FOLFIRI or FOLFOX With or Without Cetuximab in Patients With Metastatic Adenocarcinoma of the Colon or Rectum

A Phase II Trial Of Irinotecan /5-FU/ Leucovorin Or Oxaliplatin /5-FU / Leucovorin With And Without Cetuximab (C225) For Patients With Untreated Metastatic Adenocarcinoma Of The Colon or Rectum

This is a randomized phase II study trial that has served as a screening trial to test the increased efficacy of chemotherapy + cetuximab versus chemotherapy alone among patients with untreated, advanced or metastatic colon cancer regardless of tumor status with respect to EGFR.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: 5-FU; Drug: irinotecan; Drug: leucovorin; Drug: cetuximab; Drug: oxaliplatin

Detailed Description

CALGB 80203 was activated on December 15, 2003. In February 2004, based on the results of the randomized trial of IFL +/- cetuximab showing a significant improvement in overall survival with cetuximab, cetuximab was approved by the FDA for use as front-line therapy for patients with metastatic colon cancer. In response to this action, the Data Safety and Monitoring Board recommended closure of CALGB 80203. CALGB 80203 was subsequently closed to accrual in January 2005 with 238 of the originally targeted 2200 patients enrolled. A final decision was to "replace" CALGB 80203 with a three-treatment arm randomized trial of chemotherapy (FOLFOX or FOLFIRI) with and without cetuximab and/or bevacizumab. The protocol was amended to allow analysis of the data from CALGB 80203 as a randomized phase II trial and reporting of the results.

Patients were stratified according to prior adjuvant chemotherapy (yes vs no) and prior pelvic radiation (yes vs no). Patients must have completed any major surgery or radiotherapy (eg, chest or bone palliative RT or pelvic RT) ≥ 4 weeks from registration and completed any minor surgery ≥ 2 weeks from registration. Patients must have fully recovered from the procedure and/or radiotherapy. Patients must have initiated treatment within 7 days of registration. Patients were randomized to 1 of 4 treatment arms, please see a description of the treatment regimens in the "Arms" section. In addition, patients received concomitant and supportive therapy as appropriate per the protocol.

OBJECTIVES:

Primary

1. To determine if the addition of C225 to FOLFIRI or FOLFOX chemotherapy prolongs survival of patients with untreated, advanced or metastatic colorectal cancer.

Secondary

1. To determine if the FOLFIRI and FOLFOX regimens are equivalent in terms of survival as front-line therapy for advanced colorectal patients.
2. To determine the level of EGFR expression in patients with metastatic colorectal cancer.

Patients were followed up to 3 years post-treatment.

