EASTERN COOPERATIVE ONCOLOGY GROUP

Transcription

1 EASTERN COOPERATIVE ONCOLOGY GROUP E5204 INTERGROUP RANDOMIZED PHASE III STUDY OF POSTOPERATIVE OXALIPLATIN, 5-FLUOROURACIL AND LEUCOVORIN VS OXALIPLATIN, 5-FLUOROURACIL, LEUCOV- ORIN AND BEVACIZUMAB FOR PATIENTS WITH STAGE II OR III RECTAL CANCER RE- CEIVING PREOPERATIVE CHEMORADIATION Coordinating Group: ECOG Chairperson(s): Dr. Al Bowen Benson III Statistician: Dr. Paul Catalano Data Specialist: Ms. Lauren Mimran-Ugbabe Phase of Study: III Type of Study: Therapeutic Disease Committee: Gastrointestinal Accrual Objective: 2100 Patients Participants: ECOG, RTOG, NCCTG, CALGB, NCIC, SWOG, NSABP, ACOSOG, CTSU DCP Treatment Credit: 1.0 DCP Cancer Control Credit: 0.5 Study Status: Terminated Activated: February 17, 2006 Terminated: April 29, 2009 Final Accrual: 355 Patients SCHEMA: Stratification Factors: ECOG performance status (0 vs. 1) Rev. 11/06 R A N D O M I Z E 2 Clinical staging (High risk (T 3 N+ M 0, T 4 N any M 0 ) versus low risk (T 1-2 N+M 0, T 3 N 0 M 0 )) Pre-operative oxaliplatin vs no pre-operative oxaliplatin Radiation dose (40-50 Gy vs. > Gy pre-operatively) Arm A: Administer 12 cycles Arm B: 3 Administer 12 cycles Arm A Oxaliplatin: 85 mg/m 2 IV over 2 hours concurrent with Leucovorin: 400 mg/m 2, IV over 2 hours 5-FU: 400 mg/m 2, IV bolus injection, immediately following leucovorin dose 5-FU: 2.4 g/m 2 continuous infusion over 46 hours immediately following bolus 5-FU Cycle = 2 treatment days over 2 weeks. Repeat for 12 (2-week) cycles Arm B 3 Bevacizumab 5 mg/kg over minutes Oxaliplatin: 85 mg/m 2 IV over 2 hours concurrent with Leucovorin: 400 mg/m 2, IV over 2 hours 5-FU: 400 mg/m 2, IV bolus injection, immediately following leucovorin dose 5-FU: 2.4 g/m 2 continuous infusion over 46 hours immediately following bolus 5-FU Cycle = 2 treatment days over 2 weeks. Repeat for 12 (2-week) cycles. Treatment Modification Treatment Modification For patients who received pre-operative oxaliplatin 2 : For patients who received pre-operative oxaliplatin 2 : mfolfox6 for 9 cycles followed by Leucovorin/5-FU (as administered above) for 3 cycles mfolfox6 + Bevacizumab for 9 cycles followed by Leucovorin/5-FU + Bevacizumab (as administered above) for 3 cycles Accrual Goal: 2100 All doses based on actual body weight at the beginning of each cycle. Rev. 11/06 Rev. 11/06, 8/07 1. [Deleted footnote #1 in Addendum #1] 2. NSABP R-04 patients are eligible to participate in this trial. [Deleted NOTE in Addendum #2] 3. NOTE: As of April 29, 2009 accrual to E5204 was stopped by the ECOG Data Monitoring Committee. This action was taken as accrual to the study was slower than estimated. All patients currently being treated on E5204 should continue therapy as defined in the protocol. However, as the role of bevacizumab in this setting will not be defined, all patients assigned to ARM B of the study are to have their bevacizumab permanently discontinued. Purpose of the Study: (1) To compare the overall survival of patients with clinical Stage II and III rectal cancer who received preoperative chemoradiation and were treated with oxaliplatin, leucovorin, 5-FU with or without bevacizumab postoperatively. (2) To evaluate tolerance of treatment, patterns of failure and disease-free 54 GASTROINTESTINAL ECOG NOVEMBER 2009

