Clinical trial NCT00077233: FOLFIRI or FOLFOX With or Without Cetuximab in Patients With Metastatic Adenocarcinoma of the Colon or Rectum
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: adenocarcinoma of the colon
adenocarcinoma of the rectum
recurrent colon cancer
recurrent rectal cancer
stage IV colon cancer
stage IV rectal cancer
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
name: Bristol-Myers Squibb
name: Eli Lilly and Company
First posted: 2004-02-11
Enrollment: 238
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall survival
timeFrame: Up to 3 years of follow up
Secondary outcomes:
measure: Progression-free survival
timeFrame: Up to 18 months of follow up
measure: Complete response
timeFrame: Up to 18 months of follow up
measure: Partial response
timeFrame: Up to 18 months of follow up
measure: Proportion of patients experiencing ≥ Grade 3 diarrhea
timeFrame: Up to 30 days post-treatment
measure: Proportion of patients experiencing ≥ Grade 3 ANC
timeFrame: Up to 30 days post-treatment
measure: Percent of total dose administered
timeFrame: Up to 30 days post-treatment
measure: Proportion of patients experiencing ≥ Grade 4 toxicity on each cetuximab treatment arm
timeFrame: Up to 30 days post-treatment
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Northeast Alabama Regional Medical Center
state: Alabama
city: La Jolla
country: United States
facility: Rebecca and John Moores UCSD Cancer Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Comprehensive Cancer Center at Cedars-Sinai Medical Center
state: California
city: San Diego
country: United States
facility: Naval Medical Center - San Diego
state: California
city: San Diego
country: United States
facility: Veterans Affairs Medical Center - San Diego
state: California
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: Veterans Affairs Medical Center - San Francisco
state: California
city: Newark
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Washington
country: United States
facility: Lombardi Cancer Center at Georgetown University Medical Center
state: District of Columbia
city: Washington
country: United States
facility: Walter Reed Army Medical Center
state: District of Columbia
city: Washington
country: United States
facility: Veterans Affairs Medical Center - Washington, DC
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Broward General Medical Center
state: Florida
city: Hollywood
country: United States
facility: Memorial Regional Cancer Center at Memorial Regional Hospital
state: Florida
city: Miami Beach
country: United States
facility: CCOP - Mount Sinai Medical Center
state: Florida
city: Orlando
country: United States
facility: Florida Hospital Cancer Institute
state: Florida
city: West Palm Beach
country: United States
facility: Palm Beach Cancer Institute
state: Florida
city: Chicago
country: United States
facility: MBCCOP - University of Illinois at Chicago
state: Illinois
city: Chicago
country: United States
facility: Veterans Affairs Medical Center - Chicago (Westside Hospital)
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Chicago
country: United States
facility: Louis A. Weiss Memorial Hospital
state: Illinois
city: Evanston
country: United States
facility: CCOP - Evanston
state: Illinois
city: Peoria
country: United States
facility: CCOP - Illinois Oncology Research Association
state: Illinois
city: River Forest
country: United States
facility: West Suburban Center for Cancer Care
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology, Incorporated
state: Indiana
city: South Bend
country: United States
facility: CCOP - Northern Indiana CR Consortium
state: Indiana
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center at University of Iowa
state: Iowa
city: Louisville
country: United States
facility: Baptist Hospital East - Louisville
state: Kentucky
city: Baltimore
country: United States
facility: Greenebaum Cancer Center at University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: UMASS Memorial Cancer Center - University Campus
state: Massachusetts
city: Saint Joseph
country: United States
facility: Lakeland Cancer Care Center at Lakeland Hospital - St. Joseph
state: Michigan
city: Minneapolis
country: United States
facility: Veterans Affairs Medical Center - Minneapolis
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center
state: Minnesota
city: Columbia
country: United States
facility: Veterans Affairs Medical Center - Columbia (Truman Memorial)
state: Missouri
city: Columbia
country: United States
facility: Ellis Fischel Cancer Center at University of Missouri - Columbia
state: Missouri
city: Kansas City
country: United States
facility: CCOP - Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Barnes-Jewish Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Cancer Center
state: Missouri
city: Omaha
country: United States
facility: UNMC Eppley Cancer Center at the University of Nebraska Medical Center
state: Nebraska
city: Las Vegas
country: United States
facility: CCOP - Southern Nevada Cancer Research Foundation
state: Nevada
city: Las Vegas
country: United States
facility: Veterans Affairs Medical Center - Las Vegas
state: Nevada
city: Hooksett
country: United States
facility: New Hampshire Oncology-Hematology, PA - Hooksett
state: New Hampshire
city: Lebanon
country: United States
facility: Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: Buffalo
country: United States
facility: Veterans Affairs Medical Center - Buffalo
state: New York
city: East Syracuse
country: United States
facility: CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.
state: New York
city: Jamaica
country: United States
facility: Queens Cancer Center of Queens Hospital
state: New York
city: Manhasset
country: United States
facility: CCOP - North Shore University Hospital
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: New York Weill Cornell Cancer Center at Cornell University
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Syracuse
country: United States
facility: Veterans Affairs Medical Center - Syracuse
state: New York
city: Asheville
country: United States
facility: Veterans Affairs Medical Center - Asheville
state: North Carolina
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Concord
country: United States
facility: NorthEast Oncology Associates - Concord
state: North Carolina
city: Durham
country: United States
facility: Veterans Affairs Medical Center - Durham
state: North Carolina
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Fayetteville
country: United States
facility: Cape Fear Valley Health System
state: North Carolina
city: Goldsboro
country: United States
facility: CCOP - Southeast Cancer Control Consortium
state: North Carolina
city: Pinehurst
country: United States
facility: FirstHealth Moore Regional Hospital
state: North Carolina
city: Wilmington
country: United States
facility: Zimmer Cancer Center at New Hanover Regional Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Comprehensive Cancer Center at Wake Forest University
state: North Carolina
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital at Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Medical Center
state: Oklahoma
city: Pittsburgh
country: United States
facility: Western Pennsylvania Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Lifespan: The Miriam Hospital
state: Rhode Island
city: Dallas
country: United States
facility: Veterans Affairs Medical Center - Dallas
state: Texas
city: Dallas
country: United States
facility: Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas
state: Texas
city: Burlington
country: United States
facility: Vermont Cancer Center at University of Vermont
state: Vermont
city: Charlottesville
country: United States
facility: Martha Jefferson Hospital
state: Virginia
city: Norfolk
country: United States
facility: Virginia Oncology Associates - Norfolk
state: Virginia
city: Richmond
country: United States
facility: MBCCOP - Massey Cancer Center
state: Virginia
city: Roanoke
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia, Incorporated - Roanoke
state: Virginia
city: Huntington
country: United States
facility: St. Mary's Medical Center
state: West Virginia
Study officials:
affiliation: University of California, San Francisco
name: Alan Venook, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.