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

Sponsor

Alliance for Clinical Trials in Oncology (Other)

Overall Status

Terminated

CT.gov ID

NCT00077233

Collaborator

National Cancer Institute (NCI) (NIH), Bristol-Myers Squibb (Industry), Eli Lilly and Company (Industry)

238

Enrollment

Locations

Arms

Duration (Months)

3.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: cetuximab Drug: 5-FU Drug: irinotecan Drug: leucovorin Drug: oxaliplatin	Phase 3

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

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

Secondary

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

Patients were followed up to 3 years post-treatment.

Study Design

Study Type:

Interventional

Actual Enrollment :

238 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Dec 1, 2003

Actual Primary Completion Date :

Dec 1, 2006

Actual Study Completion Date :

Jun 1, 2010

Arms and Interventions

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: cetuximab IV Other Names: C225 Drug: 5-FU IV Other Names: 5-fluorouracil Drug: irinotecan IV Other Names: CPT-11 Drug: leucovorin IV Other Names: calcium folinate
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: cetuximab IV Other Names: C225 Drug: 5-FU IV Other Names: 5-fluorouracil Drug: leucovorin IV Other Names: calcium folinate Drug: oxaliplatin IV Other Names: Eloxatin

Outcome Measures

Primary Outcome Measures

Overall survival [Up to 3 years of follow up]

Secondary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

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.

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.

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.
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.
Age ≥ 18 years
CTC (ECOG) performance status of 0-1.
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.
Patients must have at least one paraffin block available or appropriate number of unstained slides for analysis of EGFR status.
No symptomatic sensory peripheral neuropathy of ≥ grade II at baseline.
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.

