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1 Gastrointestinal Program

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3 Gastrointestinal Program The program had a productive year in 2001 thanks to your efforts and the hard work of the personnel at the research base. Our total accrual including registrations for intergroup trials chaired by NCCTG was 1004 for treatment trials and 257 for translational trials. We opened 9 trials and closed 10 trials during the year. There are 7 studies currently in development. All 10 of the ASCO/AACR abstracts that we submitted for the 2002 meetings were accepted for presentation. In charting the momentum for our program we remain on a very positive trajectory. Colorectal/Anal Cancer Program: Adjuvant Studies: The CALGB led Stage II study (C9581) of no treatment versus 17-1A monoclonal antibody remains open. We have contributed about 238 of the 1600 patients enrolled so far. The accrual goal of 2100 patients will not likely be met for several years. An ASCO presentation this year indicates a possible advantage to use of the antibody with chemotherapy in a stage III U.S. trial. Preliminary discussions about a successor trial for Stage II patients are underway. The current concept includes enrollment of 3100 patients with mandatory tissue submission and real time testing for MSI and 18q allelic deletion. Patients deemed to be at high-risk are randomized to 5-FU/LV +/- Iressa. Low-risk patients will be followed for recurrence and survival. The Stage III trial (C89803) of the Saltz regimen versus 5-FU/leucovorin is maturing. NCCTG is leading the next Stage III adjuvant trial of 5-FU/LV administered as an infusion plus either oxaliplatin or CPT-11. We hope to open this trial by mid Tissue and blood will be requested from all patients. At least some NCCTG sites will be asked to collect frozen tissue for analysis using microarray technology in this trial. The use of rofecoxib versus placebo after completion of adjuvant therapy in patients with Stages II and III colon cancer is the subject of the VICTOR trial for which we will be the US coordinating site for. The QUASAR group from England is the lead group on this trial. We anticipate that this trial will open in Two rectal neo/adjuvant studies are planned. Patients treated preoperatively will be randomized in a two by two program to capecitabine versus infusion of 5-FU and erythropoietin or placebo. After surgery patients will be eligible for a second trial regardless of whether or not preoperative chemotherapy and radiation was given. The randomization in this study is to 5-FU/LV +/- CPT- 11. If postoperative radiation is needed it will be provided. In the setting of resectable colorectal cancer metastatic only to the liver NCCTG is leading a collaboration with the NSABP on a Phase II trial (N9945) of intraarterial FUDR, oxaliplatin + capecitabine. Because of tissue considerations, patients need to be enrolled before surgery. Subsequently, a randomized Phase III trial of capecitabine + oxaliplatin +/- intraarterial FUDR with NSABP as the lead group is planned. The RTOG led trial of 5-FU + either mitomycin or cisplatin with radiation in anal cancer remains open with modest NCCTG accrual to date. Advanced Disease: The three arm study (N9741) of the Saltz regimen versus oxaliplatin + 5-FU/leucovorin versus oxaliplatin + CPT-11 for first-line therapy is exceeding projected accrual rates. The trial

4 collapsed to two arms in March when the CPT-11/oxaliplatin arm mets its accrual goal. Blood samples for pharmacogenomic analysis and for analysis of insulin like growth factor levels are being collected. An ASCO presentation at the oral session will discuss preliminary results of this trial. A replacement randomized Phase III trial for previously untreated patients will randomize patients between 5-FU/LV by bolus or infusion given with CPT-11 plus or minus celecoxib in a 2x2 randomization scheme. The second-line study (N9841) of CPT-11 versus 5-FU/leucovorin + oxaliplatin with cross over to the other arm upon progression, is accruing more slowly than we had hoped. About 60% of patients needed are on study. Two additional treatment programs in N0048 for patients progressing after oxaliplatin/5-fu/lv using CPT-11 or after CPT-11 + oxaliplatin using 5-FU/LV are accruing more slowly than expected as well. Translational and Record Studies: Dr. Thibodeau ( ) and Dr. Witzig ( ) are both working on the analyses of the submitted blocks for their respective studies on chromosomal and flow cytometric analyses and there will be an ASCO presentation arising from the In addition an ASCO presentation by one of the members of Dr. Steven Gallinger s lab from the University of Toronto will show that patients whose tumors show high levels of microsatellite instability are actually adversely affected when given 5-FU based adjuvant chemotherapy. Tim Hobday will be presenting data from the NCCTG database that explores the characteristics of patients entered on our studies for advanced colorectal cancer who survived more than 5 years after diagnosis of advanced disease. Upper Gastrointestinal Cancer Program: Gastroesophageal Cancer: The intergroup is piloting several approaches that we expect to culminate in an adjuvant trial to open in The trial of paclitaxel, 5-FU and cisplatin with radiation and amifostine(n0044) is open. Pharmacogenomic analysis in collaboration with Dr. Howard Mcleod from Washington University will be a part of this study. The advanced esophageal and gastroesophageal junction cancer trial (N9941) of taxotere and CPT-11 is complete and will be presented as a poster at ASCO. A replacement study of oxaliplatin and capecitabine is in development. The study of CPT-11 in gastric cancer ( ) is nearing its accrual goal with 65 enrolled patients who can be evaluated of 67 required patients on study. This study requires a post treatment biopsy for immunohistochemical analysis. A follow up study of capecitabine plus taxotere is in development. Pancreatic Cancer: The pilot trial ( ) in locally advanced pancreas/gastric cancer study with gemcitabine plus cisplatin radiosensitization will be presented as a poster at ASCO this year. Accrual on the Phase II study successor trial is underway. Four cycles of gemcitabine post radiation are incorporated in the Phase II trial. The oxaliplatin + gemcitabine trial ( ) in advanced disease will be presented at an ASCO special educational session by Dr Alberts. The trial evaluating a regimen of gemcitabine plus ISIS 2503 (N0043) has been submitted to AACR as a rapid report. The next generation advanced pancreatic cancer study will randomize patients to gemcitabine plus the proteosome inhibitor PS-341 or to PS341 followed by the addition of gemcitabine to that drug at the time of progression on the single agent drug.

