PMID- 35722822 OWN - NLM STAT- MEDLINE DCOM- 20230215 LR - 20230215 IS - 1523-5866 (Electronic) IS - 1522-8517 (Print) IS - 1522-8517 (Linking) VI - 25 IP - 2 DP - 2023 Feb 14 TI - The first-in-human phase I study of a brain-penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas. PG - 326-336 LID - 10.1093/neuonc/noac155 [doi] AB - BACKGROUND: Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in the accumulation of oncometabolite D-2-hydroxyglutarate (D-2-HG); this leads to epigenetic dysregulation, oncogenesis, and subsequent clonal expansion. DS-1001 is an oral brain-penetrant mutant IDH1 selective inhibitor. This first-in-human study investigated the safety, pharmacokinetics, pharmacodynamics, and efficacy of DS-1001. METHODS: This was a multicenter, open-label, dose-escalation, phase I study of DS-1001 for recurrent/progressive IDH1-mutant (R132) glioma (N = 47) (NCT03030066). DS-1001 was administered orally at 125-1400 mg twice daily. Dose-escalation used a modified continual reassessment method. RESULTS: The maximum tolerated dose was not reached. Eight patients were continuing treatment at the data cutoff. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least 1 grade 3 AE. No grade 4 or 5 AEs or serious drug-related AEs were reported. Common AEs (>20%) were skin hyperpigmentation, diarrhea, pruritus, alopecia, arthralgia, nausea, headache, rash, and dry skin. The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. Median progression-free survival was 10.4 months (95% confidence interval [CI], 6.1 to 17.7 months) and not reached (95% CI, 24.1 to not reached) for the enhancing and non-enhancing glioma cohorts, respectively. Seven on-treatment brain tumor samples showed a significantly lower amount of D-2-HG compared with pre-study archived samples. CONCLUSIONS: DS-1001 was well tolerated with a favorable brain distribution. Recurrent/progressive IDH1-mutant glioma patients responded to treatment. A study of DS-1001 in patients with chemotherapy- and radiotherapy-naive IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272). CI - (c) The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. FAU - Natsume, Atsushi AU - Natsume A AD - Nagoya University School of Medicine, Nagoya, Japan. FAU - Arakawa, Yoshiki AU - Arakawa Y AUID- ORCID: 0000-0003-4626-4645 AD - Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Narita, Yoshitaka AU - Narita Y AUID- ORCID: 0000-0003-4303-6006 AD - National Cancer Center Japan, Tokyo, Japan. FAU - Sugiyama, Kazuhiko AU - Sugiyama K AD - Hiroshima University Hospital, Hiroshima, Japan. FAU - Hata, Nobuhiro AU - Hata N AD - Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Muragaki, Yoshihiro AU - Muragaki Y AD - Graduate School of Medicine, Tokyo Women's Medical University, Tokyo, Japan. FAU - Shinojima, Naoki AU - Shinojima N AD - Kumamoto University Hospital, Kumamoto, Japan. FAU - Kumabe, Toshihiro AU - Kumabe T AD - Kitasato University School of Medicine, Sagamihara, Japan. FAU - Saito, Ryuta AU - Saito R AD - Tohoku University Graduate School of Medicine, Sendai, Japan. FAU - Motomura, Kazuya AU - Motomura K AUID- ORCID: 0000-0002-4376-1104 AD - Nagoya University School of Medicine, Nagoya, Japan. FAU - Mineharu, Yohei AU - Mineharu Y AD - Kyoto University Graduate School of Medicine, Kyoto, Japan. FAU - Miyakita, Yasuji AU - Miyakita Y AD - National Cancer Center Japan, Tokyo, Japan. FAU - Yamasaki, Fumiyuki AU - Yamasaki F AD - Hiroshima University Hospital, Hiroshima, Japan. FAU - Matsushita, Yuko AU - Matsushita Y AD - National Cancer Center Japan, Tokyo, Japan. FAU - Ichimura, Koichi AU - Ichimura K AD - National Cancer Center Japan, Tokyo, Japan. FAU - Ito, Kazumi AU - Ito K AD - Daiichi Sankyo Co., Ltd., Tokyo, Japan. FAU - Tachibana, Masaya AU - Tachibana M AD - Daiichi Sankyo Co., Ltd., Tokyo, Japan. FAU - Kakurai, Yasuyuki AU - Kakurai Y AD - Daiichi Sankyo Co., Ltd., Tokyo, Japan. FAU - Okamoto, Naoko AU - Okamoto N AD - Daiichi Sankyo Co., Ltd., Tokyo, Japan. FAU - Asahi, Takashi AU - Asahi T AD - Daiichi Sankyo Co., Ltd., Tokyo, Japan. FAU - Nishijima, Soichiro AU - Nishijima S AD - Daiichi Sankyo Co., Ltd., Tokyo, Japan. FAU - Yamaguchi, Tomoyuki AU - Yamaguchi T AD - Daiichi Sankyo Co., Ltd., Tokyo, Japan. FAU - Tsubouchi, Hiroshi AU - Tsubouchi H AD - Daiichi Sankyo Co., Ltd., Tokyo, Japan. FAU - Nakamura, Hideo AU - Nakamura H AD - Department of Neurosurgery, Kurume University School of Medicine, Fukuoka, Japan. FAU - Nishikawa, Ryo AU - Nishikawa R AD - Saitama Medical University International Medical Center, Hidaka, Japan. LA - eng SI - ClinicalTrials.gov/NCT04458272 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't PL - England TA - Neuro Oncol JT - Neuro-oncology JID - 100887420 RN - EC 1.1.1.41 (Isocitrate Dehydrogenase) RN - 0 (Enzyme Inhibitors) RN - EC 1.1.1.42. (IDH1 protein, human) SB - IM CIN - Neuro Oncol. 2022 Dec 16;:. PMID: 36526609 MH - Humans MH - Isocitrate Dehydrogenase/genetics/metabolism MH - *Glioma/drug therapy/genetics/pathology MH - Enzyme Inhibitors/therapeutic use MH - *Brain Neoplasms/drug therapy/genetics MH - Brain/pathology MH - Mutation PMC - PMC9925696 OTO - NOTNLM OT - D-2-HG OT - DS-1001 OT - IDH1-mutant gliomas OT - brain OT - lower-grade glioma OT - penetrant selective IDH1 inhibitor EDAT- 2022/06/21 06:00 MHDA- 2023/02/16 06:00 PMCR- 2022/06/20 CRDT- 2022/06/20 04:43 PHST- 2022/06/21 06:00 [pubmed] PHST- 2023/02/16 06:00 [medline] PHST- 2022/06/20 04:43 [entrez] PHST- 2022/06/20 00:00 [pmc-release] AID - 6611503 [pii] AID - noac155 [pii] AID - 10.1093/neuonc/noac155 [doi] PST - ppublish SO - Neuro Oncol. 2023 Feb 14;25(2):326-336. doi: 10.1093/neuonc/noac155.