Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

Background

Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia.

Methods

This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801.

Findings

Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]).

Interpretation

Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia.

Funding

Sunesis Pharmaceuticals.