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.
OBJECTIVE
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.
Wilson
Peter M
PM
Department of Pathology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
El-Khoueiry
Anthony
A
Iqbal
Syma
S
Fazzone
William
W
LaBonte
Melissa J
MJ
Groshen
Susan
S
Yang
Dongyun
D
Danenberg
Kathy D
KD
Cole
Sarah
S
Kornacki
Margaret
M
Ladner
Robert D
RD
Lenz
Heinz-Josef
HJ
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000627:therapeutic use*; D002955:Leucovorin / Q000008:administration & dosage / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D017211:Treatment Failure; D000077337:Vorinostat
D006877:Hydroxamic Acids; D012333:RNA, Messenger; D000077337:Vorinostat; D013940:Thymidylate Synthase; D051548:Histone Acetyltransferases; D002955:Leucovorin; D005472:Fluorouracil