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

Tara L. Lin, Laura Newell, Robert K. Stuart, Laura C. Michaelis, Eric Rubenstein, Helen S. Pentikis, Timothy Callahan, Donna Alvarez, Barry D. Liboiron, Lawrence D. Mayer, Qi Wang, Kamalika Banerjee, Arthur C. Louie

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalCancer Chemotherapy and Pharmacology
DOIs
StatePublished - Jan 1 2019

Fingerprint

Pharmacodynamics
Daunorubicin
Pharmacokinetics
Leukemia
Cytarabine
Febrile Neutropenia
Left Ventricular Dysfunction
Encapsulation
Liposomes
Consolidation
Nausea
Fatigue
Fatigue of materials
Plasmas

Keywords

  • Acute lymphoblastic leukemia
  • Acute myeloid leukemia
  • Cardiac repolarization
  • Pharmacodynamics
  • Pharmacokinetics

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

A phase 2 study to assess the pharmacokinetics and pharmacodynamics of CPX-351 and its effects on cardiac repolarization in patients with acute leukemias. / Lin, Tara L.; Newell, Laura; 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.

In: Cancer Chemotherapy and Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

Lin, Tara L. ; Newell, Laura ; 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. / A phase 2 study to assess the pharmacokinetics and pharmacodynamics of CPX-351 and its effects on cardiac repolarization in patients with acute leukemias. In: Cancer Chemotherapy and Pharmacology. 2019.
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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.",
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AU - Lin, Tara L.

AU - Newell, Laura

AU - Stuart, Robert K.

AU - Michaelis, Laura C.

AU - Rubenstein, Eric

AU - Pentikis, Helen S.

AU - Callahan, Timothy

AU - Alvarez, Donna

AU - Liboiron, Barry D.

AU - Mayer, Lawrence D.

AU - Wang, Qi

AU - Banerjee, Kamalika

AU - Louie, Arthur C.

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N2 - 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.

AB - 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.

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KW - Acute myeloid leukemia

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KW - Pharmacodynamics

KW - Pharmacokinetics

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