Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML

Abstract

• First-line CPX-351 vs 713 control in newly diagnosed AML improves 60-day mortality, remission rate, and OS (HR 5 0.46, P 5 .01) in sAML subset.CPX-351 is a liposomal formulation of cytarabine:daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2:1 to first-line CPX-351 or 713 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission 1 incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P 5 .07), meeting predefined criteria for success (P < .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P 5 .06), and prolongation of EFS (hazard ratio [HR] 5 0.59, P 5 .08) and OS (HR 5 0.46, P 5 .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count ‡1000: 36 vs 32; platelets >100 000: 37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials. gov as #NCT00788892. (Blood. 2014;123(21):3239-3246)

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

“…A second phase 2 trial randomized 127 older patients (age 60 years or older) with newly diagnosed AML (2:1) to CPX-351 100 units/m 2 on Days 1, 3, and 5 or conventional 3 1 7 therapy. CPX-351 therapy was associated with a higher response rate, the primary endpoint of the study (67 versus 51%; p 5 0.07) [132]. This was more pronounced among patients with secondary AML (response rate 57% versus 32%; p 5 0.06), in whom CPX-351 therapy was also associated with prolongation of survival (hazard ratio 5 0.46; p 5 0.01) and event-free survival (hazard ratio 0.59; p 5 0.08).…”

Unsatisfactory efficacy in randomized study of reduced-dose CPX-351 for medically less fit adults with newly diagnosed acute myeloid leukemia or other high-grade myeloid neoplasm

“…3 In a subsequent study in fit adults age 60-75 years with newly diagnosed AML who were randomized 2:1 between CPX-351 (100 units/m 2 ) and 7+3, 60-day mortality was lower with CPX-351 (4.7% vs. 14.6%, p=0.053) while response rates were higher (66.7% vs. 51.2%, p=0.07). 4 Pre-planned subset analyses indicated improved survival in patients with secondary leukemias. 4 These observations prompted us to conduct a randomized phase 2 trial (ClinicalTrials.gov: year from another illness, uncontrolled infection, or treatment with other investigational agents were exclusions.…”

“…4 Pre-planned subset analyses indicated improved survival in patients with secondary leukemias. 4 These observations prompted us to conduct a randomized phase 2 trial (ClinicalTrials.gov: year from another illness, uncontrolled infection, or treatment with other investigational agents were exclusions. Prior low-intensity treatment, including use of DNA methyltransferase inhibitors, lenalidomide, and growth factors for low-grade myelodysplastic syndrome (<10% blasts) was permitted.…”

“…4 Pre-planned subset analyses indicated improved survival in patients with secondary leukemias. 4 These observations prompted us to conduct a randomized phase 2 trial (ClinicalTrials.gov: Because of the small sample size, randomization was stratified using a dynamic allocation scheme 11 based on: 1) TRM score (13.1-22.8 vs. >22.8); 2) cytogenetic risk (monosomal karyotype vs. other unfavorable vs. intermediate/favorable); and 3) presence/absence of secondary disease. For each dose, we used a Bayesian design that adaptively monitored response (CR achievement) and toxicity (death by day 28, excluding deaths due to progressive disease and no treatment-related toxicity).…”

Liposome and Their Applications in Cancer Therapy

“…Previously in phase II trial, CPX-351 had already showed a survival benefits and the data on over survival could be expected in the first quarter of 2016 (Lancet et al 2014). Another liposomal formulation of Celator contains irinotecan Hcl and floxuridine and registered as CPX-1.…”