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: brain, penetrant selective IDH1 inhibitor, D-2-HG, DS-1001, IDH1-mutant gliomas, lower-grade glioma
Key Points.
DS-1001 is an oral brain-penetrant selective inhibitor of mutant IDH1.
IDH1-mutant glioma patients responded to DS-1001, which was well tolerated.
This is the first report demonstrating responses including CR with an IDH inhibitor.
Importance of the Study.
Mutations of the isocitrate dehydrogenase (IDH) gene, the majority of which result in IDH1 R132H mutations, are the hallmark of lower-grade gliomas. Mutant IDH1 harbors a neomorphic activity resulting in the accumulation of the oncometabolite D-2-hydroxyglutarate (D-2-HG). In preclinical studies, DS-1001 has been shown to inhibit mutant IDH1, reducing D-2-HG levels and tumor size. This multicenter, open-label, dose-escalation, phase I study investigated the tolerability of DS-1001 administered orally at 125-1400 mg twice daily for recurrent/progressive IDH1 mutant glioma (N = 47, of which 27.7% were 1p/19q-codeleted). The objective response rates were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors. The status of 1p/19q was not associated with outcome. DS-1001 was well tolerated with favorable brain distribution and produced a reduction in tumor D-2-HG levels.
According to the latest World Health Organization (WHO) Classification of Tumours of the Central Nervous System (WHO CNS5), adult-type diffuse gliomas are classified based on isocitrate dehydrogenase 1/2 (IDH1/2) mutation and 1p/19q codeletion statuses.1–4 Oligodendrogliomas are defined by the presence of IDH1/2 mutations and 1p/19q codeletion, whereas astrocytomas are diagnosed when IDH1/2 mutations but not 1p/19q codeletion are present. Thus, the presence of IDH mutation represents a fundamental characteristic of lower-grade gliomas. The most frequent mutation (83%-90%) of IDH1/2 in lower-grade gliomas is a substitution of the amino acid residue 132 from arginine to histidine (R132H) in IDH1.5–8 While wild-type IDH1 catalyzes the oxidative decarboxylation of isocitrate and produces α-ketoglutarate in the tricarboxylic acid cycle,9 mutant IDH1 produces the oncometabolite D-2-hydroxyglutarate (D-2-HG). D-2-HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including epigenetic regulators.10–14 It has been suggested that the accumulation of D-2-HG leads to early gliomagenesis, followed by clonal expansion through epigenetic dysregulation.15,16 Complete surgical removal of IDH-mutated gliomas cannot be achieved because of their infiltrative nature, resulting in recurrence, malignant progression, and eventual fatality.2 Current treatment strategies are radiotherapy and chemotherapy. However, radiotherapy can induce sequelae such as neurocognitive and neuroendocrine dysfunction,3,17–21 and chemotherapeutic strategies are often only transiently effective, highlighting the need for novel therapeutic strategies to treat gliomas. Therefore, the neomorphic enzymatic activity of mutant IDH1 serves as a potential therapeutic target for IDH1-mutant tumors.
DS-1001 is an orally available, small molecule selective mutant IDH1-R132 inhibitor with high permeability through the blood-brain barrier. In preclinical studies, DS-1001 showed good distribution to the brain in mice.22 Tumor growth inhibition and D-2-HG reduction were also observed in an orthotopic patient-derived xenograft model by continuous administration of DS-1001. Given these findings, inhibition of mutant IDH1 by DS-1001 could provide a novel therapeutic approach in patients with IDH1-mutant gliomas.
Here, we report the results of a first-in-human study of DS-1001, which aimed to investigate the maximum tolerated dose (MTD), recommended phase II dose (RP2D), tolerability and safety profiles, pharmacokinetics (PK), pharmacodynamics (PDy), and efficacy of DS-1001 in patients with IDH1-mutant gliomas.
Patients and Methods
Study Design
This was a multicenter, phase I, open-label study (NCT03030066). We present the results up to the data cutoff (January 31, 2021). The institutional review board of each participating center approved the trial. The study was performed according to the Declaration of Helsinki (1996 revision) under the principles of good clinical practice. All participants provided written informed consent before screening and enrollment.
Patients
For inclusion in the study, patients (≥20 years old) had to meet all of the following criteria: histologically confirmed glioma (grades 2-4) with an IDH1-R132 mutation; recurrent or progressive disease (PD) following standard treatment including radiotherapy; measurable lesion(s) as per Response Assessment in Neuro-Oncology (RANO)23 and RANO-low-grade glioma (RANO-LGG)24 criteria; an expected survival of ≥3 months; Eastern Cooperative Oncology Group performance status of 0-2; adequate hematological function (absolute neutrophil count ≥1200/mm3, platelets ≥100 000/mm3, and hemoglobin ≥9.0 g/dL); hepatic function (total bilirubin ≤1.5 mg/dL, and aspartate transaminase and alanine aminotransferase ≤100 IU/L) and renal function (serum creatinine ≤1.5 mg/dL or creatinine clearance ≥60 mL/minutes). Patients underwent baseline screening evaluations within 14 days before study day 1. Background data were collected from patients’ health records; previous MRI and pathology material were also evaluated.
Treatment Regimen, Drug Administration, and Dose-Escalation
DS-1001 (supplied by Daiichi Sankyo Co., Ltd.) was administered orally twice daily (bid) in 21-day cycles until disease progression or intolerable toxicity occurred. The dose-escalation was guided by the modified continual reassessment method (mCRM) according to a Bayesian logistic regression model,25 and governed by the escalation with overdose control principle.26 Cohorts of 3-6 patients were enrolled and assessed for dose-limiting toxicity (DLT) before escalation to a higher dose. Six dose levels (125-1400 mg bid) were tested (Supplementary Table S1).
