A phase 2 study to assess the pharmacokinetics and pharmacodynamics of CPX-351 and its effects on cardiac repolarization in patients with acute leukemias

Abstract

Purpose: Daunorubicin can induce left ventricular dysfunction and QT interval prolongation. This study assessed the effects of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, on cardiac repolarization.

Methods: Twenty-six adults with acute leukemia were treated with CPX-351 for 1-2 induction cycles and ≤ 4 consolidation cycles. The primary endpoint was mean change in QTcF from baseline.

Results: Mean QTcF changes were < 10 ms at all time points. No clinically meaningful effects on heart rate, QRS interval, PR interval, or QTcB were observed. Estimated mean half-lives for total cytarabine and daunorubicin were > 30 h. Thirteen (50%) patients achieved remission. The most common adverse events were febrile neutropenia, fatigue, and nausea.

Conclusions: The cytarabine and daunorubicin in CPX-351 liposomes were metabolized and excreted similarly to conventional formulation; however, plasma pharmacokinetics were altered. CPX-351 did not prolong the QT interval, suggesting that CPX-351 may induce less cardiotoxicity than previously reported for conventional daunorubicin.

Trial registration: Clinicaltrials.gov identifier: NCT02238925.

Keywords: Acute lymphoblastic leukemia; Acute myeloid leukemia; Cardiac repolarization; Pharmacodynamics; Pharmacokinetics.

Conflict of interest statement

TLL reports honoraria from Jazz; and advisory board participation for Pfizer. RKS reports honoraria, consulting, and travel support from Sunesis; and institutional research funding from Agios, Astellas, Bayer, Celator/Jazz, Incyte, and Sunesis. LCM reports research funding from Jazz; consulting and advisory board participation for Incyte, TG Therapeutics, Novartis, and Celgene; and stock ownership in Pfizer. ER reports speakers bureau participation for Alexion Pharmaceuticals and AstraZeneca; and advisory board participation for Celgene. HSP reports paid consultation for Celator/Jazz. TC reports employment at ERT. DA, BDL, LDM, and QW report employment at and stock ownership in Celator/Jazz. KB and ACL were former employees of Jazz, and ACL reports stock ownership in Celator/Jazz. LFN reports no potential conflicts of interest.

Figures

Fig. 1

Mean change from baseline in QTcF (a) and QTcB (b). Mean values are shown with their 95% CIs. Mean changes in QTcF were < 10 ms at all time points and upper limits of the 2-sided 90% CI exceeded 10 ms at only 2 time points (Day 1 at 3 h post-SOI: 10.7 ms [mean = 5.3]; Day 1 at 4 h post-SOI: 12.3 ms [mean = 8.0]). QTcF Fridericia's corrected QT interval, CI confidence interval, QTcB Bazett's corrected QT interval, SOI start of infusion

Fig. 2

Plasma concentrations of total cytarabine (a) and daunorubicin (b). Pharmacokinetic samples from all patients (Groups A and B) were processed to determine concentrations of total plasma cytarabine and Ara-U (a) and daunorubicin and daunorubicinol (b)