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

Atsushi Natsume; Yoshiki Arakawa; Yoshitaka NaritaKazuhiko SugiyamaNobuhiro HataYoshihiro MuragakiNaoki ShinojimaToshihiro KumabeRyuta SaitoKazuya MotomuraYohei MineharuYasuji MiyakitaFumiyuki YamasakiYuko MatsushitaKoichi IchimuraKazumi ItoMasaya TachibanaYasuyuki KakuraiNaoko OkamotoTakashi AsahiSoichiro NishijimaTomoyuki YamaguchiHiroshi TsubouchiHideo NakamuraRyo Nishikawa

首页> 外文期刊>Neuro-oncology >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

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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

机译：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

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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 IDHI-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).

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来源
《Neuro-oncology》 |2023年第2期|326-336|共11页
作者
Atsushi Natsume; Yoshiki Arakawa; Yoshitaka NaritaKazuhiko SugiyamaNobuhiro HataYoshihiro MuragakiNaoki ShinojimaToshihiro KumabeRyuta SaitoKazuya MotomuraYohei MineharuYasuji MiyakitaFumiyuki YamasakiYuko MatsushitaKoichi IchimuraKazumi ItoMasaya TachibanaYasuyuki KakuraiNaoko OkamotoTakashi AsahiSoichiro NishijimaTomoyuki YamaguchiHiroshi TsubouchiHideo NakamuraRyo Nishikawa;
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Nagoya University School of Medicine, Nagoya, Japan;

Kyoto University Graduate School of Medicine, Kyoto, Japan;

National Cancer Center Japan, Tokyo, JapanHiroshima University Hospital, Hiroshima, JapanGraduate School of Medical Sciences, Kyushu University, Fukuoka, JapanGraduate School of Medicine, Tokyo Women's Medical University, Tokyo, JapanKumamoto University Hospital, Kumamoto, JapanKitasato University School of Medicine, Sagamihara, JapanTohoku University Graduate School of Medicine, Sendai, JapanDaiichi Sankyo Co., Ltd., Tokyo, JapanDepartment of Neurosurgery, Kurume University School of Medicine, Fukuoka, JapanSaitama Medical University International Medical Center, Hidaka, Japan;

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brain-penetrant selective IDH1 inhibitor; D-2-HG; DS-1001; IDH1-mutant gliomas; lower-grade glioma;

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

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