V-FAST master trial: Preliminary results of treatment with CPX-351 plus midostaurin in adults with newly diagnosed FLT3-mutated acute myeloid leukemia.

7043 Background: CPX-351 (US: Vyxeos; Europe: Vyxeos liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes in patients aged ≥1 year in the US and in adults in Europe. In a phase 3 study in older adults with newly diagnosed, high-risk/secondary AML, CPX-351 significantly improved overall survival and remission rates versus conventional 7+3, with a comparable safety profile. Preclinical data suggest CPX-351 may have synergistic activity with targeted agents, including the FLT3 inhibitor midostaurin (MID). Herein, we report preliminary results for the cohort of adults treated with CPX-351 + MID in the V-FAST (Vyxeos – First Phase Assessment with Targeted Agents) trial. Methods: V-FAST is an open-label, multicenter, multiarm, nonrandomized, phase 1b master trial (NCT04075747) to evaluate the safety and preliminary efficacy of CPX-351 combined with targeted agents (midostaurin, venetoclax, enasidenib). Eligible adults in the CPX-351 + MID cohort were aged 18 to 75 years, had newly diagnosed AML with a FLT3 internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutation, were fit for intensive chemotherapy, and had an ECOG performance status of 0 to 2. The dose-exploration phase (3+3 design) determined a recommended phase 2 dose of CPX-351 100 units/m2 (daunorubicin 44 mg/m2 + cytarabine 100 mg/m2) on Days 1, 3, and 5 + MID 50 mg BID on Days 8 to 21. There were no dose-limiting toxicities, and additional patients were enrolled in the expansion phase at this dose. Results: A total of 23 patients received CPX-351 + MID and had sufficient data to be included in the analysis (cutoff date: 1/20/2022). Patient baseline characteristics are shown in the Table. Treatment-emergent adverse events (TEAEs) in ≥40% of patients included febrile neutropenia (78%), nausea (65%), increased alanine aminotransferase (57%), leukopenia (57%), thrombocytopenia (57%), headache (43%), and hyponatremia (43%). All patients experienced a grade 3/4 TEAE, primarily hematologic events. Nonhematologic grade 3/4 TEAEs in ≥2 patients included pneumonia (17%), lung infection (13%), and hyperglycemia (9%). There were no grade 5 TEAEs and no deaths on or before Day 60. Complete remission was achieved by 18/22 (82%) evaluable patients after the first induction cycle. Conclusions: Preliminary results from the V-FAST trial suggest CPX-351 + MID is feasible, with a manageable safety profile and promising remission rates in adults with newly diagnosed AML who have a FLT3 mutation. Clinical trial information: NCT04075747. [Table: see text]