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

Abstract

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-naïve IDH1-mutated WHO grade 2 glioma is ongoing (NCT04458272).

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

Fig. 1

Efficacy of DS-1001: waterfall plot of best percentage change in target tumor size in patients with (A) enhancing tumors and (B) non-enhancing tumors, and swimmer plots of the duration of response in patients with (C) enhancing and (D) non-enhancing tumors. Patients with enhancing tumors are shown in (A) and non-enhancing tumors in (B). In 2 patients, change in tumor size could not be assessed because they had no target lesion or observed tumor hemorrhage, and thus these patients were excluded from this analysis. Two patients (denoted by *1-2) showed a change over 100%. Patients with enhancing tumors are shown in (C) and non-enhancing tumors in (D). Bar colors represent glioma type (astrocytoma or oligodendroglioma) and bar symbols represent the type of response. Arrows at the end of the bars indicate patients who remained on DS-1001. The length of the bars represents the duration of therapy. In general, long response duration was observed in those who responded to treatment regardless of whether a patient had enhancing or non-enhancing tumors. Abbreviations: CR, complete response; MR, minor response; PD, progressive disease; PR, partial response; SD, stable disease.

Fig. 2

Comparison of D-2-HG levels in archived tumor samples vs on-treatment tumor tissues according to DS-1001 dose. Circles represent individual patients, and lines represent the median average D-2-HG concentration at each DS-1001 dose or in archived samples. Tumor D-2-HG concentration at 4 DS-1001 dose levels (125-700 mg bid) is lower than archived samples. Abbreviations: bid, twice daily; D-2-HG, D-2-hydroxyglutarate.