CPX-351 plus Venetoclax in Patients with Acute Myeloid Leukemia: A Phase 2 Study

CPX-351 is a liposomal formulation of cytarabine (Ara-C). A study was designed to investigate the safety and efficacy of venetoclax (VEN) combined with CPX-351 in patients with acute myeloid leukemia (AML) based on findings that demonstrated the addition of the BCL-2 inhibitor VEN to hypomethylating agents (HMAs) improved overall response rates (ORRs) and overall survival (OS) compared with HMAs alone.

The treatment regimen used in this study was comprised of daunorubicin 44 mg/m2 plus Ara-C 100 mg/m2 intravenously on days 1, 3, and 5 for induction and daunorubicin 29 mg/m2 plus Ara-C 65 mg/m2 intravenously on days 1 and 3 for consolidation. Patients in the safety lead-in cohort had relapsed or refractory (R/R) AML and were treated with a starting effective dose of VEN of 300 mg (at dose level 1) on days 2 to 21. Interruption of VEN was permitted after day 14 if the day 14 bone marrow was hypocellular and absent evidence of leukemia. Venetoclax dose adjustments were made for patients also on moderate or strong CYP3A inhibitors. After 3 of 6 patients experienced dose-limiting toxicity (cytopenia >43 days), dose level 2 was explored (VEN 300 mg on days 2-8) and expanded. Two expansion cohorts were opened to confirm safety and efficacy once safety had been established. Cohort A was comprised of patients with R/R AML, while cohort B was comprised of patients with newly diagnosed AML. Patients with adequate organ function (Eastern Cooperative Oncology Group performance status <2) and prior VEN exposure were allowed on study.

At data cutoff, 18 patients had been treated (lead-in cohort: 12 [67%], cohort A: 5 [28%], cohort B: 1 [6%]). The median age was 51 years (range, 29-71 years). Seventeen of the 18 (94%) patients had R/R AML with a median of 2 (range, 1-8) prior therapies. One patient enrolled (6%) had newly diagnosed secondary AML. There were 9 (50%) patients with adverse karyotype, 6 (33%) with complex karyotype, and 6 (33%) with TP53 mutations. Among patients with R/R AML, 7 (41%) had prior VEN exposure.

The 1 patient with newly diagnosed AML, treated previously with HMA plus VEN and allogeneic stem-cell transplantation (allo-SCT) for myelodysplastic syndrome, achieved minimal residual disease–negative complete response (CR). There was 1 CR (6%), 6 CRs with incomplete hematologic recovery (CRi, 33%), and 1 morphologic leukemia-free state (6%) resulting in an ORR of 44% among the 16 evaluable patients with R/R AML. The ORR was 60% in patients without prior VEN exposure (6/10), compared with 17% among those with prior VEN exposure (1/6). Of the responding patients, 86% (6/7) went on to allo-SCT. The median OS overall was 6.4 months, and the landmark 6-month OS rate was 53%. The median OS and relapse-free survival (RFS) were not reached, with 6-month OS and RFS rates of 86% among responders. The 4-week and 8-week mortality rates were 11% and 22%, respectively. The starting dose level 1 was above the maximum tolerated dose of the combination (dose-limiting toxicities included prolonged neutropenia and thrombocytopenia). The most frequently reported grade 3/4 serious adverse events were infection, nausea, pneumonia, and myelosuppression.

Among patients with R/R AML, CPX-351 plus 7 days of VEN was tolerable with acceptable toxicities. CPX plus VEN demonstrated encouraging activity in this high-risk population, particularly for patients without prior VEN exposure. Almost all patients who responded to treatment moved on to allo-SCT. Enrollment in this study continues.

Reference

Kadia TM, Borthakur G, Takahashi K, et al. Phase II Study of CPX-351 Plus Venetoclax in Patients with Acute Myeloid Leukemia (AML). Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 28.

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