PMID- 29108334 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231104 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 8 IP - 45 DP - 2017 Oct 3 TI - Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer. PG - 79546-79555 LID - 10.18632/oncotarget.18554 [doi] AB - SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m(2)) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort (N = 19; unselected population, including three patients with MET-amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m(2). Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade >/= 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m(2) in the dose-expansion cohort, comprising patients with MET-amplified tumors (N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m(2) has acceptable tolerability and modest antitumor activity in patients with MET-amplified gastric cancer. FAU - Shitara, Kohei AU - Shitara K AD - Department of Experimental Therapeutics and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. FAU - Kim, Tae Min AU - Kim TM AD - Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. FAU - Yokota, Tomoya AU - Yokota T AD - Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan. FAU - Goto, Masahiro AU - Goto M AD - Cancer Chemotherapy Center, Osaka Medical College Hospital, Osaka, Japan. FAU - Satoh, Taroh AU - Satoh T AD - Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, Japan. FAU - Ahn, Jin-Hee AU - Ahn JH AD - Department of Oncology, Asan Medical Center, Seoul, Korea. FAU - Kim, Hyo Song AU - Kim HS AD - Division of Medical Oncology, Yonsei University College of Medicine, Seoul, Korea. FAU - Assadourian, Sylvie AU - Assadourian S AD - Research and Development, Sanofi, Paris, France. FAU - Gomez, Corinne AU - Gomez C AD - Pharmacokinetics and Distribution, Sanofi, Paris, France. FAU - Harnois, Marzia AU - Harnois M AD - Research and Development, Sanofi, Paris, France. FAU - Hamauchi, Satoshi AU - Hamauchi S AD - Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan. FAU - Kudo, Toshihiro AU - Kudo T AD - Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka, Japan. FAU - Doi, Toshihido AU - Doi T AD - Department of Experimental Therapeutics and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan. FAU - Bang, Yung-Jue AU - Bang YJ AD - Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea. LA - eng PT - Journal Article DEP - 20170616 PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 PMC - PMC5668067 OTO - NOTNLM OT - Asian population OT - MET amplification OT - gastric cancer OT - phase I trial COIS- CONFLICTS OF INTEREST K.S. has received research grants from Sanofi. T.S. has received consulting fees from Eli Lilly and Daiichi Sankyo; consulting fees and honoraria from Chugai Pharmaceutical Co. Ltd, Merck Serono Co. Ltd, Bristol-Myers K.K., Taiho Pharmaceutical Co. Ltd, and Takeda Pharmaceutical Co. Ltd; and departmental research grants from Chugai Pharmaceutical Co. Ltd, ONO Pharmaceutical Co. Ltd, and Yakult Honsha Co. Ltd. S.A., C.G., and M.H. are employees of Sanofi, and Y.-J.B. serves in an advisory and consulting role for Sanofi. T.K. received honoraria from Chugai Pharmaceutical Co. Ltd, Merck Serono Co. Ltd, Eli Lilly Japan K.K., Taiho Pharmaceutical Co. Ltd, and Takeda Pharmaceutical Co. Ltd. Our department is an endowment department, supported with an unrestricted grant from Chugai Pharmaceutical Co. Ltd, ONO Pharmaceutical Co. Ltd, and Yakult Honsha Co. Ltd. T.M.K., M.G., J.H.A., H.S.K., S.H., T.D., and T.Y. have no conflicts of interest to disclose. EDAT- 2017/11/08 06:00 MHDA- 2017/11/08 06:01 PMCR- 2017/10/03 CRDT- 2017/11/08 06:00 PHST- 2017/01/17 00:00 [received] PHST- 2017/06/04 00:00 [accepted] PHST- 2017/11/08 06:00 [entrez] PHST- 2017/11/08 06:00 [pubmed] PHST- 2017/11/08 06:01 [medline] PHST- 2017/10/03 00:00 [pmc-release] AID - 18554 [pii] AID - 10.18632/oncotarget.18554 [doi] PST - epublish SO - Oncotarget. 2017 Jun 16;8(45):79546-79555. doi: 10.18632/oncotarget.18554. eCollection 2017 Oct 3.