflammatory drugs such as ibuprofen (Advil or Motrin),
naproxen (Aleve, Naprosyn or Anaprox), etodolac (Lodine), oxaprozin
(Daypro), diflunisal (Dolobid), nabumetone (Relafen), tolmetin (Tolectin), or
valdecoxib (Bextra). Patients currently receiving NSAIDs must be off all NSAIDs
(except low dose aspirin) for at least 14 days prior to treatment.
4.1.11 No myocardial infarction, unstable angina, symptomatic congestive heart failure,
serious uncontrolled cardiac arrhythmia, cerebrovascular accident or transient
ischemic attack, pulmonary embolism, symptomatic carotid artery or peripheral
vascular disease, deep vein thrombosis, or other significant thromboembolic
event in the past 6 months.
4.1.12 Non-pregnant and non-nursing because of significant risk to the fetus/infant.
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CALGB 30801
4.1.13 Required Initial Laboratory Data:
Granulocytes
Platelets
Calculated Creatinine Clearance
Bilirubin
AST and ALT
4.2
≥1,500/µl
≥100,000/µl
≥ 45 ml/min
≤1.5 mg/dl
≤2.0 x ULN (≤ 5.0 x ULN if liver mets)
Registration Eligibility Criteria
4.2.1 COX-2 index ≥2
4.2.2 Prior radiotherapy: Prior radiation therapy must be completed two weeks before
protocol therapy begins.
4.2.3 Registration Laboratory Requirements
Granulocytes
Platelets
Calculated Creatinine Clearance
Bilirubin
AST and ALT
Serum albumin
5.0
≥1,500/µl
≥100,000/µl
≥ 45 ml/min
≤1.5 mg/dl
≤2.0 x ULN (≤ 5.0 x ULN if liver mets)
≥ 2.5 g/dl
PRE-REGISTRATION, REGISTRATION/RANDOMIZATION AND STRATIFICATION
Patients with a tissue specimen available will be eligible for pre-registration. The tissue
will be submitted for COX-2 testing, and those patients with COX-2 index ≥2 will be
registered/randomized.
The CT/MRI scan is required within 30 days prior to registration. The scan may be
obtained after pre-registration, but must be obtained prior to registration.
5.1
Pre-registration Requirement
Informed Consent: The patient must be aware of the neoplastic nature of his/her
disease and willingly consent after being informed of the procedure to be followed,
the experimental nature of the therapy, alternatives, potential benefits, side-effects,
risks, and discomforts. Human protection committee approval of this protocol and
consent form is required.
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CALGB 30801
5.2
Patient Pre-registration Procedures
This study uses the CALGB Web-based Patient Registration system. Pre-registration
will be accepted only through CALGB Main Member Institutions, selected affiliate
institutions and CCOPs using the Web-based Patient Registration system. Confirm
pre-eligibility criteria (Section 4.1). Complete the Pre-registration Worksheet. Access
the Web-based Patient Registration system via the Patient Registration tab on the
CALGB Member Website at www.calgb.org. If the study does not appear on the list of
studies in the Patient Registration system, the registration must be performed by the
CALGB Registrar via phone or fax. If the registering CRA requires assistance, he/she
may consult the on-line help file at the bottom of the screen or call the IS Help Desk
at 1-888-44CALGB. If further assistance is required, the registering CRA may call the
CALGB Registrar (919)-668-9396, Monday-Friday, 9 AM – 5 PM, Eastern Time. Enter
the following information:
CALGB patient ID #, if applicable
Study
Name of group (CALGB)
Name of institution where patient is being treated
Name of treating physician
NCI investigator number
Name of person in contact with the patient record (responsible contact)
CRA’s name, telephone number and e-mail address
Protocol IRB approval date
Date of signed consent
Treatment Start Date
Date [of] HIPAA authorization signed by the patient
Patient’s initials
Patient’s gender
Patient’s race
Patient’s ethnicity
ECOG performance status
Patient’s height (cm) and weight (kg)
Type of insurance (Method of Payment)
Patient’s postal code
Disease, type and stage, if applicable
Eligibility criteria met (no, yes)
Companion studies patient has consented
When the patient is pre-registered, a CALGB patient identification number will be
generated. Please write the number in your records, as it will be needed for the
registration/randomization.
The Main Member Institution and registering institution will receive a Confirmation
of pre-registration. Please check the confirmation for errors. Submit corrections in
writing to the data coordinator at the CALGB Statistical Center, Data Operations,
2424 Erwin Rd, Ste 802 Hock Plaza, Durham, NC 27705, or fax to 919-668-9397.
5.3
Patient Registration/Randomization Procedures
Tumor specimens must be submitted for COX-2 analysis at pre-registration. Upon
completion of COX-2 analysis at the CALGB Pathology Coordinating Office (PCO), the
results will be sent (within 72 hours of specimen receipt) to the CALGB Statistical
Center; the PCO will also notify the institution of eligibility status within 72 hours.
Those patients that have a COX-2 score <2 will not be registered/randomized. Those
patients with a COX-2 score ≥2 should be registered/randomized. To
register/randomize the patient access the Web-based Patient Registration system via
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CALGB 30801
the Patient Registration tab on the CALGB Member Website at www.calgb.org. Enter
the CALGB ID number obtained at pre-registration and the stratification factors into
the online registration system.
NOTE: No blinded starter supplies will be available for this study. Initial blinded,
patient-specific clinical supplies of celecoxib / placebo will be shipped from the
Pharmaceutical Management Branch (PMB) to the registering investigator at the time
of patient randomization and should arrive within 10 to 14 days of randomization
(see Section 10.7).
Registration to the optional PET and correlative science substudies will be done at
the same time as registration to the treatment study. Registration to both the
treatment trial and the substudies will not be completed if eligibility requirements are
not met.
5.4
Registration to Companion Studies
There are two substudies within CALGB 30801. These correlative science studies
must be offered to all patients enrolled on CALGB 30801 (although patients may
opt to not participate). These substudies does not require separate IRB approval. The
substudies included within CALGB 30801 are:
•
CALGB 150908: Urinary PGE-M (see Section 15.2)
•
CALGB 60904: PG and PK studies (Sections 15.3 and 15.4)
If a patient answers “yes” to “I agree that my blood may be used for the research
study described above” question #1 in the model consent, they have consented to
participate in CALGB 60904. If a patient answers “yes” to “I agree that my specimens
may be used for the research described above” question #2 in the model consent,
they have consented to participate in CALGB 150908.
The patient should be registered to CALGB 150908 and CALGB 60904 at the same
time they are randomized to the treatment trial (CALGB 30801). Samples should be
submitted per Section 6.1.2, 6.1.3, and 6.1.4.
5.5
Stratification Factors
Sex: Male vs. female
Stage: IIIB vs. IV
Histology: Squamous vs. non-squamous
Smoking status: Never/former light smoker (defined as ≤10 pack years AND quit ≥ 1
year ago) vs smoker
COX-2 expression status: COX-2 index ≥4 vs COX-2 index ≥2 but <4 (to be entered
by the Statistical Center; both patient and institution are blinded to this)
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CALGB 30801
6.0
DATA AND SAMPLE SUBMISSION
Forms should be submitted to the CALGB Statistical Center, Data Operations, in
compliance with the Data Submission schedule below. There are three options for
submitting forms that use the Teleform barcode and cornerstones:
•
The forms may be faxed to 919-416-4990. Please note that the four cornerstones and
the form id (“bitmap”) must appear on the form. Copies must be 100% of the original
form size.
•
The forms may be mailed to the CALGB Statistical Center, Hock Plaza, 2424 Erwin
Road, Suite 802, Durham, NC 27705. Please note that the four cornerstones and the
form id (“bitmap”) must appear on the form. Copies must be 100% of the original form
size.
•
Data may be entered electronically by logging onto the CALGB web site and locating
the specific web-ready form.
Form*
Submission Schedule
1
Pre-Registration
30801 COX-2 Sample Submission Form
C-1872
30801 Sample Submission Form (for those
C-1873
patients that consent to 60904))
Baseline
C-1868 30801 On-Study
Report
Pathology/Cytology Report
Report
Baseline CT Scan or MRI Reports
C-2000 Solid Tumor Evaluation Form (RECIST 1.1)
C-1959 Non-small cell lung cancer staging form
Sample Submission
C-1873
30801 Specimen Submission Form
C-1917
30801 PK Sample Submission Form
Within one month of registration
Submit copy to PCO with
samples to PCO and original to
Statistical Center.
Submit copy to Dr. Egorin’s lab
with samples and original to
Statistical Center
During Treatment2
C-1869 30801 Treatment Form
C-1870 30801 Adverse Event Form3
C-1871
C-2000
Report
Submit to PCO with preregistration sample. Submit copy
to CALGB Statistical Center.
Each
cycle
therapy.
30801 Follow-up and Response Form
Solid Tumor Evaluation Form (RECIST 1.1)
CT Scan or MRI Reports
Follow-up (Post-treatment)4
C-1871 Follow-up and Response Form
C-2000 Solid Tumor Evaluation Form (RECIST 1.1)
Report
CT Scan or MRI Reports
during
protocol
Every 2 cycles during protocol
therapy.
Every 2 months for 2 yrs, then
every 6 months for 3 yrs. (After
progression submit only C-1871.)
This study will use NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
for routine toxicity reporting on study forms.
*
1
2
Use CALGB Remarks Addenda (C-260) if additional comments are necessary or additional
writing space is needed.
If patient is determined to be ineligible during COX-2 analysis, no additional data is
required. Only submit C-1873 and PG samples for consenting patients.
S-060 30801 Medication Calendar has been provided for patient and institutional use.
This form does not need to be submitted to the Statistical Center.
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CALGB 30801
3
4
Submit AE form until all protocol treatment related events have resolved or until nonprotocol treatment begins.
If patient never starts treatment, submit the following: all baseline data, Form C-1869 to
report the reason for not starting protocol therapy, C-1871, C-2000 and CT/MRI reports as
specified in the follow-up (post-treatment) section.
6.1
Correlative Studies: The following sections will provide details about how specimens
will be collected, when they will be collected, and where they will be submitted.
Briefly, the samples which will be submitted as part of CALGB 30801 are as follows:
Timepoint
Pre-registration
Tissue to PCO
for COX-2
testing
(Section 6.1.1)
Blood to PCO
for DNA
(Section 6.1.2)
X
X
Blood to Univ.
of Pitt. for PK
(Section 6.1.3)
Prior to treatment
X
8 days after start of
celecoxib/placebo,
Cycle 1*
*
Urine to PCO
(Section 6.1.4)
X
X
Samples are to be collected eight days after the start of celecoxib/placebo therapy. Blood
and urine should be obtained PRIOR to therapy on that day.
Tissue for COX-2 testing is required for all patients. Blood for DNA, blood for PK and
urine studies must be offered to all patients, although patients may choose not to
participate.
6.1.1 Tissue Sample Submission for Analysis of COX-2
COX-2 expression will be assessed in all patients prior to registration. Patients
should not be pre-registered unless a paraffin block is available. The
results of the COX-2 test will not be given to the physician or patient at any time.
Submit an adequate sized paraffin block with tumor tissue/cells taken at the
time of initial diagnosis (or subsequently), patient’s pathology report, and Form
C-1872 to the CALGB PCO:
CALGB Pathology Coordinating Office
The Ohio State University
Innovation Centre
Columbus, OH 43240
Tel: 614-293-7073
Please consider using a secure and temperature-safe method of packaging your
specimens. [Extreme heat precautions should be taken when packaging blocks.]
Use of a shipping method that is traceable is recommended.
The CALGB has instituted special considerations for the small percentage of
hospitals whose policy prohibits long-term storage of blocks or the release of any
block. If, due to institutional policy, a block cannot be sent, please call the
CALGB PCO at 614-293-7073 to obtain a protocol for other options.
The goal of the PCO is to provide investigators with quality histology sections for
their research while maintaining the integrity of the tissue. All paraffin blocks
that are to be stored at the PCO will be vacuum-packed to prevent oxidation and
will be stored at 4ºC to minimize degradations of cellular antigens. For these
reasons, it is preferred that the PCO bank the block until the study investigator
requests thin sections. Please contact the PCO if additional assurances with your
hospital pathology department are required.
6.1.2 Blood Collection for Pharmacogenomics (CALGB 60904)
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CALGB 30801
1. For those patients who consent, collect 10 ml of whole blood in EDTA (purpletop) tube at pre-registration. Either peripheral or central venous access is
acceptable. Immediately after collection, gently invert at least five times to mix
completely.
2. Store (without centrifugation) at 4oC until shipping.
3. Label the sample permanently and indelibly labeled with patient’s initials,
(last, first, middle), CALGB number, study number, and date drawn.
4. On the same day the sample is obtained, ship it on a cold pack (not dry ice)
in an insulated container by overnight express courier. DO NOT FREEZE.
Send the completed form C-1686 with the samples to the CALGB PCO:
CALGB Pathology Coordinating Office (PCO)
Innovation Centre
Columbus, OH 43240
Tel: 614-293-7073
Fax: 614-293-7967
Send a copy of Form C-1873 to the CALGB Statistical Center, Data Operations.
The sample should be logged and shipped via the LabTrak application. Use a
method of shipping that is secure and traceable. Extreme heat precautions
should be taken when necessary. Samples should be shipped Monday-Friday by
overnight service to arrive Tuesday-Saturday. IF SHIPPING ON FRIDAY, FEDEX
OR UPS MUST BE USED AND THE AIR BILL MUST BE MARKED “FOR
SATURDAY DELIVERY.” DO NOT SHIP SPECIMENS ON SATURDAYS.
6.1.3 Blood Collection for Pharmacokinetics (CALGB 60904)
1. Collect one pediatric (5 ml) green-top vacutainer (containing heparin anticoagulant) of venous blood from a peripheral vein 8 days after the start of
celecoxib/placebo. Samples should be collected before treatment is given on
the 8th day.
2. Immediately after sample collection, the blood sample should be gently
inverted several times to mix the anti-coagulant completely. The tube should
then be placed into an ice bath.
3. Within 2-3 hours after collection, each blood sample should be centrifuged
at approximately 1,000xg to separate the cellular elements from the plasma.
Plasma should be transferred to a screw-cap polypropylene tube and the
tube clearly and indelibly labeled.
4. Plasma samples should be stored at -20°C or colder. Frozen samples should
be shipped to the analytical laboratory on dry ice.
5. Record the date, planned time and actual time of collection for the specimen
on the pharmacokinetic form: the study number and the patient’s unique
patient identifier should be included on this form. In addition, the date and
exact time when the celecoxib/placebo dose was ingested should be recorded
on the appropriate pharmacokinetic form.
6. The shipment of human blood samples must comply with appropriate
regulations as specified by the carrier. At a minimum, all samples must be
packaged within two containers with absorbent material between containers
to control any spill or leakage. The outer container must be punctureresistant (e.g. cardboard mailing tube, corrugated cardboard box).
A
biohazard sticker must be affixed to both the inner and outer containers.
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CALGB 30801
7. All samples should be shipped via overnight express courier in insulated
containers with enough dry ice to maintain the samples in a frozen state. A
copy of the C-1917 should be included with each shipment.
8. All specimens are to be shipped to:
University of Pittsburgh Cancer Institute
Room G.28 Hillman Research Laboratories
5117 Centre Avenue
Pittsburgh, PA 15213.
Please notify the lab at 412-623-3216 or 412-623-1213 at least 24 hours
prior to shipment. Samples should be shipped only Monday-Wednesday
for Tuesday-Thursday delivery. A name, phone number, fax number, or
email address should be included with samples so that receipt can be
acknowledged.
6.1.4 Urine Collection for PGE-M Analysis (CALGB 150908)
1. Collect urine in a urine cup before any protocol treatment and then 8 days
after the start of celecoxib/placebo, prior to treatment on the 8th day.
2. After collection, transfer 10 mL of urine to five 2ml cyrovials and keep at 4oC
until frozen. Samples should be frozen within several hours of collection, at
-80oC. Frozen samples should be shipped to the repository on dry ice.
The CALGB strongly recommends the usage of 2 ml cryovials for storage of urine
specimens. Acceptable cryovials include:
Company name
Nalgene
Fisher brand
Corning
VWR
Catalog number
03-337-7Y (through Fisher)
NNI No.: 5012-0020
05-669-57 (through Fisher)
03-374-21 (through Fisher)
CLS430659 (through Sigma)
Corning: 430488
16001-102
All samples should be permanently or indelibly labeled with patient’s last, first
and middle initials, CALGB patient ID number, CALGB study number, sample
type (i.e., urine) and date drawn.
The aliquoted, frozen urine samples should be shipped within 30 days on dry ice
by overnight express courier. Send the completed form C-1873 with the samples
to the CALGB PCO, with a copy to the CALGB Statistical Center, Data Operations
at the time of shipment.
CALGB Pathology Coordinating Office (PCO)
Innovation Centre
Columbus, OH 43240
Tel: 614-293-7073
Fax: 614-293-7967
Samples should be logged and shipped via the LabTrak application. Please be
sure to use a method of shipping that is secure and traceable. Extreme heat
cautions should be taken when necessary. Samples should be shipped MondayFriday by overnight service to arrive Tuesday-Saturday. IF SHIPPING ON FRIDAY,
FEDEX OR UPS MUST BE USED AND THE AIR BILL MUST BE MARKED “FOR
SATURDAY DELIVERY.” DO NOT SHIP SPECIMENS ON SATURDAYS.
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CALGB 30801
7.0
REQUIRED DATA
To be completed within 16 days before pre-registration:
- All blood work
To be completed within 30 days before registration:
- Any X-ray, scan of any type or ultrasound which is utilized for tumor measurement
per protocol.
To be completed within 42 days before pre-registration:
- Any x-ray, scan of any type or ultrasound of uninvolved organs which is not utilized
for tumor measurement.
Prior to
Day 1 of Each
Post-Treatment
Test & Observation
Pre-reg
Cycle*
Follow-up**
History & Physical exam
X
X
X
Performance Status
X
X
X
X
X
Weight /BSA
Pulse/Blood pressure
X
X
Tumor Measurements
X
q 2 cycles
X
Tumor specimen for COX-2
X
Toxicity Assessments
X
Ψ
Laboratory Studies
CBC, Diff, Platelets
Serum
Creatinine
(Calc.