5 Hepatobiliary cancer: The gemcitabine + docetaxel for primary hepatocellular cancer (N0041) and 5-FU/leucovorin + gemcitabine (N0042) for gall bladder and bile duct cancers are open for accrual. The former trial has have a pharmacokinetic component with the first cycle. A dose reduction in N0041 is in process because of first cycle toxicity rates that are too high. Goals for the near future include: identifying active regimens for phase II testing based on preclinical leads identified in collaboration with the Novel Therapeutics Committee and maintaining a strong record of accrual. The integration of translational studies whenever appropriate and incorporation of QOL measures into trials are also priorities.

6 Program Status Reports for GASTROINTESTINAL - April 2002 Lower A Phase III Prospective Randomized Trial ComparingLaparoscopic- Assisted Colectomy Versus Open Colectomy for Colon Cancer A Phase II Study of Patients With Unresectable Hepatic Metastases frommetastatic Adenocarcinoma of the Colon or Rectum Page 1 3 C9581 N0048 N0148 N9741 N9841 N9945 N9946 R9811 Phase III Randomized Study of Adjuvant Immunotherapy With MonoclonalAntibody 17-1A Versus No Adjuvant Therapy Following Resection forstage II (Modified Astler-Coller B2) Adenocarcinoma of the Colon Phase II Studies of Irinotecan (CPT-11) or 5-Fluorouracil(5-FU)/Leucovorin (CF) in Patients With Metastatic ColorectalCarcinoma Previously Treated With Oxaliplatin (OXAL) or a Combinationof CPT-11 and OXAL Study to Estimate the Benefit of 5-FU-Based Treatment as SurgicalAdjuvant Therapy by Gender, Primary Site and Nodal Stage in Patientswith Dukes' C Colon Cancer Compared to Controls Who Were Not Treated A Randomized Phase III Trial of Combinations of Oxaliplatin (OXAL),5-Fluorouracil (5-FU), and Irinotecan (CPT-11) as Initial Treatment ofpatients With Advanced Adenocarcinoma of the Colon and Rectum A Randomized Phase III Equivalence Trial of Irinotecan (CPT-11) VersusOxaliplatin (OXAL)/5-Fluorouracil (5-FU)/Leucovorin (CF) in PatientsWith Advanced Colorectal Carcinoma Previously Treated With 5-FU A Phase II Trial Evaluating Multiple Metastasectomy Combined With- Hepatic Artery Infusion of Floxuridine (FUDR) and Dexamethasone (DXM)Alternating With Systemic Oxaliplatin (OXAL) and Capecitabine (CAPCIT)for Colorectal Carcinoma Metastatic to the Liver A Phase II Study of Oxaliplatin (OXAL), 5-Fluorouracil (5-FU), andleucovorin (CF)in Patients With Metastatic Colorectal CarcinomaPreviously Treated With Irinotecan (CPT-11) A Phase III Randomized Study of 5-fluorouracil, Mitomycin-C, andradiotherapy Versus 5-fluorouracil, Cisplatin and Radiotherapy incarcinoma of the Anal Canal NCCTG Committee Table of Contents - Page 1 of 5

7 Program Status Reports for GASTROINTESTINAL - April 2002 Upper A Phase II Trial of CPT-11 in Patients With Advanced Adenocarcinoma ofthe Stomach or Gastroesophageal Junction Incorporating Pretreatmentand Posttreatment Biopsies for Evaluation of Tumor Thymidylate- Synthase, MIB-1, Topoisomerase I, and p Phase I Study of Gemcitabine, Cisplatin and Radiation Therapy inpatients with Locally Advanced Pancreatic and Gastric Cancer A Phase I (Limited)/Phase II Study of Oxaliplatin (OXAL) andgemcitabine (GEMZAR) in Patients with Metastatic Pancreatic Carcinoma N0041 N0042 N0043 N0044 N9941 N9942 Phase II Trial of Gemcitabine and Docetaxel in Patients WithMeasurable Unresectable or Metastatic Hepatocellular Carcinoma Phase II Trial of Gemcitabine, 5-Fluouracil, and Leucovorin inpatients With Unresectable or Metastatic Biliary Tract Carcinoma(Intrahepatic, Extrahepatic, Ampulla of Vater) and GallbladderCarcinoma Phase II Trial of Gemcitabine and ISIS 2503 in Patients With Locally- Advanced or Metastatic Pancreatic Adenocarcinoma A Phase II Trial of Preoparative Radiation and Chemotherapy(Paclitaxel, Carboplatin, and Continuous Infusion 5-FU) in CombinationWith Subcutaneous Amifostine for Locally Advanced Esophageal Cancer A Phase II Study of Taxotere and Irinotecan (CPT-11) in Patients with- Advanced Adenocarcinoma of the Lower Esophagus, Esophagogastric- Junction, and Gastric Cardia A Phase II Study of Gemcitabine, Cisplatin and Radiation Therapy inpatients with Locally Advanced Pancreatic Cancer Translational Studies Apoptosis, Cell Proliferation, and DNA Ploidy in Patients with Dukes'B2 and C Stage Adenocarcinoma: An Ancillary Study to NCCT- GChemotherapy Protocols for Colon Cancer The Clinical and Pathologic Significance of Allelic Imbalance of 8p inpatients With Colorectal Cancer NCCTG Committee Table of Contents - Page 2 of 5

