A Phase I Study of the First-in-Class Anti-Mitochondrial Metabolism Agent, CPI-613, in Patients with Advanced Hematologic Malignancies
| Autor: | King Chung Lee, Timothy S. Pardee, John Luddy, Sarah Dralle, Robin Harrelson, David D. Hurd, Leslie R. Ellis, Bayard L. Powell, Robert J. Rodriguez, Kristin Stadelman, Claudia Maturo, Megan Manuel, Denise Levitan, Scott Isom, Susan Lyerly, Lance D. Miller |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Adult
Male Cancer Research medicine.medical_specialty Alpha (ethology) Antineoplastic Agents Mitochondrion Sulfides Peripheral blood mononuclear cell Gastroenterology Article Drug Administration Schedule Young Adult Pharmacokinetics Refractory Internal medicine Cell Line Tumor Medicine Humans Aged Neoplasm Staging Aged 80 and over Leukemia business.industry Cancer Middle Aged medicine.disease Mitochondria Clinical trial Treatment Outcome Oncology Hematologic Neoplasms Positron-Emission Tomography Immunology Female Caprylates business Tomography X-Ray Computed |
| Popis: | Purpose: The lipoate derivative CPI-613 is a first-in-class agent that targets mitochondrial metabolism. This study determined the effects of CPI-613 on mitochondrial function and defined the MTD, pharmacokinetics, and safety in patients with relapsed or refractory hematologic malignancies. Experimental Design: Human leukemia cell lines were exposed to CPI-613 and mitochondrial function was assayed. A phase I trial was conducted in which CPI-613 was given as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days. Results: CPI-613 inhibited mitochondrial respiration of human leukemia cells consistent with the proposed mechanism of action. In the phase I trial, 26 patients were enrolled. CPI-613 was well tolerated with no marrow suppression observed. When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3,780 mg/m2, there were two dose-limiting toxicities (DLT). At a dose of 2,940 mg/m2 over 2 hours, no DLTs were observed, establishing this as the MTD. Renal failure occurred in a total of 4 patients and resolved in all but 1, who chose hospice care. CPI-613 has a triphasic elimination with an alpha half-life of approximately 1.34 hours. Of the 21 evaluable, heavily pretreated patients, 4 achieved an objective response and 2 achieved prolonged stabilization of disease for a clinical benefit rate of 29%. Following drug exposure, gene expression profiles of peripheral blood mononuclear cells from responders demonstrated immune activation. Conclusion: CPI-613 inhibits mitochondrial function and demonstrates activity in a heavily pretreated cohort of patients. Clin Cancer Res; 20(20); 5255–64. ©2014 AACR. |
| Databáze: | OpenAIRE |
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