CrCl), BUN
Serum Electrolytes, LDH
Alk.Phos., Bilirubin, Ca
ALT, AST
Tot. Prot. Albumin
Pregnancy test in women of
child-bearing potential
Ψ
X
X
Day 1 and 8***
X
X
X
X
X
X
X
X
X
X
XA
q 2 cycles
Radiologic Studies
CT Chest & Upper Abd. (w/
adrenals and liver) or MRIA
Brain MRI
X
PRN
Substudies
Urine for PGEM analysis
Blood for PK/PG
B
C
B
C
*
Pre-registration labs may be used for day 1 of cycle 1 tests if obtained within 7 days
prior to day 1 of Cycle 1. For subsequent cycles labs may be obtained within 48
hours prior to day of treatment.
**
Every 2 months for 2 years, then q 6 months for 3 years until disease progression.
***
Day 1 for all patients; day 8 for those patients receiving gemcitabine.
Ψ
It is not necessary to change the dose of chemotherapy unless the calculated dose
changes by ≥ 10%.
A.
CT/MRI scan is required within 30 days prior to registration. The scan may be
obtained after pre-registration, but must be obtained prior to registration. CT Scan
requirements for this protocol:
Optimal Technique: The requirements listed below are to be used for the chest CT
scan whenever possible.
•
•
•
Scanning mode: Helical
Patient position: Supine, arms up
Scan extent: Thoracic inlet through adrenal glands
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•
•
•
•
Scan time: Single breath-holding period, in full inspiration
Section thickness: 1.5mm or less
Enhancement: Intravenous contrast unless contraindicated by allergy
Reconstruction: Contiguous or overlapping sections; no gaps
Minimum CT requirements are listed below. Note that a chest CT scan made as
part of a PET-CT is acceptable if it meets these requirements. Any CT scan that
does not meet these minimal requirements must be repeated.
B.
C.
8.0
•
Scanning mode: Helical
•
Patient position: Supine
•
Scan extent: Thoracic inlet through adrenal glands
•
Scan time: Single breath-holding period, in full inspiration
•
Section thickness: 5mm or less
•
Enhancement: Preferred but not required
•
Reconstruction: Contiguous or overlapping sections; no gaps
For patients who consent to CALGB 150908, urine should be collected prior to
starting any treatment and then 8 days after the start of celecoxib/placebo, before
treatment on the 8th day.
For patients who consent to CALGB 60904, blood should be collected at preregistration for DNA and then 8 days following the start of celecoxib/placebo, before
therapy on the 8th day.
TREATMENT PLAN
NOTE: No blinded starter supplies will be available for this study. Initial blinded, patientspecific clinical supplies of celecoxib / placebo will be shipped from the Pharmaceutical
Management Branch (PMB) to the registering investigator at the time of patient
randomization and should arrive within 10 to 14 days of randomization (see Section
10.7).
Treatment will begin within 14 days of randomization. Treatment with celecoxib/placebo
may be delayed up to 14 days after the start of chemotherapy. Patients that are COX-2 ≥
2 will be randomized to receive one of the following treatments:
8.1
Arm A
Gemcitabine 1000 mg/m2 IV days 1 and 8. Repeat every 21 days for up to 6 cycles.
Carboplatin AUC=5.5 IV day 1 every 21 days for up to 6 cycles (following the
administration of gemcitabine on day 1). Patients with prior chest radiotherapy
should receive carboplatin at an AUC = 5.0
Celecoxib 400 mg (1 capsule) orally twice daily until progression, starting on day 1
(or up to 14 days following the start of chemotherapy)
OR
For Non-squamous Carcinoma
Pemetrexed* 500 mg/m2 IV day 1. Repeat every 21 days for up to 6 cycles.
Carboplatin AUC=6.0 IV on day 1 every 21 days for up to 6 cycles (following the
administration of pemetrexed).
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Celecoxib 400 mg (1 capsule) orally twice daily until progression, starting on day 1
(or up to 14 days following the start of chemotherapy)
*
Pemetrexed Premedications:
Folic Acid: Start a low-dose oral folic acid preparation or multivitamin with folic
acid at least 1 week before the first pemetrexed dose and continue for 21 days
after the last dose of pemetrexed.
Vitamin B12: Vitamin B12 1000 mcg IM injection. A vitamin B12 injection must be
administered at least 1 week before the initial pemetrexed dose and repeated
every 3 cycles while on pemetrexed.
Dexamethasone: Dexamethasone (or equivalent) 4 mg orally should be
administered BID daily the day before, the day of, and the day after each dose of
pemetrexed, for a total of 6 doses per cycle.
8.2
Arm B
For Squamous Carcinoma
Gemcitabine 1000 mg/m2 IV days 1 and 8, every 21 days for up to 6 cycles
Carboplatin AUC= 5.5 IV day 1 every 21 days for up to 6 cycles (following the
administration of gemcitabine on day 1). Patients with prior chest radiotherapy
should receive carboplatin at an AUC = 5.0
Placebo (1 capsule) orally twice daily until progression, starting on day 1 (or up to 14
days following the start of chemotherapy)
OR
For Non-squamous Carcinoma
Pemetrexed* 500 mg/m2 IV day 1. Repeat every 21 days for up to 6 cycles
Carboplatin AUC=6.0 IV on day 1 every 21 days for up to 6 cycles (following the
administration of pemetrexed)
Placebo (1 capsule) orally twice daily until progression, starting on day 1 (or up to 14
days following the start of chemotherapy)
*
Pemetrexed Premedications:
Vitamin B12: Vitamin B12 1000 mcg IM injection. A vitamin B12 injection must
be administered at least 1 week before the initial pemetrexed dose and repeated
Dexamethasone: Dexamethasone (4 mg orally or equivalent) should be
8.3
Patients may receive a maximum of 6 cycles of therapy (1 cycle = 21 days). Following
six cycles of therapy, those patients with responding or stable disease will continue
on the celecoxib/placebo until disease progression or unacceptable toxicity.
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8.4
Calculation of Carboplatin Dose
* Creatinine clearance (CrCl) will be calculated using the Cockroft-Gault
equation as follows:
CrCI (ml/min) =
(140-age) x actual wt (in kg)
72 x serum creatinine (mg/dl)
FOR FEMALES, USE 85% OF CALCULATED CrCI VALUE
Dose of carboplatin (mg) for squamous patients= 5.5 x [CrCI (ml/min) + 25] OR in
patients with prior chest radiation therapy, dose of carboplatin = 5 x [CrCI (ml/min) +
25]
Dose of carboplatin (mg) for non-squamous patients= 6 x [CrCI (ml/min) + 25]
Use the serum Cr value reported by the laboratory; do not apply any correction
factors to the reported value.
The maximum CrCl that can be used in this calculation, for both women and
men, is 125 mL/min.
For squamous carcinoma patients the maximum carboplatin dose is 825 mg
for patients who have not had prior chest radiotherapy. For patients with prior
chest radiotherapy the maximum carboplatin dose is 750 mg.
For non-squamous carcinoma patients the maximum carboplatin dose is 900
mg.
In the case of low creatinine values resulting in high CrCl values that seem to
overestimate renal function, a 24-hour urine collection for determination of CrCl
is recommended.
9.0
DOSE MODIFICATIONS AND MANAGEMENT OF TOXICITIES
9.1
General Guidelines
•
If more than one of the dose modifications apply, use the most stringent (i.e., the
greatest dose reduction).
•
Celecoxib/placebo will be continued when chemotherapy is held for toxicities.
•
Chemotherapy will be continued when celecoxib/placebo is held for toxicities.
•
The following dose levels are used for dose modifications. If dose reduction below
level -2 is required, discontinue the drug causing the toxicity, and continue the
other drug. Continue the celecoxib/placebo.
Dose Level
Pemetrexed
2
Carboplatin
Gemcitabine
100%
1000 mg/m2
0
500 mg/m
-1
375 mg/m2
75%
750 mg/m2
-2
250 mg/m2
50%
500 mg/m2
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9.2
9.3
Hematologic Toxicity
•
For ANC <1,500 or platelets <100,000 on day 1, delay treatment with carboplatin
and pemetrexed or gemcitabine until ANC ≥1,500 and platelets ≥100,000, then
resume at the previous doses. If treatment is delayed for ≥ 3 weeks, discontinue
all protocol treatment.
•
For platelets <25,000, decrease carboplatin and pemetrexed or gemcitabine by
one dose level for all subsequent doses. Hold celecoxib/placebo until platelets
>25,000.
•
For febrile neutropenia occurring at any time during a cycle, decrease carboplatin
and pemetrexed or gemcitabine by one dose level for all subsequent doses.
•
For ANC 500-999 or platelets 50,000 – 74,999 on day 8, decrease gemcitabine by
one dose level for the current and all subsequent doses.
•
For ANC <500 or platelets <50,000 on day 8, skip gemcitabine and decrease
gemcitabine by one dose level for all subsequent doses.
•
For a second episode of thrombocytopenia <25,000 or febrile neutropenia,
decrease carboplatin and pemetrexed or gemcitabine by one dose level for all
subsequent doses.
Gastrointestinal Toxicity
9.3.1 Diarrhea
For grade 3 or 4 diarrhea despite antidiarrheal medication and prophylactic
vitamin supplementation, delay carboplatin and pemetrexed and interrupt
celecoxib/placebo in non-squamous carcinoma. Once diarrhea resolves to ≤ grade
2, resume therapy with carboplatin and celecoxib/placebo at the previous dose,
and one dose level reduction of pemetrexed for all subsequent cycles. If treatment
is delayed for ≥ 3 weeks, discontinue all protocol therapy.
There are no dose modifications for diarrhea for carboplatin and gemcitabine in
squamous carcinoma.
9.3.2 Mucositis
For grade 3 or 4 mucositis despite prophylactic vitamin supplementation, delay
carboplatin and pemetrexed and interrupt celecoxib/placebo in non-squamous
carcinoma until toxicity resolves to ≤ grade 2. When mucositis resolves to ≤ grade
2, resume carboplatin at the previous dose and pemetrexed with a one level dose
reduction for all subsequent cycles and resume celecoxib/placebo. If treatment is
delayed for > 3 weeks, discontinue all protocol therapy.
There are no dose modifications for mucositis for carboplatin and gemcitabine in
squamous carcinoma.
9.3.3 For GI bleeding not associated with thrombocytopenia (platelets <75,000), or for
GI ulceration, discontinue celecoxib/placebo. Continue carboplatin/pemetrexed
or carboplatin/gemcitabine.
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9.4
Nephrotoxicity
If creatinine clearance is < 45ml/min, delay carboplatin and pemetrexed in nonsquamous carcinoma, carboplatin and gemcitabine in squamous carcinoma and
interrupt celecoxib/placebo until CrCl ≥ 45 ml/min. When CrCl improves to ≥ 45
ml/min, resume carboplatin and pemetrexed (or gemcitabine) at the previous doses
and resume celecoxib/placebo at 400 mg BID. If treatment is delayed/interrupted for
≥ 3 weeks, discontinue all protocol therapy.
9.5
Clinically Significant Effusions
For patients who develop clinically significant pleural or pericardial effusions (on the
basis of symptoms or physical examination) during therapy, consideration should be
given to draining the effusion prior to the next dose of pemetrexed. However, in the
opinion of the treating physician, if the effusion represents progression of disease,
the patient should discontinue protocol therapy.
9.6
Pulmonary Toxicity
Gemcitabine may rarely cause pulmonary toxicity characterized by dyspnea and
interstitial pneumonitis. The pneumonitis will usually respond to steroids. Other
causes of dyspnea should be excluded (i.e., anemia, cardiac, COPD exacerbation,
etc.) before concluding that pulmonary toxicity is drug associated.
9.7
•
For grade 2 pulmonary toxicity due to gemcitabine, hold protocol treatment.
Patients may be retreated with a two level dose reduction in gemcitabine dose on
the next and all subsequent cycles at the physician’s discretion if pulmonary
symptoms improve to grade 0-1 within 3 weeks.
•
For grade 3 and 4 pulmonary toxicity, discontinue protocol therapy.
Skin Toxicity
Gemcitabine
•
Grade 2: Decrease gemcitabine by one dose level.
•
Grade 3 or 4: Discontinue gemcitabine.
Pemetrexed
•
9.8
Grade 3: Hold pemetrexed until toxicity improves to ≤ grade 1, then resume
pemetrexed at the previous dose level. For recurrent grade 3 skin toxicity, hold
pemetrexed until toxicity improves to ≤ grade 1, then resume pemetrexed with
one dose level reduction. If pemetrexed is held for skin toxicity for 3 weeks,
discontinue pemetrexed.
Cardiovascular Toxicity
For grade 3 or 4 thrombosis or cardiac ischemia, or ≥ grade 2 stroke, discontinue
celecoxib/placebo. Continue carboplatin/pemetrexed or carboplatin/ gemcitabine.
9.9
Hypersensitivity Reactions
For grade 3 allergic or anaphylaxis reactions thought to be due to carboplatin,
gemcitabine or pemetrexed discontinue all protocol therapy.
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9.10 Other Non-Hematologic
Grade 3 Toxicity (not described above): Delay all drugs until toxicity improves to ≤
grade 2, then resume treatment with one dose level reduction for each agent except
celecoxib/placebo. If treatment is delayed for > 3 weeks, discontinue all protocol
therapy.
For recurrent other non-hematologic grade 3 toxicity: Discontinue all protocol
therapy.
Grade 4 Toxicity (not described above): Discontinue all protocol therapy.
10.0 DRUG FORMULATION, AVAILABILITY AND PREPARATION
10.1 Qualified personnel who are familiar with procedures that minimize undue exposure
to themselves and to the environment should undertake the preparation, handling,
and safe disposal of chemotherapeutic agents in a self-contained, protective
environment.
10.2 Discard unused portions of injectable chemotherapeutic agents that do not contain a
bacteriostatic agent or are prepared with unpreserved diluents (i.e., Sterile Water for
Injection USP or 0.9% Sodium Chloride for Injection USP) within eight hours of vial
entry to minimize the risk of bacterial contamination.
10.3 The total administered dose of chemotherapy may be rounded up or down within a
range of 5% of the actual calculated dose.
10.4 Carboplatin
Please refer to the FDA approved package insert for additional information.
Availability
Carboplatin is commercially available and supplied as a sterile lyophilized powder
available in single-dose vials containing 50 mg, 150 mg and 450 mg of carboplatin.
Each vial contains equal parts by weight of carboplatin and mannitol.
Preparation
Immediately before use the content of each vial must be reconstituted with either
Sterile Water for Injection, USP, 5% dextrose in water, or 0.9% Sodium Chloride for
Injection, USP according to the following schedule:
Vial Strength
Diluent Volume
50 mg
5 ml
150 mg
15 ml
450 mg
45 ml
These dilutions all produce a carboplatin concentration of 10 mg/ml. When prepared
as directed, carboplatin solutions are stable for eight hours at room temperature.
There is no antibacterial preservative in the formulation, therefore, it is
recommended that carboplatin solutions be discarded eight hours after dilution.
Note: Aluminum reacts with carboplatin causing precipitate formation and loss of
potency: therefore, needles or intravenous sets containing aluminum parts that may
come in contact with the drug must not be used for the preparation or
administration of carboplatin.
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Storage and Stability
Unopened vials of carboplatin are stable for the life indicated on the package when
stored at controlled room temperature and protected from light.
Administration
See Sections 8.1 and 8.2.
AUC dosing will be used to determine carboplatin dosing. The protocol permits use of
the Cockcroft-Gault formula to estimate creatinine clearance. However, in markedly
obese patients, the Cockcroft-Gault formula will tend to overestimate the creatinine
clearance. The actual body weight (in kilograms) will be utilized in the CockcroftGault formula. However, if the calculated creatinine clearance exceeds an upper limit
for creatinine clearance, as specified below, then this ceiling value for creatinine
clearance, rather than the calculated creatinine clearance, will be used in the Calvert
formula to calculate the dose of carboplatin.
The maximum allowable creatinine clearance for males and females is 125 ml/min.
Alternatively, at the treating physician's discretion, a measured 24 hour creatinine
clearance can be obtained. In this case, the measured creatinine clearance can be
used to calculate the carboplatin dose in the Calvert formula.
Toxicities
Myelosuppression, nausea and vomiting, peripheral neuropathy, nephrotoxicity,
hepatotoxicity, electrolyte imbalance, hypomagnesemia, hypocalcemia, and allergic
reactions.
10.5 Gemcitabine
Availability
Gemcitabine HCl (2’2’-difluorodeoxicytidine) is a nucleoside analogue that exhibits
antitumor activity. It is commercially available and supplied as a lyophilized powder
in sterile glass vials containing 200 mg or 1000 mg of active drug as the
hydrochloride salt (expressed as the free base), mannitol, and sodium acetate.
Preparation
The appropriate dose of gemcitabine should be diluted in 250 mL of normal saline
(maximum concentration of 40 mg/mL) and administered intravenously as a
constant infusion over 30 minutes. Normal saline is the only diluent approved; do
not use other diluents. Nothing else should be added to the bag. Since gemcitabine is
NOT a vesicant, extravasation should be handled according to local hospital policy
concerning extravasation of drugs.
The intact vials should be stored at controlled room temperature between 59°-86°F
(15°-30°C). The intact vials are stable for 3 years at controlled room temperature.
Reconstituted solutions should be used within 24 hours; unused portions should be
discarded.
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Administration
See Sections 8.1 and 8.2.
Toxicity
The DLT is myelosuppression. Other possible clinical toxicities include fever, chills,
nausea, vomiting, diarrhea, constipation, skin rash or confluent erythema, edema,
paresthesia, fatigue, anorexia, headache, muscle aches, cough, rhinitis, insomnia,
sweating, drowsiness, hypotension, and mucositis.
Dyspnea on exertion or at rest has occasionally been reported after gemcitabine
therapy. Nonprogressive liver function abnormalities and dip-stick-positive
proteinuria, or hematuria may occur. Episodes of hemolytic uremic syndrome have
been reported in patients treated with gemcitabine. There were no reports of injection
site necrosis with gemcitabine in US trials. There may be some local irritation and
injection site pain due to the low pH of the solution (pH≈3).