Safety Evaluation
Safety assessments included adverse events (AEs), serious AEs (SAEs), treatment-emergent AEs (TEAEs), physical examination findings, Karnofsky performance status, and laboratory parameters (hematology and serum chemistry). TEAEs were documented at each study visit and were graded according to the Common Terminology Criteria for Adverse Events (version 4.0). DLTs are those not associated with the underlying disease or its progression, complications, or concomitant drugs and are detected during the 21-day treatment cycle. Cardiac toxicity was monitored by left ventricular ejection fraction assessments using echocardiography or multiple gated acquisition.
Pharmacokinetics
Blood samples were collected for PK analysis for DS-1001 at protocol-defined time points. Each patient underwent serial blood sample collection by venipuncture at DS-1001 pre-dose and at 0.5, 1, 1.5, 2, 4, 6, and 8 hours after morning dose on days 1 and 8 in cycle 1. Additionally, a single pre-dose blood sample was collected on days 4, 6, and 15 of cycle 1 and day 1 of cycle 2. Plasma PK parameters for DS-1001, including the maximum plasma concentration (Cmax), the time to Cmax (Tmax), and the area under the plasma concentration-time curve up to 8-hour post-dose (AUC0-8 h), were calculated by non-compartmental methods using Phoenix WinNonlin version 8.1 (Certara, Princeton, NJ, USA). For exploratory purpose, cerebrospinal fluid (CSF) samples were collected at screening and on day 15 of cycle 1 (±3 days). Patients in the exploratory study received DS-1001 treatment until surgery, and plasma and tumor samples were obtained prior to salvage surgical resection. DS-1001 concentrations in plasma, CSF, and resected tumor tissue samples were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Efficacy Measurements
Malignant transformation of grade 2 gliomas is often associated with tumor contrast enhancement on T1-weighted brain MRI. Therefore, patients were divided into enhancing and non-enhancing groups based on the presence or absence of tumor contrast enhancement judged by each investigator at the time of enrollment to estimate the grade at the time of drug administration.
Using MRI, investigators assessed treatment efficacy every 6 weeks. Tumor response was assessed by RANO for enhancing tumors and RANO-LGG for non-enhancing tumors. Briefly, the area of the longest diameter of the lesion and the largest size orthogonal to the longest diameter (as the shorter diameter) were measured in the largest slice of the flare high or T2 images, as described previously.27 A second scan confirmed the best overall response at 4 weeks or more after the initial assessment. Endpoints included best overall response and objective response rate (ORR) (defined as proportion of patients with a confirmed best overall response of complete response [CR], partial response [PR], or minor response [MR]). Progression-free survival (PFS) was defined as the interval from the first dose to disease progression or death from any cause, whichever occurred first.
We also performed an exploratory analysis in patients who planned to undergo salvage surgery after developing PD, had provided informed consent, and received DS-1001 treatment until surgery. Tumor samples were obtained from those patients to measure the free form of DS-1001 and D-2-HG levels for PK and PDy analyses.
Pharmacodynamic D-2-HG Assessment
Patients who planned to undergo salvage surgery after developing PD and provided informed consent received DS-1001 treatment until surgery. Tumor samples and corresponding plasma samples were provided on the day of the surgery. DS-1001 concentrations in the resected tumor samples and corresponding plasma samples were measured using validated LC-MS/MS methods. Tumor tissues were homogenized in 0.1 w/v% bovine serum albumin solution. Then, D-2-HG concentrations in the tissues were measured by LC-MS/MS after derivatization with diacetyl-l-tartaric anhydride.28 Commercially available D-2-HG (Sigma-Aldrich Co. LLC, Tokyo, Japan) was used as a reference standard. This analysis was conducted at Shin Nippon Biomedical Laboratories, Ltd. (Wakayama, Japan).
1p/19q Detection
Multiplex ligation-dependent probe amplification analysis of initial tumor biopsy samples was implemented to determine the 1p/19q deletion status for the diagnosis of oligodendroglioma. The analysis to determine the 1p/19q deletion status for the diagnosis of oligodendroglioma was performed using the SALSA MLPA Probemix P088 kit and Coffalyser.Net software (MRC Holland, Amsterdam, the Netherlands) according to the manufacturer’s recommendation.29
Statistical Analysis
The minimum number of patients necessary to accurately select the MTD and/or RP2D using the mCRM was set at 18. The maximum number of patients was set at 60 considering potential drop-outs and evaluating safety, tolerability, PK, PDy, and preliminary antitumor effect.
All patients who received at least one dose of DS-1001 were included in the safety analyses, with the MTD analysis only including patients who met predefined adequate exposure criteria. Efficacy analyses included patients who had at least one available efficacy measurement after the start of study treatment. PK analyses included patients who had at least one PK sample obtained, analyzed, and measured. Analyses of AEs included TEAEs (ie, those who started or worsened in severity on or after initiating treatment until 28 days after the last dose of DS-1001). AEs were counted once per patient using coded preferred terms at the worst severity and strongest causality. Medical coding of AEs was based on the Medical Dictionary for Regulatory Activities version 23.1, and AEs and laboratory test results were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Demographics, safety, efficacy, and PK data were summarized descriptively. We used SAS version 9.3 (SAS Institute Inc., Cary, NC, USA) for statistical analyses.
