A phase 1/2 study of NS-87/CPX-351 (cytarabine and daunorubicin liposome) in Japanese patients with high-risk acute myeloid leukemia

Abstract

Objectives: NS-87/CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. NS-87/CPX-351 exerts antileukemic action by maintaining a synergistic molar ratio of cytarabine to daunorubicin of 5:1 within the liposome while in circulation. Patients with high-risk acute myeloid leukemia (AML), which includes therapy-related AML and AML with myelodysplasia-related changes (AML-MRC), have poorer outcomes than those with other AML.

Methodology: This open-label phase 1/2 (P1/2) study was conducted in 47 Japanese patients aged 60-75 years with newly diagnosed high-risk AML to evaluate the pharmacokinetics, safety, and efficacy of NS-87/CPX-351.

Results: In the 6 patients enrolled in the P1 portion, no dose-limiting toxicities (DLTs) were reported, and 100 units/m² during the induction cycle was found to be acceptable. Cytarabine and daunorubicin had a long half-life in the terminal phase (32.8 and 28.7 h, respectively). In the 35 patients enrolled in the P2 portion, composite complete remission (CRc; defined as complete remission [CR] or CR with incomplete hematologic recovery [CRi]) was achieved in 60.0% (90% CI: 44.7-74.0) of the patients. Adverse events due to NS-87/CPX-351 were well tolerated.

Outcomes: NS-87/CPX-351 can be considered as a frontline treatment option for Japanese patients with high-risk AML.

Keywords: Acute myeloid leukemia; CPX-351; Cytarabine; Daunorubicin; Liposomal formulation.

Fig. 1

Study design and treatment. CR Complete Remission, CRi Complete Remission with Incomplete Blood Count Recovery, PK pharmacokinetics, DLT dose-limitting toxicity, MLFS morphologic leukemia-free state (bone marrow blasts <5% and absence of Auer rods and/or extramedullary disease). *1 Investigators treating patients with cumulative anthracycline exposure ≥500 mg/m² had the option to receive an alternative consolidation regimen of intermediate-dose cytarabine, 1.5 g/m² BID on Days 1, 3 and 5. Patients with less than 500 mg/m² cumulative anthracycline exposure, including the study treatment, who have a >10% absolute decrease in LVEF to less than 50%, received the alternative consolidation regimen of intermediate-dose cytarabine as described above

Fig. 2

Deposition of patients. *1 Completed treatment is a patient group that completed the treatment (induction and consolidation cycles). HCT hematopoietic cell transplantation, CR complete remission, CRi CR with incomplete recovery

Fig. 3

Pharmacokinetics. A Plasma concentration curves for cytarabine and daunorubicin after a 90-min intravenous infusion of NS-87/CPX-351 100 units/m² on Day 5 (semi-log scale). Each plot represents the mean + SD of 6 subjects. B Molar ratio curve for cytarabine/daunorubicin after a 90-min intravenous infusion of NS-87/CPX-351 100 units/m² on Day 5 (normal scale). Each plot represents the mean ± SD of 6 subjects. C Serum concentration curves for copper after a 90-min intravenous infusion of NS-87/CPX-351 100 units/m² on Day 5 (normal scale). Each plot represents the mean ± SD of 6 subjects. The dotted line represents the upper 95% confidential interval of the mean baseline copper levels (1.63 μg/mL)