Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

RATIONALE: Drugs used in chemotherapy, such as fluorouracil, leucovorin, irinotecan, and oxaliplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining more than one drug with a monoclonal antibody may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective with or without cetuximab in treating metastatic adenocarcinoma (cancer) of the colon or rectum.

PURPOSE: Randomized phase III trial to compare the effectiveness of combining fluorouracil and leucovorin with either irinotecan or oxaliplatin with or without cetuximab in treating patients who have metastatic cancer of the colon or rectum.

Further Study Information

OBJECTIVES:

Primary

• 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

• Determine the level of epidermal growth factor receptor (EGFR) expression in patients treated with these regimens.

• 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.

• 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.

• Correlate expression of putative prognostic markers in the tumor with tumor response, time to tumor progression, and survival of patients treated with these regimens.

• 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.

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.

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

Eligibility 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

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Granulocyte count ≥ 1,500/mm^3

• Hemoglobin ≥ 9.0 g/dL (transfusion allowed)

• Platelet count ≥ 100,000/mm^3

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

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)

Trial Contact Information

Trial Lead Organizations/Sponsors

Cancer and Leukemia Group B

Alan Paul Venook

Study Chair

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00077233
Information obtained from ClinicalTrials.gov on December 14, 2011

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