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

Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00077233
• Other study ID #: CALGB 80203
• Secondary ID: U10CA031946CDR00
• Status: Terminated
• Phase: Phase 3
• Start date: December 2003
• Est. completion date: June 2010

Study information

• Verified date: May 2018
• Source: Alliance for Clinical Trials in Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 238
• Est. completion date: June 2010
• Est. primary completion date: December 2006
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Drug:
• cetuximab
IV
• 5-FU
IV
• irinotecan
IV
• leucovorin
IV
• oxaliplatin
IV

Locations

Country	Name	City	State
United States	Northeast Alabama Regional Medical Center	Anniston	Alabama
United States	Veterans Affairs Medical Center - Asheville	Asheville	North Carolina
United States	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Veterans Affairs Medical Center - Buffalo	Buffalo	New York
United States	Vermont Cancer Center at University of Vermont	Burlington	Vermont
United States	Cooper University Hospital	Camden	New Jersey
United States	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Martha Jefferson Hospital	Charlottesville	Virginia
United States	Louis A. Weiss Memorial Hospital	Chicago	Illinois
United States	MBCCOP - University of Illinois at Chicago	Chicago	Illinois
United States	University of Chicago Cancer Research Center	Chicago	Illinois
United States	Veterans Affairs Medical Center - Chicago (Westside Hospital)	Chicago	Illinois
United States	Ellis Fischel Cancer Center at University of Missouri - Columbia	Columbia	Missouri
United States	Veterans Affairs Medical Center - Columbia (Truman Memorial)	Columbia	Missouri
United States	Arthur G. James Cancer Hospital at Ohio State University	Columbus	Ohio
United States	NorthEast Oncology Associates - Concord	Concord	North Carolina
United States	Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Veterans Affairs Medical Center - Dallas	Dallas	Texas
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Veterans Affairs Medical Center - Durham	Durham	North Carolina
United States	CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.	East Syracuse	New York
United States	CCOP - Evanston	Evanston	Illinois
United States	Cape Fear Valley Health System	Fayetteville	North Carolina
United States	Broward General Medical Center	Fort Lauderdale	Florida
United States	Fort Wayne Medical Oncology and Hematology, Incorporated	Fort Wayne	Indiana
United States	CCOP - Southeast Cancer Control Consortium	Goldsboro	North Carolina
United States	Memorial Regional Cancer Center at Memorial Regional Hospital	Hollywood	Florida
United States	New Hampshire Oncology-Hematology, PA - Hooksett	Hooksett	New Hampshire
United States	St. Mary's Medical Center	Huntington	West Virginia
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	Queens Cancer Center of Queens Hospital	Jamaica	New York
United States	CCOP - Kansas City	Kansas City	Missouri
United States	Rebecca and John Moores UCSD Cancer Center	La Jolla	California
United States	CCOP - Southern Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Veterans Affairs Medical Center - Las Vegas	Las Vegas	Nevada
United States	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Cedars-Sinai Comprehensive Cancer Center at Cedars-Sinai Medical Center	Los Angeles	California
United States	Baptist Hospital East - Louisville	Louisville	Kentucky
United States	CCOP - North Shore University Hospital	Manhasset	New York
United States	North Shore University Hospital	Manhasset	New York
United States	CCOP - Mount Sinai Medical Center	Miami Beach	Florida
United States	University of Minnesota Cancer Center	Minneapolis	Minnesota
United States	Veterans Affairs Medical Center - Minneapolis	Minneapolis	Minnesota
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	New York Weill Cornell Cancer Center at Cornell University	New York	New York
United States	CCOP - Christiana Care Health Services	Newark	Delaware
United States	Virginia Oncology Associates - Norfolk	Norfolk	Virginia
United States	Oklahoma University Medical Center	Oklahoma City	Oklahoma
United States	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska
United States	Florida Hospital Cancer Institute	Orlando	Florida
United States	CCOP - Illinois Oncology Research Association	Peoria	Illinois
United States	FirstHealth Moore Regional Hospital	Pinehurst	North Carolina
United States	Western Pennsylvania Hospital	Pittsburgh	Pennsylvania
United States	Lifespan: The Miriam Hospital	Providence	Rhode Island
United States	MBCCOP - Massey Cancer Center	Richmond	Virginia
United States	West Suburban Center for Cancer Care	River Forest	Illinois
United States	Oncology and Hematology Associates of Southwest Virginia, Incorporated - Roanoke	Roanoke	Virginia
United States	Lakeland Cancer Care Center at Lakeland Hospital - St. Joseph	Saint Joseph	Michigan
United States	Missouri Baptist Cancer Center	Saint Louis	Missouri
United States	Siteman Cancer Center at Barnes-Jewish Hospital	Saint Louis	Missouri
United States	Naval Medical Center - San Diego	San Diego	California
United States	Veterans Affairs Medical Center - San Diego	San Diego	California
United States	UCSF Comprehensive Cancer Center	San Francisco	California
United States	Veterans Affairs Medical Center - San Francisco	San Francisco	California
United States	CCOP - Northern Indiana CR Consortium	South Bend	Indiana
United States	SUNY Upstate Medical University Hospital	Syracuse	New York
United States	Veterans Affairs Medical Center - Syracuse	Syracuse	New York
United States	Lombardi Cancer Center at Georgetown University Medical Center	Washington	District of Columbia
United States	Veterans Affairs Medical Center - Washington, DC	Washington	District of Columbia
United States	Walter Reed Army Medical Center	Washington	District of Columbia
United States	Palm Beach Cancer Institute	West Palm Beach	Florida
United States	Zimmer Cancer Center at New Hanover Regional Medical Center	Wilmington	North Carolina
United States	Comprehensive Cancer Center at Wake Forest University	Winston-Salem	North Carolina
United States	UMASS Memorial Cancer Center - University Campus	Worcester	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Alliance for Clinical Trials in Oncology	Bristol-Myers Squibb, ImClone LLC, National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (2)

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,

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival		Up to 3 years of follow up
Secondary	Progression-free survival		Up to 18 months of follow up
Secondary	Complete response		Up to 18 months of follow up
Secondary	Partial response		Up to 18 months of follow up
Secondary	Proportion of patients experiencing = Grade 3 diarrhea		Up to 30 days post-treatment
Secondary	Proportion of patients experiencing = Grade 3 ANC		Up to 30 days post-treatment
Secondary	Percent of total dose administered		Up to 30 days post-treatment
Secondary	Proportion of patients experiencing = Grade 4 toxicity on each cetuximab treatment arm		Up to 30 days post-treatment