MURAGAKI Yoshihiro    Department   School of Medicine(Tokyo Women's Medical University Hospital), School of Medicine    Position   Visiting Professor
Article types	Original article
Language	English
Peer review	Peer reviewed
Title	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.
Journal	Formal name：Neuro-oncology Abbreviation：Neuro Oncol ISSN code：15235866/15228517
Domestic / Foregin	Foregin
Volume, Issue, Page	25(2),pp.326-336
Author and coauthor	NATSUME Atsushi†, ARAKAWA Yoshiki, NARITA Yoshitaka, SUGIYAMA Kazuhiko, HATA Nobuhiro, MURAGAKI Yoshihiro, SHINOJIMA Naoki, KUMABE Toshihiro, SAITO Ryuta, MOTOMURA Kazuya, MINEHARU Yohei, MIYAKITA Yasuji, YAMASAKI Fumiyuki, MATSUSHITA Yuko, ICHMURA Koichi, ITO Kazumi, TACHIBANA Masaya, KAKURAI Yasuyuki, OKAMOTO Naoko, ASAHI Takashi, NISHIJIMA Soichiro, YAMAGUCHI Tomoyuki, TSUBOUCHI Hiroshi, NAKAMURA Hideo, NISHIKAWA Ryo
Publication date	2022/06
Summary	BACKGROUND:Approximately 70% of lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) mutations, resulting in 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 cut-off. Most adverse events (AEs) were grade 1-2. Twenty patients (42.6%) experienced at least one 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-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).
DOI	10.1093/neuonc/noac155
PMID	35722822