A phase I, pharmacokinetic, and pharmacodynamic study of two schedules of vorinostat in combination with 5-fluorouracil and leucovorin in patients with refractory solid tumors.
OBJECTIVE
We conducted a phase I clinical trial to determine the maximum tolerated dose (MTD) of daily or twice daily vorinostat x 3 days when combined with fixed doses of 5-fluorouracil (FU) and leucovorin every 2 weeks.


METHODS
Vorinostat doses were escalated in a standard 3 x 3 phase I design. FU/leucovorin was started on day 2 of vorinostat and consisted of leucovorin 400 mg/m(2) i.v. over 2 hours followed by FU 400 mg/m(2) i.v. bolus and 2,400 mg/m(2) over 46 hours (sLV5FU2).


RESULTS
Forty-three patients were enrolled. Grade 3 fatigue, and hand and foot syndrome were the dose-limiting toxicities (DLT) at the 2,000 mg vorinostat once-daily dose level. Grade 3 fatigue and mucositis were DLTs at the 800 mg vorinostat twice-daily dose level. None of six patients at the 1,700 mg once daily or six patients at the 600 mg twice daily dose levels had a DLT; those dose levels represent the MTD. Twenty-one of 38 patients with FU-refractory colorectal cancer had stable disease, and one had a partial response. Vorinostat maximum serum concentrations at the MTD exceeded concentrations associated with thymidylate synthase downregulation in vitro. No pharmacokinetic interactions were noted between vorinostat and FU.


CONCLUSIONS
The MTD of vorinostat in combination with sLV5FU2 is 1,700 mg orally once daily x 3 or 600 mg orally twice daily x 3 days every 2 weeks. Clinical activity in refractory colorectal cancer supports further clinical development of this combination.
Fakih
Marwan G
MG
Department of Medicine, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York 14263, USA. marwan.fakih@roswellpark.org
Fetterly
Gerald
G
Egorin
Merrill J
MJ
Muindi
Josephia R
JR
Espinoza-Delgado
Igor
I
Zwiebel
James A
JA
Litwin
Alan
A
Holleran
Julianne L
JL
Wang
Kangsheng
K
Diasio
Robert B
RB
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005500:Follow-Up Studies; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D000077337:Vorinostat
D004338:Drug Combinations; D006877:Hydroxamic Acids; D000077337:Vorinostat; D002955:Leucovorin; D005472:Fluorouracil
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