10.6 Pemetrexed
Availability
Pemetrexed is available commercially as a lyophilized powder for reconstitution in
single-use vials containing 500 mg pemetrexed.
Intact vials of pemetrexed should be stored at room temperature. The reconstituted
and further diluted solutions for infusions are stable for up to 24 hours when
refrigerated or stored at room temperature.
Preparation
Each 500 mg of pemetrexed is reconstituted with 20 mL of 0.9% sodium chloride for
injection, resulting in a concentration of 25 mg/mL. The desired dose should be
withdrawn and further diluted in 100 mL of 0.9% sodium chloride for injection, for IV
infusion.
Administration
Pemetrexed will be administered as an IV infusion every 21 days. Pemetrexed
premedications include:
Vitamin B12: Vitamin B12 1000 mcg IM injection. A vitamin B12 injection must
be administered at least 1 week before the initial pemetrexed dose and repeated
Dexamethasone: Dexamethasone (4 mg orally or equivalent) should be
Toxicities
The most common toxicities reported with pemetrexed to date include
myelosuppression, GI toxicities, rash and fatigue. Neutropenia is more common than
thrombocytopenia, and it is minimized with vitamin supplementation. Specifically,
folic acid and Vitamin B12 starting before pemetrexed and continuing throughout
pemetrexed therapy are recommended. It is thought that severe pemetrexed toxicity
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is due to a subclinical folate deficiency, as may be documented by an elevated
plasma homocysteine. Similarly, diarrhea and mucositis are also minimized with the
use of folic acid and B12. Single agent pemetrexed was associated with nausea and
vomiting in approximately 30% of patients. In the majority of patients, nausea and
vomiting were ≤ grade 2 severity. The incidence and severity of pemetrexed-induced
rash appears to be decreased with the administration of dexamethasone, beginning
the day before pemetrexed. Fatigue, grade 1-3 severity, is also common.
Drug Interactions
As is the case with methotrexate, the potential exists for various drugs (e.g., NSAIDs,
probenecid, salicylates, sulfonamides) to delay pemetrexed renal clearance and
increase toxicity (see Section 11.4).
10.7 Celecoxib (NSC #719627, CALGB IND #107051) / Placebo
Availability
Celecoxib (NSC 719627) and matching Placebo will be provided free of charge by
Pfizer and distributed by the Pharmaceutical Management Branch (PMB), Cancer
Therapy Evaluation Program (CTEP), Division of Cancer Treatment and Diagnosis
(DCTD), National Cancer Institute (NCI).
Celecoxib and matching Placebo will be supplied in bottles containing 100 – 400mg
capsules (Celecoxib) or 100 – 0mg capsules (Placebo) with a child-resistant cap and a
tamper-evident seal. Each blinded, patient-specific bottle will be labeled with:
´•
the protocol number (i.e., “CALGB-30801”)
´•
the bottle number (i.e., “Bottle 1 of 3”, “Bottle 2 of 3”, “Bottle 3 of 3”)
´•
the number of capsules (i.e., “100 capsules”)
´•
the patient ID number (e.g., “999999", where “999999” represents a unique
patient identifier assigned by CALGB at pre-registration)
´•
the patient initials (i.e., last initial, first initial, middle initial [e.g., "L,FM"])
´•
the agent identification (i.e., “Celecoxib 400 mg or Placebo”)
´•
a blank line for the pharmacist to enter the patient’s name
´•
administration instructions (i.e., “Take one capsule twice daily with food.”)
´•
storage instructions (i.e., “Store at room temperature (15ºC to 25ºC, 59ºF to
77ºF).”)
´•
emergency contact instructions
´•
a Julian date
The Julian date indicates the day the bottle was labeled and shipped and is
composed of the last two digits of the calendar year (e.g., 2009 = 09, 2010 = 10) and
a day count (e.g., January 1 = 001, December 31 = 365). For example, a bottle
labeled and shipped on January 1, 2009 would have a Julian date of ‘09001’ and a
bottle labeled and shipped on December 31, 2010 would have a Julian date of
‘10365’. The Julian date will be used by PMB for recalls. When a lot expires, PMB
will determine the last date the expired lot was shipped and will recall all bottles (i.e.,
both Celecoxib and Placebo) shipped on or before that date thus eliminating any
chance of breaking the blind.
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Questions about drug orders, transfers, returns, or accountability should be
addressed to the PMB by calling 301-496-5725 Monday through Friday between
8:30AM
and
4:30PM
Eastern
Time
or
by
emailing
<PMBAfterHours@mail.nih.gov> anytime.
Drug Ordering
No blinded starter supplies will be available for this study. Blinded, patient
specific clinical supplies will be sent to the registering investigator at the time of
randomization and should arrive within approximately 10 to 14 days. Shipments to
United States sites can be expedited (i.e., receipt on Thursday in example
above) by the provision of an express courier account name and number to the
CALGB Statistical Center at the time the patient is randomized. The
randomization will be performed by the CALGB Statistical Center in Durham, NC.
The assigned CALGB patient ID number must be recorded by the registering
institution for proper bottle dispersion. Once a patient has been registered with the
CALGB Statistical Center, the CALGB Statistical Center will electronically transmit a
clinical drug request for that patient to the PMB. This request will be entered and
transmitted by the CALGB Statistical Center the day the patient is registered and will
be processed by the PMB the next business day and shipped the following business
day. Shipments within the United States will be sent by US Priority Mail (generally
two to three day delivery) and shipments to Canada will be sent by FedEx (generally
one to two day delivery). Thus, if a patient is registered on Monday, CALGB would
enter a clinical drug request for that patient on Monday and PMB would process that
request on Tuesday and ship the drug on Wednesday. United States sites could
expect to receive their order approximately Friday or Monday (see table) and
Canadian sites could expect to receive their order either Thursday or Friday.
Shipments to United States sites can be expedited (i.e., receipt on Thursday in
example above) by the provision of an express courier account name and
number to the CALGB Statistical Center at the time the patient is randomized.
The initial request will be for 3 – 100 capsule bottles (a 6-cycle / 18 week supply at
a dose of one capsule twice daily) of Celecoxib or matching Placebo. At the start of
the sixth (6th) cycle (3 weeks before needed), sites may reorder an additional 3 – 100
capsule bottles (a 6-cycle / 18 week supply at a dose of one capsule twice daily) by
completing an NCI Clinical Drug Request form and faxing it to the PMB at 301-4804612. The NCI Clinical Drug Request form is available on the CTEP home page
(http://ctep.cancer.gov). The protocol number (i.e., CALGB-30801), the assigned
patient ID number (e.g., "999999"), the patient initials (e.g., "L,FM"), and the number
of bottles remaining from the previous shipment should be entered on each order.
All drug orders will be shipped directly to the registering physician at the shipping
address listed on their most recent Supplemental Investigator Data Form (IDF) on file
with CTEP. The registering investigator must maintain an active investigator status
with CTEP, DCTD through the annual submission of an FDA Form 1572 (Statement
of Investigator), a Curriculum Vitae, a Supplemental Investigator Data Form (IDF),
and
a
Financial
Disclosure
Form
(FDF)
(http://ctep.cancer.gov/InvestigatorResources/investigator_registration.htm).
CALGB-30801 Shipment Schedule
Patient Randomized
Initial e-Order
Initial e-Order Received
Initial Order
with CALGB
Sent by CALGB
and Approved by PMB
Shipped By PMB
Monday
Monday
Tuesday
Wednesday
Tuesday
Tuesday
Wednesday
Thursday
Wednesday
Wednesday
Thursday
Friday
Thursday
Thursday
Friday
Monday
Friday
Friday
Monday
Tuesday
** arrival time approximate / shipments sent by US Priority Mail
Initial Order
Received at Site **
Monday
Tuesday
Wednesday
Thursday
Friday
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How Supplied
"Celecoxib" and matching "Placebo" are supplied as a size 0 white to off-white opaque
hard gelatin capsule for oral administration. Each tamper-evident, child-resistant,
180ml, square, white, opaque, high-density polyethylene (HDPE) bottle contains 100
capsules.
For “Celecoxib”, each capsule contains 400mg of celecoxib with
croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium
stearate, povidone, and sodium lauryl sulfate. For “Placebo”, each capsule contains
croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium
stearate, povidone, and sodium lauryl sulfate.
"Celecoxib" and matching "Placebo" are shipped at room temperature by US Priority
Mail and by FedEx to Canada. The capsules should be stored at controlled room
temperature (15ºC to 25ºC, 59ºF to 77ºF). The intact bottles of 100 capsules are
stable for five years when stored at controlled room temperature.
Route of Administration
Oral. Celecoxib/placebo at doses of 400mg orally twice daily should be administered
with food to improve absorption.
Drug Transfers
Bottles may NOT be transferred from one patient to another patient or from one
protocol to another protocol. All other transfers (e.g., a patient moves from one
participating clinical site to another participating clinical site, the investigator at a
given clinical site changes) must be approved in advance by the PMB. To obtain an
approval for transfer, investigators should complete and submit to the PMB (fax
number 301-402-0429) a Transfer Investigational Agent Form available on the CTEP
home page (http://ctep.cancer.gov). The patient ID number (e.g., "999999"') and the
patient initials (e.g., "L,FM") must be entered in the "Received on NCI Protocol No."
and the "Transferred to NCI Protocol No." fields in addition to the protocol number
(i.e., "CALGB-30801").
Drug Returns
Only undispensed clinical supplies should be returned to the PMB. When it is
necessary to return study drug (e.g., sealed bottles remaining when a patient
permanently discontinues protocol treatment, expired bottles recalled by the PMB),
investigators should return the study drug to the PMB using the NCI Return Drug
List available on the CTEP home page (http://ctep.cancer.gov). The patient ID
number (e.g., "999999") and the patient initials (e.g., "L,FM") should be entered in the
"Lot Number" field. A separate line item is required for each patient ID number (e.g.,
"999999") being returned. Dispensed bottles with remaining tablets should be
documented in the patient-specific NCI Investigational Agent Accountability
Record (i.e., logged is as “returned by patient” and logged out as “destroyed on
site”) and destroyed on site in accordance with institutional policy.
Drug Accountability
The investigator, or a responsible party designated by the investigator, must
maintain a careful record of the receipt, disposition, and return of all drugs received
from the PMB using the NCI Investigational Agent Accountability Record available on
the CTEP home page (http://ctep.cancer.gov) or by calling the PMB at 301-496-5725.
A separate NCI Investigational Agent Accountability Record must be maintained for
each patient ID number (e.g., "999999") on this protocol. It is recommended that the
combination julian date / order number in the upper right hand corner of the
patient-specific bottle label be recorded as the lot number.
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Unblinding Procedures
Unblinding can be done only in the case of an emergency. Follow the directions below
to unblind patient treatment. Please note that, if treatment is unblinded due to an
emergency, the patient must permanently discontinue all protocol therapy.
Emergency Unblinding Procedures
Examples of emergencies include …
1) a life threatening unexpected adverse event that is at least possibly related to the
investigational agent and for which unblinding would influence treatment
decisions
OR
2) a medication error, such as an accidental overdose.
Expected adverse events are listed in the “Toxicities” section below.
Contact a CALGB Approving Physician (i.e., Executive Officer) by calling the pager
number, 773-652-0098. If an Executive Officer cannot be reached, contact the
CALGB Statistical Center at 1-877-442-2542 and the Statistical Center will contact
an Approving Physician. Note: The Statistical Center cannot give permission for
unblinding; only a CALGB Approving Physician can authorize emergency unblinding.
The following information will be required when contacting the CALGB Approving
Physician:
•
CALGB study number (i.e., “CALGB-30801”)
•
CALGB patient ID number (e.g., “999999”)
•
Patient initials (e.g., “L,FM”)
•
Institution name
•
Name and telephone number of treating physician
•
Name and telephone number of person requesting the unblinding procedure
•
Name and telephone number of contact person to inform of treatment assignment
•
Reason for emergency unblinding
After authorization by a designated CALGB Approving Physician, the treatment
assignment will be provided to the contact person by the CALGB Statistical Center.
Toxicities
Celecoxib/placebo is generally well tolerated and has no overlapping toxicities with
gemcitabine or carboplatin. The most common toxicity reported in arthritis trials is
headache. Other possible toxicities include peripheral edema, insomnia, dizziness,
skin rash, dyspepsia, diarrhea, abdominal pain, nausea, flatulence, back pain, upper
respiratory tract infection, sinusitis, pharyngitis, and rhinitis.
The incidence of GI ulcers documented by endoscopy in arthritis trials is 7%. GI
bleeding is more likely to occur in patients with a history of peptic ulcer disease
and/or GI bleeding. The risk of GI ulceration, bleeding or perforation with celecoxib
is increased with concomitant use of aspirin. Chronic use of aspirin (>325 mg/day)
or other NSAIDs is not allowed on this trial (see also Section 4.1.10).
As is the case with non-selective NSAIDS, celecoxib may be associated with
nephrotoxicity in patients in whom renal prostaglandins are important in
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maintenance of renal blood flow. Specifically, patients with pre-existing renal
dysfunction, heart failure, liver dysfunction or dehydration, elderly patients, or
patients taking diuretics or ACE inhibitors are at the greatest risk for significant
inhibition of renal blood flow and nephrotoxicity. In addition, long-term use of
NSAIDs has been associated with renal injury, including renal papillary necrosis.
Unlike other non-selective NSAIDS, celecoxib does not appear to inhibit platelet
aggregation.
A safety analysis performed in December, 2004, of several long term celecoxib trials
was conducted following the removal of rofecoxib from the market because of an
increased risk of adverse cardiovascular events. The celecoxib analysis resulted in
the suspension of drug use for patients enrolled in the Adenoma Prevention with
Celecoxib (APC) trial. In this trial, the risk of cardiovascular death, myocardial
infection or stroke in the celecoxib groups was 2-3 times higher than the risk in the
placebo group. This increased hazard with celecoxib was not observed in another
long term trial.
Drug Interactions
Celecoxib is metabolized in the liver by cytochrome P450 2C9. Drugs that inhibit
(e.g., fluconazole) or induce (e.g., rifampin) the 2C9 isoenzyme might be expected to
result in increased toxicity or decreased effect of celecoxib, respectively. In addition,
celecoxib is reported to inhibit the 2D6 isoenzyme, potentially enhancing the effects
of drugs metabolized by this isoenzyme.
The following describes possible drug interactions:
ACE-inhibitors: NSAIDs may diminish the antihypertensive effect of ACE-inhibitors.
Coumadin: Celecoxib does not alter PT/INR; there have been reports of prolonged
prothrombin time and bleeding in elderly patients taking both coumadin and
celecoxib.
Fluconazole: Concomitant administration of celecoxib and fluconazole results in a
two-fold increase in celecoxib levels.
Lithium: Concomitant administration of celecoxib and lithium results in an increase
in steady-state lithium levels.
11.0 ANCILLARY THERAPY
11.1 Patients should receive full supportive care, including transfusions of blood and
blood products, antibiotics, antiemetics, etc., when appropriate. Steroids may be
used as antiemetics in this study. The reason(s) for treatment, dosage, and the dates
of treatment should be recorded on the remarks addendum.
11.2 Treatment with other chemotherapeutic agents or hormones (except for Megace, if
used for appetite stimulation) will result in the patient's removal from protocol
therapy,
11.3 CALGB Policy Concerning the Use of Growth Factors
11.3.1 Epoietin (EPO)
The use of EPO is permitted at the discretion of the treating physician.
11.3.2 Filgrastim (G-CSF), pegfilgrastim and sargramostim (GM-CSF)
1. Filgrastim (G-CSF) or pegfilgrastim and sargramostim (GM-CSF) may be used
in accordance with ASCO guidelines.
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2. For the treatment of febrile neutropenia, the use of CSFs should not be
routinely instituted as an adjunct to appropriate antibiotic therapy. However,
the use of CSFs may be indicated in patients who have prognostic factors that
are predictive of clinical deterioration such as pneumonia, hypotension,
multi- organ dysfunction (sepsis syndrome) or fungal infection, as per the
ASCO guidelines. Investigators should therefore use their own discretion in
using the CSFs in this setting. The use of CSF (filgrastim or sargramostim)
must be documented and reported on flow sheets.
3. If growth factors are used, they must be obtained from commercial sources.
11.4 Concomitant Medications
Patients should be instructed to avoid NSAIDs, such as rofecoxib (Vioxx), aspirin
(≤325 mg daily is allowed), choline Mg, trisalicylate (Trilisate), or other nonsteroidal anti-inflammatory drugs such as ibuprofen (Advil or Motrin), naproxen
(Aleve, Naprosyn or Anaprox), etodolac (Lodine), oxaprozin (Daypro),
diflunisal (Dolobid), nabumetone (Relafen), or tolmetin (Tolectin).
11.5 Palliative Radiotherapy
Palliative radiation for the treatment of painful bone lesions that were previously
known (i.e., do not represent new and therefore progressive lesions) and are less than
5% of marrow is permitted.
12.0 CRITERIA FOR RESPONSE, PROGRESSION, AND RELAPSE
For the purposes of this study, patients should be reevaluated every 6-8 weeks. In
addition to a baseline scan, confirmatory scans should also be obtained ≥ 4 weeks
following initial documentation of objective response.
12.1 Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total,
representative of all involved organs, should be identified as target lesions and will be
recorded and measured at baseline. Target lesions should be selected on the basis of
their size (lesions with the longest diameter), be representative of all involved organs,
and should be chosen based on their suitability for accurate repetitive
measurements. It may be the case that, on occasion, the largest lesion does not lend
itself to reproducible repeated measurements in which case the next largest lesion
which can be measured reproducibly should be selected. A sum of the diameters
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will
be calculated and reported as the baseline sum diameters. If lymph nodes are to be
included in the sum, then only the short axis is added into the sum. The baseline
sum LD will be used as reference to further characterize the objective tumor response
of the measurable dimension of the disease.
12.1.1 Complete Response: Disappearance of all target lesions. Any pathological
lymph nodes (whether target or non-target) must have reduction in short axis to
< 10 mm.
12.1.2 Partial Response (PR): At least a 30% decrease in the sum of the diameters of
target lesions, taking as reference the baseline sum diameters.
