MDS-265: Ivosidenib (IVO) in Patients with IDH1-Mutant Relapsed/Refractory Myelodysplastic Syndrome (R/R MDS): Updated Enrollment of a Phase 1 Dose Escalation and Expansion Study

Context: IVO is an oral, potent, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, approved in the US for the treatment of AML with a susceptible IDH1 mutation in adults with newly diagnosed AML ≥75 years of age or having comorbidities precluding intensive induction chemotherapy, and in adults with R/R AML. In a phase 1 dose escalation and expansion study of IVO in mIDH1 advanced hematologic malignancies (NCT02074839), 12 patients with R/R MDS received IVO 500 mg once daily (QD). Median age was 72.5 years (range 52–78). All patients had received prior treatment for MDS, with 3 (25.0%) and 1 (8.3%) having received 2 or ≥3 prior therapies, respectively. Investigator-assessed ORR (CR + PR + marrow CR) per International Working Group 2006 criteria was 75.0% (95% CI 42.8%, 94.5%) with a median duration of 21.4 months (95% CI 2.3, not estimable). Nine patients (75.0%) were transfusion independent for ≥56 days during study treatment. Based on these data, the FDA recently granted a Breakthrough Therapy Designation status for IVO monotherapy in this indication, and the study has been amended to enroll additional mIDH1 R/R MDS patients. Objective: To assess safety, tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of IVO in patients with mIDH1 R/R MDS. Design: This is a sub-study of the phase 1 study of IVO in mIDH1 advanced hematologic malignancies to evaluate patients with mIDH1 R/R MDS. Patients must have R/R disease after treatment with standard agents indicated for MDS and high disease burden based on cytopenia and/or transfusion dependence at baseline. IVO will be administered at a dose of 500 mg QD orally on Days 1–28 of 28-day cycles. Results: The study is open and will enroll ∼23 patients from the US and France; results not yet available. Conclusions: The favorable efficacy and safety of IVO in the small population of patients with mIDH1 R/R MDS in the phase 1 clinical study supports further evaluation in this MDS sub-study. This sub-study will provide additional insights into safety, tolerability, clinical activity, and pharmacokinetics/pharmacodynamics of treatment with IVO in patients with mIDH1 R/R MDS. Funding: Agios.