2 survival. (3) To prospectively assess long-term rectal function using the Patient Bowel Function/Uniscale questionnaire and the FACT-Diarrhea subscale in patients who received preoperative chemoradiation and were treated with oxaliplatin, leucovorin, 5-FU, with our without bevacizumab. (4) To validate the FACT-Diarrhea subscale. (5) To prospectively assess long-term symptoms of oxaliplatin-related neurotoxicity using the FACT/GOG-Ntx subscale in patients who received preoperative chemoradiation and were treated with oxaliplatin, leucovorin, 5-FU, with our without bevacizumab. (6) To correlate TS, DPD and TP expression (key targets for 5-FU); retention of chromosome 18q alleles and MSI with TGFβ1RII mutation (markers for 5-FU efficacy); ERCC1, ERCC2 and XPF expression (participants in repair of adducts from oxaliplatin); p53 gene mutation and possibly other molecular markers pertinent to VEGF in tumor tissue specimens with treatment efficacy. (7) To correlate tumor molecular prognostic markers (chromosome 18q allelic loss and MSI) with survival. (8) To determine the impact of diabetes mellitus on cancer recurrence and survival among patients with stage II and III rectal cancer. (9) To determine the impact of body mass index and weight gain on cancer recurrence and survival among patients with stage II and III rectal cancer. Summary This study activated on February 17, 2006 and terminated on April 29, 2009 due to poor accrual. At closure, 355 patients have accrued to the study (46% from ECOG). Table 1 shows accrual by cooperative group. Table 2 reports record status as of June 30, Toxicity data as of August 26, 2009 are shown in Table 3. In addition, there have been two grade 5 AdEERS reports submitted both on Arm B (case 52062, a lower GI hemorrhage after 5 cycles, felt possibly due to bevacizumab and also possibly due to surgery, and case 52355, a cardiac ischemia after 6 cycles, but the event was felt unlikely related to treatment and possibly related to hyperlipidemia and hypertension). The distribution of the reasons for discontinuation of protocol treatment is given in Table 4. Table 5 summarizes the quality of life forms submission. Outcome data are not included in this report, but will be presented to the Data Monitoring Committee when appropriate. Administrative Information Table 1. Accrual by Group ECOG 163 RTOG 8 NCCTG 25 CALGB 27 GOG 1 NCIC 27 SWOG 74 NSABP 25 ACOSOG 2 CTSU 3 Total 355 Table 2. Record Status as of June 30, 2009 Cases Entered 355 No On-study: < 3 months 0 > 3 months 13 Ineligible 1 Never Started Assigned Therapy 4 NOVEMBER 2009 ECOG GASTROINTESTINAL 55

3 Reasons for ineligibility: Disallowed pre-operative oxaliplatin (52046). Reasons for not starting assigned therapy: Toxicity Ineligible per institution (not yet centrally reviewed at ECOG Coordinating Center) (52033); Refused treatment (52060, 52191, 52250). Table 3. Toxicity Incidence Treatment Arm A (n=165) B (n=162) Toxicity Type (%) (%) (%) (%) (%) (%) Allergic reaction Bone marrow cellularity Hemoglobin Leukocytes Lymphopenia Neutrophils Platelets Hematologic-other Cardiac-ischemia Hypertension Fatigue Fever w/o neutropenia Weight gain Hand-foot reaction Wound - non-infectious Anorexia Dehydration Periodontal disease Diarrhea w/o prior colostomy Dysphagia Fistula, Colon/cecum/appendix Fistula, Rectum Ileus Muco/stomatitis (symptom) oral cavity Muco/stomatitis (symptom) pharynx Nausea Obstruction, small bowel NOS Proctitis Vomiting Lower GI, hemorrhage NOS Rectum, hemorrhage Febrile neutropenia Infection Gr0-2 neut, pelvis NOS Infection Gr0-2 neut, sm bowel Infection Gr0-2 neut, urinary tract Infection w/ unk ANC bladder GASTROINTESTINAL ECOG NOVEMBER 2009

4 Table 3. Toxicity Incidence continued Treatment Arm A (n=165) B (n=162) Toxicity Type (%) (%) (%) (%) (%) (%) ALT, SGPT AST, SGOT Creatinine Hyperglycemia Hypokalemia Proteinuria Hyponatremia Fracture Laryngeal nerve dysfunction Neuropathy-motor Neuropathy-sensory Syncope Abdomen, pain Bone, pain Chest/thoracic pain NOS Extremity-limb, pain Head/headache Joint, pain Dyspnea Hypoxia Voice changes/dysarthria Incontinence urinary Urinary retention Thrombosis/thrombus/embolism WORST DEGREE Table 4. Reasons Off Treatment (Includes all patients who started treatment and for whom off-treatment data have been submitted.) Reasons N % Treatment completed per protocol criteria Disease progression, relapse during active treatment Adverse events/side effects/complications Patient withdrawal / refusal after beginning protocol therapy Alternative therapy Patient off treatment for other complicating disease Other Unknown reason Total off treatment NOVEMBER 2009 ECOG GASTROINTESTINAL 57

5 Table 5. Quality of Life Compliance* Patients Reaching % Forms QOL Timepoint Timepoint Completed Baseline End Treatment Months Post Chemotherapy Months Post Chemotherapy * NOTE: Patients enrolled in NSABP protocol R-04 are exempt from participating in the QOL assessments. Patients without a functioning rectum are exempt from the FACT-D and Bowel Function/Uniscale assessments. At the time this table was created, 65 patients from R-04 have been enrolled to this study, and 86 patients have been reported as having a non-functioning rectum. If they have reached the timepoint, these patients are included in the Patients Reaching Timepoint column in the table above. 58 GASTROINTESTINAL ECOG NOVEMBER 2009