Results
Patient Characteristics
Between January 2017 and January 2021, 47 patients were enrolled in the study. Patient characteristics are shown in Table 1. Four of the 47 patients had oligodendroglioma (IDH-mutant, grade 2) and 11 had oligodendroglioma (IDH-mutant, grade 3). Twelve had astrocytoma (IDH-mutant, grade 2), 11 had astrocytoma (IDH-mutant, grade 3), and 7 had astrocytoma (IDH-mutant, grade 4). Thirty-five patients had enhancing tumors, and 12 had non-enhancing tumors. The presence of IDH1 mutations was determined by the local investigators at each site. All patients received radiotherapy prior to enrollment in the study; 30 of the 35 patients (85.7%) with enhancing tumors, and 8 of the 12 patients (66.7%) with non-enhancing tumors received chemotherapy prior to enrollment in the study. The median times since the end of the last systemic therapy and radiotherapy were 2.8 months and 35.7 months, respectively.
Table 1.
Patient Characteristics
| Characteristic | Enhancing (n = 35) | Non-enhancing (n = 12) | Total (N = 47) |
|---|---|---|---|
| Median age, years (min, max) | 46.0 (29, 77) | 38.5 (28, 49) | 44.0 (28, 77) |
| Female, n (%) | 14 (40.0) | 4 (33.3) | 18 (38.3) |
| ECOG PS, n (%) | |||
| 0 | 19 (54.3) | 8 (66.7) | 27 (57.4) |
| 1 | 13 (37.1) | 4 (33.3) | 17 (36.2) |
| 2 | 3 (8.6) | 0 (0.0) | 3 (6.4) |
| IDH1 mutation, n (%) | |||
| R132H | 34 (97.1) | 12 (100.0) | 46 (97.9) |
| R132L | 1 (2.9) | 0 (0.0) | 1 (2.1) |
| Most recent diagnosis, n (%) | |||
| Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted, grade 2 | 2 (5.7) | 2 (16.7) | 4 (8.5) |
| Oligodendroglioma, IDH-mutant, and 1p/19q-codeleted, grade 3 | 10 (28.6)a | 1 (8.3) | 11 (23.4) |
| Oligodendroglioma, grade 3, NOS | 1 (2.9) | 0 (0.0) | 1 (2.1) |
| Astrocytoma, IDH-mutant, grade 2 | 6 (17.1) | 6 (50.0) | 12 (25.5) |
| Astrocytoma, IDH-mutant, grade 2, NOS | 0 (0.0) | 1 (8.3) | 1 (2.1) |
| Astrocytoma, IDH-mutant, grade 3 | 9 (25.7) | 2 (16.7) | 11 (23.4) |
| Astrocytoma, IDH-mutant, grade 4 | 7 (20.0) | 0 (0.0) | 7 (14.9) |
| 1p19q statusb, n (%) | |||
| Non-codeleted | 22 (62.8) | 8 (66.7) | 30 (63.8) |
| Codeleted | 10 (28.6) | 3 (25.0) | 13 (27.7) |
| Not evaluated | 3 (8.6) | 1 (8.3) | 4 (8.5) |
| Number of prior recurrences, n (%) | |||
| 1 | 13 (37.1) | 7 (58.3) | 20 (42.6) |
| 2 | 11 (31.4) | 5 (41.7) | 16 (34.0) |
| ≥3 | 11 (31.4) | 0 (0.0) | 11 (23.4) |
| Median duration from initial diagnosis, years (min, max) | 4.9 (0.5, 15.3) | 5.8 (2.4, 12.6) | 5.2 (0.5, 15.3) |
| Prior radiation therapy, n (%) | 35 (100.0) | 12 (100.0) | 47 (100.0) |
| Prior chemotherapy, n (%) | 30 (85.7) | 8 (66.7) | 38 (80.9) |
| Temozolomide | 30 (85.7) | 5 (41.7) | 35 (74.5) |
| Nimusutine | 8 (22.9) | 6 (50.0) | 14 (29.8) |
| Bevacizumab | 7 (20.0) | 0 (0.0) | 7 (14.9) |
| Median time since last radiation therapy, months (range) | 29.9 (3.8, 175.9) | 64.9 (3.5, 125.8) | 35.7 (3.5, 175.9) |
| Median time since last chemotherapy, months (range) | 2.1 (1.1, 103.8) | 33.1 (2.6, 81.9) | 2.8 (1.1, 103.8) |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; IDH1, isocitrate dehydrogenase 1; NOS, not otherwise specified.
aTwo of the 10 patients were presumed to have oligodendroglioma based on the telomerase reverse transcriptase promoter and IDH1 mutations.
bThe evaluation was performed collectively and centrally, not by local judgment at each facility.
A total of 39 patients discontinued the study: 30 discontinued due to PD, 1 discontinued due to an AE of alanine aminotransferase increased, 7 withdrew consent, and 1 discontinued for a reason unrelated to the treatment. At the time of the data cutoff (January 31, 2021), 8 patients were receiving ongoing treatment in this study.
Safety
All 47 patients were evaluable for safety. The MTD was not reached, even at the highest dose level of 1400 mg bid. One DLT, grade 3 white blood cell count decreased, occurred at a dose of 1000 mg bid. Most patients (45 of 47 [95.7%]) experienced at least 1 AE of any grade or causality. The most common AEs (≥20%) were skin hyperpigmentation (53.2%), diarrhea (46.8%), pruritus (29.8%), alopecia (27.7%), arthralgia (27.7%), nausea (25.5%), headache (23.4%), rash (23.4%), back pain (21.3%), and dry skin (21.3%) (Table 2). Most AEs were grade 1-2. No grade 4 or 5 AEs or serious drug-related AEs were reported. Twenty (42.6%) patients experienced at least 1 grade 3 TEAE. Grade 3 events that were reported in more than 1 patient were neutrophil count decreased (12.8%), alanine aminotransferase increased (6.4%), white blood cell count decreased (6.4%), aspartate aminotransferase increased (4.3%), diarrhea (4.3%), and hypophosphatemia (4.3%)
Table 2.
