NCCTG Status Report for Study N May 2010

Transcription

1 MARVEL: Marker Validation of Erlotinib in Lung Cancer - A Phase III Biomarker Validation Study of Second-Line Therapy in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Randomized to Pemetrexed Versus Erlotinib Purpose of - Primary: Study: 1) To evaluate whether there are differences in progression-free survival due to treatment with erlotinib compared to pemetrexed for subsets of previously treated NSCLC patients defined by epidermal growth factor receptor (EGFR)-FISH positivity versus negativity. - Secondary: 1) To ascertain the presence or absence of true differences due to treatment in the objective clinical endpoints of overall survival, confirmed response rate, and adverse event profile for subsets of patients defined on the basis of the EGFR-FISH positivity versus negativity. 2) To ascertain the presence or absence of true differences due to treatment in objective clinical endpoints for subsets of patients defined on the basis of EGFR expression as measured by immunohistochemistry (IHC). 3) To ascertain the presence or absence of true differences due to treatment in objective clinical endpoints for subsets of patients defined on the basis of EGFR gene mutation status (MUT). 4) To evaluate the prognostic effect of EGFR copy number as measured by FISH, EGFR expression as measured by IHC, and EGFR gene mutation status. 5) To prospectively test the hypothesis that functionally relevant polymorphisms in the genes encoding for pemetrexed targets and in the EGFR gene, either singly or in combination, play a role in the efficacy and/or toxicity of erlotinib. 6) To evaluate proteomic signatures in blood samples of patients as predictors of response and survival to treatment with erlotinib. 7) To evaluate the following variables measured in tumor samples, as predictors of response and survival: expression of thymidylate synthase, dihydrofolate reductase and GAR formyltransferase genes, and methylthioadenosine phosphorylase expression by IHC or quantitative PCR. 8) To evaluate the following variables measured in tumor samples, as predictors of response and survival: Ras mutational status, EGFR mutational status, and epithelial to mesenchymal transition (EMT) status (measured by E- cadherin expression and vimentin expression) by IHC. Study Chairs: Alex A. Adjei M.D. Kendrith M. Rowland Jr. M.D. QC Specialist: Rachael Meyers Statistician: Sumithra J. Mandrekar Ph.D. Nurse Resource: Susan Haithcox OCN, CCRP NCCTG Committee N Page 1 of 6

2 Status: 10/01/ /04/2009 Activated Perm. Closed Projected Number of Patients: 957 Excluded: 2 Final Accrual: 23 Stratification FISH Status: Positive vs Negative Factors: ECOG PS: 0 vs 1 vs 2 Gender: Male vs Female Smoking: Never vs Light vs Heavy Histology: Adenocarcinoma vs Others Best Response: CR/PR vs SD vs PD Schema: Pre-Registration Central Pathology review and EGFR gene copy number measured by FISH Treating Schedule: Randomization Erlotinib Pemetrexed Arm Agent Dose Route Days Freq A Erlotinib 150 mg (1 tablet) Oral once a day 1-21 Continuous Administration B Folic Acid*** mcg (or equivalent)* By mouth At least 5 or the 7 days prior to first dose of pemetrexed B Vitamin B12*** 1000 mcg Intramuscular injection Same day as start of folic acid or 7 days** B Dexamethasone 4 mg By mouth twice a day Day before, day of, and the day after all doses of pem B Pemetrexed 500 mg/m2 IV in 100 ml NS over 10 minutes daily until 3 weeks after last dose of pemetrexed (pem) Every 9 weeks until 3 weeks after last dose of pem Every 21 days 1 Every 21 days *An acceptable range of folic acid intake is given above. If a patient is already on vitamin supplement that includes folic acid and is getting between 350 and 600 mcg, this is acceptable and nothing further needs to be taken. **Same day as start of folic acid or 7 days prior to first dose of pemetrexed if patient is already on an adequate vitamin supplement. ***While awaiting result of central pathology review, any patient may start on vitamin B12 and folic acid supplementation upon the discretion of the treating physician. NCCTG Committee N Page 2 of 6