8 Program Status Reports for GASTROINTESTINAL - April 2002 MC9944 Colorectal Cancer Screening: Fecal Blood vs. DNA 86 N0144 Profile of Long-Term Survivors on NCCTG Advanced Colorectal CancerTreatment Trials 89 Other Closed Trials A Controlled Phase III Evaluation of 5FU Combined with Levamisole andleucovorin as Surgical Adjuvant Treatment Following Total Gross- Resection of Metastatic Colorectal Cancer (RTOG 9405) A Phase III Intergroup Randomized Comparison of CombinedModalityTherapy for Carcinoma of the Esophagus: High Dose Vs.Conventional Dose Radiation Therapy Intergroup - Phase III Study of Radiation Therapy, Levamisole, and5- Fluorouracil vs 5-Fluorouracil and Levamisole in Selected PatientsWith Completely Resected Colon Cancer A Phase III Evaluation of High-Dose Levamisole Plus 5-Fluorouracil andleucovorin as Surgical Adjuvant Therapy for High Risk Colon Cancer Phase II Trial: Evaluation of the Role of Multiple MetastasectomyCombined with Systemic and Hepatic Artery Infusion Chemotherapy forcolorectal Carcinoma Metastatic to the Liver Evaluation of Tumor Thymidylate Synthase, Ki-67, DCC, and p53 asprognostic Parameters in Patients With High-Risk Primary Colon Cancer Postoperative Evaluation of 5FU by Bolus Injection VS5FU by ProlongedVenous Infusion Prior to and Following Combined Prolonged VenousInfusion Plus Pelvic XRT Vs. Bolus 5FU Plus Leucovorin Plus LevamisolePrior to and Following Combined PelvicXRT in Patients With RectalCancer, Phase III A Phase II Trial of a Seven Day Regimen of Oral 776C85 and Oral5- Flourouracil (5-FU) in Untreated Patients with Unresectable ormetastatic Colorectal Cancer Phase II Study of CPT-11 in Patients With Advanced Gallbladder or BileDuct Tumors NCCTG Committee Table of Contents - Page 3 of 5

9 Program Status Reports for GASTROINTESTINAL - April Phase I Study of Capecitabine (Xeloda) as a Radiation Enhancer inlocally Unresectable, Residual, or Recurrent Colorectal CancerLocalized in the Pelvis 92 C89803 C9781 JCO10 N004A N9742 N9743 N9949 S9415 Phase III Intergroup Trial of Irinotecan (CPT-11) (NSC #616348) Plus- Fluorouracil/Leucovorin (5-FU/LV) Versus Fluorouracil/Leucovorin AloneAfter Curative Resection for Patients with Stage III Colon Cancer A Prospective Randomized Phase III Trial Comparing Trimodality Therapy(Cisplatin, 5-FU, Radiotherapy, and Surgery) to Surgery Alone ForEsophageal Cancer. A Phase III Study of Immediate versus Delayed Chemotherapy forasymptomatic Advanced Colorectal Cancer Study to Estimate the Toxicity, Dose Intensity, and Benefit of5-fu- Based Treatment by Age Group in Patients with Advanced ColonCancer An Analysis of the Incidence by Grade of Acute GastrointestinalToxicity in Patients Receiving Adjuvant Continuous InfusionChemotherapy and Radiotherapy for High-Risk Rectal Carcinoma Study to Estimate the Benefit of 5-FU-Based Treatment assurgicaladjuvant Therapy by Age Group in Patients With ResectableHigh-Risk Colon cancer Compared to Controls Who Were Not Treated Women Experience Greater Toxicity With 5FU-Based Chemotherapy (CTX)for Colorectal Cancer (CC): A North Central Cancer Treatment Group(NCCTG) Meta-Analysis A Phase III Randomized Trial of 5-FU/Leucovorin/Levamisole Versus 5-FUContinuous Infusion/Levamisole as Adjuvant Therapy for High- RiskResectable Colon Cancer Protocol Concepts N0093 Topoisomerase Inhibitors in Gastric and Glioma Tumors 95 N004B Phase III Randomized, Double-Blind, Placebo-Controlled Study ofro- FECOXIB (VIOXX) in Colorectal Cancer Patients Following PotentiallyCurative Therapy 95 NCCTG Committee Table of Contents - Page 4 of 5