Safety
| AE | All gradesa | Grade 3a |
|---|---|---|
| All AEs, n (%) | 45 (95.7) | 20 (42.6) |
| Preferred term, n (%)b | ||
| Skin hyperpigmentation | 25 (53.2) | 0 |
| Diarrhea | 22 (46.8) | 2 (4.3) |
| Pruritus | 14 (29.8) | 0 |
| Alopecia | 13 (27.7) | 0 |
| Arthralgia | 13 (27.7) | 1 (2.1) |
| Nausea | 12 (25.5) | 0 |
| Headache | 11 (23.4) | 1 (2.1) |
| Rash | 11 (23.4) | 0 |
| Back pain | 10 (21.3) | 0 |
| Dry skin | 10 (21.3) | 0 |
| Vomiting | 9 (19.1) | 0 |
| Neutrophil count decreased | 7 (14.9) | 6 (12.8) |
| Nasopharyngitis | 7 (14.9) | 0 |
| Feces soft | 6 (12.8) | 0 |
| Decreased appetite | 5 (10.6) | 0 |
| Alanine aminotransferase increased | 4 (8.5) | 3 (6.4) |
| Aspartate aminotransferase increased | 3 (6.4) | 2 (4.3) |
| White blood cell count decreased | 3 (6.4) | 3 (6.4) |
| Hypophosphatemia | 2 (4.3) | 2 (4.3) |
Abbreviation: AE, adverse event.
aSafety analysis set, N = 47.
bPatients were only counted once even if the same AE was reported more than once.
Twenty-seven (57.4%) patients had at least 1 dose interruption due to TEAEs. Most frequently reported TEAEs (≥10%) leading to dose interruption included neutrophil count decreased (6 [12.8%]) and arthralgia (5 [10.6%]). TEAEs associated with dose reduction were reported in 13 patients (27.7%), most of which were pain-related events (arthralgia [10.6%], back pain [6.4%], and neck pain [2.1%]) or laboratory test-related events (neutrophil count decreased [6.4%], alanine aminotransferase increased [4.3%], and white blood cell count decreased [4.3%]). These pain-related TEAEs were characterized as late-onset, mostly grade 1 or 2, and reversible, and they persisted for a long time while the study drug was being administered in some of the patients. Overall, DS-1001 had a favorable safety profile.
Pharmacokinetics
Following oral administration of DS-1001, the median Tmax was observed at 2-6 hours on day 1 of cycle 1 and 2-4 hours on day 8 of cycle 1 across the dose range of 125-1400 mg bid (Supplementary Table S2). Mean plasma trough concentration reached a plateau after the pre-dose at day 4, except for the 1400 mg bid dose, suggesting that the steady-state levels were achieved by day 4 of DS-1001 dosing at most dose levels (data not shown).
On day 1 and day 8 of cycle 1, the increase in Cmax and AUC0-8 h was approximately dose-proportional from 125 to 700 mg bid and was less than dose-proportional from 700 to 1400 mg bid (Supplementary Table S2, Supplementary Figure S1). DS-1001 also appeared in CSF on day 15 of cycle 1, which demonstrated the distribution of DS-1001 in the CNS (Supplementary Figure S2).
Efficacy
All 47 patients were evaluable for efficacy. In the 35 enhancing tumors assessed by RANO, we observed 2 CRs and 4 PRs. In the 12 non-enhancing tumors assessed by RANO-LGG, we found 1 PR and 3 MRs. The ORRs were 17.1% for enhancing tumors and 33.3% for non-enhancing tumors (Table 3). The waterfall plot shows the best percentage change in target tumor size (Figure 1A and B). In patients with measurable disease at baseline, tumor measurements decreased from baseline in 15 of the 35 patients with enhancing tumors (42.9%) and 11 of the 12 patients with non-enhancing tumors (91.7%; Figure 1A and B). Notably, among the 35 patients with enhancing tumors, 2 patients showed CR. The patient with astrocytoma (IDH-mutant, grade 4) has experienced CR for approximately 174 weeks and is still on treatment. The other patient with IDH1-mutant anaplastic oligodendroglioma has experienced CR for approximately 95 weeks and is still on treatment. Furthermore, 3 patients with enhancing tumors showed significant tumor shrinkage, approaching CR. MRI scans of a patient who showed CR and a patient who showed MR are shown in Supplementary Figure S3. Five of the 10 responders have had a continuous response and remain on treatment. The treatment duration was from 123 weeks to 207 weeks. The median response duration has not been reached for both lesion types.
Table 3.
Best Overall Response
| Response | Enhancing (n = 35) | Non-enhancing (n = 12) |
|---|---|---|
| Confirmed best overall response, n (%) | ||
| Complete response | 2 (5.7) | 0 (0.0) |
| Partial response | 4 (11.4) | 1 (8.3) |
| Minor responsea | NA | 3 (25.0) |
| Stable disease | 11 (31.4) | 8 (66.7) |
| Progressive disease | 17 (48.6) | 0 (0.0) |
| Not evaluated | 1 (2.9)b | 0 (0.0) |
| Objective response rate, n (%) | 6 (17.1) | 4 (33.3) |
Abbreviation: NA, not applicable.
aCategory of minor response is applied to patients meeting the Response Assessment in Neuro-Oncology-low-grade glioma criteria only.
bStudy treatment was discontinued before the first response assessment.
