Phase II Study of CPX-351 (Cytarabine: Daunorubicin) Liposome Injection in Patients (Pts) with Newly Diagnosed Acute Myeloid Leukemia (AML) at High Risk for Induction Mortality

Background: CPX-351 is a liposomal formulation of 5:1 molar combination of cytarabine and daunorubicin (Leukemia research 2010; 34: 1214). Subset analysis in a Phase II study reported improved outcomes in first relapse AML pts with European Prognostic Index defined poor-risk disease (Cancer 2015; 121: 234). In a phase 3 randomized study among fit pts, 60-75 years (yrs) of age with high-risk AML, that compared induction CPX-351 (100 U/m2, days 1, 3, 5) and vs 7+3; CPX-351 significantly improved response, event free and overall survival (Journal of Clinical Oncology 2016; 34(15_suppl): 7000). Observations from the Phase I study of responses occurring at dose levels of one third to one half the MTD (32 to 43 U/m2), suggest that doses of 75 and 50 units/m2 may still be effective and better tolerated among pts at high risk for toxicity. Hypothesis: Reduced dose CPX-351 as induction therapy may improve the outcome of pts with AML at high risk for 60-day mortality and not ordinarily offered induction therapy. Design: We designed an open-label, phase II trial of CPX-351 administered on days 1, 3, and 5 at 50 (arm 1) or 75 (arm 2) units/m2 as induction. Fifteen pts each were to be randomly assigned to these two arms. As these doses are below the original MTD dose of 100 units/m2, a cohort of 15 pts were to be studied at 100 units/m2 provided the first two dose levels were safe. At the end of the study a single dose level was to be chosen based on efficacy and safety i.e. dose limiting toxicity (DLT) The primary objective is to assess preliminary efficacy (CR/CRp/ CRi within 2 induction cycles) in pts with newly diagnosed AML at high risk for induction mortality, defined as 30-50% predicted risk of death by Day 60, and to select the most promising dose level for further efficacy testing. To be considered at high risk for induction mortality pts ≥60 yrs must have at least 1 and pts 1.3 g/dL. Pts with ejection fraction Results: Based on safety of 2 dose levels (50 units/m2 and 75 units/m2) of CPX-351, one additional cohort with a dose of 100 units/m2 was opened. Fifty-two pts (15 at 50 U/m2, 25 at 75 U/m2 and 12 at 100 U/m2) have been treated (4 screen failures). Median age is 68 yrs (range 54-84) and 19 (37%) pts are females. Ninety percent of pts had prior MDS or T-AML, 81% had therapies for MDS and 54% had adverse cytogenetics. Patient characteristics are outlined in Table 1. Median number of cycles to response has been 1 (range 1-2) and median number of cycles administered is 2 (range 1-5). Twenty (38%) pts have responded; 15 achieving CR, 3 CRi, 2 CRp. Six of 15 pts with CR were MRD negative at response. Responses (CR/CRp/CRi) are, arm 1=3/0/0 (20%), arm 2= 6/2/2 (40%) and arm 3= 6/0/1 (47%). With median follow up of 5.3 months, median survival in the entire cohort is 5.9 months and median remission (CR/CRp) duration 5.3 months (Fig 1a and b). Median time to recovery of counts for responding patients was 35 day (range, 16-153 days). Response rate trended to be lower among pts with mutant TP53 (20% vs 46%, p=.08), therapy related AML (0% versus 48%, p=.02) and younger than Deaths within 60 days were 11 (21%), all due to sepsis, multi-organ failure or disease progression; 5 in arm 1 (33%), and 3 each in arms 2 (12%) and 3 (25%). Most frequent grade 3-5 toxicities, irrespective of attribution, were febrile neutropenia (38%) and respiratory failure (17%). Conclusion : In a very high-risk elderly cohort of newly diagnosed pts with AML, CPX-351 induction yielded promising remission rates at all 3 doses tested. The efficacy, toxicity and early mortality profile favors the use of CPX-351 at 75u/m2 on days 1, 3 and 5 as the preferred induction schedule. Presence of TP53 mutation or T-AML potentially defines groups with low probabilities of response. Disclosures Kantarjian: Delta-Fly Pharma: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. DiNardo: AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding. Daver: Bristol-Myers Squibb Company: Consultancy, Research Funding; Otsuka America Pharmaceutical, Inc.: Consultancy; Incyte Corporation: Honoraria, Research Funding; Kiromic: Research Funding; Immunogen: Research Funding; Karyopharm: Consultancy, Research Funding; Jazz: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Daiichi-Sankyo: Research Funding; Pfizer Inc.: Consultancy, Research Funding. Jabbour: Bristol-Myers Squibb: Consultancy. Pemmaraju: LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; cellectis: Research Funding; Incyte Corporation: Consultancy, Honoraria; novartis: Consultancy, Honoraria, Research Funding; roche diagnostics: Consultancy, Honoraria; abbvie: Research Funding. Wierda: Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Karyopharm: Research Funding; Emergent: Consultancy, Honoraria, Research Funding; Kite: Research Funding; The University of Texas MD Anderson Cancer Center: Employment; Acerta: Research Funding; Juno: Research Funding; GSK/Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Merck: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jain: Verastem: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Novimmune: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity9s Board of Directors or advisory committees; BMS: Research Funding; Incyte: Research Funding. Cortes: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; ImmunoGen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.