Abstract
Purpose
This open-label, phase I, dose-escalation part of a phase I/II study evaluated the safety, pharmacokinetics, and preliminary efficacy of nintedanib, a triple angiokinase inhibitor, combined with pemetrexed in Japanese patients with advanced non-small cell lung cancer (NSCLC) after first-line chemotherapy.
Methods
A fixed dose of pemetrexed (500 mg/m2 iv) was administered on Day 1 of each 21-day cycle followed by oral nintedanib twice daily (bid) on days 2–21, starting at 100 mg bid and escalating to 200 mg bid in 50-mg intervals, using a standard 3 + 3 design. After ≥4 cycles of combination therapy, patients could continue nintedanib monotherapy until disease progression or undue adverse events (AEs). Primary endpoints were maximum tolerated dose (MTD), defined as the highest dose at which the incidence of dose-limiting toxicities (DLTs) was <33.3 % during the first treatment course, and AEs (CTCAE v3.0). DLTs were primarily defined as grade ≥3 non-hematologic or grade 4 hematologic AEs.
Results
Eighteen patients were included in the analysis. DLTs were experienced by 2/9 patients receiving 200 mg bid, 1/6 receiving 150 mg bid, and 0/3 receiving the lowest dose. The MTD of nintedanib plus pemetrexed was 200 mg bid. The most common drug-related AEs were elevated liver enzymes and gastrointestinal AEs. Two patients achieved partial response, and 10 had stable disease.
Conclusions
Nintedanib plus pemetrexed had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese patients with advanced NSCLC. As in Caucasian patients, the MTD of nintedanib was 200 mg bid.
Clinical trial information NCT00979576.
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Acknowledgments
Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Aurora O’Brate of inVentiv Medical Communications during the preparation of this manuscript.
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Conflict of interest
K. Yoh has received personal fees from Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Eli Lilly and Company, Sanofi, and Boehringer Ingelheim. K. Goto has received grants and personal fees from Boehringer Ingelheim, and Eli Lilly and Company. K. Konishi, A. Sarashina, and R. Kaiser are employees of Boehringer Ingelheim. H. Daga, K. Takeda, H. Okada, M. Miyazaki, S. Ueda, H. Kaneda, I. Okamoto, T. Tanaka, and K. Nakagawa declare no conflict of interest.
Ethical approval
The trial was conducted in compliance with the protocol, the principles laid down in the Declaration of Helsinki, and Good Clinical Practice guidelines. The protocol and all amendments were approved by the local institutional review board. All patients provided written informed consent.
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Daga, H., Takeda, K., Okada, H. et al. Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer. Cancer Chemother Pharmacol 76, 1225–1233 (2015). https://doi.org/10.1007/s00280-015-2896-3
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DOI: https://doi.org/10.1007/s00280-015-2896-3