12.1.3 Progressive Disease (PD): At least a 20% increase in the sum of the diameters
of target lesions, taking as reference the smallest sum on study (this includes
the baseline sum if that is the smallest on study). In addition to the relative
increase of 20%, the sum must also demonstrate an absolute increase of at least
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5 mm. (Note: the appearance of one or more new lesions is also considered
progression).
12.1.4 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD taking as references the smallest sum diameters while
on study.
12.2 Non-target Lesions
All other lesions (or sites of disease) including any measurable lesions over and above
the 5 target lesions should be identified as non-target lesions and should also be
recorded at baseline. Measurements of these lesions are not required, but the
presence, absence, or in rare cases unequivocal progression of each should be noted
throughout follow-up.
12.2.1 Complete Response (CR): Disappearance of all non-target lesions and
normalization of tumor marker level. All lymph nodes must be non-pathological
in size (<10 mm short axis). Note: If tumor markers are initially above the upper
normal limit, they must normalize for a patient to be considered in complete
clinical response.
12.2.2 Non-complete response (non-CR)/Non-progression (non-PD): Persistence of
one or more non-target lesion(s) and/or maintenance of tumor marker level
above the normal limits.
12.2.3 Progressive Disease (PD): Appearance of one or more new lesions and/or
unequivocal progression of existing non-target lesions. Unequivocal progression
should not normally trump target lesion status. It must be representative of
overall disease status change, not a single lesion increase.
Although a clear progression of non-target lesions only is exceptional, the
opinion of the treating physician should prevail in such circumstances, and the
progression status should be confirmed later on by the review panel (or Study
Chair).
12.2.4 FDG-PET While FDG-PET response assessments need additional study, it is
sometimes reasonable to incorporate the use of FDG-PET scanning to
complement CT scanning in assessment of progression (particularly possible
'new' disease). New lesions on the basis of FDG-PET imaging can be identified
according to the following algorithm:
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign
of PD based on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT,
this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site
of disease on CT, additional follow-up CT scans are needed to determine if
there is truly progression occurring at that site (if so, the date of PD will be
the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at
follow-up corresponds to a pre-existing site of disease on CT that is not
progressing on the basis of the anatomic images, this is not PD.
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to
a biopsy in cases where a residual radiographic abnormality is thought to
represent fibrosis or scarring. The use of FDG-PET in this circumstance
should be prospectively described in the protocol and supported by diseasespecific medical literature for the indication. However, it must be
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acknowledged that both approaches may lead to false positive CR due to
limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an
uptake greater than twice that of the surrounding tissue on the attenuation
corrected image.
12.3 Cytology and Histology
If the measurable disease is restricted to a solitary lesion, its neoplastic nature
should be confirmed by cytology/histology.
These techniques can be used to differentiate between PR and CR in rare cases (for
example, residual lesions in tumor types such as germ cell tumors, where known
residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or
worsens during treatment when the measurable tumor has met criteria for response
or stable disease is mandatory to differentiate between response or stable disease (an
effusion may be a side effect of the treatment) and progressive disease.
12.4 Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the
treatment until disease progression/recurrence (taking as reference for progressive
disease the smallest measurements recorded since the treatment started). The
patient’s best response assignment will depend on the achievement of both
measurement and confirmation criteria (see Section 12.6.1).
For Patients with Measurable Disease (i.e., Target Disease)
Target Lesions
Non-target
Lesions
New Lesions
Overall
Response
Best Overall
Response when
Confirmation is
Required
CR
CR
No
CR
≥ 4 wks
confirmation*
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/NonPD/not evaluated
No
PR
SD
Non-CR/NonPD/not evaluated
No
SD
PD
Any
Yes or No
PD
Any
PD**
Yes or No
PD
Any
Any
Yes
PD
*
≥ 4 wks
confirmation*
Documented at
least once ≥ 4
wks from
baseline*
No prior SD, PR
or CR
Only for non-randomized trials with response as the primary endpoint.
** In exceptional circumstances, unequivocal progression in non-target lesions may
be accepted as disease progression.
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Note:
•
Patients with a global deterioration of health status requiring discontinuation of
treatment without objective evidence of disease progression at that time should
be reported as “symptomatic deterioration” on the Off-treatment Form (C-300)
under “other.” Every effort should be made to document the objective progression
even after discontinuation of treatment.
For Patients with Non-measurable Disease (i.e., Non-target Disease)
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD*
Not all evaluated
No
not evaluated
Unequivocal PD
Yes or No
PD
Any
Yes
PD
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is
increasingly used as an endpoint for assessment of efficacy in some trials so to assign
this category when no lesions can be measured is not advised
12.5 Guidelines for Evaluation of Measurable Disease
All measurements should be taken and recorded in metric notation using a ruler or
calipers. All baseline evaluations should be performed as closely as possible to the
beginning of treatment and never more than 4 weeks before the beginning of the
treatment.
The same method of assessment and the same technique should be used to
characterize each identified and reported lesion at baseline and during follow-up.
Imaging-based evaluation is preferred to evaluation by clinical examination unless
the lesion(s) being followed cannot be imaged but are assessable by clinical exam.
12.5.1 Clinical Lesions will only be considered measurable when they are superficial
(e.g., skin nodules, palpable lymph nodes) and ≥ 10 mm diameter as assessed
using calipers (e.g., skin nodules). For the case of skin lesions, documentation
by color photography, including a ruler to estimate the size of the lesion, is
recommended.
12.5.2 Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when
they are clearly defined and surrounded by aerated lung. However, CT is
preferable.
12.5.3 Conventional CT and MRI: This guideline has defined measurability of lesions
on CT scan based on the assumption that CT slice thickness is 5 mm or less. If
CT scans have slice thickness greater than 5 mm, the minimum size for a
measurable lesion should be twice the slice thickness. MRI is also
acceptable in certain situations (e.g., for body scans). Use of MRI remains a
complex issue. MRI has excellent contrast, spatial, and temporal resolution;
however, there are many image acquisition variables involved in MRI, which
greatly impact image quality, lesion conspicuity, and measurement.
Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is
performed, the technical specifications of the scanning sequences used should
be optimized for the evaluation of the type and site of disease. Furthermore, as
with CT, the modality used at follow-up should be the same as was used at
baseline and the lesions should be measured/assessed on the same pulse
sequence. It is beyond the scope of the RECIST guidelines to prescribe specific
MRI pulse sequence parameters for all scanners, body parts, and diseases.
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Ideally, the same type of scanner should be used and the image acquisition
protocol should be followed as closely as possible to prior scans. Body scans
should be performed with breath-hold scanning techniques, if possible.
12.5.4 PET-CT: At present, the low dose or attenuation correction CT portion of a
combined PET-CT is not always of optimal diagnostic CT quality for use with
RECIST measurements. However, if the site can document that the CT performed
as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV
and oral contrast), then the CT portion of the PET-CT can be used for RECIST
measurements and can be used interchangeably with conventional CT in
accurately measuring cancer lesions over time. Note, however, that the PET
portion of the CT introduces additional data which may bias an investigator if it
is not routinely or serially performed.
12.5.5 Ultrasound (US): Ultrasound is not useful in assessment of lesion size and
should not be used as a method of measurement. Ultrasound examinations
cannot be reproduced in their entirety for independent review at a later date and,
because they are operator dependent, it cannot be guaranteed that the same
technique and measurements will be taken from one assessment to the next. If
new lesions are identified by ultrasound in the course of the study, confirmation
by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI
may be used instead of CT in selected instances.
12.5.6 Endoscopy and Laporascopy: The utilization of these techniques for objective
tumor evaluation is not advised. However, such techniques may be useful to
confirm complete pathological response when biopsies are obtained or to
determine relapse in trials where recurrence following complete response (CR) or
surgical resection is an endpoint.
12.5.7 Tumor Markers alone cannot be used to assess response. If markers are
initially above the upper normal limit, they must normalize for a patient to be
considered in complete clinical response.
12.6 Confirmation Measurement/Duration of Response
12.6.1 Confirmation
To be assigned a status of PR or CR, changes in tumor measurements must be
confirmed by repeat studies that should be performed no less than 4 weeks
after the criteria for response are first met. In the case of SD, follow-up
measurements must have met the SD criteria at least once after study entry at a
minimum interval of 6 weeks.
12.6.2 Duration of Overall Response
The duration of overall response is measured from the time measurement
criteria are met for CR/PR (whichever is first recorded) until the first date that
recurrent or progressive disease is objectively documented (taking as reference
for progressive disease the smallest measurements recorded since the treatment
started).
The duration of overall complete response is measured from the time
measurement criteria are first met for CR until the first date that progressive
disease is objectively documented.
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12.6.3 Duration of Stable Disease
Stable disease is measured from the start of the treatment until the criteria for
progression are met, taking as reference the smallest measurements recorded
since the treatment started, including the baseline measurements.
13.0 REMOVAL OF PATIENTS FROM PROTOCOL THERAPY
13.1 Duration of Treatment
Patients will receive six cycles of chemotherapy with carboplatin/gemcitabine or
carboplatin/pemetrexed as well as celecoxib/placebo. After completion of the six
cycles of cytotoxic chemotherapy patients will continue to receive the
celecoxib/placebo until unacceptable toxicity or disease progression. Patients with
disease progression or unacceptable toxicities at any time during protocol
therapy will discontinue treatment.
13.2 Extraordinary Medical Circumstances or withdrawal of consent by the patient:
If, at any time, the constraints of this protocol are detrimental to the patient’s health
and/or the patient no longer wishes to continue protocol therapy, the patient shall be
withdrawn from protocol therapy. In this event:
•
•
•
Notify the Study Chair.
Document the reason(s) for withdrawal on the C-1869 and Remarks Addenda.
Follow the patient for disease progression and survival.
14.0 STATISTICAL CONSIDERATIONS
14.1 Study Design and Objectives
The primary endpoint of this trial is progression-free survival. Current regimens in
an unselected population produce a median survival of approximately 8 to 10 months
and 30-40% one year survival. In ECOG 4599, the selected population median
survival was 12 months and the control was 10 months. Hence, the selection criteria
of E4599 biased the study towards a favorable group. Based upon CALGB 30203,
COX-2 overexpression will select for an unfavorable group of patients. We
conservatively estimate that patients with COX-2 expression index of ≥ 4 will have a
median progression-free survival of 4.0 months and overall survival of 6.0 months.
Our hypothesis is that if these patients receive celecoxib + chemotherapy, this
median progression free survival will increase to 6.2 months and the median overall
survival will increase to 9.2 months.
14.2 Efficacy Endpoint
The primary objective of this phase III trial is to evaluate the benefit of COX-2
inhibition combined with chemotherapy (arm A) as compared to chemotherapy only
(arm B) in advanced NSCLC patients who have “over-expressed” COX-2 (COX-2 index
≥ 4). The primary endpoint used for sample size calculation is progression free
survival (PFS), but overall survival (OS) will be used in the interim analyses to decide
if the trial can be stopped early for superiority and futility. The secondary objectives
are: (i) to determine response rate and toxicity; (ii) to evaluate the survival benefit of
arm A over arm B in patients with COX-2 index ≥ 2; (iii) to verify the adverse
prognostic value of COX-2 expression.
Eligible patients will be approached for pre-registration. After the expression level of
COX-2 is determined, the CALGB Statistical Center will be notified by email. Based
on the result, pre-registered patients will be classified as “over-expressed” (COX-2
index ≥ 4), “moderately expressed” (2 ≤ COX-2 index <4), and “negative” (COX-2 index
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<2). In order to address the secondary objective ii, all COX-2 “expressed” patients
(COX-2 index ≥ 2) will be randomized with equal allocation to arm A and arm B. To
ensure balance, randomization will be implemented using a permuted-block scheme
(24) stratified by sex (female vs. male), Stage (IIIb vs. IV), histology (squamous vs
non-squamous), smoking status (never/light smoker defined as ≤ 10 pack years AND
quit > 1 year ago vs. smoker) and the COX-2 expression status (COX-2 index ≥4, ≥2
but <4).
Approximately 792 eligible patients will be pre-registered. With an allowance of 25%
registered patients who fail to yield high quality specimens for COX-2 analysis, we
expect that 594 patients will have COX-2 measured. Of them, 297 patients (50%) are
COX-2 expressers (COX-2 index ≥2) and are randomized to arm A and arm B. Of
these patients, 208 patients have COX-2 index ≥4, At a monthly rate of 19 patients,
the study is expected to accrue 792 patients over a period of approximately 42
months. All patients are required to be followed for 4 years or to death, whichever
comes first.
Power Analysis for COX-2 Over-expression (COX-2 index ≥4)
CALGB 30203 enrolled 140 patients within one year. A total of 107 specimens were
submitted. Of them, 82 (77%) were of adequate quality for COX-2 analysis and 53
(35%) had COX-2 index ≥ 4 (COX-2 “overexpressed”). The study found that patients
receiving celecoxib (with or without zileuton) who had over-expressed COX-2
demonstrated superior survival compared with over-expressed patients who did not
receive celecoxib: the median survival (OS) is 11.3 months (95%CI: 9.2-17.6) for overexpressed patients receiving celecoxib and 3.8 months (95%CI: 0.9-10.5) for overexpressed patients not receiving celecoxib - HR=0.34 (95%CI: 0.16-0.75). Similarly,
the median progression free survival (PFS) is 6.5 months (95%CI: 4.8-8.46) for overexpressed patients receiving celecoxib and 3.4 months (95%CI: 0.8-6.4) for overexpressed patients not receiving celecoxib - HR=0.29 (95%CI: 0.13-0.68).
For the current study the sample size is determined to have adequate power to detect
the benefit of over-expressed patients (COX-2 ≥ 4) on arm A against those on arm B
in terms of progression-free survival. The following assumptions are made: (1) 75% of
specimens submitted by registered patients yield evaluable specimens for COX-2
assays; (2) 35% of evaluable patients are COX-2 over-expressed (COX-2 index ≥4); (3)
the median PFS is 6.2 months for arm A and is 4.0 months for arm B, corresponding
to a hazard ratio λA/λB of 0.645 (1/1.55) under constant hazards; (4) an accrual
period of 42 months at a monthly rate of 19 registered patients; (5) a minimum
follow-up of 6 months after enrollment. Under these assumptions, we expect that a
total of 792 patients will be pre-registered to the study; 594 will be COX-2 evaluable
patients; 208 will be COX-2 over-expressed (COX-2 ≥ 4) and will be randomized with
equal allocation to arm A and arm B. At the time of final analysis, or approximately
48 months after the first enrollment, a total of 192 events are expected on the
celecoxib arm (93 events) and on the placebo arm (99 events) under alternative
hypotheses. Under fixed sample size design, the power in detecting the expected PFS
benefit for arm A over arm B is at least 85% using a log-rank test at a two-sided
significance level of 0.05. With the same study size and the same assumptions, the
study has about 81% power to detect a median OS of 9.2 months for arm A and 6
months for arm B (a hazard ratio λA/λB of 0.652). At the final analysis, a total of 177
deaths are expected, with 84 deaths on arm A and 93 on arm B under alternative
hypotheses.
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14.3 Correlative Science Endpoints
14.3.1 PGE-M analysis
One primary objective of the correlative study is to correlate the change of urinary
PGE-M (from baseline to one week of treatment) with overall survival for patients
on arm A. Csiki et al. have shown that the greater the drop of PGE-M at one week
of treatment relative to baseline, the longer the survival (15). Assuming at least
77 deaths are observed over a 3.25 year period on arm A, we are able to detect a
covariate effect of PGE-M change with 80% power at 5% Type I error (2-sided
test), when the increase in log(hazard) per unit s.d. shift in the covariate is 0.32,
which corresponds to a hazard ratio of Δ=1.38 per unit s.d. shift in the covariate
of PGE-M change. Patients in arm A will be classified as High, Moderate and Low
of PGE-M change according to the 67% and 33% percentiles. Univariate analysis
will be performed using a log rank test to correlate overall survival and the group
of PGE-M change. A Cox proportional hazard regression will be used to correlate
the change of PGE-M as a continuous predictor with overall survival with and
without adjusting for other prognostic factors. Similar univariate and multivariate
analyses will be conducted for progression-free survival. Correlation between
PGE-M and COX2 at baseline will be evaluated using Spearmen’s rank
correlation.
In addition to the methodology described above, aliquots of urine will be stored at
the PCO for potential evaluation of alternative methodologies for determining
urinary PGE-M.
14.3.2 Statistical Considerations for the Pharmacogenetic Companion Study
The primary statistical objective for the pharmacogenetic companion of this study
is to investigate the potential association between COX-2 protein expression and
a PTGS2 polymorphism (rs20417). COX-2 expression will be determined using the
described method of intensity scoring (<4 vs ≥ 4) as a binary outcome (underversus moderate/over-expressed). It is hypothesized that the presence of the C
allele is associated with lower COX-2 expression.
Assumptions: The assumed putative allelic relative frequency for rs20417 is 0.30
(C allele). Furthermore, it will be assumed that the genotypic distribution for this
single nucleotide polymorphism (SNP) is not dependent on African ancestry. The
assumed putative probability for being under-expressed in this population is
0.61. The assumed yield of evaluable specimens for COX-2 staining is a target
sample size for the main study of 594 patients. It will be assumed that the
typical rate of consent to a companion genetic study and yield of usable germline
DNA samples will be a rate similar to previous CALGB studies (0.8), therefore, the
expected sample size is at least 475.
The analysis will be formulated within the framework of a 2x2 contingency table.
Let pA denote the probability of being COX-2 under-expressed for patients with at
least one copy of the C allele and pB denote the probability of being COX-2
under-expressed for patients with no copies of the C allele. The power of Fisher’s
test, at the one-sided level of 0.05, is illustrated in Table 1. For a given pA, p is
chosen so as to satisfy 0.61=pA*0.3+pB*0.7. The corresponding effect size (oddsratio) is denoted by OR.
pA
0.50
0.52
0.54
pB
0.657
0.649
0.640
OR
1.92
1.70
1.51
Power
0.93
0.81
0.63
Table 1: Power Illustration
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The SNP will be tested for Hardy-Weinberg Equilibrium (HWE). The degree of
association between COX-2 expression and rs20417 will be estimated using the
conditional Maximum-Likelihood Estimator (MLE) point and interval estimator for
the OR. The association between rs20417 and clinical endpoints of the study will
be explored. A one-sided level will be used for the primary hypotheses while a
two-sided unadjusted level of 0.05 will be used for all secondary tests and
estimators.
