V-FAST: a phase 1b master trial to investigate CPX-351 combined with targeted agents in adults with newly diagnosed AML.

Preclinical data suggest CPX-351, approved for patients with newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes, may exhibit synergy with targeted agents, suggesting a rationale for combining targeted agents with CPX-351 as a chemotherapy backbone. The V-FAST (Vyxeos - First Phase ASsessment With Targeted Agents) phase 1b trial evaluated CPX-351 with the targeted agents venetoclax (arm A), midostaurin (arm B), and enasidenib (arm C) in adults with newly diagnosed AML fit for intensive chemotherapy. The dose exploration phase used a 3+3 design to determine the recommended phase 2 dose (RP2D) for each combination. The expansion phase enrolled additional patients to confirm the RP2D. Primary end points were the RP2D and safety. Secondary end points included initial efficacy assessments. Overall, 57 patients were enrolled (arm A, n = 27; arm B, n = 23; arm C, n = 7). In arms A and B, the RP2D was established: CPX-351 (daunorubicin 44 mg/m and cytarabine 100 mg/m) plus venetoclax 400 mg or midostaurin 50 mg, respectively. Arm C was stopped early by the sponsor (not due to safety concerns), and the RP2D was not determined. The safety profiles of the combinations were consistent with those known for CPX-351, venetoclax, and midostaurin alone; the most common adverse events were hematologic and gastrointestinal. The best response (complete remission [CR]/CR with incomplete/partial hematologic recovery) was 44% (12/27 patients) and 86% (19/22 patients) in arms A and B, respectively. Although few patients received CPX-351 with enasidenib, these results suggest that CPX-351 may be safely combined with venetoclax or midostaurin. This trial was registered at www.clinicaltrials.gov as #NCT04075747.