OBJECTIVES:

Primary

• Determine the maximum tolerated dose of erlotinib in combination with bevacizumab and fluorouracil, leucovorin calcium, and oxaliplatin (FOLFOX-4) in patients with metastatic or locally advanced colorectal cancer.
• Determine the toxicity profile of this regimen in these patients.
• Determine the antitumor activity of this regimen in these patients.

Secondary

• Determine the pharmacokinetics of this regimen in these patients.
• Correlate expression and activation of epidermal growth factor receptor and related signaling pathways with outcome of patients treated with this regimen.
• Determine the biological effects of erlotinib in these patients and its relationship with dose and plasma concentration.
• Determine whether fludeoxyglucose F 18 positron emission tomography scan can predict the biological effects in and outcome of patients treated with this regimen.

OUTLINE: This is a dose-escalation study of erlotinib.

Patients receive oral elotinib alone once daily for 1 week before the beginning of course 1. Patients then receive oral erlotinib once daily on days 1-28; oxaliplatin IV over 2 hours on day 1; and leucovorin calcium IV over 2 hours and fluorouracil IV over 22 hours on days 1 and 2. Patients also receive bevacizumab IV over 30-90 minutes on day 15 of course 1 and on days 1 and 15 of all subsequent courses. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of erlotinib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which no more than 2 of 6 patients experience dose-limiting toxicity.

PROJECTED ACCRUAL: Approximately 38 patients will be accrued for this study within 19-38 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed colorectal adenocarcinoma

  • Metastatic or locally advanced
• Not amenable to curative therapy

• Unidimensionally measurable disease

  • At least 1 lesion at least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan

  • The following are not considered measurable disease:

    • Bone lesions
    • Leptomeningeal disease
    • Ascites
    • Pleural/pericardial effusion
    • Inflammatory breast disease
    • Lymphangitis cutis/pulmonis
    • Abdominal masses that are not confirmed and followed by imaging techniques
    • Cystic lesions
• No known brain metastases

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1 OR
• Karnofsky 60-100%

Life expectancy

• More than 12 weeks

Hematopoietic

• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic

• Bilirubin no greater than 2 mg/dL
• AST and ALT no greater than 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastasis is present)

Renal

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance at least 60 mL/min
• No nephrotic syndrome

Cardiovascular

• No congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No uncontrolled hypertension

• None of the following thromboembolic events within the past 12 months:

  • Myocardial infarction
  • Transient ischemic attack
  • Stroke
  • Angina

Gastrointestinal

• No gastrointestinal disease resulting in an inability to take oral medication
• No requirement for intravenous alimentation
• No active peptic ulcer disease

Ophthalmic

• No abnormalities of the cornea (e.g., dry eye syndrome or Sjögren's syndrome)
• No abnormal slit-lamp examination using a vital dye (e.g., fluorescein or Bengal-Rose)
• No congenital abnormality (e.g., Fuch's dystrophy)
• No abnormal corneal sensitivity test (Schirmer test or similar tear production test)

Other

• Not pregnant
• No nursing during and for at least 3-4 months after study participation
• Negative pregnancy test
• Fertile patients must use effective contraception during and for at least 3-4 months after study participation
• Sufficient central venous access
• No significant traumatic injury within the past 28 days
• No prior allergic reactions attributed to compounds of similar chemical or biological composition to erlotinib, fluorouracil, leucovorin calcium, or oxaliplatin
• No significant neuropathy greater than grade 2
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No other concurrent uncontrolled illness that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Prior bevacizumab allowed

Chemotherapy

• At least 28 days since prior chemotherapy for metastatic disease
• At least 120 days since prior adjuvant chemotherapy, including adjuvant therapy with oxaliplatin
• No prior oxaliplatin for metastatic disease

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• More than 28 days since prior major surgery and recovered
• No prior surgical procedures affecting absorption

Other

• No prior epidermal growth factor receptor-targeting therapy
• No concurrent phenytoin
• No concurrent carbamazepine
• No concurrent rifampin
• No concurrent phenobarbital
• No concurrent Hypericum perforatum (St. John's wort)
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational or commercial agents or therapies intended to treat the malignancy