Polymorphisms of CYP2C9 have been implicated in altered metabolism (25). This
may relate to both toxicity and potentially efficacy (26, 27) As a secondary
analyses, we seek to investigate if the relative harm (or benefit) attributed to
celoxib depends on the genotype. To this end, we will consider potential SNP by
celoxib interactions with respect to toxicity and survival among the randomized
patients. These analyses will be carried out within the framework of multiplicative
logistic (for toxicity) and Cox (for censored time-to-event outcomes) ANOVA
models. Additionally, we will seek to explore a potential association between
trough plasma celecoxib concentration and CYP2C9. The Kruskal-Wallis test will
be used for this purpose.
An unadjusted two-sided level of 0.05 will be used for all secondary analyses.
14.4 Analytic Methods
Overall survival is defined as the time between randomization and death from all
causes. Progression-free survival is defined as the time between randomization and
disease relapse or death from any cause, whichever comes first. Overall survival and
progression-free survival (PFS) will be characterized by the Kaplan-Meier method
(28). The primary analysis is to test the survival benefit of arm A over arm B using
log rank test in the intent-to-treat population (29). As secondary analysis, the
treatment difference will be evaluated using a Cox’s proportional hazard model (30)
with the significant prognostic factors as initial model covariates, such as sex, stage,
presence of CNS metastatses, age, smoking status, and histological type. A stepdown procedure that consists of dropping the least significant covariates, one at a
time, will be used to obtain a more parsimonious model. The multivariate analyses
will be done for both the intent-to-treat population and the as-treated population.
Similar analyses will be conducted for progression-free survival (PFS).
Response rate and its 95% confidence interval will be estimated by treatment arm.
The association of response rate will be tested by Fisher’s exact test and will be
modeled using the logistic regression (31) with other prognostic factor eligible to enter
the model.
The survival benefit of a COX-2 inhibitor in patients with COX-2 ≥ 2 will also be
evaluated using a similar procedure. The differential survival benefit for patients with
COX-2 index ≥ 4 and patients with COX-2 index ≥2 but <4 will be tested.
The prognostic value of the COX-2 index will be evaluated for the correlation with OS
and PFS in patients on placebo.
Contingency tables will be used to summarize the frequency of toxicity by severity
and treatment. For comparison of the frequency of toxic events, the Cochran-MantelHaenszel test will be used to take advantage of the trend effect among toxicity grades.
14.5 Logistics of Study Conduct
14.5.1 Accrual
Once 792 patients have been pre-registered to this trial or 208 patients with
COX-2 index ≥ 4 have been randomized, whichever comes later, a notice to close
the study will be issued to the Group via an e-mail broadcast effective within 14
43
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CALGB 30801
days. According to CALGB 30203, more than 50% of COX-2 evaluable patients
have index ≥2. We expect that approximately 297 patients with COX-2 ≥2 of
which 89 patients have COX-2 index ≥2 but <4 and 208 have COX-2 index ≥4 will
be randomized at study closure. Based on the result of interim analysis, a
recommendation for early stopping of the trial is also possible. Based on the
experience of CALGB 30203 and with the participation of other cooperative
groups, a registration rate of 19 patients per month is expected. At this rate, a
period of approximately 42 months is needed to reach accrual target. In order to
observe the full overall survival curve, a follow-up period of 5 years is required for
all patients after enrollment.
14.5.2 Plan for Interim Analysis
The CALGB DSMB will review the study data at each of its semiannual meetings
after study activation (32). This will include toxicity, progression-free survival and
overall survival. Early stopping of this trial could occur for superiority (arm A is
superior to arm B) and for futility (arm A is equivalent or inferior to arm B). Since
there is interest in both the PFS and OS results, to be conservative, we will base
the decision of early stopping of the trial on the result of the interim analyses on
overall survival and we will start the futility monitoring 6 months after the
superiority monitoring starts. The first formal interim analysis on superiority will
occur after 46 deaths have been observed or approximately 1.5 years after study
activation. The rest of the formal interim analyses on superiority and futility will
be conducted at years 2, 2.5, 3, 3.5 and the final analysis at year 4,
corresponding to approximately 71, 98, 127, 155 and 177 deaths. The stratified
log rank test will be used to generate the one-sided p-values for these interim
tests. Using S+SeqTrial (33) we will construct the superiority in the spirit of
O’Brien and Fleming (34) with a use of the Lan-DeMets alpha spending function
(50), and nominal p-value will be truncated at 0.001 in the spirit of Freidlin and
Korn (35). The futility boundary is based on testing the alternative hypothesis at
a one-sided 0.005 alpha level. Specifically, Z-score futility boundary is calculated
as -2.576 – log (0.652)*sqrt (n/4), where n is the total number of observed deaths.
Because of the negligible impact of interim analyses under these boundaries on
the type I error, the final analysis will be conducted using a 2-sided significance
level of 0.05. The following table displays the operating characteristics on survival
comparison between treatment arms, including power, average number of deaths,
stopping probabilities under true hazard ratios λA/ λB of 1.25, 1.0, 0.85, 0.652
and 0.45.
Hazard Ratio
(λA/ λB)
1.25
1.0
0.85
0.652
0.45
Averge Number
of Deaths
94
133
155
133
76
Prob. for Crossing
Superiority Boundary
0.0004
0.0189
0.1380
0.7055
0.9977
Prob. For Crossing
Futility Boundary
0.9433
0.5916
0.2311
0.0124
0.0000
44
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CALGB 30801
14.5.3 Long-term Follow-up
Patients will be followed for 5 years or until death, whichever comes earlier.
15.0 CORRELATIVE SCIENCES METHODOLOGY
15.1 COX-2 Determination by Immunohistochemistry
The COX-2 immunohistochemistry assay will be performed to determine if patients
are eligible for the clinical trial. The same method for COX-2 determination will be
employed as was performed in CALGB 30203. If the patient’s COX-2 index is equal to
2 or greater then they are eligible for the study and will be randomized to the trial
therapies.
The CALGB Molecular Pathology Reference Laboratory will be performing the COX-2
immunohistochemistry assay for the CALGB 30801 trial. The laboratory is located in
the Department of Pathology at The Ohio State University Comprehensive Cancer
Center Innovation Centre. The laboratory is CLIA approved and CAP accredited. The
laboratory participates in proficiency testing for all assays to ensure that methology
and test results achieve national clinical laboratory standards. Each new assay is
validated against sets of clinical cases and verified by other national laboratories
performing the same clinical tests. The CALGB Molecular Pathology Reference
laboratory is located in the suite of laboratories including the laboratories that
comprise the CALGB Pathology Coordinating Office (CALGB PCO). Thus a seamless
interaction exists between the CALGB PCO and the IHC laboratory and thus the
operations are set up such that receipt, management and analysis of biospecimens
can occur rapidly and this will allow for rapid turnaround time of molecular results
needed for this trial. The CALGB Pathology Coordinating Office and Molecular
Pathology Reference Laboratory operations are managed by Dr. Scott Jewell.
COX-2 expression will be assessed in all patients at the time of pre-registration. An
adequate sized paraffin block with tumor tissue/cells taken at the time of initial
diagnosis (or subsequently) will be submitted to the CALGB PCO. A secure and
temperature-safe method of packaging will be used and the shipment will be
traceable via courier. Once the samples arrive at the PCO they will be processed
immediately to obtain the COX-2 results within 72 hours of receipt of the sample.
Residual material will be stored appropriately as to ensure integrity of the antigen by
vacuum sealing and refrigerating the material in a Rees monitored biorepository.
Paraffin embedded tissue is cut at 4um and placed on positively charged slides.
Slides with specimens will then be placed in a 60 degree oven for 1 hour, cooled, and
deparaffinized and rehydrated through xylene and graded alcohol solutions to water.
All slides are quenched for 5 minutes in 3% hydrogen peroxide in water to block for
endogenous peroxidase. Antigen retrieval is performed using Dako's TRS, pH 6.1, in
a vegetable steamer. Slides are then placed on a Dako Autostainer for automated
staining. An antibody to Cox-2, clone SP21 (Labvision Corp), is diluted 1:50 and
incubated for 1 hour at room temperature.
The detection system used is a Labeled Streptavidin-Biotin Complex. This method is
based on the consecutive application of 1.) A primary antibody against the antigen to
be localized, 2.) biotinylated linking antibody, 3.) enzyme conjugated streptavidin,
and 4.) substrate chromogen (DAB). Tissues are avidin and biotin blocked prior to
the application of the biotinylated secondary reagent. Slides are then counterstained
in Richard Allen Hematoxylin, dehydrated through graded ethanol solutions and
coverslipped.
After the Cox-2 immunohistochemistry assay is performed, images of the slides along
with the pathology reports will be electronically transferred for reading by the study
pathologist(s). The CALGB-PCO has implemented a virtual microscopy system, which
allows CALGB pathologists to view the tissues via the internet. The slide scanning
system (Aperio Scanscope XT) and the server are located and maintained at the
CALGB
PCO.
The
process
has
been
developed
to
improve
or
45
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CALGB 30801
minimize a number of operating issues such as packaging, shipping, and return
shipment of original glass H&E slides. The slides will be annotated electronically by
Drs. Jon Ritter, Kisha Mitchell and Richard Cheney, members of the CALGB
Respiratory Pathology Cadre and certified anatomical pathologists. All slides are
reviewed by a certified anatomical pathologist without knowledge of the patient
history.
The scoring procedure for COX-2 expression is semi-quantitative/ordered categorical.
The neoplastic cells for any given case represented by one stained slide are scored for
intensity (range of scores 0-3) and percentage of cells 0 (0%), 1 (1-9%), 2 (10-49%), 3
(50-100%) staining. An immunohistochemistry (IHC) index (range of scores 0-9) is
defined as the product of the intensity and percentage of cells staining.
Accuracy is determined by comparing the measurement against the true or accepted
value. An accuracy measurement of COX-2 by immunohistochemistry (IHC) as
defined against a true or accepted value was not performed in developing the present
IHC test simply because there is currently no gold standard for measuring COX-2
protein product in tissue. The accuracy of the COX-2 IHC assay is determined to be
acceptable based on the monoclonal rabbit anti-human COX-2 antibody that will be
used for the assay has been shown to be specific to the antigen as it was used to
isolate COX-2 in both western blotting and precipitation of COX-2 as determined by
HPLC.
Precision is the degree of refinement with which an operation is performed or a
measurement stated. We have performed two forms of precision testing for the COX-2
assay. First, we have stained a set of samples with a range of IHC indices on
consecutive days and had them analyzed by the study pathologist. This experiment
measures the day-to-day variability of the assay and the consistency with which the
assay performs. The results were extremely reproducible. The two readings of COX-2
did not have any significant differences on any of the samples. All the 95% CI for the
estimates of Alpha contain 0, and all the 95% CI for the estimate for Beta contain 1.
The intraclass correlation and Kappa coefficient were all above 0.8636, suggesting a
strong correlation between the readings.
The second assay precision experiment involved a set of 26 specimens and these
specimens were stained and analyzed by two pathologists in order to evaluate the
consistency of values in two separate sets of observations. The results of this
analysis show that the two readings are strongly correlated with one another and do
not have any significant differences. A linear model was fitted with the measure from
one pathologist as the outcome variable and that of the other pathologist as the
explanatory variable. The 95% confidence interval for the intercept estimate contains
0, and that of the slope estimate contains 1. The joint test for the intercept=0 and the
slope=1 is not statistically significant (p-value=0.5156). Similar findings held for
COX-2 intensity and COX-2 percents. The intraclass correlation is 0.81260 for COX2 index, 0.81308 for intensity, and 0.67726 for percentage. After dichotomizing
COX-2 index at 2, the agreement between RC and CM as measured by Kappa
coefficient (0.7797; 95%CI: 0.3666, 1.000) is also good. All these findings suggest
the reading of COX-2 expression can be reproduced by different pathologists
Proficiency standards for IHC assays are often provided by CAP. When CAP does not
offer proficiency standards it is up to individual laboratories to exchange tissue
specimens. We are in the process of setting up proficiency testing using a small set of
cases that can be tested by both the CALGB Molecular Pathology Reference
Laboratory and the OSU clinical immunohistochemistry laboratory. Both laboratories
are CLIA licensed and CAP certified. Other CALGB pathology labs that are CLIA
certified may also participate in the proficiency testing.
A training set demonstrating the degrees of percent positive cells and intensity of
COX-2 staining in tumor tissues will be established as a reference to assist
pathologist in maintaining a consistency in reading cases.
46
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CALGB 30801
The turn around time for the assay is 72 hours from receipt of the tissue sample at
the testing laboratory. The failure rate of the assay is <5%. Controls for the assay will
include both negative and positive controls as well as an isotype negative control.
Human lung tissue that has been typed as negative and positive will be assayed with
each study specimen run and an isotype negative control reagent (substitution of
non-specific matched isotype antibody in place of the primary antibody) will be
assayed for each study specimen.
15.2 Correlation of Urinary PGE-M Determination with COX-2 Expression, COX-2
Inhibition and Outcome
Changes in urinary PGE-M have been demonstrated to correlate with response to
COX-2 inhibition in studies at Vanderbilt and UCLA (15). Similar results have been
reported from the UCLA group (36). While intriguing, both studies were small, lacked
adequate controls and were inadequately powered to establish whether urinary
PGEM could be utilized as a surrogate for the determination of COX-2 dependency in
advanced NSCLC. Determination of urinary PGE-M may provide a method of
determining possible COX-2 dependence of NSCLC without the requirement for initial
tissue for IHC and may also be an early marker for response to therapy.
The urinary PGE-M assay that will be used in the CALGB 30801 trial will be
performed in the Eicosanoid Core Laboratory at Vanderbilt University Medical Center
under the direction of the laboratory director, Dr. Ginger Milne. The Vanderbilt group
first identified the metabolite of PGE2 in the 1970’s and developed the current
methodology to quantify it in 2004. Since then they have been extremely active in the
field, analyzing 12,000-15,000 eicosanoid samples per year. Specifically for the
metabolite of PGE2, they analyze between 100-200 samples per month.
The urinary PGE-M assay to be used in the CALGB 30801 trial is described in detail
in a publication by the Vanderbilt group entitled “Quantification of the major urinary
metabolite of PGE2 by a liquid chromatographic/mass spectrometric assay:
determination of cyclooxygenase-specific PGE2 synthesis in healthy humans and
those with lung cancer. (Analytical Biochemistry 334 (2004) 266–275).
In brief, urine (1 ml) is acidified to pH 3 with 1M HCl, and endogenous PGE-M is
then converted to the O-methyloxime derivative by treatment with 0.5ml of 16% (w/v)
methyloxime HCl in 1.5M sodium acetate buffer (pH 5). Following a 1-h incubation,
the methoximated PGE-M is extracted with 10ml water adjusted to pH 3, and the
aqueous sample is applied to a C-18 Sep-Pak (Waters, Milford, MA, USA) that has
been preconditioned with 5ml methanol and 5ml water (pH 3). The Sep-Pak is
washed with 20 ml water (pH 3) and 10ml heptane. PGE-M is then eluted from the
Sep-Pak with 5ml ethyl acetate, and any residual aqueous material is removed from
the eluate by aspiration. The [2H6]Omethyloxime PGE-M internal standard (6.2 ng in
10 ul ethanol) is then added, and the eluate is evaporated under a continuous
stream of nitrogen at 37 °C. The dried residue is resuspended in 50 ul mobile phase
A (95:4.9:0.1 (v/v/v) 5mM ammonium acetate:acetonitrile: acetic acid) and is filtered
through a 0.2-micron Spin-X Filter (Corning, Corning, NY, USA). Sample analysis is
performed by LC/MS/MS.
LC is performed on a 2.1 x 50-mm, 5 um particle Zorbax Eclipse XDB-C18 column
(Aligent, Palo Alto, CA, USA) attached to a Surveyor MS Pump (Thermo- Finnigan,
San Jose, CA, USA). Samples are separated by a gradient of 98–40% of mobile phase
A over 15min at a flow rate of 75 ul/min prior to delivery to a ThermoFinnigan TSQ
Quantum triple quadrupole mass spectrometer operating in the selected reaction
monitoring (SRM) mode. The mass spectrometer is operated in the negative ion mode
with a capillary temperature of 210 °C, a spray voltage of 3.0kV, and a tube lens
voltage of 118V. The source collision-induced dissociation (CID) is set at 10eV.
Precursor ions (m/z 385 and 391 for unlabeled PGE-M and the [2H6]PGE-M internal
standard, respectively) are collisionally activated at 22 eV under 1.5mT argon gas.
47
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CALGB 30801
For endogenous PGE-M, the predominant product ion m/z 336 representing [M(OCH3+H2O)]- and the analogous ion, m/z 339 [M-(OC[2H3]+H2O)]-, for the deuterated
internal standard are monitored in SRM mode. Quantification of endogenous PGE-M
uses the ratio of the mass chromatogram peak areas of the m/z 336 and 339 ions.
Data are expressed after correction for urinary creatinine (Cr) concentrations and are
reported as nanograms per milligram Cr. Urine Cr is measured by an Autoanalyzer
technique (Technicon, Buffalo Grove, IL, USA).
Though the original studies were performed utilizing aliquots from 24-hour urine
collections, more recent data indicate that spot urine samples are adequate
(Johnson, personal communication). Therefore, the additional burden on the
investigator is minimal as only two collection timepoints are required on this study.
