Phase 1b/2 Study of Decitabine and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Olutasidenib for Patients with Relapsed/Refractory AML, High Risk MDS, or Newly Diagnosed AML Not Eligible for Chemotherapy with an IDH1 Mutation

Background and Significance:

Outcomes for most patients with AML remain poor. Efforts to improve both the remission rate and the durability of remission in patients of all ages are paramount. IDH1 mutations occur in 7-14% of patients with AML, often enriched in older patients, and both hypomethylating agents in combination with venetoclax, and IDH1 inhibitors are effective, albeit non-curative, strategies.

Preliminary outcomes of “IDH1 triplet regimens” including azacitidine, venetoclax and ivosidenib and oral decitabine/cedazuridine, venetoclax and ivosidenib, have confirmed IDH1-triplet regimens are well tolerated and highly effective for both newly diagnosed (ND) and relapsed/refractory (R/R) patients with IDH1 mutated AML and high-risk MDS. This will be the first study to evaluate the efficacy of the triplet regimen of the IDH1 inhibitor olutasidenib in combination with decitabine + venetoclax therapy.

Study Design and Methods:

This multicenter investigator-initiated study under the MDACC-Rigel Research Alliance will be a Phase 1b/2, open-label, non-randomized trial with dual primary objectives of assessing the safety and efficacy of decitabine (IV or oral) in combination with venetoclax (VEN) and the mutant targeted IDH1 inhibitor olutasidenib (OLUTA).

Eligibility includes adult patients with a confirmed IDH1 mutation and a diagnosis of R/R AML, high risk MDS (defined as > 5% blasts), or ND AML not eligible for intensive chemotherapy. Newly diagnosed patients will be eligible for the Phase 2 portion only.

In the Phase 1 portion, patients will be enrolled in cohorts of 3 beginning with dose level 1. The starting dose will evaluate the approved doses of decitabine (or oral decitabine/cedazuridine) on days 1-5, VEN 400mg qDAY on days 1-14, and OLUTA 150mg BID continuously starting on C1D8. Dose level 2 will evaluate VEN at 600 mg daily on days 1-14, due to the potential drug-drug interaction of OLUTA on lowering venetoclax exposure, related to in vitro evidence that OLUTA functions as a CYP3A inducer and thus is anticipated to lead to decreased venetoclax AUC. The combination RP2D will be selected at the end of the phase I portion based on analysis of safety, efficacy, and PK guidance.

Up to sixty patients will be treated in the Phase 2 portion; 30 per cohort (newly diagnosed (Part 2A) and relapsed/refractory (Part 2B) at the combination RP2D. Treatment cycles will begin on day 1 of each new HMA cycle. Patients will continue study therapy unless they have evidence of progressive disease, unacceptable toxicity, or discontinue therapy (i.e. due to transition to allogeneic SCT).

The maximum number of patients treated on this investigational study will be 78. It is anticipated that 5-6 US centers will participate. The study is planned to activate and initiate enrollment in August 2024.

Primary objectives in the phase 1b are the safety and tolerability and recommended phase 2 combination dose (RP2D). Dose-limiting toxicities will be monitored during the first 2 cycles of study. Primary objectives in the phase 2 are to determine the complete remission rate (CR) within 5 cycles of treatment for newly diagnosed (Arm A) or relapsed/refractory (Arm B) patients with IDH1-mutated myeloid malignancy.

Key secondary objectives are to determine composite remission rate (CRc; CR, CRh, and CRi) and overall response rate (ORR; CR, CRh, CRi, MLFS and PR) as well as the duration of response, event-free survival, and overall survival along with evaluation of occurrence of minimal residual disease (MRD) negative status by multiparameter flow cytometry and molecular evaluation. In addition, characterization of the PK profiles of VEN and OLUTA in plasma samples will be performed in the Phase 1b portion.