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
| Autor: | Birgit Gaschler-Markefski, Gerd Munzert, Scott A. Laurie, Holger Fritsch, Peter M. Ellis, Quincy Chu, Natasha B. Leighl, Steve Gyorffy |
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| Rok vydání: | 2012 |
| Předmět: |
Pulmonary and Respiratory Medicine
Adult Male Cancer Research medicine.medical_specialty Guanine Lung Neoplasms Neutropenia Maximum Tolerated Dose medicine.medical_treatment Cell Cycle Proteins Pemetrexed Pharmacology Protein Serine-Threonine Kinases Gastroenterology Disease-Free Survival Pharmacokinetics Glutamates Internal medicine Carcinoma Non-Small-Cell Lung Proto-Oncogene Proteins Antineoplastic Combined Chemotherapy Protocols medicine Humans Drug Interactions Enzyme Inhibitors Lung cancer Adverse effect Fatigue Aged Chemotherapy business.industry Pruritus Pteridines Nausea Middle Aged medicine.disease Rash Treatment Outcome Oncology Response Evaluation Criteria in Solid Tumors Administration Intravenous Female Drug Eruptions medicine.symptom business medicine.drug |
| Zdroj: | Clinical lung cancer. 14(1) |
| ISSN: | 1938-0690 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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