A phase I/II study of pemetrexed in combination with carboplatin in patients with platin sensitive recurrent ovarian or peritoneal cancer (PSOC)

Abstract

16513 Background: Carboplatin (Cb)-based combinations are used commonly in platin-sensitive recurrent ovarian or peritoneal cancer (PSOC) (Parmar 2003, Pfisterer 2006). Pemetrexed (Pem) is a multi-targeted antifolate whose primary mechanism of action is the inhibition of thymidylate synthase (TS). Methods: The primary objective of phase I was to determine the MTD, DLT, quantitative and qualitative toxicities of combination Pem and Cb. A standard 3-patient cohort dose escalation was planned starting at Cb AUC 5 and Pem 500 mg/m2. Inclusion criteria were: women age > 18 years, contraception use if still fertile, PSOC (defined as recurrence 6 months after first-line therapy), measurable (RECIST criteria) or evaluable disease (CA125 only), adequate organ function and ability to continue follow-up. Two dose levels of Cb (AUC 5, 6) and five levels of Pem (500, 600, 700, 800, 900 mg/m2) were evaluated. DLTs were defined based on cycle 1. Results: Twenty patients, median age 57.4 years (37.3–75.3) were enrolled. Three patients had a PS of 0 and the remaining 17 patients had a PS of 1. Three patients had measurable disease and the remaining 17 patients had CA125 - only evaluable disease. There were no deaths on study. There were no protocol-defined DLTs in cycle 1 and no serious adverse events (SAEs) related to study therapy. There were 2 SAEs noted, one at dose level 1 and one at dose level 6. The 20 patients completed 112 cycles of Cb including 104 as planned and 115 cycles of Pem, including 112 as planned. Five patients required dose adjustments. Dose level 6 was well tolerated. Conclusions: Combination Cb and pemetrexed is well tolerated. However, subsequent to data lock for this trial, data from a randomized Phase II comparing 500 vs. 900 mg/m2 pemetrexed in PSOC demonstrated numerically greater Grade 3 and 4 SAEs with the 900 mg/m2 dose (data on file). A Phase II trial utilizing pemetrexed 500 mg/m2 and Cb AUC 6 is underway. Dose Level Pem mg/m 2 Cb AUC Patients per Dose Level 1 500 5 4 2 600 5 3 3 600 6 4 4 700 6 3 5 800 6 3 6 900 6 3 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly and Company Eli Lilly and Company Eli Lilly and Company, GlaxoSmithKline, Schering-Plough Eli Lilly and Company, GlaxoSmithKline, Schering-Plough