10 Program Status Reports for GASTROINTESTINAL - April 2002 N004C N0147 N0149 N014A N014C Evaluation of the Predictive Ability of Defective Mismatch Repair(MMR) (Measured either by Microsatellite Instability (MSI-H) orabsence of Protein Expression for hmlh1 and hmsh2) for Efficacy of5-fu Based Adjuvant Therapy for Stage II and III Colon Cancer Phase III Trial of Irinotecan (CPT-11) Plus 5-Fluorouracil(5-FU)/Leucovorin (CF) Versus Oxaliplatin (OXAL) Plus5-Fluoracil/Leucovorin After Curative Resection for Patients withstage III Colon Cancer A Phase II Study of Oxaliplatin and Capecitabine in Patients withmetastatic Adenocarcinoma of the Esophagus, Gastroesophageal Junction,and Gastric Cardia A Phase II Study of Oxaliplatin, 5-Fluorouracil, Leucovorin, and C225for Patients With Unresectable Hepatic Metastases from MetastaticAdenocarcinoma of the Colon or Rectum Phase II Study of PS-341 and Gemcitabine in Patients with Advanced ormetastatic Pancreatic Adenocarcinoma to Other Potentially Curative- Therapy NCCTG Committee Table of Contents - Page 5 of 5

11 NCCTG Status Report for Study April 2002 A Phase III Prospective Randomized Trial Comparing Laparoscopic-Assisted Colectomy Versus Open Colectomy for Colon Cancer Purpose of Study: 1) The primary aim of the study is to test the hypothesis that disease-free survival and overall survival are equivalent, regardless of whether patients receive LAC or open colectomy. 2) The secondary aim of the study is to determine the safety of LAC compared to open colectomy, specifically with respect to early and late morbidities and 30-day mortality. 3) The tertiary aim of the study is to test for differences in quality of life, costs, and cost effectiveness between LAC and open colectomy. Study Chairs: Heidi Nelson M.D. Data Monitor: Linda G. Healy Statistician: Daniel J. Sargent Ph.D. Nurse Resource: Linda Arneson R.N. Status: 08/02/ /31/2001 Activated Perm. Closed Projected Number of Patients: 900 Excluded: 13 Final Accrual: 870 Stratification Schema: None Randomize A) Open colectomy B) Laparoscopic-assisted colectomy Treating Schedule: Not applicable Study Design: The need for a controlled trial to evaluate the role of the laparoscopic-assisted colectomy for colon cancer was recognized by early A timely study was essential to provide critical appraisal before the procedure became widely practiced. Because of the complexity of the study and the need to ensure that all laparoscopic procedures are performed according to uniform guidelines, only designated surgeons who are experienced at laparoscopic-assisted colectomy are able to participate. This is a randomized phase III trial designed to test the hypothesis that disease-free survival and overall survival are equivalent, regardless of whether patients receive LAC or open colectomy. This design calls for 1200 patients. A secondary aim is to determine the safety of LAC compared to open colectomy, specifically with respect to early and late morbidities and 30-day mortality. Accrual: This study completed accrual on August 31, 2001 with a total accrual of 870 patients. See Accrual Table. NCCTG Committee Page 1 of 2

12 NCCTG Status Report for Study April 2002 Available Information: There have been six ineligible patients, four due to liver metastasis at time of surgery, one had previous prostate cancer within 5 years and for one patient, the participating institution did not have full IRB approval. There have been four cancellations due to patient refusal after randomization. To date, early evaluation data is available on 840 patients (96%). Adverse Events: There have been 6 postoperative mortalities (3 on the open arm and 3 on the LAC arm). Two patients (.2%) have had a severe complication (both on the LAC arm), sixtyfour (7.6%) patients have had moderate complications (32 open colectomy patients and 32 LAC patients) and an additional 81 (9.7%) patients have had mild complications (41 open colectomy patients and 40 LAC patients). Study Status: This study is now closed to enrollment. A paper reporting on the Quality of Life outcomes in the initial 576 patients appeared recently in the Journal of the American Medical Association, (JAMA 287(3): , 2002). Accrual Table: Randomizing Membership Total Entered Past 6 Months Past 12 Months Ann Arbor Mayo Mo Valley Scottsdale Total Membership Accrual Randomizing Group Total Entered Past 6 Months Past 12 Months NCCTG ECOG SWOG RTOG CALGB NCIC CTG NSABP Total Group Accrual NCCTG Committee Page 2 of 2

13 NCCTG Status Report for Study April 2002 A Phase II Study of Patients With Unresectable Hepatic Metastases from Metastatic Adenocarcinoma of the Colon or Rectum Purpose of Study: 1) To evaluate the resectability rate of this patient population group after treatment with OXAL, 5-FU and CF. 2) To assess the response rate, toxicity and overall survival of this same group. Study Chairs: Steven R. Alberts M.D. William C. Sternfeld M.D. William L. Horvath M.D. Data Monitor: Deborah J. Papenfus Statistician: Michelle R. Mahoney M.S. Nurse Resource: Tammy Fischer R.N. Status: 03/26/ /31/2001 Activated Perm. Closed Projected Number of Patients: 44 Excluded: 1 Final Accrual: 44 Stratification Schema: None Register OXAL + 5FU + CF Treating Schedule: Arm Agent Dose Route Days Freq OXAL 85 mg/m2 IV over 2 hrs 1 2 wks CF 200 mg/m2 IV over 2 hrs 1, 2 2 wks 5FU 400 mg/m2 IV bolus after CF 1, 2* 2 wks 5FU 600 mg/m2 Continuous IV infusion after bolus 5FU 1, 2 2 wks *Patient receive bimonthly high-dose CF with 5FU bolus and continuous infusion for 2 consecutive days. CF is given at 200 mg/m2/day as a 2-hr infusion followed by IV bolus 5FU at 400 mg/m2/day and 22-hr infusion 5FU 600 mg/m2/day, all repeated for 2 consecutive days. Study Design: The primary endpoint is the surgical complete response (surgical CR) rate. Thirty-nine evaluable patients will be enrolled with the provision that if 0 or more than 2 patients in the first 28 evaluable demonstrate a surgical CR, we will stop accrual to either report a poor result or a promising result, respectively. If 1 in 28 evaluable patients demonstrate a surgical CR, we will accrue an additional 11 patients. If 1 in 39 show surgical CR, we will conclude inactivity of this treatment in this population. If 2 or more in 39 patients demonstrate a surgical CR, we will consider the study of this treatment in larger studies. NCCTG Committee Page 1 of 4

