Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Fluorouracil and Leucovorin Plus Either Irinotecan or Oxaliplatin With or Without Cetuximab in Treating Patients With Previously Untreated Metastatic Adenocarcinoma of the Colon or Rectum

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Closed	18 and over	NCI	CALGB-80203 NCT00077233

Special Category: CTSU trial

Objectives

Primary

1. Compare the survival rate of patients with previously untreated metastatic adenocarcinoma of the colon or rectum treated with fluorouracil and leucovorin calcium with oxaliplatin or irinotecan and with or without cetuximab.

Secondary

1. Determine the level of epidermal growth factor receptor (EGFR) expression in patients treated with these regimens.
2. Determine whether expression of EGFR activity, markers of EGFR activity, and serum levels of insulin-like growth factor-1, C-peptide, and insulin-like growth factor binding protein 3 are independent predictors of response rate, time to tumor progression, and survival of patients treated with these regimens.
3. Correlate specific germline polymorphisms related to chemotherapy metabolism and resistance with treatment-related toxicity, tumor response, time to tumor progression, and survival of patients treated with these regimens.
4. Correlate expression of putative prognostic markers in the tumor with tumor response, time to tumor progression, and survival of patients treated with these regimens.
5. Correlate diet, obesity, physical activity, and other lifestyle habits with treatment-related toxicity, progression-free survival, and overall survival of patients treated with these regimens.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed metastatic colorectal adenocarcinoma
  • Primary site of disease in the large bowel as determined endoscopically, surgically, or radiologically
  • Histologic or cytologic confirmation is not required for recurrent metastatic disease in patients with prior colorectal cancer treated with surgery unless either of the following criteria are met:
    • More than 5 years have elapsed between the prior primary surgery and the development of metastatic disease
    • Primary cancer was stage I



• Tumor tissue available for epidermal growth factor receptor (EGFR) status analysis



• No pleural effusion or ascites that causes grade 2 or greater dyspnea



• No known CNS metastases or carcinomatous meningitis

Prior/Concurrent Therapy:

Biologic therapy

• No prior biologic therapy for metastatic colorectal cancer
• No prior chimerized or murine antibodies
• No prior cetuximab
• No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)

Chemotherapy

• See Radiotherapy
• More than 12 months since prior chemotherapy
• No prior chemotherapy for metastatic colorectal cancer
• No prior irinotecan or oxaliplatin in the adjuvant or metastatic setting
• No more than 6 months or 4 courses of prior adjuvant chemotherapy
• No other concurrent chemotherapy

Endocrine therapy

• No prior endocrine therapy for metastatic colorectal cancer
• No concurrent hormonal therapy except the following:
  • Steroids for adrenal failure
  • Hormones administered for non-disease-related conditions (e.g., insulin for diabetes)
  • Intermittent use of dexamethasone as an antiemetic

Radiotherapy

• More than 4 weeks since prior radiotherapy
• No prior radiotherapy for metastatic colorectal cancer
• No prior radiotherapy to more than 25% of bone marrow
• Prior standard adjuvant chemoradiotherapy for rectal cancer allowed
• Prior adjuvant radiotherapy with radiosensitizing chemotherapy allowed
• No concurrent palliative radiotherapy except whole brain radiotherapy for documented CNS disease

Surgery

• See Disease Characteristics
• More than 4 weeks since prior major surgery*
• More than 2 weeks since prior minor surgery* and recovered
• No prior surgery for metastatic colorectal cancer

 [Note: *Insertion of a vascular device is not considered major or minor surgery]

Other

• At least 4 weeks since prior itraconazole or ketoconazole
• No other prior treatment for metastatic colorectal cancer
• No prior EGFR inhibitors
• No prior tyrosine kinase inhibitors
• No other concurrent investigational agents
• No concurrent agents to minimize neurotoxicity of oxaliplatin (e.g., carbamazepine, magnesium, or calcium)

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Granulocyte count ≥ 1,500/mm³
• Hemoglobin ≥ 9.0 g/dL (transfusion allowed)
• Platelet count ≥ 100,000/mm³

Hepatic

• Bilirubin ≤ 1.5 mg/dL
• AST ≤ 5.0 times upper limit of normal (ULN)
• Albumin ≥ 2.5 g/dL
• No evidence of Gilbert's syndrome

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• No unstable angina
• No congestive heart failure
• No prior myocardial infarction
• No prior stroke
• No other significant cardiac disease
• LVEF ≥ normal by echocardiogram or MUGA

Pulmonary

• No interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung

Neurologic

• No uncontrolled seizure disorder
• No Temporarily closed neurological disease
• No symptomatic sensory peripheral neuropathy grade 2 or greater

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No predisposing uncontrolled colonic or small bowel disorder as evidenced by > 3 watery or soft stools daily at baseline*
• No known sensitivity to chimerized or murine antibodies, cetuximab or other EGFR inhibitors, or tyrosine kinase inhibitors
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

 [Note: *In patients without a colostomy or ileostomy; patients with a colostomy or ileostomy are eligible at the discretion of the investigator]

Expected Enrollment

Approximately 2,200 patients (550 per treatment arm) will be accrued for this study within 4.6 years.

Outline

This is a randomized, open-label, multicenter study. Patients are stratified according to prior adjuvant therapy (yes vs no) and prior pelvic radiotherapy (yes vs no). Patients are randomized to 1 of 4 treatment arms.

• Arm I (FOLFIRI): Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours on days 1, 15, 29, and 43 and fluorouracil IV continuously over 46-48 hours beginning on days 1, 15, 29, and 43.



• Arm II (FOLFIRI and cetuximab): Patients receive FOLFIRI as in arm I and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50.



• Arm III (FOLFOX): Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on days 1, 15, 29, and 43 and fluorouracil IV continuously over 46-48 hours beginning on days 1, 15, 29, and 43.



• Arm IV (FOLFOX and cetuximab): Patients receive FOLFOX as in arm III and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50.

In all arms, courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

Patients are followed every 2 months for 2 years and then every 3 months for 3 years.

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.

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Alan Venook, MD, Protocol chair		Ph: 415-353-7065; 800-888-8664 Email: venook@cc.ucsf.edu
Charles Fuchs, MD, Protocol co-chair		Ph: 617-632-5840; 866-790-4500

Registry Information
Official Title		A Phase III 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
Trial Start Date		2004-01-08
Registered in ClinicalTrials.gov		NCT00077233
Date Submitted to PDQ		2003-12-16
Information Last Verified		2004-07-22
NCI Grant/Contract Number		CA31946