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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00077233
Recruitment Status : Terminated (Poor accrual)
First Posted : February 11, 2004
Last Update Posted : May 16, 2018
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Bristol-Myers Squibb
Eli Lilly and Company
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Tracking Information
First Submitted Date  ICMJE February 10, 2004
First Posted Date  ICMJE February 11, 2004
Last Update Posted Date May 16, 2018
Study Start Date  ICMJE December 2003
Actual Primary Completion Date December 2006   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 7, 2014)
Overall survival [ Time Frame: Up to 3 years of follow up ]
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 7, 2014)
  • Progression-free survival [ Time Frame: Up to 18 months of follow up ]
  • Complete response [ Time Frame: Up to 18 months of follow up ]
  • Partial response [ Time Frame: Up to 18 months of follow up ]
  • Proportion of patients experiencing ≥ Grade 3 diarrhea [ Time Frame: Up to 30 days post-treatment ]
  • Proportion of patients experiencing ≥ Grade 3 ANC [ Time Frame: Up to 30 days post-treatment ]
  • Percent of total dose administered [ Time Frame: Up to 30 days post-treatment ]
  • Proportion of patients experiencing ≥ Grade 4 toxicity on each cetuximab treatment arm [ Time Frame: Up to 30 days post-treatment ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE FOLFIRI or FOLFOX With or Without Cetuximab in Patients With Metastatic Adenocarcinoma of the Colon or Rectum
Official Title  ICMJE 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
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Colorectal Cancer
Intervention  ICMJE
  • Drug: cetuximab
    IV
    Other Name: C225
  • Drug: 5-FU
    IV
    Other Name: 5-fluorouracil
  • Drug: irinotecan
    IV
    Other Name: CPT-11
  • Drug: leucovorin
    IV
    Other Name: calcium folinate
  • Drug: oxaliplatin
    IV
    Other Name: Eloxatin
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: 5-FU
    • Drug: irinotecan
    • Drug: leucovorin
  • 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.
    Interventions:
    • Drug: cetuximab
    • Drug: 5-FU
    • Drug: irinotecan
    • Drug: leucovorin
  • 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.
    Interventions:
    • Drug: 5-FU
    • Drug: leucovorin
    • Drug: oxaliplatin
  • 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.
    Interventions:
    • Drug: cetuximab
    • Drug: 5-FU
    • Drug: leucovorin
    • Drug: oxaliplatin
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: April 12, 2011)
238
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date  ICMJE June 2010
Actual Primary Completion Date December 2006   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00077233
Other Study ID Numbers  ICMJE CALGB 80203
U10CA031946 ( U.S. NIH Grant/Contract )
CDR0000350016 ( Other Identifier: Physician Data Query )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alliance for Clinical Trials in Oncology
Study Sponsor  ICMJE Alliance for Clinical Trials in Oncology
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Bristol-Myers Squibb
  • Eli Lilly and Company
Investigators  ICMJE
Study Chair: Alan Venook, MD University of California, San Francisco
PRS Account Alliance for Clinical Trials in Oncology
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP