A Phase I Study of 5-FU (Plus Leucovorin) and Arsenic Trioxide for Patients With Refractory/Relapsed Metastatic Colorectal Carcinoma
- Determine the maximum tolerated dose and best dose combination of fluorouracil and
arsenic trioxide when given together with leucovorin calcium in patients with relapsed
or refractory stage IV colorectal cancer.
- Determine if arsenic trioxide down regulates the expression of thymidylate synthase in
tumor and in peripheral blood mononuclear cells in these patients.
OUTLINE: This is a dose-escalation study of fluorouracil and arsenic trioxide.
Patients receive arsenic trioxide IV over 1-4 hours on days 1-5, 8, 11, 15, 18, and 22 and
fluorouracil IV over 24 hours and leucovorin calcium IV over 24 hours on days 8, 15, and 22.
Treatment repeats every 5 weeks for up to 8 courses in the absence of disease progression or
Cohorts of 1-6 patients receive escalating doses of fluorouracil and arsenic trioxide until
the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding
that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6
patients are treated at the MTD.
Patients undergo peripheral blood mononuclear cell (PBMC) collection and fine-needle tumor
aspiration periodically to determine the effects of arsenic trioxide on thymidylate synthase
expression in the tumor and in PBMCs.
After completion of study treatment, patients are followed periodically for 3 years.
PROJECTED ACCRUAL: A total of 20 patients will be accrued for this study.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose
The objective of this phase I study is to determine a phase II dose of combination of 5-FU and ATO that can be safely used for the treatment of 5-FU resistant colon cancer. Following the dose escalation/de-escalation procedure described in section 4.2, the recommended phase II dose of the combination 5-FU with ATO will be established as the maximum tolerated dose (MTD), defined as the highest dose level combination at which <=1 out of 6 patients experiencing DLT.
At study completion
Bach Ardalan, MD
University of Miami Sylvester Comprehensive Cancer Center
United States: Food and Drug Administration
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