• Response (complete response and partial response) [ Designated as safety issue: No ]
• Progression-free survival [ Designated as safety issue: No ]
• Time to treatment failure [ Designated as safety issue: No ]
• Duration of tumor response [ Designated as safety issue: No ]

• Comparison of response (complete response and partial response)
• Comparison of progression-free survival
• Comparison of time to treatment failure
• Comparison of duration of tumor response
• Treatment-related toxicity (grade 3 or greater diarrhea or neutropenia)
• Comparison of 60-day survival

RATIONALE: Monoclonal antibodies, such as cetuximab and bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as fluorouracil, leucovorin, oxaliplatin, and irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving monoclonal antibodies together with combination chemotherapy may kill more tumor cells. It is not yet known whether combination chemotherapy is more effective with cetuximab and/or bevacizumab in treating patients with colorectal cancer.

PURPOSE: This randomized phase III trial is studying cetuximab and/or bevacizumab when given together with combination chemotherapy to compare how well they work in treating patients with metastatic colorectal cancer.

OBJECTIVES:

Primary

• Compare overall survival of patients with previously untreated metastatic colorectal cancer treated with cetuximab and/or bevacizumab in combination with either oxaliplatin, fluorouracil, and leucovorin calcium (FOLFOX) OR irinotecan hydrochloride, fluorouracil, and leucovorin calcium (FOLFIRI). (Arm III [cetuximab and bevacizumab in combination with FOLFOX or FOLFIRI] closed to accrual as of 09/10/2009)

Secondary

• Compare response, progression-free survival, time to treatment failure, and duration of response in patients with unresectable disease treated with these regimens.
• Compare toxicity and 60-day survival of patients with unresectable disease treated with these regimens.
• Determine whether patients with unresectable disease become eligible for surgical resection after treatment with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to physician-selected chemotherapy (oxaliplatin, leucovorin calcium, and fluorouracil [FOLFOX] vs irinotecan hydrochloride, leucovorin calcium, or fluorouracil [FOLFIRI]), prior adjuvant chemotherapy (yes vs no), and prior pelvic radiotherapy (yes vs no). Patients are randomized to 1 of 3 treatment arms. (Arm III closed to accrual as of 09/10/2009)

• Arm I: Patients receive oxaliplatin IV over 2 hours or irinotecan hydrochloride IV over 30-90 minutes; leucovorin calcium IV over 2 hours; fluorouracil IV continuously over 46-48 hours; and bevacizumab IV over 30-90 minutes on days 1, 15, 29, and 43.
• Arm II: Patients receive oxaliplatin or irinotecan hydrochloride, leucovorin calcium, and fluorouracil as in arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50.
• Arm III (closed to accrual as of 09/10/2009): Patients receive oxaliplatin or irinotecan hydrochloride, leucovorin calcium, fluorouracil, and bevacizumab as in arm I. Patients also receive cetuximab as in arm II.

In all arms, treatment repeats every 56 days for at least 2 courses in the absence of disease progression, unacceptable toxicity, or planned surgery with curative intent.

For patients whom elective surgery is contemplated, bevacizumab must be discontinued for at least 8 weeks before surgery and may not be resumed for at least 4 weeks after surgery. Patients who undergo complete resection of metastatic disease are removed from study.

After completion of study treatment, patients are followed up every 2 months for 5 years and then every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 2,900 patients will be accrued for this study.

• Biological: bevacizumab
  Given IV
• Biological: cetuximab
  Given IV
• Drug: fluorouracil
  Given IV
• Drug: irinotecan hydrochloride
  Given IV
• Drug: leucovorin calcium
  Given IV
• Drug: oxaliplatin
  Given IV

• Active Comparator: Arm I
  Patients receive oxaliplatin IV over 2 hours or irinotecan hydrochloride IV over 30-90 minutes; leucovorin calcium IV over 2 hours; fluorouracil IV continuously over 46-48 hours; and bevacizumab IV over 30-90 minutes on days 1, 15, 29, and 43.
  Interventions:

  • Biological: bevacizumab
  • Drug: fluorouracil
  • Drug: irinotecan hydrochloride
  • Drug: leucovorin calcium
  • Drug: oxaliplatin
• Experimental: Arm II
  Patients receive oxaliplatin or irinotecan hydrochloride, leucovorin calcium, and fluorouracil as in arm I. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, 36, 43, and 50
  Interventions:

  • Biological: cetuximab
  • Drug: fluorouracil
  • Drug: irinotecan hydrochloride
  • Drug: leucovorin calcium
  • Drug: oxaliplatin
• Experimental: Arm III (closed to accrual as of 09/10/2009)
  Patients receive oxaliplatin or irinotecan hydrochloride, leucovorin calcium, fluorouracil, and bevacizumab as in arm I. Patients also receive cetuximab as in arm II.
  Interventions:

  • Biological: bevacizumab
  • Biological: cetuximab
  • Drug: fluorouracil
  • Drug: irinotecan hydrochloride
  • Drug: leucovorin calcium
  • Drug: oxaliplatin

• Venook AP, Blanke CD, Niedzwiecki D, Lenz HJ, Taylor JR, Hollis DR, Sutherland S, Goldberg RM. Revisiting the Cancer and Leukemia Group B/Southwest Oncology Group 80405 Trial: A Phase III Trial of Chemotherapy and Biologic Agents for Patients with Untreated Advanced Colorectal Adenocarcinoma. Clin Colorectal Cancer. 2007 May;7(1):536-8. No abstract available.
• Venook AP, Blanke CD, Niedzwiecki D, Lenz HJ, Taylor JR, Hollis DR, Sutherland S, Goldberg RM. Cancer and Leukemia Group B/Southwest Oncology Group trial 80405: a phase III trial of chemotherapy and biologics for patients with untreated advanced colorectal adenocarcinoma. Clin Colorectal Cancer. 2005 Nov;5(4):292-4. No abstract available.
• Schrag D, Naughton M, Kesselheim A, et al.: Clinical trial participants' strategies for coping with prescription drug costs: A companion study to CALGB 80405. [Abstract] J Clin Oncol 27 (Suppl 15): A-9503, 2009.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed adenocarcinoma of the colon or rectum

