A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy

Peter M Wilson, Anthony El-Khoueiry, Syma Iqbal, William Fazzone, Melissa J LaBonte, Susan Groshen, Dongyun Yang, Kathy D Danenberg, Sarah Cole, Margaret Kornacki, Robert D Ladner, Heinz-Josef Lenz, Melissa LaBonte Wilson

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

PURPOSE: We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS).

METHODS: Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients.

RESULTS: Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels -1 and -2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation > or = 50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment.

CONCLUSIONS: The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.

Original languageEnglish
Pages (from-to)979-88
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume65
Issue number5
DOIs
Publication statusPublished - Apr 2010

Keywords

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols
  • Colorectal Neoplasms
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Female
  • Fluorouracil
  • Histone Acetyltransferases
  • Humans
  • Hydroxamic Acids
  • Leucovorin
  • Leukocytes, Mononuclear
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • RNA, Messenger
  • Thymidylate Synthase
  • Treatment Failure

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