Introduction: Isocitrate dehydrogenase (IDH) enzymes catalyze the NADP-dependent interconversion of isocitrate and α-ketoglutarate. R132* IDH1 mutations lead to cellular accumulation of 2-hydroxyglutarate (2-HG), an oncometabolite that promotes tumorigenesis. IDH1 mutations are found in glioma (~80%), chondrosarcoma (~50%), cholangiocarcinoma (~20% intrahepatic), acute myeloid leukemia (AML; ~6-9%), and myelodysplastic syndrome (MDS; ~3%). IDH305 is a potent, orally available, mutant-selective, allosteric IDH1 inhibitor. IDH305 suppresses mutant IDH1-dependent 2-HG production and cell proliferation with an IC50 of 24 nM, and has antitumor activity in preclinical studies.

Methods: The objectives of this ongoing phase I clinical trial in patients with advanced cancers are to evaluate the safety and tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and preliminary antitumor activity of IDH305 (IDH305X2101, NCT02381886). This trial is specifically designed to evaluate the safety of IDH305 both across and within 3 broad disease areas: glioma, AML/MDS, and other/non-CNS solid tumors with the IDH1R132 mutation. IDH305 is orally administered twice a day (BID) in continuous 21-day cycles. The starting dose of 75 mg BID was determined from 4-week toxicology studies following ICH Guideline S9. Dose escalation is guided by a Bayesian hierarchical model (BHM), which evaluates the dose-limiting toxicity (DLT) relationship to the collective population, as well as to specific disease areas, across dose levels, to model the similarity in the rate of DLTs during the first cycle of treatment. The BHM permits the declaration of different maximum tolerated doses (MTDs)/recommended doses for expansion (RDEs) for 3 disease areas, if suggested by the data. Dose expansions in disease-specific cohorts are designed to further characterize safety and explore antitumor activity. Pre- and on-treatment specimens (blood, tumor) are being collected for PK and PD evaluations.

Results: As of the data cut-off, March 30, 2016, 81 patients have been enrolled: glioma (n=32), AML (n=21), MDS (n=3), other/non-CNS solid tumors (n=24), and unknown (n=1). Patients were treated with IDH305 on a BID schedule at various doses: 75 mg (n=6), 150 mg (n=11), 300 mg (n=16), 450 mg (n=9), 550 mg (n=16), 750 mg (n=10), and 900 mg (n=13). During dose escalation, DLTs of Grade 3 elevated bilirubin were observed in 2 patients with solid tumors (2 at 550 mg BID), 1 patient with glioma (900 mg BID) who also experienced a DLT of Grade 3 elevated lipase, and 1 patient with AML (750 mg BID). A DLT of Grade 3 rash was observed in 1 patient with a solid tumor (750 mg BID). All DLTs resolved and were considered reversible.

MTDs for each disease area were not determined. RDE was determined for glioma (550 mg BID) and solid tumors (550 mg BID). Dose escalation continues for AML/MDS. Across all 3 disease areas, the most common adverse events (AE) reported as suspected of being related to IDH305 (>10%, all grades) included: bilirubin increased (30.9%); aspartate aminotransferase (AST) increased (17.3%); alanine aminotransferase (ALT) increased (16.0%); and nausea (13.6%). Grade 3 AEs suspected to be related to IDH305 that occurred in >1 patient included: bilirubin increased (8.6%)/hyperbilirubinemia (2.5%); AST increased (2.5%); and ALT increased (3.7%). Among 24 AML/MDS patients (21 relapsed/refractory AML and 3 MDS), the most common suspected AEs reported as being related to IDH305 (>5%, all grades) included: raised bilirubin and lipase (8.3% each). There was one Grade 3 AE of increased bilirubin that was also a DLT. Objective responses were reported in 7 (33%) AML patients: complete remission in 2 (9.5%), complete remission with incomplete recovery in 1 (4.8%), and partial remission in 4 (19.0%) patients. Responses appear durable. PK, PD, and updated clinical safety and efficacy data will be reported.

Conclusion: Preliminary clinical data suggest that IDH305 has a favorable safety profile and promising antitumor activity in IDH1-mutated AML. Studies to further evaluate the safety, tolerability, and antitumor activity of IDH305 as a single agent and in combination are ongoing.


DiNardo:Agios: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding. Schimmer:Novartis: Honoraria. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Carvajal:Novartis: Consultancy. Janku:Agios: Research Funding; Novartis: Consultancy, Research Funding. Bedard:Novartis: Research Funding. van den Bent:Novartis, Roche, AbbVie, Celgene, BMS: Consultancy. O'Keeffe:Novartis: Employment. Chen:Novartis Pharmaceuticals Corporation: Employment. Pagliarini:Novartis Institutes for Biomedical Research: Employment, Equity Ownership, Patents & Royalties. Schuck:Novartis: Employment. Myers:Novartis Institutes of Biomedical Research: Employment, Equity Ownership. Wei:Novartis: Honoraria, Research Funding.

Author notes


Asterisk with author names denotes non-ASH members.