• Study Type: Interventional
• Enrollment (Actual): 238
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Northeast Alabama Regional Medical Center
  • California
    • La Jolla, California, United States, 92093-0658
      • Rebecca and John Moores UCSD Cancer Center
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Comprehensive Cancer Center at Cedars-Sinai Medical Center
    • San Diego, California, United States, 92161
      • Veterans Affairs Medical Center - San Diego
    • San Diego, California, United States, 92134-3202
      • Naval Medical Center - San Diego
    • San Francisco, California, United States, 94115
      • UCSF Comprehensive Cancer Center
    • San Francisco, California, United States, 94121
      • Veterans Affairs Medical Center - San Francisco
  • Delaware
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Veterans Affairs Medical Center - Washington, DC
    • Washington, District of Columbia, United States, 20007
      • Lombardi Cancer Center at Georgetown University Medical Center
    • Washington, District of Columbia, United States, 20307-5001
      • Walter Reed Army Medical Center
  • Florida
    • Fort Lauderdale, Florida, United States, 33316
      • Broward General Medical Center
    • Hollywood, Florida, United States, 33021
      • Memorial Regional Cancer Center at Memorial Regional Hospital
    • Miami Beach, Florida, United States, 33140
      • CCOP - Mount Sinai Medical Center
    • Orlando, Florida, United States, 32804
      • Florida Hospital Cancer Institute
    • West Palm Beach, Florida, United States, 33401
      • Palm Beach Cancer Institute
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Veterans Affairs Medical Center - Chicago (Westside Hospital)
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60640
      • Louis A. Weiss Memorial Hospital
    • Chicago, Illinois, United States, 60612
      • MBCCOP - University of Illinois at Chicago
    • Evanston, Illinois, United States, 60201
      • CCOP - Evanston
    • Peoria, Illinois, United States, 61615-7828
      • CCOP - Illinois Oncology Research Association
    • River Forest, Illinois, United States, 60305
      • West Suburban Center for Cancer Care
  • Indiana
    • Fort Wayne, Indiana, United States, 46885-5099
      • Fort Wayne Medical Oncology and Hematology, Incorporated
    • South Bend, Indiana, United States, 46601
      • CCOP - Northern Indiana CR Consortium
  • Iowa
    • Iowa City, Iowa, United States, 52242-1009
      • Holden Comprehensive Cancer Center at University of Iowa
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Baptist Hospital East - Louisville
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
    • Worcester, Massachusetts, United States, 01655
      • UMASS Memorial Cancer Center - University Campus
  • Michigan
    • Saint Joseph, Michigan, United States, 49085
      • Lakeland Cancer Care Center at Lakeland Hospital - St. Joseph
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • Veterans Affairs Medical Center - Minneapolis
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Cancer Center
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Veterans Affairs Medical Center - Columbia (Truman Memorial)
    • Columbia, Missouri, United States, 65203
      • Ellis Fischel Cancer Center at University of Missouri - Columbia
    • Kansas City, Missouri, United States, 64131
      • CCOP - Kansas City
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Cancer Center
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital
  • Nebraska
    • Omaha, Nebraska, United States, 68198-7680
      • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • CCOP - Southern Nevada Cancer Research Foundation
    • Las Vegas, Nevada, United States, 89106
      • Veterans Affairs Medical Center - Las Vegas
  • New Hampshire
    • Hooksett, New Hampshire, United States, 03106
      • New Hampshire Oncology-Hematology, PA - Hooksett
    • Lebanon, New Hampshire, United States, 03756-0002
      • Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper University Hospital
  • New York
    • Buffalo, New York, United States, 14215
      • Veterans Affairs Medical Center - Buffalo
    • East Syracuse, New York, United States, 13057
      • CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.
    • Jamaica, New York, United States, 11432
      • Queens Cancer Center of Queens Hospital
    • Manhasset, New York, United States, 11030
      • CCOP - North Shore University Hospital
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10021
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10021
      • New York Weill Cornell Cancer Center at Cornell University
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • Syracuse, New York, United States, 13210
      • Veterans Affairs Medical Center - Syracuse
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • North Carolina
    • Asheville, North Carolina, United States, 28805
      • Veterans Affairs Medical Center - Asheville
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
    • Concord, North Carolina, United States, 28025
      • NorthEast Oncology Associates - Concord
    • Durham, North Carolina, United States, 27705
      • Veterans Affairs Medical Center - Durham
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
    • Fayetteville, North Carolina, United States, 28302-2000
      • Cape Fear Valley Health System
    • Goldsboro, North Carolina, United States, 27534-9479
      • CCOP - Southeast Cancer Control Consortium
    • Pinehurst, North Carolina, United States, 28374
      • FirstHealth Moore Regional Hospital
    • Wilmington, North Carolina, United States, 28402-9025
      • Zimmer Cancer Center at New Hanover Regional Medical Center
    • Winston-Salem, North Carolina, United States, 27157-1082
      • Comprehensive Cancer Center at Wake Forest University
  • Ohio
    • Columbus, Ohio, United States, 43210-1240
      • Arthur G. James Cancer Hospital at Ohio State University
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Western Pennsylvania Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • Lifespan: The Miriam Hospital
  • Texas
    • Dallas, Texas, United States, 75219
      • Veterans Affairs Medical Center - Dallas
    • Dallas, Texas, United States, 75390-8852
      • Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas
  • Vermont
    • Burlington, Vermont, United States, 05401-3498
      • Vermont Cancer Center at University of Vermont
  • Virginia
    • Charlottesville, Virginia, United States, 22902
      • Martha Jefferson Hospital
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates - Norfolk
    • Richmond, Virginia, United States, 23298-0037
      • MBCCOP - Massey Cancer Center
    • Roanoke, Virginia, United States, 24014
      • Oncology and Hematology Associates of Southwest Virginia, Incorporated - Roanoke
  • West Virginia
    • Huntington, West Virginia, United States, 25701
      • St. Mary's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

1. Locally Advanced or Metastatic Colorectal Cancer

   • Eligible patients must have histologically or cytologically documented locally advanced or metastatic colorectal cancer. The site of the primary lesion must be or have been confirmed endoscopically, surgically or radiologically to have been in the large bowel.

