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

• Published in: Cancer chemotherapy and pharmacology Vol. 84; no. 1; pp. 163 - 173
• Main Authors: Lin, Tara L., Newell, Laura F., Stuart, Robert K., Michaelis, Laura C., Rubenstein, Eric, Pentikis, Helen S., Callahan, Timothy, Alvarez, Donna, Liboiron, Barry D., Mayer, Lawrence D., Wang, Qi, Banerjee, Kamalika, Louie, Arthur C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2019; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Cancer Research; Cardiotoxicity; Cytarabine; Cytarabine - administration & dosage; Cytarabine - adverse effects; Cytarabine - pharmacokinetics; Daunorubicin; Daunorubicin - administration & dosage; Daunorubicin - adverse effects; Daunorubicin - pharmacokinetics; Drug Combinations; Electrocardiography; Female; Half-Life; Heart rate; Humans; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Liposomes; Male; Medicine; Medicine & Public Health; Middle Aged; Nausea; Neutropenia; Oncology; Original; Original Article; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Prolongation; Remission; Treatment Outcome; Ventricle; Cardiac repolarization; Pharmacodynamics; Acute lymphoblastic leukemia; Pharmacokinetics; Acute myeloid leukemia
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-019-03856-9

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.