PMID- 26560486 OWN - NLM STAT- MEDLINE DCOM- 20160412 LR - 20221207 IS - 1432-0843 (Electronic) IS - 0344-5704 (Linking) VI - 76 IP - 6 DP - 2015 Dec TI - Phase I study of nintedanib in combination with pemetrexed as second-line treatment of Japanese patients with advanced non-small cell lung cancer. PG - 1225-33 LID - 10.1007/s00280-015-2896-3 [doi] AB - 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. FAU - Daga, Haruko AU - Daga H AD - 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. FAU - Takeda, Koji AU - Takeda K AD - Department of Medical Oncology, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka, 534-0021, Japan. FAU - Okada, Hideaki AU - Okada H AD - Department of Medical Oncology, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka, 534-0021, Japan. FAU - Miyazaki, Masaki AU - Miyazaki M AD - Department of Internal Medicine, Suita Municipal Hospital, 2-13-20 Katayamamach, Suita City, Osaka, 564-0082, Japan. FAU - Ueda, Shinya AU - Ueda S AD - Nara Hospital, Kinki University Faculty of Medicine, 1248-1 Otodacho Ikoma, Nara, 630-0227, Japan. FAU - Kaneda, Hiroyasu AU - Kaneda H AD - Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan. FAU - Okamoto, Isamu AU - Okamoto I AD - Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Yoh, Kiyotaka AU - Yoh K AD - Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. FAU - Goto, Koichi AU - Goto K AD - Department of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. FAU - Konishi, Koichi AU - Konishi K AD - Clinical Trial Management Department, Nippon Boehringer Ingelheim Co., Ltd., Think Park Tower 2-1-1 Osaki, Shinagawa, Tokyo, 141-6017, Japan. FAU - Sarashina, Akiko AU - Sarashina A AD - Clinical PK/PD Department, Nippon Boehringer Ingelheim Co., Ltd., 6-7-5 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan. FAU - Tanaka, Tetsuya AU - Tanaka T AD - Statistical Analysis Department 1, EPS Corporation, Acropolis TOKYO Building, 6-29 Shinogawamachi, Shinjuku-ku, Tokyo, 162-0814, Japan. FAU - Kaiser, Rolf AU - Kaiser R AD - Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397, Biberach an der Riss, Germany. FAU - Nakagawa, Kazuhiko AU - Nakagawa K AD - Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan. LA - eng SI - ClinicalTrials.gov/NCT00979576 PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151111 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Indoles) RN - 04Q9AIZ7NO (Pemetrexed) RN - G6HRD2P839 (nintedanib) SB - IM MH - Adult MH - Aged MH - Antineoplastic Combined Chemotherapy Protocols/adverse effects/pharmacokinetics/*therapeutic use MH - Area Under Curve MH - Asian People MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/ethnology MH - Diarrhea/chemically induced MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - Female MH - Humans MH - Indoles/administration & dosage/adverse effects/pharmacokinetics MH - Japan MH - Lung Neoplasms/*drug therapy/ethnology MH - Male MH - Metabolic Clearance Rate MH - Middle Aged MH - Nausea/chemically induced MH - Pemetrexed/administration & dosage/adverse effects/pharmacokinetics MH - Treatment Outcome MH - Vomiting/chemically induced OTO - NOTNLM OT - Angiogenesis inhibitor OT - Clinical trial OT - Nintedanib OT - Non-small cell lung cancer OT - Pemetrexed OT - Phase I EDAT- 2015/11/13 06:00 MHDA- 2016/04/14 06:00 CRDT- 2015/11/13 06:00 PHST- 2015/09/11 00:00 [received] PHST- 2015/10/21 00:00 [accepted] PHST- 2015/11/13 06:00 [entrez] PHST- 2015/11/13 06:00 [pubmed] PHST- 2016/04/14 06:00 [medline] AID - 10.1007/s00280-015-2896-3 [pii] AID - 10.1007/s00280-015-2896-3 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2015 Dec;76(6):1225-33. doi: 10.1007/s00280-015-2896-3. Epub 2015 Nov 11.