Phase Ib/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib: 2023 Update

Background

Isocitrate Dehydrogenase (IDH) 1 or 2 mutations occur in ~20% of acute myeloid leukemia (AML). Both venetoclax (VEN)-based and targeted IDH-inhibitor (IDHi) therapies are effective treatment options for IDH mutated AML in combination with hypomethylating agents (HMA). ASTX727 is an oral, fixed dose (35 mg/100 mg) combination of decitabine and cedazuridine with bioequivalency to IV decitabine. Herein we report interim results including completion of the Phase 1b portion of the first all-oral triplet regimen of ASTX727 (day 1-5) + VEN (day 1-14) in combination with a targeted mutant IDH1i ivosidenib (IVO) or IDH2i enasidenib (ENA), for IDH mutated AML.

Methods

Eligible patients (pts) were > 18 years old with newly diagnosed (ND) AML not eligible for intensive chemotherapy, or relapsed/refractory (R/R) IDH1 or IDH2 mutated AML. Prior VEN, HMA, and/or IDHi use was not exclusionary in the R/R cohort. The primary objectives were to determine safety and the recommended phase 2 dose (RP2D) of ASTX727 and VEN with IVO (Arm A) or ENA (Arm B) [Phase 1b], and to determine the composite remission rate (CRc; CRh+CRi+CR) for both arms [Phase 2].

Results

A total of 51 pts (1b: 26 pts, 2: 25 pts) have been enrolled. The phase 1b portion is completed and the RP2D is established at VEN 600mg in combination with IVO (due to the CYP3A4 inducing effects of ivosidenib requiring a higher dose of VEN to maintain therapeutic concentrations), and VEN 400mg in combination with ENA.

There are currently 50 evaluable pts (Arm A: 20, Arm B: 30); median follow up is 11.0 months (mos) for ND pts and 14.6 mos for R/R pts. Median age at enrollment was 72 years (41 – 86). 48% (n=24) pts had ND-AML (A: 10, B: 14) and 52% (n = 26) with R/R AML (A: 10, B: 16). ELN 2022 classification was intermediate or adverse in 87% of ND-AML and 92% of the R/R AML cohorts. Median variant allele frequency in ND pts was 22% (7-38, IDH1) and 36% (4-49, IDH2) and was 29% (8-45, IDH1) and 37% (2-48, IDH2) in the R/R arms. Patients with R/R-AML received a median of 2 lines of prior therapy, including 20 pts having received prior VEN and 7 receiving prior IDH-inhibitor.

The composite remission rate (CRc), defined as CR + CRh + CRi, was 96% (n=23) in ND-AML and 46% (n=12) with R/R disease (Table 1). Of pts who received prior VEN, 30% (n=6) achieved a CRc (3 CR, 2 CRi, 1CRh) and in those with prior IDHi exposure, 71% (n=5) achieved a CRc (4 CR, 1 CRh)(Table 2). Measurable residual disease (MRD) negative CRc by flow cytometry was achieved as best response in 91% of the responding ND pts (35% IDH1 and 56% IDH2) and 67% (42% IDH1 and 25% IDH2) of R/R pts. Duration of response (DOR) was not reached (NR) for ND pts and 16.1 mos in R/R pts. Event free survival (EFS) was NR and 5.9 mos (2.76 – NA), respectively. Overall survival (OS) was NR for ND and 10.4 mos (4.7 – NA) for R/R AML.

The most common non-hematologic grade 3/4 AEs included indirect hyperbilirubinemia (n=3, 6%) all in enasidenib-treated pts, and two pts (4%) had grade 3 mucositis, one which was attributed to prior cytoreductive therapy. AEs of special interest regardless of grade included differentiation syndrome in 10% (n=5, A:3; B:2), all successfully managed with corticosteroids and diuresis. 4% (n=2) had TLS which was medically managed, one pt required CRRT briefly with full recovery of renal function. 19 pts remain on study, 8 transitioned to SCT in response, and 5 pts (4 ND, 1 R/R) withdrew from the study, including 4 in CRc response, after 2 (n=2), 5 (n=1) and 8 (n=1) cycles of protocol therapy.

Conclusions

Triplet therapy with ASTX727 + VEN + IDH1/2 inhibition appears safe and preliminarily effective for IDH mutated AML, with high rates of MRD-negative CRc particularly in ND pts and in R/R pts not having received prior VEN or IDHi. AEs were anticipated and tolerable. Enrollment is ongoing.