Several procedures were performed to establish the accuracy of this assay. Initially,
to assess the linearity of response of the assay, varying amounts of unlabeled PGE-M
were added to a fixed amount of the [2H6]PGE-M internal standard and were
analyzed. The ratio of the measured signal of the product ions, m/z 336 and 339,
was plotted as a function of expected ratio. The results of this analysis showed that
the response is linear over a 1000- fold range. In another experiment to esatblish the
accuracy of the assay, a known amount (8.4 ng) of chemically synthesized PGE-M
was added to five additional 1-ml aliquots of the urine sample from the precision
determination and was analyzed. The concentration of endogenous PGE-M was
subtracted from the total measured concentration, and the accuracy of measurement
of the added 8.4 ng of PGE-M was calculated. The accuracy of the assay was
established to be 93% (n=4, separate experiments). As the response of PGE-M over a
wide concentration range is linear, we expect that PGE-M can be accurately
quantified at both very high and very low levels. To this end, we recently had the
opportunity to measure levels of PGE-M in samples containing known amounts of
newly synthesized PGE-M. We measured samples containing 70 ng and 5.5 ng in
duplicate and obtained the following results: 71.09/76.05 and 5.16/5.11,
respectively.
To establish assay precision, five 1-ml aliquots of urine from the same larger sample
were individually prepared and analyzed. The coefficient of variation of PGE-M
concentrations as determined from the mass chromatograms was determined to be
only 7.2% (n=4, separate experiments).
In addition to establishing the accuracy and precision of the assay, the investigators
assessed the recovery of PGE-M through the assay. Recovery through the extraction
process was determined using [3H7]PGE2. When added to a urine sample,
methoximated, and extracted, 97% of radioactivity was recovered in the purified
sample.
It has been reported previously that storage of urine at -20 °C results can result in a
progressive decomposition of PGE-M over a few months. Therefore, in this trial we
have decided to store the urine at -70 °C or colder. To assess the stability of PGE-M
in urine samples stored at -70 °C and under various other conditions, several
experiments were performed. Multiple aliquots of the same sample were frozen at -70
°C and analyzed over the course of 12 months and were compared with the value for
PGE-M obtained when an aliquot was analyzed at the time of collection. There was
no effect of storage on urinary PGE-M concentrations. The concentration of PGE-M at
the time of collection was 10.9 +/- 1.0 ng/mg Cr, and after 12 months it was 12.0
+/- 3.1 ng/mg Cr (P=ns).
Reference samples have been collected from a 24-hour urine sample donated by a
volunteer and will be used as controls for the assay. The 24-hour urine sample has
been divided into 1mL aliquots that have been frozen and stored. Levels of PGE-M
were measured in 12 of the aliquots and the average PGE-M value and standard
deviation were calculated. A range of acceptable PGE-M values for this sample was
then determined to be +/- two standard deviations (< 20% variability) from the
48
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CALGB 30801
average PGE-M value of the aliquots. To control for quality each day, reference
samples are analyzed side-by-side with study samples. If the PGE-M value of the
reference sample is outside of the accepted range, the analysis is repeated. On the
mass spectrometer each day, a standard (consisting of synthesized PGE-M) is also
analyzed to determine sensitivity and performance of the instrument. If an LC/MS
chromatogram of a sample is determined to be uninterpretable, the sample analysis
will be performed a second time. If, after two analyses, an acceptable result is not
obtained the sample will be reported as “no result”. Additionally, for this study,
calibration curves. will be repeated once per month to maintain that the response is
still linear.
15.3 Association Between the -765G/C Polymorphism
Expression in Non-small Cell Lung Cancer Specimens
in
PTGS2
and
COX-2
The effects of celecoxib on survival for NSCLC patients with tumors that stain
intensely for COX-2 in CALGB 30203 suggests better understanding the biology of
COX-2 expression in NSCLC could improve treatment outcomes for a subset of
NSCLC patients. Based on these data, tumor expression of COX-2 by IHC is the best
available assay, but additional phenotyping assays are proposed in this study.
Evidence from other fields of medicine suggests a germline genetic test might be
useful, with a specific role for rs20417, the common promoter single nucleotide
polymorphism -765G>C of PTGS2 (the gene encoding COX-2), in cell and tissue
expression of COX-2. There are no data available on the relationship between PTGS2
-765 genotype and lung tumor expression of COX-2. However, Cipollone, et al.
demonstrated reproducible associations between the G allele and expression of COX2 detected by IHC in atheromatous plaques and by immunoblot in peripheral blood
mononuclear cells. Homozygosity for the G allele was associated with the highest
level of COX-2 expression, while CC homozygosity the lowest. The lower expressing
allele was associated with lower circulating concentrations of serum CRP and lower
risk for myocardial infarction or stroke in a >1700 patient case/control study.
Brosens, et al. demonstrated the same trend in association between rs20417 allele
and COX-2 expression in duodenal mucosa of patients with familial adenomatous
polyposis. In tumor tissue, somatic mutation and epigenetic regulation might or
might not dramatically alter these relationships. If in NSCLC they do not, then
rs20417 genotyping might be a useful method to screen for NSCLC patients that will
have intense COX-2 staining and be appropriate for further testing for COX-2 tumor
expression. The primary objective of the correlative study therefore is to determine
the association between rs20417 genotype and the rate of NSCLC tumors with > 4
intensity score for COX-2 protein expression on IHC.
Celecoxib metabolism may be affected by cytochrome P450 polymorphisms.
Specifically, polymorphisms of CYP2C9 have been implicated in altered metabolism
(38). This may relate to both toxicity and potentially efficacy (39, 40). Drug related GI
bleeding was found to be related to CYP2C9 polymorphisms with CYP2C9*1/*3 and *
1/*2 associated with significantly greater risk of GI bleeding (OR 12,9 and 3.8,
respectively). There is a possible association between the COX-2 polymorphism 765G>C and the efficacy of NSAID use as a preventative agent for colorectal polyps
(p=.07).
The randomized design of this investigation and the number of NSCLC patients
enrolled provides an opportunity to collect sufficient genomic DNA samples to
consider genome-wide association approaches to identifying heritable factors
associated with good and poor prognosis, good and poor response to the addition of
celecoxib, toxicities from celecoxib, changes in proximal phenotypes such as PGE-M,
and more exploratory investigations.
49
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CALGB 30801
15.4 Pharmacokinetics of Celecoxib
Celecoxib concentrations will be determined with an HPLC assay that has been
validated to FDA guidelines in the CALGB Pharmacology Reference Laboratory (41).
The assay is a rapid and sensitive HPLC method using a monolithic column with UV
detection, which enables the determination of celecoxib with good accuracy at low
drug concentrations in plasma using single-step extraction procedure. Separation
will be performed on a reversed-phase monolithic column, which has lower
separation impedance compared with the particulate packings, and therefore, it
allows easy optimizing chromatographic conditions to obtain desirable resolution in a
short time. The sample preparation only involves a simple one-step protein
precipitation and no evaporation step is required.
450 ul of plasma in a glass-stoppered 15-ml centrifuge tube is added to 50 ul of
mefenamic acid, 500 ul of acetonitrile and 100-mg NaCl. After mixing for 30 seconds,
the mixture is centrifuged for 15 min at 8000 rpm. 20ul of the supernatant is
injected into liquid chromatograph. The separation is performed on Chromolith
Performance column from Merck (Darmstadt, Germany). The wavelength is set at 254
nm.
16.0 ADVERSE EVENT (AER) REPORTING
Investigators are required by Federal Regulations to report serious adverse events as
defined in the table below. CALGB investigators are required to notify the CALGB Central
Office, the Study Chair, and their Institutional Review Board if a patient has a reportable
serious adverse event. The descriptions and grading scales found in the revised NCI
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for
AE reporting beginning October 1, 2010. All appropriate treatment areas should have
access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be
downloaded from the CTEP web site (http://ctep.cancer.gov). All reactions determined to
be “reportable” in an expedited manner must be reported using the NCI Adverse Event
Expedited Reporting System (AdEERS).
Phase 2 and 3 Trials: AdEERS Expedited Reporting Requirements for Adverse
Events That Occur Within 30 Days1 of the Last Dose of Treatment
Grade 1
Grade 2
Grade 2
Grade 3
Grade 3
Grades
4&5
Grades
4&5
Unexpected
Expected
Unexpected
and
with
without
with
without Unexpected Expected
Unexpected Expected
Expected
Hospitali- Hospitali- Hospitali- Hospitalization
zation
zation
zation
Unrelated
Unlikely
Not
Required
Not
Required
Not
Required
Not
Required
Not
Required
Not
Not
10 Calendar
Required Required
Days
Possible
Probable
Definite
Not
Required
Not
Required
Not
Required
Not
Required
Not
Required
Not
Not
Required Required
1
10
Calendar
Days
10
Calendar
Days
10
Calendar
Days
Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last
dose of treatment require reporting as follows:
AdEERS 10 calendar day report:
•
Grade 4 unexpected events
•
Grade 5 expected or unexpected events
March 2005
50
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CALGB 30801
Note: All deaths on study require both routine and expedited reporting
regardless of causality. Attribution to treatment or other cause should be
provided.
•
Expedited AE reporting timelines defined:

"10 calendar days" - A complete AdEERS report on the AE must be submitted
within 10 calendar days of the investigator learning of the event.
•
Any event that results in persistent or significant disabilities/incapacities,
congenital anomalies, or birth defects must be reported via AdEERS.
•
Use the NCI protocol number and the protocol-specific patient ID provided during
trial registration on all reports.
Additional Instructions or Exclusions from AdEERS Expedited Reporting
Requirements:
•
Deaths occurring greater than 30 days after the last dose of treatment that are
due to disease progression do not require AdEERS expedited reporting.
•
All grade 4 events that are unexpected and that are at least possibly related to
treatment must be reported via AdEERS within 10 calendar days.
•
Grade 4 events that are expected do not require AdEERS expedited reporting,
even if they result in hospitalization.
•
Adverse events include those listed in Section 10.0 and in the package inserts.
•
AdEERS reports should be submitted electronically to the CALGB Central Office
(calgb@uchicago.edu).
•
All adverse events reported via AdEERS (i.e., serious adverse events) should also
be forwarded to your local IRB.
•
The reporting of adverse events described in the table above is in addition to and
does not supplant the reporting of adverse events as part of the report of the
results of the clinical trial, e.g., study summary forms or cooperative group data
reporting forms (see Section 6.1 for required CALGB forms).
•
Cases of secondary AML/MDS are to be reported using AdEERS. The event(s)
may be reported as either: 1) Leukemia secondary to oncology chemotherapy; 2)
Myelodysplastic syndrome; or 3) Treatment related secondary malignancy.
•
New primary malignancies should be reported using study form C-1001.
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CALGB 30801
17.0 REFERENCES
1.
Bonomi P, Kim K, Fairclough D, et al. Comparison of survival and quality of life in
advanced non-small-cell lung cancer patients treated with two dose levels of
paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an
Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000 Feb;18:623-31.
2.
Wozniak AJ, Crowley JJ, Balcerzak S, et al. Randomized trial comparing cisplatin
with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung
cancer: A cooperative group study. J Clin Oncol 10:1066-1073, 1992.
3.
Sandler A, Nemunatis J, Denham C, et al. Phase III trial of gemcitabine plus
cisplatin versus cisplatin alone in patients with locally advanced and metastatic
non-small cell lung cancer. J Clin Oncol 18:122-130, 2000.
4.
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Kelly K, Crowley J, Bunn PA et al. Randomized phase three trial of paclitaxel plus
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Oncol 19:3210-8, 2001.
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Khuri FR, Hong W, Lee JJ et al. Cyclooxygenase 2 overexpression is a marker of
poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res 7: 861-7,
2001.
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Wolff, K. Saukkonen, et al. (1998). “Expression of cyclooxygenase-2 in human lung
carcinoma.” Cancer Research 58(22): 4997-5001
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Ochiai, M., T. Oguri, et al. (1999). “Cyclooxygenase-2 (COX-2) mRNA expression
levels in normal lung tissues and non-small cell lung cancers.” Japanese Journal of
Cancer Research 90(12): 1338-43
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Masferrer, J. L., K. M. Leahy, et al. (2000). “Antiangiogenic and antitumor activities
of cyclooxygenase-2 inhibitors.” Cancer Research 60(5): 1306-11.
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Asktorab H, Larbi D, Tackey R, et al. Cyclooxygenase-2 inhibitor celecoxib alone and
in combination with folic acid inhibits proliferation of colon cancer cell lines. Proc
AACR 42: abstr 3305, 2001.
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Pyo H, Choy H, Amorino GP et al. A selective cyclooxygenase-2 inhibitor, ns-398,
enhances the effect of radiation in vitro and in vivo preferentially on the cells that
express cycloxygenase-2. Clin Cancer Res 2998-3005, 2001.
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Ratnasinghe, D., P. J. Daschner, et al. (2001). “Cyclooxygenase-2, P-glycoprotein170 and drug resistance; is chemoprevention against multidrug resistance
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Steinbach G, Lynch PM, Phillips RKThe effect of celecoxib, a cyclooxygenase-2
inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000 Jun
29;342(26):1946-52
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Moysich KB, Menezes RJ, Ronsani A et al. Regular aspirin use and lung cancer risk.
BMC Cancer. 2002 Nov 26;2:31
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15.
Csiki I, Morrow JD, Sandler A. et al. Targeting cyclooygenase-2 in recurrent nonsmall cell lung cancer: a phase II trial of celecoxib and docetaxel. Clin Ca Res
2005:11; 6634-6640.
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Altorki NK, Port JL, Zhang F et al. Chemotherapy induces the expression of
cyclooxygenase-2 in non-small cell lung cancer. Clin Ca Res 2005; 11, 4191-4197.
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Edelman MJ, Watson D, Xiaofei W, Morrison C, Kratzke RA, Jewell S, Hodgson L,
Mauer AM, Gajra A, Masters GA, Bedor M, Green MJ, Vokes EE. Eicosanoid
modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive
predictive factor for celecoxib + chemotherapy--Cancer and Leukemia Group B Trial
30203. J Clin Oncol, . 2008;26:848-55.
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Rini BL, Weinberg V,Dunlap S et al. Maximal COX-2 immunostaining and clinical
response to celecoxib and interferon alpha therapy in metastatic renal cell
carcinoma. Cancer 2006;106:566-75.
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Fidler M, Argiris A, Patel JD, Johnson DH, Sandler A, Villaflor V, Coon J,
Buckingham L, Bonomi P. The potential predictive value of cyclooxygenase -2
expression and increased risk of gastrointestinal hemorrhage in advanced non-small
cell lung cancer patients treated with celecoxib and erlotinib. IASLC Novel Agents
Symposium (Santa Monica, CA), 2007.
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Fabi A, Metro G, Papaldo P Impact of celecoxib on capecitabine tolerability and
activity in pretreated metastatic breast cancer: results of a phase II study with
biomarker evaluation. Cancer Chemother Pharmacol. 2008 Sep;62(4):717-25
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Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to
the expression of COX-2. N Engl J Med. 2007 May 24;356:2131-42
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Solimon SD, McMurray JJV, Pheffer MA, et al. Cardiovascular risk associated with
celecoxib in aclinical trial for colorectal adenoma prevention. N Engl J Med
2005;352:1071-80.
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Johnson DH, Zhu J, Schiller J et al. E-1594- A randomized phase III trial in
metastatic non-small cell lung cancer (NSCLC)- outcome of PS 2 patients (pts): An
Eastern Cooperative Group Trial (ECOG). Proc Am Soc Clin Oncol 18:461a (#1779),
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Zelen M. The randomization and stratification of patients to clinical trials. J Chronic
Dis 1974;27:365-75
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Kirchheiner J, Störmer E, Meisel C, Steinbach N, Roots I, Brockmöller J. Influence
of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its
metabolites. Pharmacogenetics. 2003 Aug;13(8):473-80
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Pilotto A, Seripa D, Franceschi M, Scarcelli C, Colaizzo D, Grandone E, Niro V,
Andriulli A, Leandro G, Di Mario F, Dallapiccola B. Genetic susceptibility to
nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of
cytochrome P450 2C9 polymorphisms. Gastroenterology. 2007 Aug;133(2):465-71.
Epub 2007 May 21.
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Cross JT, Poole EM, Ulrich CM. A review of gene-drug interactions for nonsteroidal
anti-inflammatory drug use in preventing colorectal neoplasia. Pharmacogenomics
J. 2008 Jan 15 [Epub ahead of print]
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28.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am
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Mantel N. Evaluation of survival data and two new rank order statistics arising in its
consideration. Cancer Chemother Rep 1966;50:163-70.
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Cox DR, Snell EJ. Analysis of binary data. 2nd ed. London: Chapman & Hall, 1989.
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Freidlin B, Korn EL, George SL. Data monitoring committees and interim monitoring
guidelines. Control Clinical Trials. 1999; 20(5):395-407.
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Emerson, S. (2000). S+SEQTRIAL: Technical Overview. Research Report No. 98,
Data Analysis Products Division, MathSoft, Inc.
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O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics.
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Freidlin B, Korn EL, George SL. Data monitoring committees and interim monitoring
guidelines. Control Clinical Trials. 1999; 20(5):395-407.
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Reckamp KL, Krysan K, Morrow JD et al. A phase I trial to determine the optimal
biological dose of celecoxib when combined with erlotinib in advanced non-small cell
lung cancer. Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3381-8
37.
Murphey LJ, Williams MK, Sanchez SC et al. Quantification of the major urinary
metabolite of PGE2 by a liquid chromatographic/mass spectrometric assay:
determination of cyclooxygease-specific PGE2 synthesis in healthy humans and
those with lung cancer. Analytical Biochem 2004 334:266-275.
38.
Kirchheiner J, Störmer E, Meisel C, Steinbach N, Roots I, Brockmöller J. Influence
of CYP2C9 genetic polymorphisms on pharmacokinetics of celecoxib and its
metabolites. Pharmacogenetics. 2003 Aug;13(8):473-80
39.
Pilotto A, Seripa D, Franceschi M, Scarcelli C, Colaizzo D, Grandone E, Niro V,
Andriulli A, Leandro G, Di Mario F, Dallapiccola B. Genetic susceptibility to
nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of
cytochrome P450 2C9 polymorphisms. Gastroenterology. 2007 Aug;133(2):465-71.
Epub 2007 May 21.
