Haruko Daga1, Koji Takeda2, Hideaki Okada2, Masaki Miyazaki3, Shinya Ueda4, Hiroyasu Kaneda5, Isamu Okamoto6, Kiyotaka Yoh7, Koichi Goto7, Koichi Konishi8, Akiko Sarashina9, Tetsuya Tanaka10, Rolf Kaiser11, Kazuhiko Nakagawa5. 1. Department of Medical Oncology, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka, 534-0021, Japan. haruko-d@zeus.eonet.ne.jp. 2. Department of Medical Oncology, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka, 534-0021, Japan. 3. Department of Internal Medicine, Suita Municipal Hospital, 2-13-20 Katayamamach, Suita City, Osaka, 564-0082, Japan. 4. Nara Hospital, Kinki University Faculty of Medicine, 1248-1 Otodacho Ikoma, Nara, 630-0227, Japan. 5. Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan. 6. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 7. Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. 8. Clinical Trial Management Department, Nippon Boehringer Ingelheim Co., Ltd., Think Park Tower 2-1-1 Osaki, Shinagawa, Tokyo, 141-6017, Japan. 9. Clinical PK/PD Department, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. 10. Statistical Analysis Department 1, EPS Corporation, Acropolis TOKYO Building, 6-29 Shinogawamachi, Shinjuku-ku, Tokyo, 162-0814, Japan. 11. Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany.
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/m(2) 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.
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/m(2) 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.
Authors: Jeronimo Rafael Rodríguez-Cid; Saul Campos-Gomez; Vanessa García-Montes; Manuel Magallanes-Maciel; Rodrigo Rafael Flores-Mariñelarena; Valeria Michelle Fernández-Garibay; Iván Romarico González-Espinoza; Juan Paulo Ceja-García; Juan Carlos Cázarez-Price; Luis Martínez-Barrera; Leopoldo Barriguete-Parra; Carlos Jose Zuloaga-Fernandez; Roberto Kuri-Exsome; David Suárez-García; Jorge Ignacio Gonzalez-Villanueva; Noé Flores-Anaya; Jose Antonio Acevedo-Delgado; Alma Magdalena Astorga-Ramos; Raquel Gerson-Cwilich; Alberto Villalobos-Prieto; Claudia Rodríguez-Silva; Maria Fernanda Noriega-Iriondo; Leticia Vázquez-Cortés; Eusebio Perales-Rodríguez; Alicia Acosta-Espinoza; Yareni Perez-Lozano; Daniel Capdeville-García; Jorge Arturo Alatorre-Alexander Journal: JCO Glob Oncol Date: 2020-03