PMID- 29992354 OWN - NLM STAT- MEDLINE DCOM- 20190809 LR - 20190809 IS - 1432-0843 (Electronic) IS - 0344-5704 (Print) IS - 0344-5704 (Linking) VI - 82 IP - 3 DP - 2018 Sep TI - An early clinical trial of Salirasib, an oral RAS inhibitor, in Japanese patients with relapsed/refractory solid tumors. PG - 511-519 LID - 10.1007/s00280-018-3618-4 [doi] AB - PURPOSE: Patients with RAS-positive tumors respond poorly to chemotherapies and have a few treatment options. Salirasib is an oral RAS inhibitor that competitively blocks the membrane association of RAS proteins. The aim of this phase I multiple-ascending-dose clinical trial was to investigate the safety and pharmacokinetics of Salirasib in Japanese patients with relapsed/refractory solid tumors and to explore its efficacy. METHODS: Salirasib was started at a dose of 100-mg twice-daily and escalated to a maximum of 1000-mg twice-daily from days 1 to 21 of a 28-day regimen. The pharmacokinetics was evaluated on days 1 and 21. Dose-limiting toxicity (DLT) and adverse events (AEs) were monitored throughout the trial. Patients with stable disease or better repeated the dosing regimen. RESULTS: A total of 21 patients received Salirasib. Among 14 patients tested, 4 had KRAS mutations. C(max) and AUC(inf) were maximal at 800 mg. No maximum tolerable dose was discerned, as no DLT was observed in any dosing group. The most frequently observed AEs were gastrointestinal disturbances, including diarrhea, abdominal pain, and nausea. No AEs led to discontinuation. All patients completed the first regimen and 11 patients repeated the regimen (median: 2 cycles; range: 1-13). Patients with KRAS mutations showed median progression-free survival of 227 days (range: 79-373). CONCLUSION: Salirasib was safe and well tolerated in Japanese patients, and 800-mg twice-daily is recommended for phase II trials. Although the number of participants with KRAS mutations was limited, the remarkably long progression-free period warrants further investigation. CLINICAL TRIAL REGISTRATION: JAPIC Clinical Trials Information; JapicCTI-121751. FAU - Furuse, Junji AU - Furuse J AD - Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan. jfuruse@ks.kyorin-u.ac.jp. FAU - Kurata, Takayasu AU - Kurata T AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. FAU - Okano, Naohiro AU - Okano N AD - Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan. FAU - Fujisaka, Yasuhito AU - Fujisaka Y AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. FAU - Naruge, Daisuke AU - Naruge D AD - Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan. FAU - Shimizu, Toshio AU - Shimizu T AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. FAU - Kitamura, Hiroshi AU - Kitamura H AD - Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan. FAU - Iwasa, Tsutomu AU - Iwasa T AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. FAU - Nagashima, Fumio AU - Nagashima F AD - Department of Medical Oncology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan. FAU - Nakagawa, Kazuhiko AU - Nakagawa K AD - Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180710 PL - Germany TA - Cancer Chemother Pharmacol JT - Cancer chemotherapy and pharmacology JID - 7806519 RN - 0 (Antineoplastic Agents) RN - 0 (Enzyme Inhibitors) RN - 0 (Salicylates) RN - 0 (farnesylthiosalicylic acid) RN - 4602-84-0 (Farnesol) RN - EC 3.6.5.2 (ras Proteins) MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/administration & dosage/adverse effects/pharmacokinetics MH - Dose-Response Relationship, Drug MH - Enzyme Inhibitors/administration & dosage/adverse effects/pharmacokinetics MH - Farnesol/administration & dosage/adverse effects/*analogs & derivatives/pharmacokinetics MH - Female MH - Humans MH - Male MH - Middle Aged MH - Neoplasm Staging MH - Neoplasms/*drug therapy/metabolism/pathology MH - Salicylates/*administration & dosage/adverse effects/pharmacokinetics MH - ras Proteins/*antagonists & inhibitors PMC - PMC6105164 OTO - NOTNLM OT - KRAS mutation OT - Phase I clinical trial OT - Relapsed/refractory solid tumors OT - S-trans OT - Salirasib OT - Trans-farnesylthiosalicylic acid COIS- CONFLICT OF INTEREST: Junji Furuse has received honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Yakult, Kyowa Hakko Kirin, Eli Lilly Japan, Ono Pharmaceutical, Eisai, Bayer Pharmaceutical, Zeria Pharmaceutical, Fujifilm, Merck Serono, Novartis, J-Pharma, Otsuka Pharmaceutical, Boehringer Ingelheim, Takeda Pharmaceutical, Daiichi Sankyo, Astra Zeneca, Astellas Pharma, Mitsubishi Tanabe Pharma, Bristol-Myers Squibb, MSD, Meiji Seika Pharma, Ajinomoto Pharmaceuticals, Nippon Kayaku, Sumitomo Dainippon Pharma, Sawai, Sandoz, Mochida Pharma and Shionogi, and research funding from Taiho Pharmaceutical, Ono Pharmaceutical, Onco Therapy Science, Merck Serono, Zeria Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Pharmaceutical, Glaxo Smith Kline, Yakult, Sumitomo Dainippon Pharma, Daiichi Sankyo, Shionogi, Novartis, Torii Pharma, J-Pharma, Nippon Kayaku, Bristol-Myers Squibb, Janssen Pharmaceutical, Sanofi, Kyowa Hakko Kirin, Mochida Pharma, Astellas Pharma, Hisamitsu Pharmaceutical and Pfizer. Takayasu Kurata has received honoraria from Ono Pharmaceutical. Naohiro Okano and Daisuke Naruge have received research funding from Taiho Pharmaceutical, Ono Pharmaceutical, Onco Therapy Science, Merck Serono, Zeria Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Pharmaceutical, Glaxo Smith Kline, Yakult, Sumitomo Dainippon Pharma, Daiichi Sankyo, Shionogi, Novartis, Torii Pharma, J-Pharma, Nippon Kayaku, Bristol-Myers Squibb, Janssen Pharmaceutical, Sanofi, Kyowa Hakko Kirin, Mochida Pharma, Astellas Pharma, Hisamitsu Pharmaceutical and Pfizer. Fumio Nagashima has received honoraria from Taiho Pharmaceutical, Chugai Pharmaceutical, Kyowa Hakko Kirin, Merck Serono, Takeda Pharmaceutical, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Bristol-Myers Squibb, Nippon Kayaku and Sumitomo Dainippon Pharma, and research funding from Taiho Pharmaceutical, Ono Pharmaceutical, Onco Therapy Science, Merck Serono, Zeria Pharmaceutical, Eli Lilly Japan, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer Pharmaceutical, Glaxo Smith Kline, Yakult, Sumitomo Dainippon Pharma, Daiichi Sankyo, Shionogi, Novartis, Torii Pharma, J-Pharma, Nippon Kayaku, Bristol- Myers Squibb, Janssen Pharmaceutical, Sanofi, Kyowa Hakko Kirin, Mochida Pharma, Astellas Pharma, Hisamitsu Pharmaceutical and Pfizer. Kazuhiko Nakagawa has received honoraria from Astellas Pharma, AstraZeneca K.K., Chugai Pharmaceutical, Nippon Boehringer Ingelheim, Eli Lilly Japan K.K., Pfizer Japan and Novartis Pharma K.K., and research funding from Chugai Pharmaceutical, Astellas Pharma, MSD K.K., Ono Pharmaceutical, EPS Associates, Quintiles, Daiichi Sankyo, Japan Clinical Research Operations, Eisai, Kyowa Hakko Kirin, Pfizer Japan, Takeda Pharmaceutical, Nippon Boehringer Ingelheim, Bristol-Myers Squibb, and PPD-SNBL K.K.. The other authors declare no conflict of interest. ETHICAL APPROVAL: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. INFORMED CONSENT: Informed consent was obtained from all individual participants included in the study. EDAT- 2018/07/12 06:00 MHDA- 2019/08/10 06:00 PMCR- 2018/07/10 CRDT- 2018/07/12 06:00 PHST- 2018/02/06 00:00 [received] PHST- 2018/06/04 00:00 [accepted] PHST- 2018/07/12 06:00 [pubmed] PHST- 2019/08/10 06:00 [medline] PHST- 2018/07/12 06:00 [entrez] PHST- 2018/07/10 00:00 [pmc-release] AID - 10.1007/s00280-018-3618-4 [pii] AID - 3618 [pii] AID - 10.1007/s00280-018-3618-4 [doi] PST - ppublish SO - Cancer Chemother Pharmacol. 2018 Sep;82(3):511-519. doi: 10.1007/s00280-018-3618-4. Epub 2018 Jul 10.