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Cross JT, Poole EM, Ulrich CM. A review of gene-drug interactions for nonsteroidal
anti-inflammatory drug use in preventing colorectal neoplasia. Pharmacogenomics
J. 2008 Jan 15 [Epub ahead of print]
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Zarghi A, Shafaati A, Foroutan SM, Khoddam A. Simple and rapid high-performance
liquid chromatographic method for determination of celecoxib in plasma using UV
detection: application in pharmacokinetic studies.J Chromatogr B Analyt Technol
Biomed Life Sci. 2006 May 1;835:100-104
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Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R,
Johnson DH Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell
lung cancer. . N Engl J Med. 2006 Dec 14;355(24):2542-50.
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43
Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C,
Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park
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D.Phase III study comparing cisplatin plus gemcitabine with cisplatin plus
pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell
lung cancer.J Clin Oncol. 2008 Jul 20;26(21):3543-51
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Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J,
Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R,
Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. 2004.
Randomized phase III trial of pemetrexed versus docetaxel in patients with nonsmall-cell lung cancer previously treated with chemotherapy. J Clin Oncol
22(9):1589-1597.
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Hughes A, Calvert P, Azzabi A, Plummer R, Johnson R, Rusthoven J, Griffin M,
Fishwick K, Boddy AV, Verrill M, Calvert H. 2002. Phase I clinical and
pharmacokinetic study of pemetrexed and carboplatin in patients with malignant
pleural mesothelioma. J Clin Oncol 20(16):3533-3544.
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Scagliotti GV, Kortsik C, Dark GG, Price A, Manegold C, Rosell R, O’Brien M,
Peterson PM, Castellano D, Selvaggi G, Novello S, Blatter J, Kayitalire L, Crino L,
Paz-Ares L. 2005. Pemetrexed combined with oxaliplatin or carboplatin as first-line
treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase
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Obasaju CK, Hong WK, Herbst RS. 2005. Phase II study of pemetrexed in
combination with carboplatin in the first-line treatment of advanced nonsmall cell
lung cancer. Cancer 104(11):2449-2456.
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when coadministered with aspirin or Ibuprofen in patients with advanced cancer.
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Lan K, DeMets D. Discrete sequential boundaries for clinical trials. Biometrika.
1983; 70:659-653.
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18.0 MODEL CONSENT FORM
A RANDOMIZED PHASE III DOUBLE BLIND TRIAL EVALUATING SELECTIVE COX-2
INHIBITION IN COX-2 EXPRESSING ADVANCED NON-SMALL CELL LUNG CANCER
This is a clinical trial, a type of research study. Your study doctor will explain the
clinical trial to you. Clinical trials include only people who choose to take part.
Please take your time to make your decision about taking part. You may discuss
your decision with your friends and family. You can also discuss it with your
health care team. If you have any questions, you can ask your study doctor for
more explanation.
You are being asked to take part in this study because you have non-small cell
lung cancer.
Why is this study being done?
The purpose of this study is to compare the effects, good and/or bad, of adding an
experimental drug, celecoxib, to chemotherapy. This research is being done
because current standard treatments for your type of lung cancer are usually not
effective in preventing the cancer from growing. In this study we will test a
sample of your cancer to see if it has an enzyme called COX-2. It is thought that
cancers that have high levels of this enzyme may benefit from the addition of
celecoxib to standard chemotherapy.
You will receive standard chemotherapy of either gemcitabine and carboplatin or
pemetrexed and carboplatin, depending on the type of non-small cell lung cancer
you have. Along with standard chemotherapy, you will get either celecoxib or a
placebo (a substance that looks like celecoxib, but contains no medication). We
do not know whether or not adding celecoxib to the chemotherapy is beneficial.
Celecoxib is not approved by the Food and Drug Administration (FDA) for the
treatment of lung cancer.
How many people will take part in the study?
About 300 people will take part in this study.
What will happen if I take part in this research study?
Before you begin the study….
Required Test
Recent studies have shown that people who have high levels of COX-2 in tumor
tissue appear to benefit from treatment with celecoxib or other similar drugs. For
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this reason, your tumor sample will be tested to find out if it has high levels of
COX-2 since this study is evaluating treatments that contain celecoxib. This test
can be done on tumor tissue that was removed at any time. If the test shows that
your tumor does not have a high level of COX-2 you will not continue with
treatment on this trial. You and your doctor will then decide on the appropriate
treatment strategy outside of this clinical trial. The results of the COX-2 test will
not ever be given to you or your doctor.
Optional Test
We are also interested in studying the DNA in your blood to determine: a)
whether or not it has certain characteristics that can predict if you will have high
or low levels of COX-2 and b) how the activity of certain genes influence the
effectiveness and side effects of the drugs used in this study.
Before it is determined whether you are eligible for the study, we would like to
collect about 2 teaspoons of blood for research purposes only, to study the DNA
in your blood. This research blood test will not be used to determine your
eligibility.
The blood sample will be processed to collect your DNA. DNA is the substance
that makes up your genes. Genes are the units of inheritance that are passed down
from generation to generation. They are responsible for eye color, hair color,
blood type, and hundreds of other traits. Genetic studies use DNA to study your
genes. There are specific risks associated with genetic studies. To help you make
your decision, additional information is included at the end of this consent form.
This information describes how your personal information will be protected by
the CALGB and its researchers.
New scientific tools will now allow researchers to look at your whole DNA, not
just one part or gene. This kind of research can provide information to researchers
about the development of cancer and response to treatment. It can also provide
information about a variety of other conditions and diseases, including heart
disease, diabetes and Alzheimer’s disease.
Because the information gained in these DNA wide studies can be very valuable,
especially when they are shared with the research community, the National
Institutes of Health (NIH) has requested that this data be placed in a central
location housed at the NIH. The idea behind this is to speed up the process for
discovery of new treatments, prevention and diagnosis of disease. Researchers
must get approval from the NIH, before they can access the research results and
clinical information from your specimen. All information will be coded with a
unique number. Researchers will not have access to your identity; they will only
see coded information.
While we believe that the risks to you and your family are very low, we cannot
tell you exactly what all of the risks are from taking part in genetic research
studies. Your privacy and confidentiality will be protected to the fullest extent
possible.
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The choice to provide this blood sample is up to you. The test is optional and no
matter what your decide to do, it will not affect your care.
1)
I agree that my blood may be used for the research study described above.
_________ Yes
__________ No
________ Initials
Medical Tests
If you take part in this study, you will have the following tests and procedures:
•
Blood tests
•
CT scan or MRI of chest and abdomen
Several of these tests will be repeated during the study. If you participate in this
study, some of these tests may be done more frequently than if you were not
taking part in this research study.
Treatment Plan
You will be "randomized" into one of the study groups described below.
Randomization means that you are put into a group by chance. A computer
program will place you in one of the study groups. Neither you nor your doctor
can choose the group you will be in. You will have an equal chance of being
placed in either group. You and your doctor will not know which group you are
assigned to. However, your treatment information will be available to your doctor
in case of emergency.
Within each group there are 2 treatments, and the treatment you will receive will
depend on the type of lung cancer you have. There are 3 different types of nonsmall cell lung cancer: adenocarcinoma, squamous cell carcinoma and large cell
carcinoma. Past studies have shown that patients with squamous cell lung cancer
have many more side-effects when treated with pemetrexed. Therefore, patients
with squamous cell carcinoma will be treated with gemcitabine. All other patients
will be treated with pemetrexed. The possible treatments are listed below:
Group A:
Treatment with one of the below combinations, depending on which type of nonsmall cell lung cancer you have:
Gemcitabine by IV (by vein) on days 1 and 8 of each treatment cycle
Carboplatin (immediately after the gemcitabine) by IV on day 1
Celecoxib, one capsule, taken by mouth 2 times daily
Or
Pemetrexed by IV (by vein) on day 1
Carboplatin (immediately after the pemetrexed) by IV on day 1
Celecoxib, one capsule, taken by mouth 2 times daily
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OR
Group B:
Treatment with one of the below combinations, depending on which type of nonsmall cell lung cancer you have:
Gemcitabine by IV on days 1 and 8 of each treatment cycle
Carboplatin (immediately after the gemcitabine) by IV on day 1
Placebo, one capsule, taken by mouth 2 times daily every day
Or
Pemetrexed by IV on day 1
Carboplatin (immediately after the pemetrexed) by IV on day 1
Placebo, one capsule, taken by mouth 2 times daily every day
The treatment will be repeated every 21 days (1 cycle = 21 days). You will
receive up to 6 cycles of treatment. When the 6 cycles (18 weeks) are over you
may continue to take the celecoxib/placebo, as long as your tumor does not grow.
While on this study you will be asked to avoid taking aspirin or other nonsteroidal anti-inflammatory drugs such as rofecoxib (Vioxx), aspirin (≤325 mg
per day is allowed), choline Mg, trisalicylate (Trilisate), or other non-steroidal
anti-inflammatory drugs such as ibuprofen (Advil or Motrin), naproxen
(Aleve, Naprosyn or Anaprox), etodolac (Lodine), oxaprozin (Daypro),
diflunisal (Dolobid), nabumetone (Relafen), or tolmetin (Tolectin).
How long will I be in the study?
We think your treatment will last about 5 months, but could last longer,
depending upon how your disease responds and what kind of side-effects you
experience. You and your doctor may decide to continue on the celecoxib/placebo
if, after 6 cycles of chemotherapy, your tumor is shrinking or staying the same.
Following treatment, you will receive follow-up examinations at least every 2
months for 2 years and then at least 6 months for 3 years. Your doctor will discuss
these tests with you.
The researcher or your doctor may decide to take you off study treatment if:
•
The treatment does not work in your cancer.
•
Your health gets worse.
•
Your cancer begins to grow.
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You can stop participating at any time. However, if you decide to stop
participating in the study, we encourage you to talk to the researcher and your
doctor first.
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking
about stopping or decide to stop. He or she will tell you how to stop safely.
It is important to tell the study doctor if you are thinking about stopping so any
risks from the drugs can be evaluated by your doctor. Another reason to tell your
doctor that you are thinking about stopping is to discuss what followup care and
testing could be most helpful for you.
The doctor may stop you from taking part in this study at any time if he/she
believes it is in your best interest; if you do not follow the study rules; or if the
study is stopped.
What side effects or risks can I expect from being in the study?
You may have side effects while on the study. Everyone taking part in the study will be
watched carefully for any side effects. However, doctors don’t know all the side effects
that may happen. Side effects may be mild or very serious. Your health care team may
give you medicines to help lessen side effects. Many side effects go away soon after you
stop taking the therapy. In some cases, side effects can be serious, long lasting, or may
never go away. There also is a risk of death.
You should talk to your study doctor about any side effects that you have while taking
part in the study.
The risks and side effects of gemcitabine, carboplatin and celecoxib are listed below. If
you are randomized to the gemcitabine, carboplatin and placebo you will not be receiving
the active drug celecoxib. Sometimes, even while taking placebo, people experience side
effects. These side-effects may or may not be due to the placebo. Some side-effects for
patients on placebo may or may not be similar to the side effects of celecoxib.
Celecoxib
Less Likely
• Headache.
• Heartburn.
• Diarrhea
• Belly pain.
• Bleeding in some organ(s) of the digestive tract, for example, blood in your stool.
• Nausea and vomiting
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• Hypertension
• Swelling in the arms and legs
Rare but Serious
• Kidney damage.
• Heart attack
• Stroke
• Chest pain (angina)
• Blood clots
Patients who continue to take the celecoxib/placebo after 1 year may be more likely to
have a heart attack, stroke, or other cardiovascular problems.
Carboplatin
Likely
• Lowered white blood cell count* that may lead to infection.
• Lowered platelets* that may lead to an increase in bruising or bleeding.
• Lowered red blood cells* that may cause anemia, tiredness, or shortness of breath.
• Nausea, vomiting.
• Abnormal liver function blood tests.
• Time away from work.
*
Should this occur it can be treated with blood products (transfusions for low platelets
and red blood cells), antibiotics for low white blood cells, and a reduction in the
amount of drug given to you for low white blood cells and platelets.
Less Likely
• Tingling, like pins and needles, in your hands and feet.
• Hearing loss (rare).
• Allergic reactions.
• Constipation or diarrhea.
• Hair loss.
• Stomach pain.
• Abnormal kidney function blood tests.
Gemcitabine
Likely
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•
•
•
Lowered white blood cell count that may lead to an increased risk of infection
Lowered platelet count that may lead to increased bruising or bleeding
Lowered red blood cell count that may cause anemia, tiredness, or shortness of
breath.
• Nausea, vomiting, diarrhea.
• Flu-like symptoms that may include: muscle aches, fatigue, fever and/or chills,
sweating, joint or chest pain, headache or cough.
• Swelling in arms and/or legs.
• Rash, usually mild, sometimes with itching.
Less likely
• Hair loss.
• Constipation.
• Numbness in fingers and toes.
• Mouth or throat sores.
• Shortness of breath or difficulty breathing.
• Mild allergic reaction (rash, hives, watery or itchy eyes).
Rare, but serious
• Kidney damage that could lead to renal failure.
• Breathing difficulties resulting from damage to the lungs which could be permanent.
Pemetrexed
Likely
• Nausea and/or vomiting
• Feeling tired
Less Likely
• Lowered platelet count that may lead to increased bruising or bleeding
• Lowered white blood cell count that may lead to an increased risk of infection
• Lowered red blood cell count that may cause anemia, tiredness, or shortness of
breath.
• Abnormal kidney function blood tests.
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•
•
•
•
Burning, itchy, watery eyes
Numbness, tingling in the hands and feet
Muscle weakness
Rash, mouth sores and diarrhea
Reproductive risks: You should not become pregnant or father a baby while on this
study because the drugs in this study can affect an unborn baby. Women should not
breastfeed a baby while on this study. It is important you understand that you need to use
birth control while on this study. Check with your study doctor about what kind of birth
control methods to use and how long to use them. Some methods might not be approved
for use in this study.
For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better. While doctors hope
that using celecoxib with chemotherapy will be more useful against cancer compared to
the usual treatment, there is no proof of this yet. We do know that the information from
this study will help doctors learn more about celecoxib as a treatment for cancer. This
information could help future cancer patients.
What other choices do I have if I do not take part in this study?
Your other choices may include:
• Getting treatment or care for your cancer without being in a study
• Taking part in another study
• Getting no treatment
• Getting comfort care, also called palliative care. This type of care helps reduce pain,
tiredness, appetite problems and other problems caused by the cancer. It does not
treat the cancer directly, but instead tries to improve how you feel. Comfort care tries
to keep you as active and comfortable as possible.
Talk to your doctor about your choices before you decide if you will take part in this
study.
Will my medical information be kept private?
We will do our best to make sure that the personal information in your medical record
will be kept private. However, we cannot guarantee total privacy. Your personal
information may be given out if required by law. If information from this study is
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published or presented at scientific meetings, your name and other personal information
will not be used.
Organizations that may look at and/or copy your medical records for research, quality
assurance, and data analysis include:
• Cancer and Leukemia Group B (CALGB)
• The National Cancer Institute (NCI) and other government agencies, like the Food
and Drug Administration (FDA), involved in keeping research safe for people
• Pfizer, Inc, the maker of the celecoxib and placebo
• Lilly, a company that is helping pay for the distribution of the celecoxib and placebo
If your doctor is participating in this study through the Cancer Trials Support Unit (the
CTSU is a clinical trials mechanism sponsored by the NCI to provide greater access to
phase III trials), a record of your progress will also be kept by the CTSU. If your record is
used or disseminated for such purposes, it will be done under conditions that will protect
your privacy to the fullest extent possible consistent with laws relating to public
disclosure of information and the law-enforcement responsibilities of the agency.
The CALGB has received a Certificate of Confidentiality from the federal government,
which will help us to protect your privacy. The Certificate protects against the
involuntary release of information about you collected during the course of the study. The
researchers involved in this project may not be forced to identify you in any legal
proceedings (criminal, civil, administrative, or legislative) at the federal, state, or local
level. However, some information may be required by the Federal Food, Drug, and
Cosmetic Act, the U.S. Department of Health and Human Services, or for purposes of
program review or audit. Also, you may choose to voluntarily disclose the protected
information under certain circumstances. For example, if you or your guardian requests
the release of information about you in writing (through, for example, a written request to
release medical records to an insurance company), the Certificate does not protect against
that voluntary disclosure.
What are the costs of taking part in this study?
You and/or your health plan/ insurance company will need to pay for some or all of the
costs of treating your cancer in this study. Some health plans will not pay these costs for
people taking part in studies. Check with your health plan or insurance company to find
out what they will pay for. Taking part in this study may or may not cost your insurance
company more than the cost of getting regular cancer treatment.
The gemcitabine, or pemetrexed, and carboplatin will be charged to you/your insurance
company.
Pfizer, Inc. will supply the celecoxib/placebo at no charge while you take part in this
study, the National Cancer Institute will distribute it, and Lilly, Inc. will pay for the
distribution. Pfizer, Lilly, and the National Cancer Institute will not cover the cost of
getting the celecoxib/placebo ready and giving it to you, so you or your insurance
company may have to pay for this.
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Even though it probably won’t happen, it is possible that the Pfizer may not continue to
provide the celecoxib/placebo to the National Cancer Institute for some reason. If this
would occur, other possible options are:
• You might be able to get the celecoxib from the manufacturer or your pharmacy but
you or your insurance company may have to pay for it.
• If there is no celecoxib available at all, no one will be able to get more and the study
would close.
If a problem with getting celecoxib occurs, your study doctor will talk to you about these
options.
You will not be paid for taking part in this study.
For more information on clinical trials and insurance coverage, you can visit the
National Cancer Institute’s Web site at
http://cancer.gov/clinicaltrials/understanding/insurance-coverage . You can print a copy
of the “Clinical Trials and Insurance Coverage” information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and
ask them to send you a free copy.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor, __________________ [investigator’s
name(s)], if you feel that you have been injured because of taking part in this study. You
can tell the doctor in person or call him/her at __________________ [telephone
number].
You will get medical treatment if you are injured as a result of taking part in this study.
You and/or your health plan will be charged for this treatment. The study will not pay
for medical treatment.
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take
part in the study. If you decide to take part in this study, you may leave the study at any
time. No matter what decision you make, there will be no penalty to you and you will
not lose any of your regular benefits. Leaving the study will not affect your medical care.
You can still get your medical care from our institution.
We will tell you about new information or changes in the study that may affect your
health or your willingness to continue in the study.