14 NCCTG Status Report for Study April 2002 Accrual: This study has completed accruing patients. See NCCTG 2001 book for accrual information. Patient Characteristics: The distribution of patient characteristics at study entry is located in the Patient Characteristics Table. Available Information: One patient is ineligible due to extrahepatic metastases. All other patients are eligible. Adverse Events: Toxicity data is available for 40 eligible patients. Grade IV toxicity has been minimal (diarrhea-2 pts, arrythmia-1 pt, vomiting-1 pt, hypokalemia-1 pt). See Adverse Event Table for further details. Study Status: This study is closed to accrual and data is maturing. An abstract accepted for poster discussion at the ASCO 2001 meetings appeared in the 2001 NCCTG meeting book. A replacement study is currently in development and anticipated to open in early Accrual Table: Randomizing Membership Total Entered Past 6 Months Past 12 Months Carle Cedar Rapids Des Moines Duluth Fargo Geisinger Mayo Mo Valley Peoria Sioux City Sioux Falls Toledo Wichita Total Membership Accrual Baseline Characteristics Table: Gender Characteristics Arm A NCCTG Committee Page 2 of 4

15 NCCTG Status Report for Study April 2002 Characteristics Arm A f 20 m 24 Liver Metastases MULTIPLE 21 ILL-LOCATED 3 LARGE 3 COMBINATION 15 Race Black 1 Native Americian 1 White 42 NCCTG Committee Page 3 of 4

16 NCCTG Status Report for Study April 2002 Adverse Event Table: Arm A Evaluable Patients: 42 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % Hematology NEUTROPENIA A LEUKOPENIA A ANEMIA A THROMBOCYTOPENIA A Cardiovascular ARRHYTHMIA-SVT A Constitutional Symptoms FATIGUE A Dermatology/Skin ALOPECIA A RASH A Gastrointestinal ANOREXIA A NAUSEA A STOMATITIS A VOMITING A DIARRHEA-NO COLOSTOM A Hepatic SGOT (AST) A ALK PHOS A BILIRUBIN A Metabolic/Laboratory HYPOKALEMIA A HYPERGLYCEMIA A Neurology NEURO A Pain PAIN-ABDOMINAL A Renal/Genitourinary CREATININE A Maximum Toxicity A NCCTG Committee Page 4 of 4

17 NCCTG Status Report for Study C April 2002 Phase III Randomized Study of Adjuvant Immunotherapy With Monoclonal Antibody 17-1A Versus No Adjuvant Therapy Following Resection for Stage II (Modified Astler-Coller B2) Adenocarcinoma of the Colon Purpose of Study: 1) To determine whether adj MoAb 17-1A will improve overall/disease-free survival, and increase disease-free intervals in study patients. 2) To evaluate prognostic markers in order to correlate survival and recurrence for study patients. Study Chairs: Richard M. Goldberg M.D. Rex B. Mowat M.D. Fredric H. Itzkowitz D.O. Data Monitor: Carol A. Leonard Statistician: Nurse Resource: Status: 11/26/1997 Activated Projected Number of Patients: 2100 Excluded: None Final Accrual: NA Stratification Histology-degree of differentiation Histology-vascular or lymphatic invasion Factors: Preoperative serum CEA Schema: Randomize A) MoAb-17 B) Observation Treating Schedule: Arm Agent Dose Route Days Freq A MOAB 17-1A 500 MG INFUSION OVER 2 HRS 1 CYCLE 1 ONLY A MOAB 17-1A 100 MG INFUSION OVER 2 HRS 1 EVERY 28 DAYS CYCLES 2-5 Study Design: The goal of this CALGB-coordinated study is to determine whether adjuvant immunotherapy with infusion of MoAb 17-1A improves the overall and disease-free survival of patients with Stage B2 colon cancer compared to an observation group receiving the current recommended standard of care, i.e., no adjuvant therapy after surgical resection. In addition, this study will evaluate a panel of prognostic markers, in order to correlate these measures with survival and recurrence after adjuvant therapy in patients who have undergone resection of a Stage II (pt3n0 or pt4bn0) colon cancer. Accrual: As of 8/31/2001, this study has an accrual of 1449 patients, including 238 from the NCCTG. See Accrual Table. NCCTG Committee C Page 1 of 2

18 NCCTG Status Report for Study C April 2002 Adverse Events: With toxicity information available on 836 patients, there have been 46 instances of Grade 3 toxicities and 11 instances of Grade 4 toxicity. The Grade 4 toxicities include diarrhea (6), dyspnea (1), vomiting (1), lymphocytopenia (1), dysrhythemias (1), and allergy (2). Study Status: The study is currently open with an accrual goal of 2100 patients. Accrual Table: Randomizing Membership Total Entered Past 6 Months Past 12 Months Ann Arbor Bismarck Carle Cedar Rapids Des Moines Duluth Fargo Grand Forks Mayo Mo Valley Rapid City Saskatchewan Scottsdale Sioux City St. Cloud Toledo Total Membership Accrual NCCTG Committee C Page 2 of 2

