A Phase 2 Trial of CPX-351 Combined With Venetoclax in Relapsed or Refractory Acute Myeloid Leukemia

Outcomes in patients with relapsed/refractory (RR) AML are poor. We sought to investigate if CPX-531 in combination with venetoclax (CPX + VEN) was tolerable and effective in RR AML. This was a single institution phase 1b/2 trial of CPX + VEN. Patients aged ≥ 18 years with RR AML who were fit for intensive chemotherapy were eligible. Prior venetoclax exposure was allowed. The phase 1b portion followed a 3 + 3 design to identify the recommended phase 2 dose (RP2D) for the expansion cohort. At the starting dose level of −1, prolonged myelosuppression was observed, leading to dose level −2 (CPX-351 dosed at daunorubicin 44 mg/m² on days 1,3, and 5 and venetoclax 300 mg days 2–8) being chosen as the RP2D. Thirty three patients with a median age of 58 years (range, 26–72) were treated. Patients were heavily pretreated, with 58% with prior venetoclax exposure, 44% in the second salvage or later, and 30% with prior stem cell transplant (SCT). Adverse cytogenetics were present in 51% of patients, with myelodysplasia-related mutations in 64%, and TP53^mut in 21%. The overall response rate (ORR) was 46% (95% CI, 30–62), with a composite CR rate (CRc) of 39% (95% CI, 25–56). Patients in first salvage with wildtype TP53 had a CRc rate of 70% (95% CI, 40–89), with undetectable MRD in 71% (95% CI, 36–92) and a 2-year OS of 49% (95% CI, 23–100). Eleven (73%) responding patients underwent SCT. The 30-day mortality was 9%, with a 60-day mortality of 21%. The most common adverse events were related to myelosuppression. CPX + VEN has activity in RR AML, particularly when used in first salvage and in patients who do not harbor TP53 mutations. ClinicalTrials.gov Identifier: NCT03629171.