A phase I/II study of pemetrexed plus cisplatin in Japanese patients with malignant pleural mesothelioma
18152 Background: Pemetrexed (pem) is globally used for the treatment of malignant mesothelioma (MPM) in combination with cisplatin (cis). Pharmacokinetic (PK) difference of pem/cis between Western and Asian population (pop) so far remains unknown. To investigate safety/efficacy of pem/cis therapy and PK profiles of pem/cis for Japanese (Jpn) MPM patients (pts), we designed a phase I/II study. Methods: Primary objectives in phase (Ph) I part were to determine a recommended dose (RD), and in Ph II part were to examine the efficacy of the RD and safety. PK profiles were to be analyzed as a secondary objective. A cohort of 6 pts, starting from a dose of pem 500 mg/m2 and cis 75 mg/m2 (level 1: LV1), was used in the dose-escalation Ph I. The efficacy of the RD was to be evaluated in at least 18 pts in the study. Key eligibility criteria were: histologic diagnosis of MPM incurable by surgery, no prior systemic chemotherapy, and a performance status 0–1. Under full vitamin supplementation, pem was administered as a 10-min. infusion on day 1 of a 21-day cycle, followed by cis administration as a 2-hr. infusion 30 min. after pem administration. For comparison of PK profiles, PK data of this study and a Western phase III study were analyzed by pop PK approach. Results: In Ph I, 13 pts were enrolled: 7 in LV1 and 6 in level -1 (LV-1: pem 500 mg/m2 and cis 60 mg/m2). Two dose-limiting toxicities were observed in LV1: pneumonitis and neutropenia. The RD were then determined to be LV1. In Ph II, 12 pts were enrolled in LV1. For safety, one drug-related death was reported among 25 pts due to worsening of underlying pneumonia observed before enrollment. The most common G3/4 toxicities were neutropenia and hemoglobin decrease. For efficacy, a partial response was achieved for 7 of 19 pts who received LV1. Response rate was 36.8% (95% CI: 16.3- 61.6). PK profiles of pem/cis in Jpn pts were similar to those in Western. The results of other secondary objectives, e.g., progression-free survival, QOL, and pulmonary function test, will be presented in the conference. Conclusions: The profiles of efficacy/safety/PK shown in this study are almost comparable to those in Western pts, and indicate that pem/cis therapy will be a promising therapy for Jpn MPM pts. No significant financial relationships to disclose.