19 NCCTG Status Report for Study N April 2002 Phase II Studies of Irinotecan (CPT-11) or 5-Fluorouracil (5-FU)/Leucovorin (CF) in Patients With Metastatic Colorectal Carcinoma Previously Treated With Oxaliplatin (OXAL) or a Combination of CPT-11 and OXAL Purpose of Study: 1) To evaluate tumor response rate to CPT-11, and 5FU/CF in this patient population. 2) To evaluate time to tumor progression, time to treatment failure, treatment toxicity, and overall survival. 3) Assess the quality-of-life during chemotherapy. Study Chairs: Henry C. Pitot IV M.D. Martin Wiesenfeld M.D. Data Monitor: Carol A. Leonard Statistician: Michelle R. Mahoney M.S. Nurse Resource: Tammy Fischer R.N. Status: 04/13/2001 Activated Projected Number of Patients: 80 Excluded: None Final Accrual: NA Stratification Schema: None Register For patients with prior OXAL A) CPT-11 For patients with prior CPT-11 + OXAL B) CF + 5FU Treating Schedule: Arm Agent Dose Route Days Freq A CPT mg/m2 IV infusion of 500 ml 1 3 wks D5W over 90 min B CF 200 mg/m2 IV over 2 hrs in 250 ml 1,2 2 wks D5W 5FU 400 mg/m2 IV bolus followed by IV 1,2 2 wks 5FU 600 mg/m2 Continuous IV infusion after bolus 5FU 1,2 2 wks Study Design: This study evaluates two treatments (i.e., Arms) in a concurrent manner. The primary endpoint of this trial is confirmed tumor response. The same statistical design will be independently applied to evaluate each arm with respect to the primary endpoint. We will enroll 20 patients onto this study. If 1 or fewer confirmed responses are observed in 20 evaluable patients, we will terminate the study. Otherwise, we will expand accrual to a total of 40 patients. Five confirmed responses in all 40 evaluable patients is considered sufficient evidence of promising activity in this patient population. NCCTG Committee N Page 1 of 3

20 NCCTG Status Report for Study N April 2002 Accrual: This study has had an accrual of 8 patients thus far. Seven patients have been accrued in the last 6 months. See Accrual Table. Patient Characteristics: The distribution of patient characteristics at study entry is located in the Patient Characteristics Table. Available Information: One patient has been registered to date. Eight patients are in active treatment and one has begun event monitoring. Adverse Events: Toxicity data is available for one patient. See Adverse Event Table for details. Study Status: This study is currently open. Patients registered to N9741 and receiving one of the OXAL-based regimens, may be eligible for this study after progression. Accrual Table: Randomizing Membership Total Entered Past 6 Months Past 12 Months Cedar Rapids Jacksonville Mayo Mo Valley Peoria Saskatchewan Total Membership Accrual Baseline Characteristics Table: Characteristics Arm A Gender f 1 2 m 4 1 Prior Treatment Received OXAL BASED CHEMO 5 0 COMBINED CPT-11 AND OXAL CHEMO 0 3 Race White 5 3 Arm B NCCTG Committee N Page 2 of 3

21 NCCTG Status Report for Study N April 2002 Adverse Event Table: Arm A Evaluable Patients: 1 Arm B Evaluable Patients: 1 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % Hematology NEUTROPENIA A B LEUKOPENIA A B ANEMIA A B THROMBOCYTOPENIA A B HAPTOGLOBIN A B Dermatology/Skin ALOPECIA A B Gastrointestinal ANOREXIA A B NAUSEA A B DIARRHEA-NO COLOSTOM A B Maximum Toxicity A B NCCTG Committee N Page 3 of 3

22 NCCTG Status Report for Study N April 2002 Study to Estimate the Benefit of 5-FU-Based Treatment as Surgical Adjuvant Therapy by Gender, Primary Site and Nodal Stage in Patients with Dukes' C Colon Cancer Compared to Controls Who Were Not Treated Purpose of Study: 1) To estimate via pooled-analysis the benefit of 5FU-based treatment as surgical adjuvant therapy by gender, primary site & nodal stage groups in patients with resectable high-risk colon cancer compared to controls who were not treated. Study Chairs: Steven R. Alberts M.D. Stephan D. Thome M.D. Data Monitor: Statistician: Daniel J. Sargent Ph.D. Nurse Resource: Status: 12/07/2001 Activated Projected Number of Patients: 3351 Stratification Factors: Schema: None Not Applicable Treating Schedule: Not applicable Study Design: This retrospective trial is using data previously collected from multiple randomized phase III trials throughout the U.S. and Europe. The goal is to determine if the benefit received from 5-FU based treatment varies by patient gender, primary site, nodal stage, and tumor grade. Study Status: Analyses are ongoing. NCCTG Committee N Page 1 of 1