No known central nervous system metastases or carcinomatous meningitis.
No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung.
No pleural effusion or ascites that causes ≥ grade 2 dyspnea.
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.
No prior exposure or known sensitivity to chimerized or murine antibodies, C225 (or other EGFR inhibitors) or any tyrosine kinase inhibitors
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.
Patients must not have an uncontrolled seizure disorder, or active neurological disease.
Patients may not have received itraconazole or ketoconazole less than 4 weeks prior to registration.
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northeast Alabama Regional Medical Center	Anniston	Alabama	United States	36207
2	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
3	Cedars-Sinai Comprehensive Cancer Center at Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
4	Naval Medical Center - San Diego	San Diego	California	United States	92134-3202
5	Veterans Affairs Medical Center - San Diego	San Diego	California	United States	92161
6	UCSF Comprehensive Cancer Center	San Francisco	California	United States	94115
7	Veterans Affairs Medical Center - San Francisco	San Francisco	California	United States	94121
8	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
9	Lombardi Cancer Center at Georgetown University Medical Center	Washington	District of Columbia	United States	20007
10	Walter Reed Army Medical Center	Washington	District of Columbia	United States	20307-5001
11	Veterans Affairs Medical Center - Washington, DC	Washington	District of Columbia	United States	20422
12	Broward General Medical Center	Fort Lauderdale	Florida	United States	33316
13	Memorial Regional Cancer Center at Memorial Regional Hospital	Hollywood	Florida	United States	33021
14	CCOP - Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
15	Florida Hospital Cancer Institute	Orlando	Florida	United States	32804
16	Palm Beach Cancer Institute	West Palm Beach	Florida	United States	33401
17	MBCCOP - University of Illinois at Chicago	Chicago	Illinois	United States	60612
18	Veterans Affairs Medical Center - Chicago (Westside Hospital)	Chicago	Illinois	United States	60612
19	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
20	Louis A. Weiss Memorial Hospital	Chicago	Illinois	United States	60640
21	CCOP - Evanston	Evanston	Illinois	United States	60201
22	CCOP - Illinois Oncology Research Association	Peoria	Illinois	United States	61615-7828
23	West Suburban Center for Cancer Care	River Forest	Illinois	United States	60305
24	Fort Wayne Medical Oncology and Hematology, Incorporated	Fort Wayne	Indiana	United States	46885-5099
25	CCOP - Northern Indiana CR Consortium	South Bend	Indiana	United States	46601
26	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa	United States	52242-1009
27	Baptist Hospital East - Louisville	Louisville	Kentucky	United States	40207
28	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
29	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
30	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
31	UMASS Memorial Cancer Center - University Campus	Worcester	Massachusetts	United States	01655
32	Lakeland Cancer Care Center at Lakeland Hospital - St. Joseph	Saint Joseph	Michigan	United States	49085
33	Veterans Affairs Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55417
34	University of Minnesota Cancer Center	Minneapolis	Minnesota	United States	55455
35	Veterans Affairs Medical Center - Columbia (Truman Memorial)	Columbia	Missouri	United States	65201
36	Ellis Fischel Cancer Center at University of Missouri - Columbia	Columbia	Missouri	United States	65203
37	CCOP - Kansas City	Kansas City	Missouri	United States	64131
38	Siteman Cancer Center at Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
39	Missouri Baptist Cancer Center	Saint Louis	Missouri	United States	63131
40	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-7680
41	CCOP - Southern Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
42	Veterans Affairs Medical Center - Las Vegas	Las Vegas	Nevada	United States	89106
43	New Hampshire Oncology-Hematology, PA - Hooksett	Hooksett	New Hampshire	United States	03106
44	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
45	Cooper University Hospital	Camden	New Jersey	United States	08103
46	Veterans Affairs Medical Center - Buffalo	Buffalo	New York	United States	14215
47	CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.	East Syracuse	New York	United States	13057
48	Queens Cancer Center of Queens Hospital	Jamaica	New York	United States	11432
49	CCOP - North Shore University Hospital	Manhasset	New York	United States	11030
50	North Shore University Hospital	Manhasset	New York	United States	11030
51	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
52	New York Weill Cornell Cancer Center at Cornell University	New York	New York	United States	10021
53	Mount Sinai Medical Center	New York	New York	United States	10029
54	SUNY Upstate Medical University Hospital	Syracuse	New York	United States	13210
55	Veterans Affairs Medical Center - Syracuse	Syracuse	New York	United States	13210
56	Veterans Affairs Medical Center - Asheville	Asheville	North Carolina	United States	28805
57	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
58	NorthEast Oncology Associates - Concord	Concord	North Carolina	United States	28025
59	Veterans Affairs Medical Center - Durham	Durham	North Carolina	United States	27705
60	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
61	Cape Fear Valley Health System	Fayetteville	North Carolina	United States	28302-2000
62	CCOP - Southeast Cancer Control Consortium	Goldsboro	North Carolina	United States	27534-9479
63	FirstHealth Moore Regional Hospital	Pinehurst	North Carolina	United States	28374
64	Zimmer Cancer Center at New Hanover Regional Medical Center	Wilmington	North Carolina	United States	28402-9025
65	Comprehensive Cancer Center at Wake Forest University	Winston-Salem	North Carolina	United States	27157-1082
66	Arthur G. James Cancer Hospital at Ohio State University	Columbus	Ohio	United States	43210-1240
67	Oklahoma University Medical Center	Oklahoma City	Oklahoma	United States	73104
68	Western Pennsylvania Hospital	Pittsburgh	Pennsylvania	United States	15224
69	Lifespan: The Miriam Hospital	Providence	Rhode Island	United States	02906
70	Veterans Affairs Medical Center - Dallas	Dallas	Texas	United States	75219
71	Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390-8852
72	Vermont Cancer Center at University of Vermont	Burlington	Vermont	United States	05401-3498
73	Martha Jefferson Hospital	Charlottesville	Virginia	United States	22902
74	Virginia Oncology Associates - Norfolk	Norfolk	Virginia	United States	23502
75	MBCCOP - Massey Cancer Center	Richmond	Virginia	United States	23298-0037
76	Oncology and Hematology Associates of Southwest Virginia, Incorporated - Roanoke	Roanoke	Virginia	United States	24014
77	St. Mary's Medical Center	Huntington	West Virginia	United States	25701