Phase I and Pharmacokinetic study of pemetrexed plus cisplatin in chemonaive patients with locally advanced or metastatic malignant pleural mesothelioma or non-small cell lung cancer

Abstract

Purpose: Pemetrexed is approved as monotherapy and in combination with cisplatin. The established combination dose was identified before the addition of folic acid and vitamin B 12 to the treatment regimen. We evaluated the toxicity and pharmacokinetics (PK) of higher pemetrexed closes with cisplatin and vitamin supplementation. Experimental Design: Patients with malignant pleural mesothelioma or non- small ceil lung cancer received pemetrexed doses from 500 to 900 mg/m 2 + 75 mg/m 2 cisplatin once every 21 days. Folic acid and vitamin B 12 were administered per label recommendations. Results: Twenty-one patients received a combined total of 84 cycles. The maximum tolerated dose was 900 mg/m 2 pemetrexed + 75 mg/m 2 cisplatin. Dose-limiting toxicities at this dose included grade 3 anemia, bronchopneumonia, and neutropenia, and 1 death from sepsis secondary to grade 4 febrile neutropenia, considered possibly related to study drugs. The recommended dose was 800 mg/m 2 pemetrexed + 75 mg/m 2 cisplatin. Pemetrexed PK were consistent across doses; pemetrexed did not seem to affect total or free platinum PK. Conclusions: Pemetrexed with vitamin supplementation was safe and well tolerated at higher closes than the currently established 500 mg/m 2 + 75 mg/m 2 cisplatin. Based on this study, the recommended dose would be 800 mg/m 2 pemetrexed + 75 mg/m 2 cisplatin. However, recent studies showed a lack of improved efficacy for 900 or 1,000 mg/m 2 single-agent pemetrexed versus 500 mg/m 2 and a lack of PK/pharmacodynamic exposure-response relationship for the pemetrexed/cisplatin combination across pemetrexed exposures corresponding to this dose range. Based on currently available evidence, we recommend retaining the established dose. © 2009 American Association for Cancer Research.