A Phase I Open-Label Dose-Escalation Study of Intravenous BI 2536 Together With Pemetrexed in Previously Treated Patients With Non-Small-Cell Lung Cancer

This phase I study investigated the maximum tolerated dose, safety, efficacy, and pharmacokinetics of BI 2536 (100-325 mg) IV in combination with standard-dose pemetrexed in 41 patients with previously treated advanced or metastatic non-small-cell lung cancer. BI 2536 200 mg combined with pemetrexed had an acceptable safety profile and encouraging antitumor activity in patients with relapsed non-small-cell lung cancer. Introduction: BI 2536 is a potent, highly selective inhibitor of polo-like kinase (Plk) 1. This open-label, phase I study investigated the maximum tolerated dose (MTD), safety, efficacy, and pharmacokinetics (PK) of BI 2536 IV in combination with standard-dose pemetrexed in previously treated advanced or metastatic non-small-cell lung cancer. Patients and Methods: A standard 3 +/- 3 design was used. The patients received 500 mg/m(2) pemetrexed and escalating doses of BI 2536 on day 1 every 3 weeks. The primary objective was the MTD of BI 2536 combined with pemetrexed. Secondary endpoints were response rate (Response Evaluation Criteria in Solid Tumors), overall safety, and PK. Results: Forty-one patients received BI 2536 (100-325 mg). Two dose-limiting toxicities (DLT) occurred at BI 2536 325 mg (grade 3 pruritus and rash; grade 4 neutropenia). Therefore, the MTD for BI 2536 in combination with pemetrexed was 300 mg. After expanding the MTD dose level, 3 additional patients experienced DLTs, which resulted in expansion of the 250 mg cohort, in which 4 of the 13 additional patients experienced DLTs. Therefore, the recommended dose of BI 2536 was 200 mg. Most frequently reported drug-related adverse events were fatigue (71%), nausea (37%), and rash (34%). Two patients had durable confirmed partial responses; 21 (54%) patients had stable disease after the treatment cycle 2. PK analysis showed that BI 2536 and pemetrexed exposure were not altered when coadministered. Conclusion: BI 2536 200 mg combined with standard-dose pemetrexed has an acceptable safety profile in relapsed non-small-cell lung cancer. The antitumor activity observed is encouraging and supports further investigation of Plk inhibitors. Clinical Lung Cancer, Vol. 14, No. 1, 19-27 (C) 2013 Elsevier Inc. All rights reserved.