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
I. To determine the maximum tolerated dose (MTD) of OSI-774 given in combination with FOLFOX
4 and Bevacizumab, in patients with advanced colorectal cancer.
II. To characterize the toxicity profile of this regimen. III. To explore the antitumor
activity of this combination.
I. To characterize the pharmacokinetics of OSI-774 given with FOLFOX 4, and Bevacizumab.
II. To determine the relationship between CYP3A4 activity and OSI-774 clearance.
III. To correlate Cytochrome P450 activity with OSI-774 PK using midazolam clearance.
IV. To determine the relationship between expression and activation of the EGFR and related
signaling pathways and outcome of patients with colorectal cancer patients who are treated
with OSI-774 in combination with FOLFOX 4 and Bevacizumab.
V. To explore the biological effects of OSI-774 in patients with advanced colorectal cancer
and its relationship with dose and plasma concentration.
VI. To explore the use of fluorodeoxy-glucose (FDG) positron emission tomography (PET) scan
to predict the biological effects and outcome of patients with colorectal cancer who are
treated with OSI-774 and FOLFOX 4 and Bevacizumab.
VII. To assess 5FU PK when given in this manner, and to correlate with several previously
characterized genetic polymorphisms and drug response VIII. To evaluate the association of
allelic variants in AAG and OSI-774 disposition.
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
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose (MTD) of OSI-774 given in combination with FOLFOX 4 and Bevacizumab, in patients with advanced colorectal cancer
Johns Hopkins University
United States: Food and Drug Administration
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