23 NCCTG Status Report for Study N April 2002 A Randomized Phase III Trial of Combinations of Oxaliplatin (OXAL), 5-Fluorouracil (5-FU), and Irinotecan (CPT-11) as Initial Treatment of Patients With Advanced Adenocarcinoma of the Colon and Rectum Purpose of Study: 1) To evaluate time to progression for the study population. 2) To evaluate toxicity, response rate, time to treatment failure and survival. 3) To compare quality of life parameters. Study Chairs: Richard M. Goldberg M.D. Roscoe F. Morton M.D. Data Monitor: Carol A. Leonard Statistician: Daniel J. Sargent Ph.D. Nurse Resource: Tammy Fischer R.N. Status: 10/27/ /24/ /28/ /25/ /29/2001 Activated Temp. Closed Reopened Temp. Closed Reopened Projected Number of Patients: 1705 Excluded: 25 Final Accrual: NA Stratification Age Dominant Disease Status Factors: Membership Prior Adjuvant Chemotherapy Prior Immunotherapy ECOG PS Schema: Randomize A) Saltz Regimen B) Mayo CPT-11 Regimen (closed) C) Wilke Regimen (closed) D) Standard 5FU/CF Regimen (closed) E) OXAL bolus Regimen (closed) F) OXAL Infusion Regimen G) OXAL + CPT-11 (closed) Treating Schedule: Arm Agent Dose Route Days Freq A CPT mg/m2 IV infusion 500 ML D5W over 90 min 1 Every 42 days (Rx Wks 1-4 Rest Wks 5 & 6) A CF 20 mg/m2 IV infusion 15 min 1-after CPT-11 Every 42 days (Rx Wks 1-4 Rest Wks 5 & 6) A 5FU 400 mg/m2 IV bolus 1-after CF Every 42 days (Rx Wks 1-4 Rest Wks 5 & 6) F OXAL 85 mg/m2 IV infusion 500 ML D5W over 120 min 1 Every 14 days (Rx Wk 1 Rest Wk 2) NCCTG Committee N Page 1 of 19

24 NCCTG Status Report for Study N April 2002 Arm Agent Dose Route Days Freq F CF 200 mg/m2 120 min infusion 1, 2 Every 14 days (Rx Wk 1 Rest Wk 2) F 5FU 400 mg/m2 then 600 mg/m2 IV BOLUS then IV infusion thru ambulatory pump over 22 hrs 1, 2 after CF Every 14 days (Rx Wk 1 Rest Wk 2) G OXAL 85 mg/m2 IV infusion in 500 ML D5W over 120 min 1 Every 21 days (Rx Wk 1 Rest Wks 2 & 3) G CPT mg/m2 30 min infusion 1 Every 21 days (Rx Wk 1 Rest Wks 2 & 3) Study Design: Two drugs are currently FDA-approved in the U.S. for treatment of colon cancer. The combination of CPT-11, 5-FU, and CF is standard therapy in the U.S. for patients with advanced disease. Oxaliplatin (OXAL) is a cisplatinum analogue with activity in colorectal cancer that is an investigational agent in the U.S. and Canada. OXAL, either administered with 5- FU and leucovorin or as a single agent, is approved for the treatment of advanced colon cancer in France. A comparison of regimens which combine 5-FU + OXAL + CF and OXAL + CPT-11 is of great interest to advance the therapy of advanced colorectal cancer. This trial's results will also provide data that can be used to help develop future adjuvant trials. The primary objective of this trial is to compare the time-to-progression in patients with locally advanced or metastatic colorectal cancer (previously untreated for advanced disease) who receive OXAL + 5-FU + CF or CPT-11 + OXAL to those receiving standard CPT FU + CF. This is a 3-arm randomized trial with equal allocation to each arm. The total sample size required is 1705 patients. Accrual: Accrual to the study with a reduced dosage on arm A reopened 6/29/01. Accrual is now quite steady at approximately 60 patients per month following the reopening. Patient Characteristics: The distribution of patient characteristics at study entry is located in the Patient Characteristics Table. NCCTG Committee N Page 2 of 19

25 NCCTG Status Report for Study N April 2002 Adverse Events: Toxicity information is available for 743 patients, 72% of the enrolled 1034 patients. In late fall 1999, multiple grade 5 toxicities were observed on arms B and E, specifically, on each of these two arms 3 patients died from at least possibly treatment related causes. These two arms were subsequently removed from the study, in part due to this toxicity. In the spring of 2001, what had been a trend toward an increased early fatality rate on arm A became more pronounced. This finding led to a suspension of accrual pending a dose modification on arm A. Subsequent to the study closing, the toxicity on arm A was extensively investigated and reported. The experience on this trial, and a related CALGB trial, were described in a letter to the editor of the New England Journal of Medicine dated July 12, Subsequently, an external, independent panel reviewed each death within 60 days of study entry on this and the related CALGB study. The report of this committee was published in the Journal of Clinical Oncology (19(18): , 2001). At this time no toxicity data is available on patients randomized to the modified arm A, although no expedited toxicity reports have been received on this arm. 36 patients have died within 60 days of study entry. No additional deaths within 60 days of study entry on any arm have been reported since the spring 2001 NCCTG meetings. The number of deaths within 60 days of study entry by arm is 12 (4.3%) on original arm A, 6 (10.5%) arm B, 1 (7.1%) arm C, 3 (5.0%) arm D, 4 (8.5%) arm E, 5 (1.9%) arm F, and 4 (1.5%) arm G. Original arm A, and arms B, C, D, and E, are now closed. The rates on arms F and G are consistent with those seen in previous large studies in advanced colorectal cancer. Regarding other toxicities, 9% of patients on the original arm A, 18% arm B, 21% arm C, 5% arm D, 13% arm E, 4% arm F, and 8% arm G have had at least one grade 4 or higher non hematologic toxicity. Alopecia, anorexia, nausea, fatigue, stomatitis, vomiting and diarrhea are the most common non hematologic toxicities. See the attached toxicity tables for complete toxicity information. Study Status: Accrual to this study continues. Detailed guidelines for dose modifications and patient monitoring have been added to the protocol. A translational component consisting of a blood draw to examine the role of pharmacogenetics and IGF levels has been added. For patients who progress on arms F or G of N9741, they may be eligible for trial NCCTG N0048. Arm G has recently closed to accrual per protocol. Additional Information: An abstract submitted to the 2002 ASCO meetings is attached. NCCTG Committee N Page 3 of 19