  • Locally advanced (unresectable) or metastatic disease

    • Patients with resected primary tumors who have documented metastases are eligible

    • Separate histological or cytological confirmation is not required from patients with a history of colorectal cancer (previously treated by surgical resection) who have now developed radiological or clinical evidence of metastatic disease, unless 1 of the following is true:

      • An interval of > 5 years has elapsed between the primary surgery and the development of metastatic disease
      • The primary cancer was stage I

• Patient must have a wildtype K-ras gene determined by the SWOG Solid Tumor Repository laboratory or by local CLIA-certified laboratory

  • Patients with a mutation in the K-ras gene not allowed

• The intent of this treatment must be indicated as follows:

  • Palliative or neoadjuvant treatment with the potential for resection of all sites of metastatic disease
• At least 1 paraffin block of previously resected primary tumor or tumor deposit available
• Patients must have a wildtype K-ras gene
• No known CNS metastases or carcinomatous meningitis

PATIENT CHARACTERISTICS:

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Hemoglobin ≥ 9.0 g/dL (transfusion allowed)
• No history of significant bleeding episodes (e.g., hemoptysis or upper or lower gastrointestinal bleeding) within the past 6 months unless the source of bleeding has been resected

Hepatic

• Bilirubin ≤ 1.5 mg/dL
• Albumin ≥ 2.5 g/dL

• No evidence of Gilbert's syndrome for patients assigned to receive FOLFIRI chemotherapy

  • Gilbert's syndrome allowed for patients assigned to receive FOLFOX chemotherapy

Renal

• Creatinine ≤ 1.5 times upper limit of normal

• Protein < 1+ by urinalysis

  • Protein < 1 g by 24-hour urine collection for patients with protein ≥ 2+ by urinalysis

Cardiovascular

• No arterial thromboembolic events within the past 6 months, including any of the following:

  • Myocardial infarction
  • Transient ischemic attack
  • Cerebrovascular accident
  • Unstable angina or angina requiring surgical or medical intervention
• No uncontrolled hypertension (i.e., blood pressure ≥ 160/90 on a regimen of antihypertensive therapy)
• No New York Heart Association class II-IV congestive heart failure
• No clinically significant peripheral artery disease (i.e., claudication on less than 1 block)

Pulmonary

• No interstitial pneumonia
• No extensive or symptomatic interstitial fibrosis of the lung
• No pleural effusion or ascites that causes ≥ grade 2 dyspnea

Gastrointestinal

• No gastrointestinal perforation within past year

• No uncontrolled, predisposing colonic or small bowel disorder (i.e., > 3 watery or soft stools daily for patients without a colostomy or ileostomy)

  • Patients with a colostomy or ileostomy are eligible at the discretion of the investigator

Neurologic

• No sensory peripheral neuropathy ≥ grade 2 for patients assigned to receive FOLFOX chemotherapy
• No uncontrolled seizure disorder
• No active neurological disease

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 2-6 months after completion of study treatment
• No serious nonhealing wound, ulcer, or bone fracture
• No known hypersensitivity to Chinese hamster ovary cell products or recombinant human or murine antibodies
• 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

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior agents that target vascular endothelial growth factor (VEGF) or EGF receptors including protein products, monoclonal antibodies, or antisense therapies
• No prior bevacizumab or cetuximab
• No concurrent prophylactic filgrastim (G-CSF), pegfilgrastim, or sargramostim (GM-CSF)

Chemotherapy

• See Radiotherapy
• More than 12 months since prior adjuvant chemotherapy (≤ 6 months in duration) that included fluorouracil alone or in combination with oxaliplatin or irinotecan hydrochloride
• No prior regional chemotherapy (e.g., hepatic arterial infusion)
• No other concurrent chemotherapy

Endocrine therapy

• No concurrent hormonal therapy except steroids for adrenal failure, hormones for noncancer-related conditions (e.g., insulin for diabetes), or intermittent dexamethasone as an antiemetic

Radiotherapy

• Prior radiotherapy with radiosensitizing chemotherapy allowed
• Prior standard adjuvant chemoradiotherapy for rectal cancer allowed
• At least 4 weeks since prior radiotherapy
• No prior radiotherapy to > 25% of bone marrow
• No concurrent palliative radiotherapy except whole brain irradiation for documented CNS disease

Surgery

• See Disease Characteristics
• At least 4 weeks since prior major surgery

• At least 2 weeks since prior minor surgery

  • Insertion of a vascular access device is not considered a prior surgery
• Recovered from all prior surgery

Other

• At least 4 weeks since prior itraconazole or ketoconazole
• No prior tyrosine kinase inhibitor therapy
• No prior systemic treatment for advanced or metastatic colorectal cancer
• No concurrent aprepitant

• Concurrent full-dose anticoagulation (i.e., warfarin) allowed provided all of the following criteria are met:

  • In-range INR (usually 2-3) on a stable dose of oral anticoagulant or stable dose of low molecular weight heparin
  • No active bleeding
  • No pathological condition with a high risk of bleeding (e.g., tumor involving major vessels or known varices)
• Concurrent antiplatelet agents allowed
• Concurrent daily prophylactic aspirin or anticoagulation for atrial fibrillation allowed

• National Cancer Institute (NCI)
• Southwest Oncology Group