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 in IDH Mutated Acute Myeloid Leukemia

Abstract

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 approved for the treatment of myelodysplastic syndrome (MDS). Herein we report the interim results 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 were > 18 years old with relapsed/refractory (R/R) IDH1 or IDH2 mutated AML, or newly diagnosed (ND) AML not eligible for intensive chemotherapy. For the R/R AML cohort, prior VEN, HMA or IDHi use was not exclusionary. The primary objectives were to determine safety and the recommended phase 2 dose (RP2D) of ASTX727 and VEN with ivosidenib (Arm A) or enasidenib (Arm B) [Phase 1b], and to determine the composite remission rate (CRc; CRh+CRi+CR) for both arms [Phase 2]. Results A total of 32 patients have enrolled, with 3 screen failures and 2 patients ongoing first cycle of therapy. There are currently 27 evaluable patients (arm A: 10, arm B: 17) with median follow up of 5.7 months. Median age at enrollment was 73 (50 - 81). 44% (n=12) had ND AML and 56% (n=15) had R/R AML. European LeukemiaNet (ELN) risk was intermediate or adverse in 52% and 44%, respectively. Patients received a median of 4 treatment cycles (ND: 5, R/R: 3). The CRc rate in the overall population was 72% (ND: 100%, R/R: 53%). Measurable residual disease (MRD) negative CRc by flow cytometry was achieved in 64% (ND: 83%, R/R: 42%). (Table 1) In the R/R cohort, 78% (n=11) patients had received prior treatment with either an HMA (azacitidine or decitabine), BCL2i and/or IDHi, with a median of 2 prior treatments. (Table 2) 5 patients did not have prior VEN exposure of which 4 (80%) achieved an MRD negative CRc. Four patients transitioned to stem cell transplant (ND: 2, R/R: 2). The most common non-hematologic grade 3/4 AEs in the overall population included hyperbilirubinemia (n=2, 7%), representing indirect bilirubin in enasidenib-treated patients and mucositis (n=2, 7%) with one considered a residual effect of prior cytoreduction. There were two patients with possible/probable differentiation syndrome which resolved with medical management (dexamethasone and diuresis). Two episodes of reversible grade 1 tumor lysis syndrome were also reported. 60-day mortality within the ND and R/R cohort was 8% (n=1) and 0%, respectively. The ND patient withdrew from the study and went home on hospice after an admission for febrile neutropenia. Conclusions The combination of ASTX727 + VEN with IDH1 or IDH2 inhibition appears to be an effective regimen for the treatment of IDH mutated AML with high response rates including MRD-negative CRc, most notably in de novo patients and R/R pts without prior VEN exposure. AEs are anticipated and tolerable. Enrollment to this study is ongoing. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal