A phase I clinical pharmacologic study of pralatrexate in combination with probenecid in adults with advanced solid tumors.
OBJECTIVE
The antifolate pralatrexate (10-propargyl-10-deazaaminopterin, PDX) demonstrates greater in vitro and in vivo antitumor efficacy than methotrexate. Preclinical models indicated that the efficacy of pralatrexate may be enhanced by coadministration with probenecid. The aim of this phase I study was to determine the maximum-tolerated dose of pralatrexate when combined with probenecid given every 2 weeks in humans.


METHODS
The starting dose was pralatrexate 40 mg/m(2) intravenously and probenecid 70 mg/m(2) intravenously administered every 14 days, where one cycle of treatment was every 28 days. The pralatrexate dose was initially fixed while probenecid dose escalation was explored. The pralatrexate area under the curve (AUC), terminal-half life (t1/2), and maximum plasma concentration (Cmax) were determined in cycle 1.


RESULTS
Seventeen patients with advanced solid tumors were treated with a median of two prior chemotherapy regimens. Stomatitis was dose-limiting with pralatrexate 40 mg/m(2) and probenecid 233 mg/m(2). Mean pralatrexate AUC and half life (t1/2) increased with increasing doses of probenecid. No objective responses were seen.


CONCLUSIONS
For patients with advanced solid tumors, the maximum-tolerated dose of this drug combination was pralatrexate 40 mg/m(2) and probenecid 140 mg/m(2). Vitamin B(12) and folate supplementation may allow for further dose escalation of pralatrexate and probenecid. This is a suitable question for a future study.
Fury
Matthew G
MG
Thoracic Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021, USA.
Krug
Lee M
LM
Azzoli
Christopher G
CG
Sharma
Sunil
S
Kemeny
Nancy
N
Wu
Nian
N
Kris
Mark G
MG
Rizvi
Naiyer A
NA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000630:Aminopterin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011339:Probenecid / Q000008:administration & dosage; D016896:Treatment Outcome
C418863:10-propargyl-10-deazaaminopterin; D000630:Aminopterin; D011339:Probenecid