   • Patients with a history of colorectal cancer treatment by surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless:

     • Either an interval of greater than five years has elapsed between the primary surgery and the development of metastatic disease OR
     • The primary cancer was stage I.
   • Clinicians should consider biopsy of lesions to establish the diagnosis of metastatic colorectal cancer in each case if there is substantial clinical ambiguity regarding the nature or source of apparent metastases.

2. No prior treatment for advanced or metastatic colorectal cancer

   • Patients may have received prior adjuvant chemotherapy (no more than 6 months or 4 cycles) or radiation with radiosensitizing chemotherapy. The last course of chemotherapy must have concluded > 12 months prior to registration. Patients may not have previously received irinotecan ≤ or oxaliplatin therapy in either the adjuvant or metastatic setting. No concurrent use of additional investigational agents is allowed while participating in this study.

3. Patients may not have had prior radiotherapy to greater than 25% of bone marrow.

   Standard adjuvant rectal cancer chemoradiation will not exclude the patient from protocol entry. Radiation must have concluded ≥ 4 weeks from registration.

4. Patients should have completed any major surgery ≥ 4 weeks from registration. Patients must have completed any minor surgery ≥ 2 weeks from registration. Patients must have fully recovered from the procedure. Insertion of a vascular access device is not considered major or minor surgery.
5. No previous or concurrent malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for five years.
6. Age ≥ 18 years
7. CTC (ECOG) performance status of 0-1.
8. No evidence of Gilbert's syndrome - Patients with Gilbert's Syndrome may have a greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38. Evidence of Gilbert's Syndrome would include a prior finding of an isolated elevation of indirect bilirubin.
9. Patients must have at least one paraffin block available or appropriate number of unstained slides for analysis of EGFR status.
10. No symptomatic sensory peripheral neuropathy of ≥ grade II at baseline.

11. Non-pregnant and non-lactating

    • Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG within 72 hours prior to initiation of treatment. This is because DNA alkylating agents are known to be teratogenic, and the effects of irinotecan, OXAL, 5-FU and C225 on a developing fetus at the recommended therapeutic doses are unknown.

    • Women of child bearing potential includes:

      • any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or
      • is not postmenopausal [defined as amenorrhea ≥ 12 consecutive months] or
      • women on hormone replacement therapy [HRT] with documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL
      • women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (eg, vasectomy), should be considered to be of child bearing potential.
    • Should a woman become pregnant or suspect she is pregnant while participating on on this study, she should inform her physician immediately. Because the risk of toxicity of these agents in nursing infants is also unknown, breastfeeding should be discontinued.
12. No known central nervous system metastases or carcinomatous meningitis.
13. No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung.
14. No pleural effusion or ascites that causes ≥ grade 2 dyspnea.
15. No predisposing colonic or small bowel disorders in which the symptoms are uncontrolled as indicated by baseline pattern of > 3 watery or soft stools daily in patients without a colostomy or ileostomy. Patients with a colostomy or ileostomy may be entered at investigator discretion.
16. No prior exposure or known sensitivity to chimerized or murine antibodies, C225 (or other EGFR inhibitors) or any tyrosine kinase inhibitors
17. No significant history of cardiac disease, such as unstable angina, CHF, MI, stroke or a LVEF below the institutional range of normal on a baseline multiple gated acquisition (MUGA) or echocardiogram.
18. Patients must not have an uncontrolled seizure disorder, or active neurological disease.
19. Patients may not have received itraconazole or ketoconazole less than 4 weeks prior to registration.