A Data Safety Monitoring Board will be regularly meeting to monitor safety and other
data related to this study. The Board members may receive confidential patient
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information, but they will not receive your name or other information that would allow
them to identify you by name.
In the case of injury resulting from this study, you do not lose any of your legal rights to
seek payment by signing this form.
Who can answer my questions about the study?
You can talk to your study doctor about any questions or concerns you have about this
study.
Contact your study doctor __________________ [name(s)] at
__________________ [telephone number].
For questions about your rights while taking part in this study, call the
________________________ [name of center] Institutional Review Board (a group of
people who review the research to protect your rights) at __________________
(telephone number). [Note to Local Investigator: Contact information for patient
representatives or other individuals in a local institution who are not on the IRB or
research team but take calls regarding clinical trial questions can be listed here.]
*You may also call the Operations Office of the NCI Central Institutional Review Board
(CIRB) at 888-657-3711 (from the continental US only). [*Only applies to sites using the
CIRB.]
Where can I get more information?
You may call the National Cancer Institute's Cancer Information Service at:
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615
You may also visit the NCI Web site at http://cancer.gov/
•
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/
•
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/
You will get a copy of this form. If you want more information about this study, ask your
study doctor.
Related research studies
Please note: The following section of the informed consent document is about
additional research studies that are being done with people who are taking
part in the main study. You may take part in these additional studies if you
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want to. You can still be part of the main study even if you say “no” to taking
part in any of these additional studies.
The results of these research studies will not be provided to you or your doctor,
nor will the results have any affect on your treatment. It is unlikely that what we
learn from these studies will have a direct benefit to you. However, the
information learned from these studies may benefit other patients in the future.
The results of these studies may be published, but individual patients will not be
identified in these publications.
There will be no charge to you for participating in these research studies. Your
samples will only be used for research and will not be sold. The research done
with your sample may help to develop new products in the future.
The greatest risk to you is the release of information from your health records. We
will do our best to make sure that your personal information will be kept private.
The chance that this information will be given to someone is very small.
If you decide now to participate and then change your mind at any time about
participating in these studies for any reason, you should contact your institution
and let them know that you do not want the researchers to use your sample. The
sample then will no longer be used for research. It will either be destroyed or
returned to your institution for storage. The sample will also be returned to your
institution upon request if needed for any other medical or legal reasons.
Please mark your choice by saying “yes” or “no” to each of the following:
Research Studies on Blood and Urine
An additional objective of this clinical trial is for investigators to study your blood
and urine to determine whether or not it has certain characteristics that may make
you more likely to respond to drugs like celecoxib. A sample of blood (about 1
teaspoon each time) will be collected before you receive treatment, and then if
you are registered to the study, another one will be collected 1 week after you
start treatment. The urine will be collected before you start treatment, and then
one week after you begin treatment. Analysis of your blood and urine specimens
will be done at a CALGB approved laboratory.
2) I agree that my specimen(s) may be used for the research described above.
_________ Yes
__________ No
________ Initials
Storage of Your Specimens:
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We would like to keep some of the tissue, blood and urine that are left over for
future research. If you agree, these specimens will be kept and may be used in
research to learn more about cancer and other diseases.
The research that may be done with your specimens is not designed specifically to
help you. It might help people who have cancer and other diseases in the future.
Reports about research done with your specimens will not be given to you or your
doctor. These reports will not be put in your health record. The research will not
have an affect on your care. The choice to let us keep left over specimens for
future research is up to you.
You have the right to receive the planned therapy on this study without allowing
your specimens to be stored for future research. Please read the sentences below
and think about your choice. After reading the sentence, please mark your choice.
No matter what you decide to do, it will not affect your care.
3) My specimen(s) may be kept for future use in research to learn about, prevent,
or treat cancer.
_________ Yes
__________ No
________ Initials
4) My specimen(s) may be kept for future use in research to learn about, prevent,
or treat other health problems (for example: diabetes, Alzheimer disease, and
heart disease).
_________ Yes
__________ No
________ Initials
5) My doctor or someone from CALGB may contact me in the future to ask me
to take part in more research.
_________ Yes
__________ No
________ Initials
Signature
I have been given a copy of all _____ [insert total of number of pages] pages of this form. I
have read it or it has been read to me. I understand the information and have had my
questions answered. I agree to take part in this study.
Participant ________________________________
Date _____________________________________
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APPENDIX I
CANCER TRIALS SUPPORT UNIT (CTSU) PARTICIPATION PROCEDURES
To submit site registration
documents:
CTSU Regulatory Office
1818 Market Street, Suite 1100
Philadelphia, PA 19103
Phone: 1-888-823-5923
Fax: 215-569-0206
For patient enrollments:
CTSU Patient Registration
Phone: 1-888-462-3009
Fax: 1-888-691-8039
Hours: 9:00 AM – 5:30 PM Eastern Time, Monday –
Friday (excluding holidays)
(Registrations received after 5:00 PM ET will be handled
the next business day. For CTSU patient enrollments
that must be completed within approximately one hour,
or other extenuating circumstances, call 301-704-2376
between 9:00 AM and 5:30 PM.)
Submit study data directly to the Lead Cooperative Group
unless otherwise specified in the protocol:
CALGB Statistical Center
Hock Plaza
2424 Erwin Road, Suite 802
Durham, NC 27705
Tel: 919-668-9350
Data Operations Fax: 919-668-9348
Teleform Fax: 919-416-4990
Sites should submit Teleforms via Fax or Mail. See Section 6.0 Data Submission
Section for details on forms submission.
Do not submit study data or forms to CTSU Data Operations. Do not copy the
CTSU on data submissions.
For patient eligibility or treatment related questions: Contact the CALGB Study Chair.
For questions unrelated to patient eligibility, treatment, or data submission contact the
CTSU Help Desk by phone or e-mail:
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and
correspondence will be triaged to the appropriate CTSU representative.
The CTSU Web site is located at: www.ctsu.org
REGISTRATION/RANDOMIZATION
Prior to the recruitment of a patient for this study, investigators must be registered members of
the CTSU. Each investigator must have an NCI investigator number and must maintain an
“active” investigator registration status through the annual submission of a complete
investigator registration packet (FDA Form 1572 with original signature, current CV,
Supplemental Investigator Data Form with signature, and Financial Disclosure Form with
original signature) to the Pharmaceutical Management Branch, CTEP, DCTD, NCI. These forms
are available on the CTSU registered member Web site (www.ctsu.org) or by calling the PMB at
301-496-5725 Monday through Friday between 8:30 AM and 4:30 PM Eastern time.
Each CTSU investigator or group of investigators at a clinical site must obtain IRB approval for
this protocol and submit IRB approval and supporting documentation to the CTSU Regulatory
Office before they can enroll patients. Study centers can check the status of their registration
packets by querying the Regulatory Support System (RSS) site registration status page of the
CTSU member web site at http://www.ctsu.org.
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All forms and documents associated with this study can be downloaded from the CALGB30801 Web page on the CTSU registered member Web site (http://www.ctsu.org). Patients can
be registered only after pre-treatment evaluation is complete, all eligibility criteria have been
met, and the study site is listed as ‘approved’ in the CTSU RSS.
Requirements for CALGB 30801 site registration:
•
•
CTSU IRB Certification
CTSU IRB/Regulatory Approval Transmittal Sheet
Prestudy requirements for patient enrollment on CALGB 30801:
•
•
•
Patient must meet all inclusion criteria, and no exclusion criteria should apply
Patient has signed and dated all applicable consents and authorization forms
All baseline laboratory tests and prestudy evaluations performed within the time period
specified in the protocol.
CTSU Procedures for Patient Enrollment
1. Contact the CTSU Patient Registration Office by calling 1-888-462-3009 between 9:00 AM
and 5:30 PM Eastern Time. Leave a voicemail to alert the CTSU Patient Registrar that an
enrollment is forthcoming. For immediate registration needs (e.g., within one hour), call the
registrar cell phone at 1-301-704-2376.
2. Complete the following forms:
•
•
CTSU Patient Enrollment Transmittal Form
CALGB Registration Worksheet (indicate participation on companion studies CALGB
150908 and CALGB 60904) Note: The patient should be registered to CALGB 150908
and/or CALGB 60904 at the same time they are registered to the treatment trial
(CALGB 30801).
3. Fax these forms to the CTSU Patient Registrar at 1-888-691-8039 between the hours of
9:00 AM and 5:30 PM, Mon-Fri, Eastern Time (excluding holidays); however, please be
aware that registrations received after 5:00 PM will be processed the next day. Registration
is limited to operating hours of the CALGB Registration office (9AM-5PM ET). The CTSU
registrar will check the investigator and site information to ensure that all regulatory
requirements have been met. The registrar will also check that forms are complete and will
follow-up with the site to resolve any discrepancies.
4. Once investigator eligibility is confirmed and enrollment documents are reviewed for
compliance, the CTSU registrar will contact the CALGB, within the confines of CALGB’s
registration hours, to obtain assignment of a unique patient ID (to be used on all future
forms and correspondence). Since this is a double-blind study, a specific treatment arm will
not be assigned. The CTSU registrar will confirm registration by fax.
Protocol therapy will begin within 14 days of registration/randomization to allow time for the
blinded, patient-specific clinical supplies of celecoxib/placebo to arrive at the study sites.
DATA SUBMISSION AND RECONCILIATION
1. All case report forms (CRFs) and transmittals associated with this study must be
downloaded from the CALGB-30801 Web page located on the CTSU registered member Web
site (http://www.ctsu.org). Sites must use the current form versions and adhere to the
instructions and submission schedule outlined in the protocol.
2. Submit all completed CRFs (with the exception of patient enrollment forms), clinical
reports, and transmittals directly to the CALGB (see contact table or section 6.0) unless an
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alternate location is specified in the protocol. Do not send study data to the CTSU. A
completed CTSU-CALGB coversheet should accompany all data submissions.
3. The CALGB Statistical Center will send (general via e-mail but may be sent via postal mail
or fax) query notices and delinquency reports directly to the site for reconciliation. Please
send query responses and delinquent data to the CALGB Statistical Center (via postal mail
or fax) and do not copy the CTSU Data Operations. Each site should have a designated
CTSU Administrator and Data Administrator and must keep their CTEP AMS account
contact information current. This will ensure timely communication between the clinical
site and the CALGB Statistical Center.
SPECIAL MATERIALS OR SUBSTUDIES
There are two sub-studies in CALGB 30801. The sub-studies must be offered to all patients,
although patients may opt not to participate. The patient should be registered to CALGB 60904
and/or CALGB 150908 at the same time they are registered to the treatment trial (CALGB
30801).
1. Specimen collection for pharmacogenetic correlatives – CALGB 60904 (protocol Section
6.1.2 and 6.1.3)
•
Collect, prepare, and submit specimens as outlined in the protocol
•
Do not send specimens, supporting clinical reports, or transmittals to the CTSU
2. Urine collection for PGE-M Analysis – CALGB 150908 (protocol section 6.1.4)
•
Submit completed forms as outlined in the protocol
•
Do not send forms to the CTSU
SERIOUS ADVERSE EVENT (AE) REPORTING (SECTION 16.0)
1. CTSU sites must comply with the expectations of their local Institutional Review Board
(IRB) regarding documentation and submission of adverse events. Local IRBs must be
informed of all reportable serious adverse reactions.
2. CTSU sites will assess and report adverse events according to the guidelines and timelines
specified in the protocol. You may navigate to the CTEP Adverse Event Expedited Report
System (AdEERS) from either the Adverse Events tab of the CTSU member home page
(http://www.ctsu.org) or by selecting Adverse Event Reporting Forms from the document
center drop down list on the protocol number Web page.
3. Do not send adverse event reports to the CTSU.
4. Secondary AML/MDS/ALL reporting: Report occurrence of secondary AML, MDS, or ALL
via the NCI/CTEP AML-MDS Report Form in lieu of AdEERS. Submit the completed form
and supporting documentation as outlined in the protocol.
DRUG PROCUREMENT (SECTION 10.0)
Investigational agents:
Celecoxib and matching placebo
Celecoxib and matching placebo will be provided free of charge by Pfizer and distributed by the
Pharmaceutical Management Branch (PMB), Cancer Therapy Evaluation Program (CTEP),
Division of Cancer Treatment and Diagnosis (DCTD), National Cancer Institute (NCI). No
blinded starter supplies will be available for this study.
1. Information on drug formulation, procurement, storage and accountability, administration,
and potential toxicities are outlined in section 10.0 of the protocol.
2. You may navigate to the drug forms by selecting Pharmacy Forms from the document
center drop down list on the CALGB-30801 Web page.
REGULATORY AND MONITORING
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Study Audit
To assure compliance with Federal regulatory requirements [CFR 21 parts 50, 54, 56, 312, 314
and HHS 45 CFR 46] and National Cancer Institute (NCI)/ Cancer Therapy Evaluation Program
(CTEP) Clinical Trials Monitoring Branch (CTMB) guidelines for the conduct of clinical trials
and study data validity, all protocols approved by NCI/CTEP that have patient enrollment
through the CTSU are subject to audit.
Responsibility for assignment of the audit will be determined by the site’s primary affiliation
with a Cooperative Group or CTSU. For Group-aligned sites, the audit of a patient registered
through CTSU will become the responsibility of the Group receiving credit for the enrollment.
For CTSU Independent Clinical Research Sites (CICRS), the CTSU will coordinate the entire
audit process.
For patients enrolled through the CTSU, you may request the accrual be credited to any Group
for which you have an affiliation provided that Group has an active clinical trials program for
the primary disease type being addressed by the protocol. Per capita reimbursement will be
issued by the credited Group provided they have endorsed the trial, or by the CTSU if the
Group has not endorsed the trial.
Details on audit evaluation components, site selection, patient case selection, materials to be
reviewed, site preparation, on-site procedures for review and assessment, and results reporting
and follow-up are available for download from the CTSU Operations Manual located on the
CTSU Member Web site.
Health Insurance Portability and Accountability Act of 1996 (HIPAA)
The HIPAA Privacy Rule establishes the conditions under which protected health information
may be used or disclosed by covered entities for research purposes. Research is defined in the
Privacy Rule referenced in HHS 45 CFR 164.501. Templated language addressing NCI-U.S.
HIPAA guidelines are provided in the HIPAA Authorization Form located on the CTSU Web site.
The HIPAA Privacy Rule does not affect participants from outside the United States.
Authorization to release Protected Health Information is NOT required from patients enrolled in
clinical trials at non-US sites.
Clinical Data System–Web (CDS-Web) Monitoring
This study will be monitored by the Clinical Data System (CDS-Web). The sponsoring Group
fulfills this reporting obligation by transmitting the CDS data collected from the study-specific
case report forms, via the Web to the NCI Center for Biometrics (NCICB). Cumulative CDS data
are submitted quarterly.
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APPENDIX II
NCI/ DCTD Standard Language to Be Incorporated into All Protocols Involving Agent(s)
Covered by a Clinical Trials Agreement (CTA) a Cooperative Research and Development
Agreement (CRADA)or a Clinical Supply Agreement, hereinafter referred to as
Collaborative Agreement:
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical
Company(ies) (hereinafter referred to as ”Collaborator(s)”) and the NCI Division of Cancer
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the
provisions
in
the
“Intellectual
Property
Option
to
Collaborator”
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within
the terms of award, apply to the use of the Agent(s) in this study:
1.
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can
Agent(s) be transferred or licensed to any party not participating in the clinical study.
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and
shall be maintained as such by the investigators. The protocol documents for studies
utilizing investigational Agents contain confidential information and should not be
shared or distributed without the permission of the NCI. If a copy of this protocol is
requested by a patient or patient’s family member participating on the study, the
individual should sign a confidentiality agreement. A suitable model agreement can be
downloaded from: http://ctep.cancer.gov.
2.
For a clinical protocol where there is an investigational Agent used in combination with
(an)other investigational Agent(s), each the subject of different collaborative agreements,
the access to and use of data by each Collaborator shall be as follows (data pertaining
to such combination use shall hereinafter be referred to as "Multi-Party Data”.):
a.
NCI will provide all Collaborators with prior written notice regarding the
existence and nature of any agreements governing their collaboration with NIH,
the design of the proposed combination protocol, and the existence of any
obligations that would tend to restrict NCI's participation in the proposed
combination protocol.
b.
Each Collaborator shall agree to permit use of the Multi-Party Data from the
clinical trial by any other Collaborator solely to the extent necessary to allow
said other Collaborator to develop, obtain regulatory approval or commercialize
its own investigational Agent.
c.
Any Collaborator having the right to use the Multi-Party Data from these trials
must agree in writing prior to the commencement of the trials that it will use the
Multi-Party Data solely for development, regulatory approval, and
commercialization of its own investigational Agent.
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative
Agreement will be made available exclusively to Collaborator(s), the NCI, and the FDA,
as appropriate and unless additional disclosure is required by law or court order..
Additionally, all Clinical Data and Results and Raw Data will be collected, used and
disclosed consistent with all applicable federal statutes and regulations for the
protection of human subjects, including, if applicable, the Standards for Privacy of
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164.
4. When a Collaborator wishes to initiate a data request, the request should first be sent
to the NCI, who will then notify the appropriate investigators (Group Chair for
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact
them.
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5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is
a DMC for this clinical trial.
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by
the Group office for Cooperative Group studies or by the principal investigator for nonCooperative Group studies for immediate delivery to Collaborator(s) for advisory review
and comment prior to submission for publication. Collaborator(s) will have 30 days
from the date of receipt for review. Collaborator shall have the right to request that
publication be delayed for up to an additional 30 days in order to ensure that
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s
intellectual property rights, are protected. Copies of abstracts must be provided to
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and
preferably at least three (3) days prior to submission, but in any case, prior to
presentation at the meeting or publication in the proceedings. Press releases and other
media presentations must also be forwarded to CTEP prior to release. Copies of any
manuscript, abstract and/or press release/ media presentation should be sent to:
Regulatory Affairs Branch, CTEP, DCTD, NCI
Executive Plaza North, Suite 7111
Bethesda, Maryland 20892
FAX 301-402-1584
Email: anshers@mail.nih.gov
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication,
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/
proprietary information.
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CANCER AND LEUKEMIA GROUP B CALGB 30801 A

Transcription

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