A randomized phase II study of two doses of vorinostat in combination with 5-FU/LV in patients with refractory colorectal cancer.
BACKGROUND
Vorinostat is synergistic with 5-FU in vitro and in vivo models. A combination of these two agents was associated with clinical activity in 5-FU refractory colorectal cancer patients in a phase I clinical trial, therefore warranting the conduct of this prospective phase II study.


METHODS
Patients with refractory metastatic colorectal cancer were randomized in a two-stage design to receive vorinostat at 800 or 1,400 mg/day once a day × 3, every 2 weeks. 5-FU, preceded by leucovorin, was administered as a bolus followed by a 46-h infusion on days 2 and 3 of vorinostat. A pre-specified 2-month progression-free survival (PFS) rate of 27/43 patients per arm was needed to deem an arm interesting for further investigation.


RESULTS
The high-dose vorinostat arm did not reach the needed efficacy endpoint at completion of the first stage, with only 8 out of 15 patients being alive and progression free at 2 months. The low-dose vorinostat arm proceeded to accrue 43 patients with a 2-month PFS rate of 53% (23 out 43), including one partial response. The median PFS and overall survival on the low-dose arm were 2.4 and 6.5 months, respectively. Both treatment arms were well tolerated. No differences were noted in the pharmacokinetics of vorinostat at the 800- or 1,400-mg dose-levels, suggesting bioavailability saturation.


CONCLUSIONS
While the addition of vorinostat to 5-FU resulted in 1 partial response and in some disease stabilizations, the limited activity does not warrant the unselected use of this combination in chemotherapy-refractory colorectal cancer.
Department of Medicine, University of Michigan, Ann Arbor, MI, USA. marwanf@med.umich.edu
M G
MG
Fakih
A
A
Groman
J
J
McMahon
G
G
Wilding
J R
JR
Muindi
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D007275:Injections, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000077337:Vorinostat
D006877:Hydroxamic Acids; D000077337:Vorinostat; D002955:Leucovorin; D005472:Fluorouracil