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

Alternate Title

Erlotinib, Bevacizumab, and Combination Chemotherapy in Treating Patients With Metastatic or Locally Advanced Colorectal Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Completed 18 and over NCI JHOC-J0220 JHOC-02072506, NCI-5869, 5869, NCT00060411

Objectives

Primary

1. 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.
2. Determine the toxicity profile of this regimen in these patients.
3. Determine the antitumor activity of this regimen in these patients.

Secondary

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

Entry Criteria

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

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

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/mm³
• Absolute neutrophil count at least 1,500/mm³
• Platelet count at least 100,000/mm³

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

Expected Enrollment

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

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.

Trial Contact Information

Trial Lead Organizations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Wells Messersmith, MD, Protocol chair		Ph: 410-502-6873 Email: wmesser1@jhmi.edu

Registry Information
Official Title		A Phase I, Pharmacological, and Biological Study of OSI-774 in Combination with FOLFOX 4 (5-FU, Leucovorin, and Oxaliplatin) and Bevacizumab (Avastin) in Patients with Advanced Colorectal Cancer
Trial Start Date		2003-04-23
Registered in ClinicalTrials.gov		NCT00060411
Date Submitted to PDQ		2003-04-04
Information Last Verified		2006-09-17
NCI Grant/Contract Number		CA06973

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