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

• DOI: 10.1007/s00280-009-1236-x
• Publication Date: 2010-01-08T08:12:08Z
• Authors: 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
• Keywords: Adult; Male; 0301 basic medicine; Maximum Tolerated Dose; Mononuclear; Messenger; Drug Resistance; Leucovorin; 610; Hydroxamic Acids; Dose-Response Relationship; 03 medical and health sciences; Antineoplastic Combined Chemotherapy Protocols; Leukocytes; Humans; RNA, Messenger; Treatment Failure; Aged; Histone Acetyltransferases; Vorinostat; Dose-Response Relationship, Drug; Thymidylate Synthase; Middle Aged; name=SDG 3 - Good Health and Well-being; 3. Good health; Drug Resistance, Neoplasm; Leukocytes, Mononuclear; Neoplasm; RNA; /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being; Female; Fluorouracil; Drug; Colorectal Neoplasms

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).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.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.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.