20. Required Initial Laboratory Values:

    • Granulocytes ≥ 1500/ µl
    • Hemoglobin ≥ 9.0 gram/dL (patient may be transfused to meet this criterion)
    • Platelet count ≥ 100,000/ µl
    • Creatinine ≤ 1.5 x Upper limits of normal (ULN)
    • Bilirubin ≤ 1.5 mg/dL
    • AST ≤ 5.0 x ULN
    • Albumin ≥ 2.5 gram/dL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A: FOLFIRI; Patients receive irinotecan 180 mg/m^2 over 90 minutes on day 1, then leucovorin 400 mg/m^2 over 2 hours followed by 5FU 400 mg/m^2 IV bolus injection then 5FU 2400 mg/m^2 continuous IV infusion over 46-48 hours repeated every 2 weeks. One cycle of therapy is 8 weeks.	Drug: 5-FU; IV; Other Names: 5-fluorouracil; Drug: irinotecan; IV; Other Names: CPT-11; Drug: leucovorin; IV; Other Names: calcium folinate
Experimental: Arm B: FOLFIRI + C225; Patients receive irinotecan 180 mg/m^2 over 90 minutes, then leucovorin 400 mg/m^2 IV over 2 hours followed by 5FU 400 mg/m^2 IV bolus injection then 5FU 2400 mg/m^2 continuous IV infusion over 46-48 hours repeated every 2 weeks. Patients also receive cetuximab 400 mg/m^2 IV over 120 minutes day 1, then 250 mg/m^2 IV over 60 minutes weekly. All patients must be premedicated with diphenhydramine hydrochloride 50 mg (or a similar agent) IV prior to the first dose of cetuximab in an effort to prevent a hypersensitivity reaction. Premedication is recommended prior to subsequent doses, but at the Investigator's discretion the dose of diphenhydramine (or a similar agent) may be reduced.	Drug: 5-FU; IV; Other Names: 5-fluorouracil; Drug: irinotecan; IV; Other Names: CPT-11; Drug: leucovorin; IV; Other Names: calcium folinate; Drug: cetuximab; IV; Other Names: C225
Active Comparator: Arm C: FOLFOX; Patients receive oxaliplatin 85 mg/m^2 IV infused over 120 minutes, then leucovorin 400 mg/m^2 IV over 2 hours followed by 5 FU 400 mg/m^2 IV bolus injection then 5 FU 2400 mg/m^2 continuous IV infusion over 46-48 hours every 2 weeks.	Drug: 5-FU; IV; Other Names: 5-fluorouracil; Drug: leucovorin; IV; Other Names: calcium folinate; Drug: oxaliplatin; IV; Other Names: Eloxatin
Experimental: Arm D: FOLFOX + C225; Patients receive oxaliplatin 85 mg/m^2 IV infused over 120 minutes, then leucovorin 400 mg/m^2 over 2 hours followed by 5 FU 400 mg/m^2 IV bolus injection then 5 FU 2400 mg/m^2 continuous IV infusion over 46-48 hours every 2 weeks. Patients also receive cetuximab 400 mg/m^2 IV over 120 minutes day 1, then 250 mg/m^2 IV over 60 minutes weekly. All patients must be premedicated with diphenhydramine hydrochloride 50 mg (or a similar agent) IV prior to the first dose of cetuximab in an effort to prevent a hypersensitivity reaction. Premedication is recommended prior to subsequent doses, but at the Investigator's discretion the dose of diphenhydramine (or a similar agent) may be reduced.	Drug: 5-FU; IV; Other Names: 5-fluorouracil; Drug: leucovorin; IV; Other Names: calcium folinate; Drug: cetuximab; IV; Other Names: C225; Drug: oxaliplatin; IV; Other Names: Eloxatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall survival	Up to 3 years of follow up

Secondary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival	Up to 18 months of follow up
Complete response	Up to 18 months of follow up
Partial response	Up to 18 months of follow up
Proportion of patients experiencing ≥ Grade 3 diarrhea	Up to 30 days post-treatment
Proportion of patients experiencing ≥ Grade 3 ANC	Up to 30 days post-treatment
Percent of total dose administered	Up to 30 days post-treatment
Proportion of patients experiencing ≥ Grade 4 toxicity on each cetuximab treatment arm	Up to 30 days post-treatment

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: Bristol-Myers Squibb; National Cancer Institute (NCI); Eli Lilly and Company

Publications and helpful links

General Publications

• Meyerhardt JA, Jackson McCleary N, Niedzwiecki D, et al.: Impact of age and comorbidities on treatment effect, tolerance, and toxicity in metastatic colorectal cancer (mCRC) patients treated on CALGB 80203. [Abstract] J Clin Oncol 27 ( Suppl 15): A-4038, 2009.
• Venook A, Niedzwiecki D, Hollis D, et al.: Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) ± cetuximab for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results. [Abstract] J Clin Oncol 24 (Suppl 18): A-3509, 2006.

Study record dates

Study Major Dates

• Study Start: December 1, 2003
• Primary Completion (Actual): December 1, 2006
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: February 10, 2004
• First Submitted That Met QC Criteria: February 10, 2004
• First Posted (Estimate): February 11, 2004

Study Record Updates

• Last Update Posted (Actual): May 16, 2018
• Last Update Submitted That Met QC Criteria: May 11, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; stage IV colon cancer; adenocarcinoma of the colon; recurrent colon cancer; recurrent rectal cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Irinotecan; Cetuximab
• Other Study ID Numbers: CALGB 80203; U10CA031946 (U.S. NIH Grant/Contract); CDR0000350016 (Other Identifier: Physician Data Query)