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.
The 1p/19q codeletion was detected in 10 of the 35 patients with enhancing tumors (28.6%) and 3 of the 12 patients with non-enhancing tumors (25.0%; Table 1). Measurable response was observed in both 1p/19q-codeleted and non-codeleted cases (Supplementary Figure S4).
At the time of the data cutoff (January 31, 2021), 8 patients (17.0%) remained on treatment, and 39 patients (83.0%) discontinued treatment, mainly due to disease progression. Patients with enhancing gliomas had a median treatment duration of 7.3 (range, 0-190) weeks, and 3 patients (8.6%) remained on treatment. In patients with non-enhancing gliomas, the median treatment duration was 91.2 (range, 15-207) weeks, and 5 of the 12 patients (41.7%) remain on treatment (Supplementary Table S3). Swimmer plots show that the duration of the response was remarkably long once the tumor responded in both enhancing and non-enhancing tumors (Figure 1C and D). The median PFS was 10.4 weeks (95% confidence interval [CI], 6.1 to 17.7 weeks) for the enhancing glioma cohorts, and not reached (95% CI, 24.1 to not reached) for the non-enhancing glioma cohorts, across all doses (Supplementary Figure S5).
Pharmacodynamic Analysis
To examine whether the drug penetrated into the brain and inhibited the production of D-2-HG in the tumor tissue, we conducted an additional exploratory study in patients with PD who underwent salvage surgery (Supplementary Figure S6). These patients continued the treatment until surgery, and the concentrations of DS-1001 and D-2-HG were measured in resected tumor tissues (Table 4). Even though the dose of DS-1001 and sampling time from the last dose varied among the patients, a high drug concentration was detected in all resected tumor samples, indicating the highly efficient brain penetration of the drug. The D-2-HG levels were also measured in the matched archived frozen tumor tissues collected at the previous surgery when available. The D-2-HG levels in the plasma were not elevated above normal levels in patients with glioma; however, the D-2-HG levels in on-treatment tumor tissues were extremely low compared with matched archived samples (Figure 2). The D-2-HG levels in archived and post-treatment tumor tissues of each patient are shown in Supplementary Table S4. The amount of D-2-HG was considerably lower after treatment than before with DS-1001. D-2-HG levels in CSF were not evaluable as a PDy marker due to being below the measurement limit (data not shown).
Table 4.
Drug Concentration in Resected Tumor Samples
| Measure | Patient #001 | Patient #002 | Patient #003 | Patient #004 | Patient #005 | Patient #006 | Patient #007 |
|---|---|---|---|---|---|---|---|
| Dose (mg bid) | 125 | 250 | 500 | 500 | 500 | 700 | 500 |
| Sampling time after last dose, h | 6.0, 6.3b | 5.5, 7.2b | 16.9 | 4.1, 4.2b | 4.4 | 7.2 | 5.0, 5.2b |
| DS-1001 concentrationa in resected tumor tissue, ng/g tissue | 555, 999b | 2770, 4310b | 5720 | 4250, 4270b | 1020, 2430b | 6130 | 2460, 3690b |
| Brain/plasma concentration ratio | 0.10, 0.18b | 0.35, 0.54b | 0.77 | 0.19 | NCc | 0.58 | 0.20, 0.30b |
Abbreviations: bid, twice daily; NC, not calculated.
aDrug concentration was expressed as a free form of DS-1001.
bData represent the range (min, max) of values as multiple samples were taken per patient.
cBrain/plasma ratio was NC as the corresponding plasma sample was taken approximately 3 hours earlier.
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.
Discussion
The rationale for targeting mutant IDH in diseases such as acute myeloid leukemia has been proven to be well founded.30,31 However, substantial clinical benefits following IDH inhibitor treatment remain to be confirmed. Nonetheless, the mutant IDH is an attractive molecular target for glioma therapy, with mutant IDH inhibitors including ivosidenib (AG-120),32,33 vorasidenib (AG-881),34,35 olutasidenib (FT-2102),36 and BAY143603237 currently being evaluated in clinical trials involving patients with gliomas. Our present study shows that twice-daily oral administration of DS-1001 resulted in antitumor activity in patients with recurrent/progressive IDH1-mutated gliomas.
The most common AE in the present study was grade 1/2 hyperpigmentation, which resembled sunburn and was observed only on the face and forearms. The mechanism of this symptom is still unknown; however, it was reversible and manageable. While most AEs were grade 1/2, at doses ≥500 mg bid, most patients who received long-term administration of DS-1001 required dose modifications due to episodes of pain. However, at doses ≤250 mg bid, there was no dose modification due to pain. Therefore, we considered <500 mg bid to be more appropriate doses for future clinical trials for diseases requiring long-term administration of DS-1001, such as chemotherapy- and radiotherapy-naïve IDH1-mutated WHO grade 2 gliomas. Although the data are limited, responses were observed at doses ≥125 mg bid. Furthermore, 125 mg bid of DS-1001-treated brain tumor samples showed significantly lower levels of D-2-HG compared with the pre-treatment samples. Considering the in vitro half-maximal inhibitory concentration data, the concentration of DS-1001 in the brain tumor was sufficient to account for this effect.22 From the PK/PDy data, the safety profile, and preliminary clinical responses, ≤250 mg bid was selected as the RP2D. DS-1001 was well tolerated and had a favorable safety profile, indicating that this agent can be administered for long-term treatment.
