Efficacy and Safety of Pemetrexed in Combination with Cisplatin for Malignant Pleural Mesothelioma: A Phase I/II Study in Japanese Patients

Background: Pemetrexed in combination with cisplatin (Pem/Cis) is used globally for the treatment of malignant pleural mesothelioma (MPM). This Phase I/II study was conducted to determine the recommended dose (RD) (Phase I) of Pem/Cis, and evaluate the efficacy and safety (Phase II) in Japanese MPM patients. Methods: Key eligibility criteria were histologic diagnosis of MPM incurable by surgery, no prior chemotherapy, and a performance status 0‐1. Under full vitamin supplementation, pemetrexed was intravenously administered on Day 1 of a 21-day cycle, followed by cisplatin. A cohort of six patients, starting from pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 (Level 1), were studied in the dose-escalation Phase I( Step 1). The RD determined in Step 1w as carried forward into Phase II (Step 2). Planned number of patients treated with Pem/Cis was 18‐38. Results: In Step 1, 13 patients were enrolled: seven in Level 1 and six in Level 21 (pemetrexed 500 mg/m 2 , cisplatin 60 mg/m 2 ). Two of six evaluable patients had dose-limiting toxicities (pneumonitis and neutropenia) in Level 1, establishing Level 1 as the RD. In Step 2, 12 patients were enrolled, for a total of 19 patients treated at the RD. Seven patients achieved a partial response among these patients, for a response rate of 36.8% (95% confidence interval: 16.3‐ 61.6); overall survival was 7.3 months. One drug-related death occurred due to worsening of a pre-existing pneumonia. Common grade 3/4 toxicities were neutropenia and decreased-hemoglobin. Conclusion: The Pem/Cis combination provides promising activity and an acceptable safety profile for chemonaive Japanese MPM patients with the same recommend dosage and schedule used in rest of the world.