https://orcid.org/0000-0003-0473-6982
Key points
CPX-351 combined with venetoclax or midostaurin demonstrated a manageable safety profile and promising remission rates (121/140 characters)
These results support further investigation of CPX-351 in combination with targeted agents in patients with newly diagnosed AML (129/140 characters)
Abstract
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 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 endpoints were the RP2D and safety. Secondary endpoints 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/m2, cytarabine 100 mg/m2) plus venetoclax 400 mg or midostaurin 50 mg, respectively. Arm C was stopped early by the sponsor (not due to safety concerns); the RP2D was not determined. Safety profiles of the combinations were consistent with that known of CPX-351, venetoclax, and midostaurin alone; most common adverse events were hematologic and gastrointestinal. 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.
Author notes
Affiliation at the time the study was conducted.
Data sharing statement
All relevant data are provided within the manuscript and supporting files. Jazz Pharmaceuticals has established a process to review requests from qualified external researchers for data from Jazz-sponsored clinical trials in a responsible manner that includes protecting patient privacy, assurance of data security and integrity and furthering scientific and medical innovation. Additional details on Jazz Pharmaceuticals data sharing criteria and process for requesting access can be found at: https://www.jazzpharma.com/science/clinical-trial-data-sharing/.
