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

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