Phase 1b Study of Lower-Dose CPX-351 Plus Venetoclax As First-Line Treatment for Patients with AML Who Are Unfit for Intensive Chemotherapy: Preliminary Safety and Efficacy Results

Background: CPX-351 (United States: Vyxeos ^®; Europe: Vyxeos ^® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in adults and pediatric patients aged ≥1 year in the United States and in adults in the European Union. In a phase 3 study in adults aged 60 to 75 years with newly diagnosed high-risk/secondary AML who were eligible for intensive chemotherapy (IC), after 5 years of follow-up CPX-351 significantly improved median overall survival versus conventional 7+3 cytarabine/daunorubicin, with a comparable safety profile. Venetoclax (VEN; BCL-2 inhibitor) + low-dose cytarabine has demonstrated efficacy in unfit patients with AML, and preclinical data support a rationale for combining CPX-351 + VEN. This study evaluates the safety and efficacy of lower-dose CPX-351 + VEN in adults with newly diagnosed AML who are considered unfit to receive IC.

Methods: This is an ongoing, open-label, multicenter, phase 1b study (NCT04038437) to determine the recommended phase 2 dose (RP2D) and evaluate the safety and efficacy of lower-dose CPX-351 + VEN in adults with newly diagnosed AML who are considered unfit to receive IC. The dose-exploration phase (3+3 design; n ≤24) evaluated multiple dose levels of CPX-351 on Days 1 and 3 + VEN 400 mg on Days 2 to 21 of each cycle to determine the RP2D. Patients who achieve at least partial remission after 1 or 2 cycles may receive up to 4 similar cycles of CPX-351 + VEN. During the expansion phase, 20 additional patients will receive CPX-351 + VEN at the RP2D. Patients are assessed for response by morphology and measurable residual disease (MRD) testing and are monitored for safety and survival.

Results: This preliminary analysis includes data from 14 enrolled patients. Patients were considered unfit for IC based on age ≥75 years (n = 7 [50%]) or health (aged 18 to 74 years with an EGOC performance status of 2 or 3 [n = 3 (21%)] and/or comorbidities [n = 5 (36%]). Overall, 50% of the patients had poor-risk cytogenetics, 64% were male, 71% had a diagnosis of de novo AML, and 29% had mutated TP53 (Table 1). Four patients received dose level 1 (CPX-351 20 units/m ² [daunorubicin 8.8 mg/m ² + cytarabine 20 mg/m ²] + VEN), with no dose-limiting toxicities (DLTs) observed in the 3 evaluable patients. Seven patients were subsequently enrolled in dose level 2 (CPX-351 40 units/m ² [daunorubicin 17.6 mg/m ² + cytarabine 40 mg/m ²] + VEN), with 6 patients evaluable for DLTs. At dose level 2, 1 patient experienced 2 DLTs (grade 3 tumor lysis syndrome and liver injury); review of the overall safety profile led to a protocol amendment that permitted de-escalation to dose level 1b (CPX-351 30 units/m ² [daunorubicin 13.2 mg/m ² + cytarabine 30 mg/m ²] + VEN). Three patients received dose level 1b with no DLTs and a safety profile comparable to dose level 1. Together, these data established dose level 1b as the RP2D.

The most common nonhematologic treatment-emergent adverse events (TEAEs) were gastrointestinal events and peripheral edema (Table 2). The majority (86%) of patients experienced a grade ≥3 TEAE, primarily myelosuppression; the only nonhematologic grade ≥3 TEAE in >10% of patients was tumor lysis syndrome (14%). No patient experienced early mortality by Day 30; the mortality rate at Day 60 was 7% due to 1 death in the dose level 1 cohort (myocardial infarction considered unrelated to treatment). Among the 12 patients evaluable for efficacy across dose levels, 8 (67%) achieved a best response of complete remission (CR): 3/4 (75%) in dose level 1, 3/5 (60%) in dose level 2, and 2/3 (67%) in dose level 1b. All patients who achieved a best response of CR entered into either CR or CR with incomplete neutrophil or platelet recovery after the first treatment cycle. Confirmation of MRD status is currently ongoing.

Conclusions: Preliminary results from this ongoing phase 1b study established a RP2D of CPX-351 30 units/m ² on Days 1 and 3 + VEN 400 mg on Days 2 to 21 in adults with newly diagnosed AML who were considered unfit to receive IC. The combination of lower-dose CPX-351 + VEN was generally well tolerated and demonstrated promising initial efficacy, with achievement of CR in the majority of patients. This study is ongoing and enrolling 20 additional patients to further evaluate the RP2D.

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