Arm A: Induction Gemcitabine 1000 mg/m 2 IV once a week for 6 weeks.

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1 ECOG-4201 (RTOG Endorsed) ECOG 4201 Pancreas (RTOG Endorsed)-1 Protocol Status: Opened: April 10, 2003 Closed: December 15, 2005 Title: A Randomized Phase III Study of Gemcitabine in Combination with Radiation Therapy versus Gemcitabine Alone in Patients with Localized, Unresectable Pancreatic Cancer Patient Population: Histologically or cytologically confirmed adenocarcinoma of the pancreas. Locally advanced or regional (encompassable within the same radiotherapy portals) disease. Adenosquamous cancers are allowed. Unresectable disease, defined as a tumor causing superior mesenteric vein or portal vein occlusion OR superior mesenteric artery or hepatic artery encasement. Measurable and/or nonmeasurable disease by CT scan or MRI. M1 disease not allowed. Must not be a candidate for surgical excision based on local extent of disease (e.g., T3, N1, M0). No prior chemotherapy for pancreatic cancer. No prior radiation therapy. Must be at least 4 weeks since prior investigational agents. Patients must be 18 years old with an ECOG Performance Status or 0 or 1 and a life expectancy of at least 12 weeks. AGC 2,000/mm3, Platelet 100,000/mm3; Bilirubin < 3 mg/dl (unless secondary to biliary obstruction or cholangitis), AST < 5 times upper limit of normal (ULN), Albumin > 2.5 g/dl; Serum Creatinine 1.5 times ULN. Not pregnant or nursing. Negative pregnancy test. Fertile patients must use effective contraception. Willing and able to attend follow-up visits. No active infection within the past 4 weeks. No other malignancy within the past 5 years except nonmelanoma skin cancer, carcinoma in situ of the cervix, or organ-confined prostate cancer (Gleason score no greater than 7). No history of active collagen vascular disease (i.e., systemic lupus erythematosus, rheumatoid arthritis, or scleroderma). No signs or symptoms of peptic or duodenal ulcer disease. No concurrent serious systemic disorders that are incompatible with study participation. Objectives: Primary: Compare the overall survival of patients with locally advanced, unresectable pancreatic cancer treated with gemcitabine with or without radiotherapy Secondary: Compare the progression-free survival of patients with locally advanced, unresectable pancreatic cancer treated with gemcitabine with or without radiotherapy To determine the objective response rate in patients treated with these regimens. To evaluate the toxicity of these regimens in these patients. Compare the quality of life (QOL) of patients treated with these regimens. Determine the effect of gemcitabine and radiotherapy on the QOL of patients with improved objective response rate and progression-free and overall survival. Schema: Stratification Factors: 1. Performace Status: 0 vs Weight Loss in previous 6 months < 10% vs. 10% R A N D O M I Z E : Induction once a week for 6 weeks. : Induction Gemcitabine 600 mg/m 2 IV once a week X 6 weeks. Concurrent RT 180 cgy/day. 5 days/week. Total dose Gy in 28 fractions 1 week rest 4 weeks rest : Consolidation once a week X 3 weeks, followed by 1 week rest X 5 cycles. 1 cycle = 4 weeks : Consolidation once a week X 3 weeks, followed by 1 week rest X 5 cycles. 1 cycle = 4 weeks

2 ECOG 4201 Pancreas (RTOG Endorsed)-2 Coordinating Group: ECOG Total patients entered: Study 74 Participants: CTSU, RTOG RTOG 1 ECOG 52 Study Chairs: Patrick J. Loehrer, M.D. (ECOG Protocol chair) SWOG 12 Christopher Crane, M.D. (RTOG Co-Chair) NCCTG 5 CALGB 2 Statistician: Donna Levy (ECOG) CTSU 1 Research Associate: NSABP 1 Liza Lucivero (ECOG Data Specialist) I. Summary: This study was activated on April 10, 2003 and closed to accrual on December 15, 2005 as a result of slow accrual. RTOG institutions accrued 1 patient. The final accrual of the study is 74 patients. Pretreatment characteristics can be found in Section III. Section IV summarizes the toxicities deemed possibly, probably, or definitely related to treatment. Toxicity information is available for 69 patients as of August 3, 2007, 35 of whom are on and 34 of whom are on. On, the rates of overall worst degree of toxicity were 71%(n=25), 6%(n=2), and 3% (n=1) for Grade 3, 4 and 5; while on, the rates were 41%(n=14), 38%(n=13), and 3%(n=1). The most common grade 3 toxicities were neutrophils. There were 2 patients experiencing lethal toxicities (detailed in Table 4.2). The final report for this trial was completed July 27, II. Administrative Information: Table 2.1 Patient Accrual Study sample size 332 Total patients entered 74 Average monthly accrual for the study 2.4 Table 2.2 RTOG Institutional Accrual by Submitting Institution (n=1) UNIVERSITY OF PENNSYLVANIA 1 Table 2.3 Case Status Total Total patients entered Ineligible Eligible With on-study information With toxicity information Table 2.4 Cases Excluded Reason (n=1) (n=2) Ineligible - Mets prior to study entry 1 (100.0%) 1 (50.0%) Ineligible - Liver mets found after registration during RT planning CT before treatment began 0 (0.0%) 1 (50.0%)