Among the 47 patients, 10 showed tumor regression, including 2 CRs, 5 PRs, and 3 MRs after DS-1001 treatment. We observed a 17.1% ORR for patients with contrast-enhancing gliomas: 2 CRs, 4 PRs, and the duration of response was sustainable. To the best of our knowledge, the ORRs reported here are the highest in this class of agents.38,39 Moreover, DS-1001 treatment showed similar response in both 1p/19q-codeleted and non-codeleted populations (Supplementary Table S5, Supplementary Figure S4). While the mutation of IDH1 is considered to occur early on during gliomagenesis,2 our findings suggest that some enhancing (malignant transformed) tumors and even recurrent malignant gliomas are still dependent on mutated IDH1 or D-2-HG production. Two patients achieved CR and showed long-term efficacy, suggesting that DS-1001 may be a promising option for such patients. As expected, the ORR was even higher at 33.3% in less aggressive non-enhancing gliomas, and many enhancing gliomas were refractory to the mutated IDH1 inhibitor. Notably, the resected tumors on treatment beyond PD displayed a significantly low amount of D-2-HG even after PD, suggesting that such refractory tumors developed mutations in other driver genes rather than acquired resistance to DS-1001 through trans/cis dimer-interface mutation within IDH1/2.40
DS-1001 is the first IDH inhibitor to elicit responses, including CR, in patients with recurrent/progressive IDH1-mutant glioma. On-treatment tumor samples showed favorable brain distribution of DS-1001 and significantly low levels of D-2-HG in brain tumors with DS-1001. Data from this first-in-human phase I study suggest that DS-1001 was well tolerated and had a favorable safety profile. Further follow-up and additional clinical studies are clearly warranted for this agent. A phase II study of DS-1001 in patients with chemotherapy- and radiotherapy-naïve IDH1-mutant WHO grade 2 gliomas is ongoing to verify the efficacy of DS-1001 as a single agent (NCT04458272). Another phase II study is planned outside Japan to evaluate the efficacy of DS-1001 (by AnHeart Therapeutics under the name AB-218), in patients with recurrent/progressive IDH1-mutant WHO grade 2/3 gliomas after receiving maximum 2 prior therapies for disease recurrence/progression (NCT05303519).
Supplementary Material
Acknowledgments
We thank the patients who participated in this study, as well as their families and caregivers. We also thank the staff and investigators at all the study sites. We also thank Hiroyuki Inoue from Daiichi Sankyo Co., Ltd. for supporting the pharmacokinetic assessments. Assistance in medical writing and editorial support were provided by Michelle Belanger, MD, of Edanz (www.edanz.com), which was funded by Daiichi Sankyo Co., Ltd. Some of the results of this article were presented at the American Society of Clinical Oncology (ASCO) 2019 congress on May 31-June 4, 2019.
Contributor Information
Atsushi Natsume, Nagoya University School of Medicine, Nagoya, Japan.
Yoshiki Arakawa, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yoshitaka Narita, National Cancer Center Japan, Tokyo, Japan.
Kazuhiko Sugiyama, Hiroshima University Hospital, Hiroshima, Japan.
Nobuhiro Hata, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yoshihiro Muragaki, Graduate School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan.
Naoki Shinojima, Kumamoto University Hospital, Kumamoto, Japan.
Toshihiro Kumabe, Kitasato University School of Medicine, Sagamihara, Japan.
Ryuta Saito, Tohoku University Graduate School of Medicine, Sendai, Japan.
Kazuya Motomura, Nagoya University School of Medicine, Nagoya, Japan.
Yohei Mineharu, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Yasuji Miyakita, National Cancer Center Japan, Tokyo, Japan.
Fumiyuki Yamasaki, Hiroshima University Hospital, Hiroshima, Japan.
Yuko Matsushita, National Cancer Center Japan, Tokyo, Japan.
Koichi Ichimura, National Cancer Center Japan, Tokyo, Japan.
Kazumi Ito, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Masaya Tachibana, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Yasuyuki Kakurai, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Naoko Okamoto, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Takashi Asahi, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Soichiro Nishijima, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Tomoyuki Yamaguchi, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Hiroshi Tsubouchi, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
Hideo Nakamura, Department of Neurosurgery, Kurume University School of Medicine, Fukuoka, Japan.
Ryo Nishikawa, Saitama Medical University International Medical Center, Hidaka, Japan.
Funding
This study (NCT03030066) was supported by Daiichi Sankyo Co., Ltd. which was involved in all aspects of study design, data collection, data analysis, and data interpretation, and provided the study drug.