3 Study Design: This is a stratified randomized Phase III marker by treatment interaction trial design with equal allocation of patients within the FISH (+) and FISH (-) subgroups to the erlotinib and pemetrexed arms. FISH results will be kept blinded and may be made available to the treating physician at the time when patient goes off treatment. The pre-registration component of the trial requires all patients to submit tissue for a central pathology review and FISH assessment. The FISH status of the patient is assessed prior to randomization (to ensure adequate number of patients with FISH (+) and FISH (-) status) in a central location (to address issues regarding standardization of assay techniques, reproducibility and interpretability of assay results). Subsequently, evaluable patients are randomized 1:1 to either erlotinib or pemetrexed within each EGFR-FISH subgroup. A total of 1196 patients with tumor tissue samples (957 with assay results, assuming an 80% assay success rate) will be pre-registered to randomize 287 (30%) FISH (+) patients and 670 (70%) FISH (-) patients. The primary endpoint in this trial is progression-free survival (PFS). Specifically, the primary goal of the study is to assess whether there are differences in PFS due to treatment with erlotinib compared to pemetrexed for subsets of previously treated NSCLC patients defined by epidermal growth factor receptor (EGFR)-FISH positivity versus negativity. The two co-primary null hypotheses of the trial that will jointly evaluate the clinical predictive utility of EGFR copy number as measured by FISH are as follows: Null Hypothesis I: FISH (+) subgroup: Erlotinib is not superior to pemetrexed. The target sample size for the FISH (+) sugroup is set so that there will be at least 90% power to reject Null Hypothesis I if the truth is that erlotinib is superior to pemetrexed with a hazard ratio of at least 1.5 in favor of erlotinib (50% improvement or 3.75 vs. 2.5 months in median PFS). Null Hypothesis II: FISH (-) subgroup: Pemetrexed is equally effective as erlotinib. The planned sample size will allow at least 90% power to reject Null Hypothesis II if the truth is that pemetrexed is superior to erlotinib with a hazard ratio =0.77 in favor of pemetrexed (30% improvement or 2.5 vs months median PFS); or if erlotinib is superior to pemetrexed with a hazard =1.3 in favor of erlotinib (30% improvement or 3.25 vs. 2.5 months median PFS). Accrual: This study was opened October 1, 2008 and was permanently closed to patient accrual on December 4, 2009 due to slow accrual partly from the changes in the standard of care of first and second-line NSCLC. Twenty-nine patients were pre-registered, of whom 4 were deemed not evaluable due to inadequate tissue, 1 patient was deemed a screen failure due to MD reasons, and 1 patient was deemed a screen failure due to patient reasons. Thus a total of 23 patients (6 FISH -; 17 FISH +) were randomized. Two randomized patients (2 FISH +) withdrew from study prior to receiving any study treatment and are excluded from the adverse events summary. NCCTG Committee N Page 3 of 6

4 Patient Characteristics: See Baseline Characteristics Table for characteristics on the 21 randomized patients. Adverse Events: Adverse Event data are available on all 21 evaluable patients. Two grade 4 events have been reported. One patient on arm B reported a grade 4 leukopenia (probably related to study treatment) and one patient on arm B reported grade 4 ischemia/infarction (not related). See the Adverse Event Table for more information. Accrual Table: Randomizing Membership Total Entered Past 6 Past 12 Ann Arbor Colorado CCOP Dayton Fargo Grand Rapids MN CGOP Oklahoma Peoria Rapid City Richmond St. Cloud Total Membership Accrual Randomizing Group Total Entered Past 6 Past 12 NCCTG CTSU Total Group Accrual Baseline Characteristics Table: Characteristics Arm A (Erlotinib) N (%) Arm B (Pemetrexed) N (%) Gender: Male 5 (45.5) 6 (50.0) Female 6 (54.5) 6 (50.0) Histology: Adenocarcinoma 7 (63.6) 7 (58.3) Others 4 (36.4) 5 (41.7) Performance Status: 0 5 (45.5) 6 (50.0) 1 5 (45.5) 6 (50.0) 2 1 ( 9.1) 0 ( 0.0) Smoking Status: Never smoked 2 (18.2) 1 ( 8.3) Light smoker 1 ( 9.1) 0 ( 0.0) NCCTG Committee N Page 4 of 6

5 Heavy smoker 8 (72.7) 11 (91.7) Prior Response: CR/PR 6 (54.5) 6 (50.0) SD 2 (18.2) 4 (33.3) PD 3 (27.3) 2 (16.7) Adverse Events Table: Arm A Evaluable Patients: 11 Arm B Evaluable Patients: 10 Adverse Event Grade N % N % N % N % Type Arm FATIGUE AB ANEMIA A B ANOREXIA A B DYSPNEA A B DIARRHEA A NAUSEA A B RASH ACNEIFORM A RASH A ABDOMINAL PAIN A LEUKOPENIA A VOMITING A WEIGHT LOSS A ASPARTATE AMINOTRANSFERASE INCRE A CREATININE INCREASED A ALANINE AMINOTRANSFERASE INCREAS A FEVER A B KERATITIS A ORAL CAV MS CE A PLATELET COUNT DECREASED BILIRUBIN A CONSTIPATION A DEHYDRATION A LYMPHOCYTE COUNT DECREASED A MUCOSITIS ORAL A NEUTROPHIL COUNT DECREASED PERIPHERAL MOTOR NEUROPATHY A NCCTG Committee N Page 5 of 6

6 PNEUMONIA GR UNK ANC A ABDOMINAL DISTENSION A ANXIETY ARTHRALGIA ATRIAL FIBRILLATION BACK PAIN A COUGH A DEPRESSION DRY EYE DYSPEPSIA HYPOALBUMINEMIA HYPOMAGNESEMIA HYPONATREMIA A HYPOTENSION A INSOMNIA ISCHEMIA/INFARCTION MUSCLE WEAKNESS A MYALGIA NAIL CHANGES A NEURALGIA PAIN-CHEST PHARYNGEAL MUCOSITIS A PHARYNX MS CE A URINARY TRACT INFECTION A NCCTG Committee N Page 6 of 6