Background: CPX-351 (US: Vyxeos; Europe: Vyxeos liposomal) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. CPX-351 is approved for newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes in patients (pts) who are candidates for intensive chemotherapy (IC) and aged ≥1 year in the US and adults in Europe. However, the appropriate dosage of CPX-351 in pts unfit for IC may be different from the label dosage. Venetoclax (VEN; BCL-2 inhibitor) + low-dose cytarabine has demonstrated efficacy in unfit pts with AML, and drug synergism/additivity in preclinical studies provided a rationale for combining CPX-351 + VEN clinically. Our study evaluates the safety and efficacy of lower-intensity CPX-351 + VEN in adults with newly diagnosed AML who are unfit for IC. Methods: This is an ongoing, open-label, phase 1b study (NCT04038437). Pts who achieve at least partial remission after 1 or 2 cycles may receive up to 4 similar cycles in the dose-exploration phase (DEP) or up to 8 similar cycles in the expansion phase (EP). Pts are assessed for response (morphology, measurable residual disease [MRD]) and monitored for safety and survival. Results: The data include 31 pts enrolled by 9/15/2021, with a data cutoff of 12/2/2021: 4 pts in DEP at dose level 1 (CPX-351 20 units/m² on Days 1 and 3 + VEN 400 mg on Days 2 to 21 of each cycle), 7 pts in DEP at dose level 2 (CPX-351 40 units/m² + VEN 400 mg), and a total of 20 pts in DEP and EP at dose level 1b (CPX-351 30 units/m² + VEN 400 mg; established as the recommended phase 2 dose). Pts were unfit for IC based on age ≥75 y (n = 15) or health (ECOG PS of 2 to 3 and/or comorbidities [n = 16]). Median age was 74 y (range: 60, 90); 65% were male; 77% had de novo AML; 58% had poor-risk disease; and 23% had a TP53 mutation. Nonhematologic treatment-emergent adverse events (TEAEs) in ≥20% of pts were diarrhea (26%), cough (23%), dyspnea (23%), and nausea (23%). Hematologic grade ≥3 TEAEs were reported in 17 (55%) pts; no nonhematologic grade ≥3 TEAE was reported in > 10% of pts. There were no deaths by Day 30; mortality at Day 60 was 13%, with deaths due to myocardial infarction unrelated to therapy (n = 1), worsening lung infection (n = 1), and disease progression (n = 2). Median (IQR) recovery times were 30 d (22, 34.5) to neutrophils ≥500/μL and 21 d (21, 27) to platelets ≥50,000/μL. Complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) was achieved by 16/28 (57%) evaluable pts. All 16 of these pts achieved remission (CR or CRi) after the first cycle. MRD negativity was achieved by 12/16 (75%) pts with CR or CRi, primarily after Cycle 1 (Cycle 1: n = 8; Cycle 2: n = 2; Cycle 3: n = 1; Cycle 4: n = 1). Survival data are not yet mature. Conclusions: Lower-intensity CPX-351 + VEN was generally well tolerated in adults with newly diagnosed AML who are unfit for IC and showed promising initial efficacy, with CR or CRi in the majority of pts. Clinical trial information: NCT04038437.