Conflict of interest statement. A.N. reports grants and personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; and grants from Takeda Pharmaceutical; grants and personal fees from Chugai Pharmaceutical; and personal fees from Eisai, SRL, Teijin Pharma, and NGK Spark Plug, outside the submitted work. Y.A. reports other fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; and personal fees from NipponKayaku, UCB, Novocure, AbbVie, and Integra Japan; grants and personal fees from Chugai Pharmaceutical, Eisai, Merck, Meiji Seika, Otsuka Pharmaceutical, Brainlab, CSL Behring, and Carl Zeiss; grants from Siemens, Philips, Nihon Medi-Physics, Tanabe Mitsubishi, Pfizer, Stryker, Astellas Pharma, and Takeda; personal fees and other fees from Ono Pharmaceutical Co., Ltd.; and other fees from Taiho Pharma, outside the submitted work. Y.N. reports grants from Daiichi Sankyo Co., Ltd. during the conduct of the study; and grants from AbbVie, Ono Pharmaceutical Co., Ltd., Dainippon-Sumitomo, Eisai, and Stella Pharma; and personal fees from Chugai Pharmaceutical Co., Ltd., outside the submitted work. K.S. reports grants and personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; and grants and personal fees from Ono Pharmaceutical Co., Ltd., MSD, Bristol Myers Squibb, Chugai Pharmaceutical, and Nobelpharma Co., Ltd.; grants from Sumitomo Dainippon Pharma; and personal fees from Meiji Seika Pharma, outside the submitted work. N.H. reports other fees from Daiichi Sankyo Co., Ltd. during the conduct of the study. Y.Muragaki has nothing to disclose. N.S. has nothing to disclose. T.K. reports personal fees from Boehringer Ingelheim Japan, Inc.; grants and personal fees from Chugai Pharmaceutical Co., Ltd., CSL Behring, Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and Teijin Pharma Ltd.; personal fees from Integra Japan, MSD (Merck Sharp and Dohme), Nobelpharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., and UCB Japan Co. Ltd.; and grants from Astellas Pharma Inc., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation, Nihon Medi-Physics Co., Ltd., Pfizer Inc., and Shionogi & Co., Ltd., outside the submitted work. R.S. has nothing to disclose. K.M. has nothing to disclose. Y.Mineharu reports other fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; and grants and personal fees from Eisai; grants from Chugai Pharmaceutical, Merck, Meiji Seika, Otsuka Pharmaceutical, Brainlab, CSL Behring, Carl Zeiss, Siemens, Philips, Nihon Medi-Physics, Tanabe Mitsubishi, Pfizer, Stryker, Astellas Pharma, and Takeda; other fees from Ono Pharmaceutical Co., Ltd., and Taiho Pharma; and personal fees from Daiichi Sankyo Co., Ltd., Sony, and Bristol Myers Squibb, outside the submitted work. Y.Miyakita reports other fees from Daiichi Sankyo Co., Ltd. during the conduct of the study. F.Y. has nothing to disclose. Y.Matsushita has nothing to disclose. K.Ichimura reports grants and personal fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; grants and personal fees from Chugai Pharmaceuticals, Sumitomo Dainippon Pharma, Leica Microsystems, and Eisai Co., Ltd.; and grants from Therabio Pharma, SRL, DENBA, AMED, and KAKENHI, outside the submitted work. K.Ito, M.T., Y.K., N.O., T.A., S.N., T.Y., and H.T. are full-time employees of Daiichi Sankyo Co., Ltd. H.N. reports grants and personal fees from Eisai and Ono Pharmaceutical Co., Ltd., outside the submitted work. R.N. reports other fees from Daiichi Sankyo Co., Ltd. during the conduct of the study; personal fees from Ono Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., and Novocure; grants and personal fees from MSD and Eisai; grants from Chugai; and other fees from AbbVie and Nihon Medi-Physics, outside the submitted work.
Authorship statement. Study concept and design: A.N., R.N., Y.N., Y.Muragaki, T.K., K.Ito, M.T., Y.K., S.N., and H.T. Provision of study materials or treatment to patients: A.N., Y.A., Y.N., K.S., N.H., Y.Muragaki, N.S., T.K., R.S., K.M., Y.Miyakita, Y.Mineharu, F.Y., H.N., and R.N. Data collection and assembly: A.N., Y.A., Y.N., K.S., N.H., Y.Muragaki, N.S., T.K., R.S., K.M., Y.Mineharu, Y.Miyakita, F.Y., R.N., K.Ichimura, Y.Matsushita, K.Ito, M.T., N.O., T.Y., S.N., and H.T. Data analysis and interpretation: A.N., Y.A., Y.N., K.S., N.H., Y.Muragaki, N.S., T.K., R.S., F.Y., H.N., R.N., K.Ichimura, Y.Matsushita, K.Ito, M.T., Y.K., N.O., T.A., T.Y., S.N., and H.T. Development of tables and figures: A.N., K.Ito, M.T., Y.K., N.O., T.A., and H.T. Writing the report: A.N., N.O., T.A., and H.T. Critical review of the manuscript and approval of the final version: all authors.
Data Availability
De-identified individual participant data and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/.
