Phase 2B Randomized Study of CPX-351 Vs. Cytarabine (CYT) + Daunorubicin (DNR) (7+3 Regimen) In Newly Diagnosed AML Patients Aged 60–75

Abstract Abstract 655 Introduction: CPX-351 is a liposomal formulation encapsulating CYT and DNR at a 5:1 molar ratio that maximizes synergy. CPX-351 was well tolerated and demonstrated markedly prolonged plasma half-life for CYT (t1/2=31.1 hours) and DNR (t1/2=21.9 hours) in Phase 1. Responses (CR + CRp) were noted in patients with prior 7+3 exposure including some with multiple relapses and primary induction failure. A Phase 2 study using 2:1 randomization to demonstrate efficacy and safety of CPX-351 versus conventional 7+3 regimen is summarized here. Methods: Subjects with de novo or 2o AML (based on history of MDS, MPD, or prior chemotherapy exposure), ECOG PS of 0–2, SCr <2.0 mg/dL, total bilirubin <2.0 mg/dL, ALT/AST <3xULN, and LVEF >50% by echo or MUGA were eligible. Subjects with acute promyelocytic leukemia [t(15;17)], known favorable cytogenetics including t(8;21) and inv(16), prior DNR-equivalent exposure >368 mg/m2, myocardial impairment resulting in heart failure (NYHA Class III/IV), uncontrolled infection, and prior treatment for AML, save hydroxyurea, were excluded. Subjects with active CNS leukemia or unable to give informed consent were also excluded. The investigational arm was CPX-351 100 units/m2 on Day 1, 3, and 5 and the control arm was CYT 100 mg/m2/d × 7 day continuous infusion + DNR 60 mg/m2/d Days 1, 2, 3. The 1o endpoint was CR + CRi rate with 2o endpoints of survival at 1-year, response duration, EFS, and 30 and 60-day mortality. Results: From 13Nov2008 to 14Oct2009 126 patients were treated, 125 of whom were eligible (84 with CPX-351 and 41 with 7+3 Control). All patients have had ≥6 months follow-up at time of abstract submission. Both study arms were well balanced for sex, age, race, time from diagnosis to treatment, de novo vs. 2o AML, presence of extramedullary disease, WBC at baseline, ECOG PS, prior anthracycline exposure and cytogenetic risk category. All of the CRi patients had delayed platelet recovery and met the definition for CRp. CPX-351 increased the rate of response (CR + CRp, 66.7% vs. 51.2%); largely due to a higher CRp rate (Table 1). Higher response rates were observed particularly for those with adverse risk cytogenetics, age >70, and 2o AML. Cytopenia-associated adverse event rates were higher in the CPX-351 treatment arm: febrile neutropenia (64.7% vs. 51.2%), infections of all grades (84.7% vs. 68.3%), bacteremia (40% vs. 22%), petechiae (32.9% vs. 12.2%) and ecchymoses (11.8% vs. 2.4%). Median time to count recovery after induction was longer after CPX-351, 38 vs. 34 days for ANC>1000 and 44 vs. 33 days for Plt>100K. CPX-351 was associated with reduced early mortality compared to 7+3 (4.7% vs. 14.6% at 60 days, p= 0.053, Chi Square). Complete analysis of adverse events will be presented. Kaplan Meier analysis reveals a hazard ratio for CPX-351 for overall survival after a minimum of 6 months follow-up to be 0.83 (95%CI: 0.62–1.13; p=0.24). The estimated mean difference within the first year was 2.2 months. Response (CR + CRp) was highly predictive of prolonged survival with the hazard ratio of responders vs. non responders of 0.55 (95% CI: 0.41–0.73; p<0.0001). Data for 1 year survival, EFS, and response duration will be presented. Conclusions: CPX-351 induction therapy in elderly patients with newly diagnosed AML was associated with a higher response rate (66.7% vs. 51.2%) and a strong trend towards reduced 60-day mortality (4.7% vs. 14.6%) compared to the 7+3 regimen. Response (CR + CRp) predicts for prolonged survival and early analyses suggest a first year difference of 2 months favoring CPX-351. In view of these positive results, a Phase 3 trial comparing CPX-351 vs. 7+3 regimen in newly diagnosed elderly AML patients is warranted. Disclosures: Lancet: Celator: Compensation donated to H. Lee Moffitt Cancer & Research Center, Membership on an entity's Board of Directors or advisory committees. Cortes:Celator: Consultancy, Membership on an entity's Board of Directors or advisory committees. Louie:Celator: Employment. Feldman:Celator: Membership on an entity's Board of Directors or advisory committees.

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