Background: Isocitrate dehydrogenase-1 mutations (IDH1⁺) result in production of the oncometabolite 2-hydroxyglutarate, arrested differentiation, and increased dependence on the anti-apoptotic protein BCL-2, enhancing susceptibility to the BCL-2 inhibitor venetoclax (VEN). Herein, we report the completed P1b portion of the P1b/II study combining the IDH1 inhibitor ivosidenib (IVO; 500 mg PO daily D15-continous) with VEN (D1-14), with or without azacitidine (AZA; 75mg/m² D1-7 every 28 days). Methods: Eligible patients age 18 with IDH1⁺ MDS, newly diagnosed (ND: de novo and secondary/treated secondary AML) or relapsed/refractory (R/R) AML were enrolled into 4 dose levels (DL): DL1 (IVO+VEN 400 mg), DL2 (IVO+VEN 800 mg), DL3 (IVO+VEN 400 mg+AZA), DL4 (IVO+VEN 800 mg+AZA). Primary objectives included safety and tolerability, and IWG defined overall response (ORR: CR+CRi+CRh+PR+ MLFS). Results: 31 patients (DL1: 6, DL2: 6, DL3: 13, DL4: 6) enrolled with a median follow-up of 26 months. Median age was 67 years (range: 44-84). 71% had AML (ND: N = 14, R/R: N = 8), 29% (N = 9) had MDS. ELN risk was intermediate and adverse in 19% (N = 6) and 55% (N = 17). Median baseline IDH1⁺ VAF was 23% (5%-48%). Median time on study was 6.4 (range: 4 -not reached [NR]) months. The ORR was 94% (DL1: 67%, DL2-DL4: 100%); Composite CR (CRc: CR+CRi+CRh) was 87% (DL1: 67%, DL2: 100%, DL3: 85%, DL4: 100%). 63% of AML patients attained measurable residual disease negative CRc by multiparameter flow cytometry (ND-AML: 64%, R/R-AML: 60%). Addition of AZA increased MRD clearance in ND-AML compared to the doublet regimen (86% vs. 25%, p: 0.09). IDH1⁺ mutation clearance by digital droplet PCR (sensitivity: 0.1-0.25%) was attained in 67% of patients (ND-AML: 83%, R/R-AML: 50%, MDS: 50%) following cycle 5. 35% of patients required dose reductions for cytopenias (DL2: 2 [33%], DL3: 6 [46%], DL4: 3 [50%]). Grade 3-5 adverse events (AEs) occurring in 10% of patients included febrile neutropenia (29%; one episode resulted in death in a R/R-AML patient relapsing on study) and pneumonia (23%). AEs of special interest (AESI) included grade 3 tumor lysis syndrome in two patients (dose-limiting toxicity in one), and differentiation syndrome in 4 (G2: N = 2, G3: N = 2) patients. All AESIs were transient and reversible. Median EFS and OS were 36 and 42 months. 24-month OS was 71% (95% CI: 55-91; [ND-AML: 67%, R/R-AML: 50%, MDS: 100%]). MRD-negative CRc improved OS (median NR vs. 8 months, p: 0.002) in ND and R/R-AML. 100% of patients (N = 4) relapsing after IDH1⁺ clearance demonstrated no IDH1⁺ at relapse. Based on efficacy and toxicity, DL3 (IVO+VEN400+AZA) was the recommended phase 2 dose. Conclusions: IVO+VEN +/- AZA is an effective treatment for IDH1⁺myeloid malignancies with an expected toxicity profile and notable efficacy across disease groups. Single-cell sequencing and CyTOF correlatives will also be presented. Phase 2 enrollment is ongoing. Clinical trial information: NCT03471260.