References
- 1. Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro Oncol. 2015;17(Supple 4):iv1–iv62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Suzuki H, Aoki K, Chiba K, et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet. 2015;47(5):458–468. [DOI] [PubMed] [Google Scholar]
- 3. Grill J, Couanet D, Cappelli C, et al. Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol. 1999;45(3):393–396. [DOI] [PubMed] [Google Scholar]
- 4. Brat DJ, Verhaak RG, Aldape KD, et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med. 2015;3728(26):2481–2498. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Hartmann C, Meyer J, Balss J, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 2009;118(4):469–474. [DOI] [PubMed] [Google Scholar]
- 6. Ohgaki H, Kleihues P. Genetic profile of astrocytic and oligodendroglial gliomas. Brain Tumor Pathol. 2011;28(3):177–183. [DOI] [PubMed] [Google Scholar]
- 7. Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–773. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Arita H, Yamasaki K, Matsushita Y, et al. A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas. Acta Neuropathol Commun. 2016;4(1):79. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Cairns RA, Mak TW. Oncogenic isocitrate dehydrogenase mutations: mechanisms, models, and clinical opportunities. Cancer Discov. 2013;3(7):730–741. [DOI] [PubMed] [Google Scholar]
- 10. Chowdhury R, Yeoh KK, Tian YM, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12(5):463–469. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474–478. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Sasaki M, Knobbe CB, Itsumi M, et al. D-2-hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 2012;26(18):2038–2049. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Koivunen P, Lee S, Duncan CG, et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature. 2012;483(7390):484–488. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2010;465(7300):966. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Noushmehr H, Weisenberger DJ, Diefes K, et al. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell. 2010;17(5):510–522. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Greenberger BA, Pulsifer MB, Ebb DH, et al. Clinical outcomes and late endocrine, neurocognitive, and visual profiles of proton radiation for pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys. 2014;89(5):1060–1068. [DOI] [PubMed] [Google Scholar]
- 18. Perkins SM, Fei W, Mitra N, et al. Late causes of death in children treated for CNS malignancies. J Neurooncol. 2013;115(1):79–85. [DOI] [PubMed] [Google Scholar]
- 19. Ris MD, Beebe DW, Armstrong FD, et al. Cognitive and adaptive outcome in extracerebellar low-grade brain tumors in children: a report from the Children’s Oncology Group. J Clin Oncol. 2008;26(29):4765–4770. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Tacke U, Karger D, Spreer J, et al. Incidence of vasculopathy in children with hypothalamic/chiasmatic gliomas treated with brachytherapy. Childs Nerv Syst. 2011;27(6):961–966. [DOI] [PubMed] [Google Scholar]
- 21. Bandopadhayay P, Bergthold G, London WB, et al. Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer. 2014;61(7):1173–1179. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Machida Y, Nakagawa M, Matsunaga H, et al. A potent blood-brain barrier-permeable mutant IDH1 inhibitor suppresses the growth of glioblastoma with IDH1 mutation in a patient-derived orthotopic xenograft model. Mol Cancer Ther. 2020;19(2):375–383. [DOI] [PubMed] [Google Scholar]
- 23. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28(11):1963–1972. [DOI] [PubMed] [Google Scholar]
- 24. van den Bent MJ, Wefel JS, Schiff D, et al. Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol. 2011;12(6):583–593. [DOI] [PubMed] [Google Scholar]
- 25. Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med. 2008;27(13):2420–2439. [DOI] [PubMed] [Google Scholar]
- 26. Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose escalation with overdose control. Stat Med. 1998;17(10):1103–1120. [DOI] [PubMed] [Google Scholar]
- 27. Chukwueke UN, Wen PY. Use of the Response Assessment in Neuro-Oncology (RANO) criteria in clinical trials and clinical practice. CNS Oncol. 2019;8(1):CNS28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Struys EA, Jansen EE, Verhoeven NM, et al. Measurement of urinary d- and l-2-hydroxyglutarate enantiomers by stable-isotope-dilution liquid chromatography-tandem mass spectrometry after derivatization with diacetyl-l-tartaric anhydride. Clin Chem. 2004;50(8):1391–1395. [Google Scholar]
- 29. Arita H, Narita Y, Fukushima S, et al. Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. Acta Neuropathol. 2013;126(2):267–276. [DOI] [PubMed] [Google Scholar]
- 30. Dang L, Su SM. Isocitrate dehydrogenase mutation and (R)-2-hydroxyglutarate: from basic discovery to therapeutics development. Annu Rev Biochem. 2017;86:305–331. [DOI] [PubMed] [Google Scholar]
- 31. Boddu P, Borthakur G. Therapeutic targeting of isocitrate dehydrogenase mutant AML. Expert Opin Investig Drugs. 2017;26(5):525–530. [DOI] [PubMed] [Google Scholar]
- 32. Mellinghoff IK, Ellingson BM, Touat M, et al. Ivosidenib in isocitrate dehydrogenase 1-mutated advanced glioma. J Clin Oncol. 2020;38(29):3398–3406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Tap WD, Villalobos VM, Cote GM, et al. Phase I study of the mutant IDH1 inhibitor ivosidenib: safety and clinical activity in patients with advanced chondrosarcoma. J Clin Oncol. 2020;38(15):1693–1701. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Konteatis Z, Artin E, Nicolay B, et al. Vorasidenib (AG-881): a first-in-class, brain-penetrant dual inhibitor of mutant IDH1 and 2 for treatment of glioma. ACS Med Chem Lett. 2020;11(2):101–107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Mellinghoff IK, Penas-Prado M, Peters KB, et al. Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; results of a first-in-human phase I trial. Clin Cancer Res. 2021;27(16):4491–4499. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Caravella JA, Lin J, Diebold RB, et al. Structure-based design and identification of FT-2102 (Olutasidenib), a potent mutant-selective IDH1 inhibitor. J Med Chem. 2020;63(4):1612–1623. [DOI] [PubMed] [Google Scholar]
- 37. Pusch S, Krausert S, Fischer V, et al. Pan-mutant IDH1 inhibitor BAY 1436032 for effective treatment of IDH1 mutant astrocytoma in vivo. Acta Neuropathol. 2017;133(4):629–644. [DOI] [PubMed] [Google Scholar]
- 38. Mellinghoff I, Penas-Prado M, Peters K, et al. ACTR-31. Phase 1 study of AG-881, an inhibitor of mutant IDH1 and IDH2: results from the recurrent/progressive glioma population (Abstract). Neuro Oncol. 2018;20(Suppl_6):vi18. [Google Scholar]
- 39. De la Fuente MI, Colman H, Rosenthal M, et al. ACTR-52. Phase 1 study of FT-2102, an inhibitor of mutant IDH1, in patients with relapsed/refractory IDH1 mutant gliomas: preliminary safety and clinical activity (E-talk). Paper presented at: 24th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology; November 20–24; 2019; Phoenix, AZ, USA.
- 40. Intlekofer AM, Shih AH, Wang B, et al. Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations. Nature. 2018;559(7712):125–129. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
De-identified individual participant data and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/.