3 ECOG 4201 Pancreas (RTOG Endorsed)-3 III. Pretreatment Characteristics: Table 3.1 Pretreatment Characteristics (n=37) (n=34) Age (years) Median Min - Max Gender Male 18 ( 48.6%) 19 ( 55.9%) Female 19 ( 51.4%) 15 ( 44.1%) Race Non-Hispanic White 35 ( 94.6%) 30 ( 88.2%) Non-Hispanic Black 2 ( 5.4%) 2 ( 5.9%) Other 0 ( 0.0%) 2 ( 5.9%) Histologic Grade Missing/Unknown 22 ( 59.5%) 13 ( 38.2%) Well differentiated (Grade I) 4 ( 10.8%) 6 ( 17.6%) Moderately differentiated (Grade II) 6 ( 16.2%) 8 ( 23.5%) Poorly differentiated (Grade III) 5 ( 13.5%) 7 ( 20.6%) Primary Site Head of pancreas 25 ( 67.6%) 20 ( 58.8%) Body of pancreas 3 ( 8.1%) 6 ( 17.6%) Tail of pancreas 2 ( 5.4%) 3 ( 8.8%) Uncinate process 4 ( 10.8%) 4 ( 11.8%) Pancreas,NOS 1 ( 2.7%) 0 ( 0.0%) Other (includes > 1 primary site) 2 ( 5.4%) 1 ( 2.9%) Previous 6 Months Weight Loss* < 10% of body weight 21 ( 56.8%) 18 ( 52.9%) >= 10% of body weight 16 ( 43.2%) 16 ( 47.1%) PS* 0 9 ( 24.3%) 6 ( 17.6%) 1 28 ( 75.7%) 28 ( 82.4%) * Stratification factor

4 ECOG 4201 Pancreas (RTOG Endorsed)-4 IV. Toxicity: Table 4.1 Post-baseline Treatment-related Toxicities by Arm for All 69 Treated Patients (Frequency) (n=35) (n=34) Grade Grade 1, , Toxicity Type (n) (n) (n) (n) (n) (n) (n) (n) Hemoglobin Leukocytes Lymphopenia Neutrophils Platelets Transfusion: Platelets Transfusion: PRBCS Cardiac-Ischemia Edema Hypotension Thrombosis/Embolism Fatigue Weight loss Rash/desquamation Anorexia Ascites Colitis Dehydration Nausea Vomiting Diarrhea w/o prior colostomy Melena/GI bleeding Alkaline phosphatase Bilirubin GGT Hypoalbuminemia SGOT SGPT Infection w/ grade 3 or 4 neutropenia Infection w/ unknown ANC Infection w/o neutropenia Hyperglycemia Hypocalcemia Hypokalemia Muscle weakness Abdominal pain Myalgia Pain-other (ARDS) Apnea Pulmonary-other Worst degree

5 ECOG 4201 Pancreas (RTOG Endorsed)-5 Table 4.2 Grade 5 Toxicities Assigned Treatment A Case Number Toxicity Cardiac Ischemia Infarction Description Patient presented to the hospital for chest pain. EKG revealed acute MI. Cardiac enzymes positive. Admitted to CCU condition continued to deteriorate. Patient did not want catheterization, CPR, surgery or intubation. Only wanted medical management. Expired after 3 days of hospitalization. B ARDS Patient admitted with septic shock and released with good response same day. Readmitted next day again with hypotension. Needed intubation, sedation, pressors, and antibiotics. PAO 86%. All cultures returned negative. Patient extubated twelve days later and expired a short time later same day.