First-In-Man Study of CPX-351: A Liposomal Carrier Containing Cytarabine and Daunorubicin in a Fixed 5:1 Molar Ratio for the Treatment of Relapsed and Refractory Acute Myeloid Leukemia
| Autor: | Christine E. Swenson, Lawrence D. Mayer, Alan F. List, Steven L. Allen, Jeffrey E. Lancet, Arthur C. Louie, Eric J. Feldman, Ekatherine Asatiani, Ellen K. Ritchie, Jonathan E. Kolitz, Gail J. Roboz |
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| Rok vydání: | 2011 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Myeloid Maximum Tolerated Dose Daunorubicin Pharmacology Gastroenterology Drug Administration Schedule Young Adult Refractory Recurrence Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Infusions Intravenous Adverse effect Aged Aged 80 and over Salvage Therapy First-in-man study Dose-Response Relationship Drug business.industry Cytarabine Myeloid leukemia ORIGINAL REPORTS Middle Aged medicine.disease Leukemia Myeloid Acute Leukemia Treatment Outcome medicine.anatomical_structure Oncology Drug Resistance Neoplasm Myelodysplastic Syndromes Liposomes Female business medicine.drug |
| Zdroj: | Journal of Clinical Oncology. 29:979-985 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | Purpose This phase I dose-escalation trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities, and pharmacokinetics of CPX-351. Patients and Methods CPX-351 induction was administered on days 1, 3, and 5 by 90-minute infusion to 48 relapsed or refractory patients with acute myeloid leukemia (AML) or high-risk myelodysplasia. Doses started at 3 units/m2 with dose doublings in single-patient cohorts until a pharmacodynamic effect (treatment-related adverse events or reduction in bone marrow cellularity or blast count) was observed, followed by 33% escalations in three patient cohorts until dose-limiting toxicity (DLT) occurred. Results The maximum-tolerated dose was 101 units/m2. DLTs consisted of hypertensive crisis, congestive heart failure, and prolonged cytopenias. Adverse events were consistent with cytarabine and daunorubicin treatment. Response occurred at doses as low as 32 units/m2. Of 43 patients with AML, nine had complete response (CR) and one had CR with incomplete platelet recovery; of patients with acute lymphoblastic leukemia, one of three had CR. Eight CRs were achieved among the 31 patients with prior cytarabine and daunorubicin treatment. CR in AML occurred in five of 26 patients age ≥ 60 years and in five of 17 patients younger than age 60 years. Median half-life was 31.1 hours (cytarabine) and 21.9 hours (daunorubicin), with both drugs and their metabolites detectable > 7 days after the last dose. The targeted 5:1 molar ratio was maintained at all dose levels for up to 24 hours. Conclusion The recommended dose of CPX-351 for phase II study is 101 units/m2. Further exploration of efficacy and safety is ongoing in phase II trials in newly diagnosed and first-relapse patients with AML. |
| Databáze: | OpenAIRE |
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