A phase I study of 5-fluorouracil/leucovorin and arsenic trioxide for patients with refractory/relapsed colorectal carcinoma

Bach Ardalan, Subbayan Pochi, Yipsel Ramos, Michael Gonzalez, Anthony Fernandez, Dmitry Mezentsev, Isildinha Reis, Robert Duncan, Lisa Podolsky, Kelvin Lee, Mayra Lima, Parvin Ganjei-Azar

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Abstract

Purpose: This Phase I study was designed to determine a safe combination dose of 5-fluorouracil (5-FU) and arsenic trioxide (ATO) to treat 5-FU-resistant relapsed/refractory colorectal cancer patients. We studied the effect of ATO in the downregulation of thymidylate synthase (TS) in peripheral blood mononuclear cells and in tumor biopsies. Experimental Design: ATO was administered for 5 consecutive days during the first week and twice during weeks 2 to 3 and once on week 4. 5-FU/leucovorin (LV) was administered on days 8, 15, and 22. A modified accelerated titration design was used. 5-FU was dose escalated first followed by a planned dose increase for ATO. Results: No dose-limiting toxicities were seen in seven patients who received 0.15 mg/kg ATO; grade 3 toxicities were as follows: neutropenia 1, diarrhea 1, and bowel obstruction 1. In patients receiving 0.20 mg/kg ATO, grade 3 toxicities were QTc prolongation 1, fatigue 4, alkaline phosphatase elevation 2, diarrhea 2, and peripheral edema 1. TS gene expression in peripheral blood mononuclear cell decreased in all patients. Eight tumors were biopsied, four showed TS downregulation, three showed upregulations, and one did not change. Estimated median progression-free survival and overall survival were 3.1 and 13.9 months, respectively. In patients who showed TS increase or no change versus TS reduction, estimated median progression-free survival was 2.6 versus 7.9 months (P = 0.188) and overall survival was 8.6 versus 11.7 months (P = 0.44), respectively. Conclusions: Thus, we determined 0.20 mg/kg ATO, 2,600 mg/m2 5-FU, and 500 mg/m2 leucovorin (LV) to be the recommended phase II dose.

Original languageEnglish
Pages (from-to)3019-3027
Number of pages9
JournalClinical Cancer Research
Volume16
Issue number11
DOIs
StatePublished - Jun 1 2010

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Leucovorin
Fluorouracil
Thymidylate Synthase
Colorectal Neoplasms
Disease-Free Survival
Diarrhea
Blood Cells
Down-Regulation
Survival
arsenic trioxide
Neutropenia
Fatigue
Alkaline Phosphatase
Edema
Neoplasms
Research Design
Up-Regulation
Biopsy
Gene Expression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase I study of 5-fluorouracil/leucovorin and arsenic trioxide for patients with refractory/relapsed colorectal carcinoma. / Ardalan, Bach; Pochi, Subbayan; Ramos, Yipsel; Gonzalez, Michael; Fernandez, Anthony; Mezentsev, Dmitry; Reis, Isildinha; Duncan, Robert; Podolsky, Lisa; Lee, Kelvin; Lima, Mayra; Ganjei-Azar, Parvin.

In: Clinical Cancer Research, Vol. 16, No. 11, 01.06.2010, p. 3019-3027.

Research output: Contribution to journalArticle

Ardalan, B, Pochi, S, Ramos, Y, Gonzalez, M, Fernandez, A, Mezentsev, D, Reis, I, Duncan, R, Podolsky, L, Lee, K, Lima, M & Ganjei-Azar, P 2010, 'A phase I study of 5-fluorouracil/leucovorin and arsenic trioxide for patients with refractory/relapsed colorectal carcinoma', Clinical Cancer Research, vol. 16, no. 11, pp. 3019-3027. https://doi.org/10.1158/1078-0432.CCR-09-2590
Ardalan, Bach ; Pochi, Subbayan ; Ramos, Yipsel ; Gonzalez, Michael ; Fernandez, Anthony ; Mezentsev, Dmitry ; Reis, Isildinha ; Duncan, Robert ; Podolsky, Lisa ; Lee, Kelvin ; Lima, Mayra ; Ganjei-Azar, Parvin. / A phase I study of 5-fluorouracil/leucovorin and arsenic trioxide for patients with refractory/relapsed colorectal carcinoma. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 11. pp. 3019-3027.
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AU - Pochi, Subbayan

AU - Ramos, Yipsel

AU - Gonzalez, Michael

AU - Fernandez, Anthony

AU - Mezentsev, Dmitry

AU - Reis, Isildinha

AU - Duncan, Robert

AU - Podolsky, Lisa

AU - Lee, Kelvin

AU - Lima, Mayra

AU - Ganjei-Azar, Parvin

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