26 Accrual Table: NCCTG Status Report for Study N April 2002 Randomizing Membership Total Entered Past 6 Months Past 12 Months Ann Arbor Bismarck Carle Cedar Rapids Des Moines Duluth Fargo Geisinger Grand Forks Mayo Metro Mo Valley Ochsner Peoria Rapid City Saskatchewan Scottsdale Sioux City Sioux Falls St. Cloud Toledo Wichita Total Membership Accrual Randomizing Group Total Entered Past 6 Months Past 12 Months NCCTG ECOG SWOG CALGB NCIC CTG EPP Total Group Accrual NCCTG Committee N Page 4 of 19

27 NCCTG Status Report for Study N April 2002 Baseline Characteristics Table: Characteristics Arm A Age < >= Disease Status MEASURABLE EVALUABLE ECOG PS Gender f m Prior Adjuvant Chemotherapy Yes No Race Asian Black Hispanic Native Americian Native Hawaiian or Other Pacific Islande Other Unknown White Arm B Arm C Arm D Arm E Arm F Arm G NCCTG Committee N Page 5 of 19

28 NCCTG Status Report for Study N April 2002 Adverse Event Table: Arm A Evaluable Patients: 270 Arm B Evaluable Patients: 55 Arm C Evaluable Patients: 14 Arm D Evaluable Patients: 60 Arm E Evaluable Patients: 44 Arm F Evaluable Patients: 276 Arm G Evaluable Patients: 269 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % Hematology NEUTROPENIA A B C D E F G LEUKOPENIA A B C D E F G ANEMIA A B C D E F G THROMBOCYTOPENIA A B C D E F G Allergy/Immunology HYPERSENSITIVITY A B C NCCTG Committee N Page 6 of 19

29 NCCTG Status Report for Study N April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % D E F G Auditory/Hearing INNER EAR A B C D E F G Cardiovascular L VENTRICULAR FAIL A B C D E F G HYPOTENSION A B C D E F G ARRYTHMIA A B C D E F G ISCHEMIA/INFARCTION A B C D E F G NCCTG Committee N Page 7 of 19

30 NCCTG Status Report for Study N April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % THROMBOSIS A B C D E F G EDEMA A B C D E F G CARDIAC TROPONIN I A B C D E F G Constitutional Symptoms FATIGUE A B C D E F G FEVER-NO ANC A B C D E F G SWEATING A B C D NCCTG Committee N Page 8 of 19

31 NCCTG Status Report for Study N April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % E F G RIGORS A B C D E F G WEIGHT LOSS A B C D E F G CONSTITUTIONAL SYMPT A B C D E F G Dermatology/Skin ALOPECIA A B C D E F G INJECTION SITE RXN A B C D E F G Gastrointestinal ANOREXIA A NCCTG Committee N Page 9 of 19

32 NCCTG Status Report for Study N April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % B C D E F G NAUSEA A B C D E F G STOMATITIS A B C D E F G DEHYDRATION A B C D E F G CONSTIPATION A B C D E F G ILEUS A B C D E NCCTG Committee N Page 10 of 19

33 NCCTG Status Report for Study N April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % F G TASTE A B C D E F G DYSPEPSIA A B C D E F G VOMITING A B C D E F G DIARRHEA-NO COLOSTOM A B C D E F G GASTROINTESTINAL A B C D E F G DIARRHEA-COLOSTOM A B NCCTG Committee N Page 11 of 19

34 NCCTG Status Report for Study N April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % C D E F G Hemorrhage MELENA A B C D E F G Hepatic HEPATIC FAILURE A B C D E F G SGOT (AST) A B C D E F G ALK PHOS A B C D E F G HYPOALBUMINEMIA A B C D E F NCCTG Committee N Page 12 of 19

35 NCCTG Status Report for Study N April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % G BILIRUBIN A B C D E F G HEPATIC A B C D E F G Infection/Febrile Neutropenia INFECTION-NO ANC A B C D E F G FEBRILE NEUTROPENIA A B C D E F G INFECTION-ANC A B C D E F G INFECTION A B C NCCTG Committee N Page 13 of 19

36 NCCTG Status Report for Study N April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % D E F G Metabolic/Laboratory HYPONATREMIA A B C D E F G HYPERKALEMIA A B C D E F G HYPOKALEMIA A B C D E F G HYPERURICEMIA A B C D E F G ACIDOSIS A B C D E F G NCCTG Committee N Page 14 of 19

37 NCCTG Status Report for Study N April 2002 Body System Adverse Event A R M Maximum Severity Per Patient Grade 1/2 Grade 3 Grade 4 Grade 5 N % N % N % N % HYPERGLYCEMIA A B C D E F G METABOLIC/LAB A B C D E F G Neurology INSOMNIA A B C D E F G DIZZINESS A B C D E F G ISCHEMIA-CEREBRAL A B C D E F G ATAXIA A B C D NCCTG Committee N Page 15 of 19