V-FAST: A Phase 1b Master Trial to Investigate CPX-351 Combined with Various Targeted Agents in Patients with Previously Untreated Acute Myeloid Leukemia
Authors: Lin Tara , Mannis Gabriel N. , Erba Harry P. , Levis Mark , Zou Heng , Faderl Stefan , Cheung Ronald S. , Pullarkat Vinod A. 
Published: November 2020

Introduction: CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio, has been approved by the US FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. A randomized phase 3 study that evaluated patients 60 to 75 years of age with newly diagnosed high-risk/secondary AML provided the basis for approval and demonstrated that induction followed by consolidation with CPX-351 significantly improved overall survival and remission rates versus conventional 7+3, with a comparable safety profile. Several targeted therapies have demonstrated efficacy when added to cytotoxic therapy for the treatment of patients with previously untreated AML, including venetoclax (Venclexta®/Venclyxto®; a B-cell leukemia/lymphoma-2 [BCL-2] inhibitor), midostaurin (Rydapt®; a FMS-related tyrosine kinase 3 [FLT3] inhibitor), and enasidenib (Idhifa®; an isocitrate dehydrogenase 2 [IDH2] inhibitor). Preclinical data indicate synergistic activity may be achieved with CPX-351 in combination with venetoclax or midostaurin. Results of these studies suggest a rationale for the combination of targeted therapies using CPX-351 as a chemotherapy backbone.
Study Design and Methods: V-FAST (Vyxeos - First Phase Assessment with Targeted Agents) is an open-label, multicenter, multi-arm, nonrandomized, phase 1b master trial (ClinicalTrials.gov #NCT04075747) to evaluate CPX-351 in combination with targeted agents (venetoclax, midostaurin, or enasidenib) in adults with previously untreated AML who are considered fit for intensive chemotherapy. As V-FAST is a master trial, it is designed to permit the expedited incorporation of CPX-351 combinations with other targeted agents into the study as it proceeds, thus ensuring a timely investigation of novel combinations moving forward. Key eligibility criteria are shown in Table 1. The primary study endpoints are to establish the recommended phase 2 dose (RP2D) and safety of each combination regimen. Secondary endpoints include remission rates (via morphologic assessment), bone marrow measurable residual disease status, and pharmacokinetics. Exploratory endpoints include duration of remission, overall survival, event-free survival, and the proportion of patients proceeding to hematopoietic cell transplantation. Patients will be monitored for safety until 1 month following the end of treatment and survival for up to 2 years following the first administration of treatment.
Cytogenetic and/or molecular testing will determine which treatment arm each patient is assigned to (ie, no FLT3 or IDH2 mutations: CPX-351 plus venetoclax; FLT3 mutation: CPX-351 plus midostaurin; IDH2 mutation: CPX-351 plus enasidenib). For each combination, a dose-exploration phase (standard 3+3 design; up to 12 patients/combination) will employ dose de-escalation or escalation of CPX-351 and/or the targeted agent based on the occurrence of dose-limiting toxicities to determine a RP2D and evaluate the safety of the combination. The initial cohort for each arm will be treated with the dosing described in Table 2. In the subsequent expansion phase for each combination, an additional 20 patients will be treated to confirm the RP2D, further evaluate safety, and provide an initial assessment of efficacy.
In both study phases, CPX-351 will be administered intravenously by 90-minute infusion on Days 1, 3, and 5; targeted therapies will be administered per a standard route for each agent. Patients may receive 1 to 2 induction cycles of combination therapy. Those achieving remission may receive up to 2 consolidation cycles with CPX-351 plus the targeted agent received during induction; hematopoietic stem cell transplantation is permitted in place of or following chemotherapy consolidation at the discretion of the treating physician.
This study is ongoing and actively enrolling patients.

Disclosures
Lin: Celgene: Research Funding; Aptevo: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Mateon Therapeutics: Research Funding; Prescient Therapeutics: Research Funding; Pfizer: Research Funding; Celyad: Research Funding; Genetech-Roche: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Bio-Path Holdings: Research Funding; Jazz: Research Funding. Mannis:AbbVie, Agios, Bristol-Myers Squibb, Genentech: Consultancy; Glycomimetics, Forty Seven, Inc, Jazz Pharmaceuticals: Research Funding. Erba:Glycomimetics: Other: member of Scientific Steering Committee; AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, PTC: Research Funding; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy; Celgene: Other: chair of the Scientific Steering Committee; Covance (AbbVie): Other: chair of the Independent Review Committee. Levis:Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Amgen: Honoraria; Menarini: Honoraria. Zou:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cheung:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Pullarkat:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

OffLabel Disclosure:
This study will explore CPX-351 in combination with targeted agents for the treatment of adults with AML.