A Phase I Study of 5-FU (Plus Leucovorin) and Arsenic Trioxide for Patients With Refractory/Relapsed Metastatic Colorectal Carcinoma
Overview
- Phase
- Phase 1
- Intervention
- Arsenic trioxide
- Conditions
- Colorectal Cancer
- Sponsor
- University of Miami
- Enrollment
- 13
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
RATIONALE: Drugs used in chemotherapy, such as fluorouracil and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Arsenic trioxide may help fluorouracil and leucovorin work better by making tumor cells more sensitive to the drugs. Giving arsenic trioxide together with fluorouracil and leucovorin may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of arsenic trioxide and fluorouracil when given together with leucovorin in treating patients with stage IV colorectal cancer that has relapsed or not responded to treatment.
Detailed Description
OBJECTIVES: * 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 unacceptable toxicity. 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Single Arm
Intervention: Arsenic trioxide
Single Arm
Intervention: Fluorouracil
Single Arm
Intervention: Leucovorin calcium
Single Arm
Intervention: Plasma levels of elemental arsenic
Single Arm
Intervention: Peripheral Blood Mononuclear Cells (PBMC) for mRNA analysis
Single Arm
Intervention: Tumor Biopsy (Fine-Needle Aspiration)
Outcomes
Primary Outcomes
Maximum tolerated dose
Time Frame: At study completion
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.
Thymidylate synthase expression
Time Frame: Baseline, Subsequent times
We will characterize TS levels in study patients at baseline and at subsequent times following initiation of treatment by descriptive statistics (minimum, maximum, average, standard deviation)