A phase 2 study of olutasidenib in combination with azacitidine followed by olutasidenib maintenance after venetoclax plus a hypomethylating agent regimen for <i>IDH1</i> -mutated acute myeloid leukemia (University of California Hematologic Malignancies Consortium Study 2441).

Abstract

TPS6603 Background: Acute myeloid leukemia (AML) with isocitrate dehydrogenase-1 (IDH1) mutations represents a subset of up to approximately 7-14% of patients. For patients with IDH1m AML ineligible for first line intensive induction, the combination of a hypomethylating agent (HMA) and venetoclax (VEN) is a standard of care based on the VIALE-A study. In patients with IDH1m, the HMA azacitidine (AZA) plus VEN regimen leads to a complete remission (CR) plus CR with incomplete count recovery (CRi) rate of 66.7%, duration of remission (DoR) 21.9 months, and median overall survival (OS) of 15.2 months. However, one of the limiting features of HMA-VEN is myelosuppression, leading to dose delays and reductions, and adverse events (AEs) led to discontinuation in up to 30% of patients on the VIALE-A study. Approaches to increase tolerability and improve outcomes are of interest. Olutasidenib (OLU) is a potent, oral and selective small-molecule IDH1m inhibitor currently approved for relapsed/refractory AML patients with an IDH1 mutation, based on the pivotal cohort of a Phase 1/2 study. Overall, this study showed that OLU alone or in combination with AZA in patients with IDH1m AML was well-tolerated and showed meaningful clinical activity, including in those with prior VEN treatment. We hypothesize that, after achieving a response on HMA-VEN, de-escalating and switching maintenance from HMA-VEN to OLU-AZA followed by OLU monotherapy will lead to improved outcomes for patients with IDH1m AML. Methods: This multicenter investigator-initiated study through the University of California Hematologic Malignancies Consortium (UCHMC) is a phase II single-arm study evaluating the combination of OLU in combination with AZA followed by OLU monotherapy as a switch maintenance approach after HMA-VEN for patients with IDH1m AML. Key eligibility criteria include a diagnosis of IDH1m AML, achievement of CR or CRi to first-line HMA-VEN with no more than 4 cycles of HMA-VEN at the time of enrollment, IDH1m inhibitor naïve, age 18+, and performance status 0-2. The primary endpoint is treatment failure, defined as AML-related death, relapse, or treatment discontinuation due to AE within 12 months from the time of CR/CRi. Secondary endpoints include treatment-related AE, time to treatment failure, relapse-free survival, DoR, OS, and rate of allotransplant. Patients will receive OLU 150mg BID in combination with standard AZA during the first 4 cycles followed by OLU 150mg BID monotherapy until any discontinuation criteria are met. Disease assessments will be performed at baseline, following cycles 4, 8, and 12, and then as clinically indicated. The trial will enroll up to 28 patients across the UCHMC. The trial is currently enrolling. Clinicaltrials.gov ID is NCT07304011. Clinical trial information: NCT07304011 .