Phase III randomized study of CPX-351 liposome for injection in older patients with newly diagnosed secondary acute myeloid leukemia

CPX-351 is a liposomal formulation of daunorubicin plus cytarabine co-encapsulated at a molar ratio of 1:5. Findings from a phase II randomized study demonstrated that CPX-351 led to higher remission rates and better survival in patients aged 60–75 years with newly diagnosed secondary acute myeloid leukemia (sAML) compared to standard 7+3 chemotherapy. As a result, a phase III open-label randomized study (NCT01696084), comparing the safety and efficacy of CPX-351 versus conventional 7+3 chemotherapy was conducted. The results from this pivotal phase III study were reported by Jeffery Lancet et al. in the Journal of Clinical Oncology.

Three-hundred and nine patients with newly diagnosed sAML were randomly assigned 1:1 to receive CPX-351 (n = 153, mean age = 67.8 years) or 7+3 (n = 156, mean age = 67.7) as induction and consolidation chemotherapy. The primary endpoint of the study was overall survival (OS).

Key findings:

• Median follow-up: 20.7 months
• Median OS in the CPX-351 and 7+3 cohort: 9.56 vs 5.95 months, HR = 0.69 (95% CI, 0.52–0.90), P = 0.003
• Median event-free survival (EFS) in the CPX-351 and 7+3 cohort: 2.53 vs 1.31 months, HR = 0.74 (95% CI, 0.58–0.96), P = 0.021
• Overall remission rate in the CPX-351 and 7+3 cohort: 47.7% vs 33.3%, P = 0.016
• Fifty-two patients of the 153 in the CPX-351 cohort and 39 patients of the 156 in the 7+3 cohort proceeded to transplant
• Most frequent grade 3–5 adverse events reported were febrile neutropenia (68.0% vs 70.9%), pneumonia (19.6% vs 14.6%) and hypoxia (13.1% vs 15.2%)
• Day-30 mortality rate in the CPX-351 and 7+3 cohort were 5.9% and 10.6% respectively, P = 0.149
• Day-60 mortality rate in the CPX-351 and 7+3 cohort were 13.7% and 21.2% respectively, P = 0.097

Findings from this pivotal phase III randomized study demonstrated that CPX-351 significantly improved OS, EFS, and remission rates compared to conventional 7+3 in older patients with newly diagnosed high-risk sAML. Based on the findings of this study, CPX-351 was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with newly diagnosed therapy-related AML (t-AML) or newly diagnosed AML with myelodysplasia-related changes (AML-MRC) in August 2017. The  European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) recently gave a positive opinion recommending marketing authorization for CPX-351 for the treatment of t-AML and AML-MRC.