Arsenic Trioxide, Fluorouracil, and Leucovorin in Treating Patients With Stage IV Colorectal Cancer That Has Relapsed or Not Responded to Treatment
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Study type: Interventional
Phase: Phase 1

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.
    

Intervention name(s): Arsenic trioxide; Fluorouracil; Leucovorin calcium; Plasma levels of elemental arsenic; Peripheral Blood Mononuclear Cells (PBMC) for mRNA analysis; Tumor Biopsy (Fine-Needle Aspiration)
Intervention type(s): Drug; Drug; Drug; Other; Genetic; Procedure
Intervention description(s): ATO will be administered at dose levels determined by the dose escalation scheme (section 4.2). Intra-venous (IV) infusion of ATO (mg/kg body weight) over 1-4 hours will be administered for 5 consecutive days (day 1 to day 5) during the first week, twice a week on weeks 2 and 3 (days 8, 11, 15, and 18), and only one day (day 22) of week 4. Treatment will continue for a maximum of 8 cycles, provided that the patient tolerates treatment and there is evidence of clinical benefit.; Escalate 5-FU, starting at dose 1600 mg/m2. On day 8, 15, and 22 the assigned dose of 5 FU plus 500 mg/m2 of leucovorin will be administered over 24 hours intravenous infusion following the administration of arsenic trioxide. Treatment will continue for a maximum of 8 cycles, provided that the patient tolerates treatment and there is evidence of clinical benefit.; On day 8, 15, and 22 the assigned dose of 5 FU plus 500 mg/m2 of leucovorin will be administered over 24 hours intravenous infusion following the administration of arsenic trioxide. Treatment will continue for a maximum of 8 cycles, provided that the patient tolerates treatment and there is evidence of clinical benefit.; Pre-Treatment and and one hour post ATO on days 1, 5, 8, 11,15, 18, and 22; Peripheral blood samples (PAXgene Blood RNA tube, Qiagen, USA) will be obtained up to 2 weeks prior to start of treatment (same day as the first FNA) and one hour post ATO on days 1, 5, 8, 11,15, 18, and 22. Along with FNA an additional blood sample will be obtained on day 23 of every odd treatment cycle.; Pre-Treatment, Day 23 of Cycles 1, 3, 5, 7
Other intervention name(s): ATO; 5-Fu; FNA
Intervention MeSH terms: Leucovorin; Fluorouracil; Arsenic Trioxide; Calcium; Levoleucovorin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: recurrent colon cancer; stage IV colon cancer; recurrent rectal cancer; stage IV rectal cancer