Clinical and pharmacokinetic phase I study of multitargeted antifolate (LY231514) in combination with cisplatin

Purpose: Multitargeted antifolate (MTA; LY231514) has broad preclinical ant itumor activity and inhibits a variety of intracellular enzymes involved in the folate pathways, This study was designed to (1) determine the maximum- tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of MTA combined with cisplatin; (2) determine a recommended dose for phase II studies; and (3) collect anecdotal information on the antitumor activity of MTA combined with cisplatin. Patients and Methods: patients with solid tumors received MTA intravenously over 10 minutes and cisplatin over 2 hours once every 21 days. In cohort 1 , both agents were administered on day 1 starting with MTA 300 mg/m(2) and cisplatin 60 mg/m(2), In cohort 2, MTA (500 or 600 mg/m(2)) was administere d on day 1, followed by cisplatin (75 mg/m(2)) on day 2. Results: In cohort 1,40 assessable patients received 159 courses of treatme nt, The MTD was MTA 600 mg/m(2)/cisplatin 100 mg/m(2). DLTs were reversible leukopenia/neutropenia and delayed fatigue, Hydration before cisplatin the rapy did not influence MTA pharmacokinetics, Eleven objective remissions in cluded one complete response in ct patient with relapsed squamous cell head and neck carcinoma, and partial responses in four of ten patients with epi thelial pleural mesothelioma. In cohort 2, 11 assessable patients received 23 courses of treatment, The MTD was MTA 600 mg/m(2) and cisplatin 75 mg/m( 2), DLTs were neutropenic sepsis, diarrhea, and skin toxicity. Two patients died of treatment-related complications during the study. Two patients had objective remissions (one mesothelioma patient, one colon cancer patient), Conclusion: The combination of MTA and cisplatin is clinically active, and administering both agents on day 1 is superior to a split schedule. Further development of this combination for mesothelioma is warranted. (C) 1999 by American Society of Clinical Oncology.