A phase I study of the first-in-class antimitochondrial metabolism agent, CPI-613, in patients with advanced hematologic malignancies

Clin Cancer Res. 2014 Oct 15;20(20):5255-64. doi: 10.1158/1078-0432.CCR-14-1019. Epub 2014 Aug 27.


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/m(2), there were two dose-limiting toxicities (DLT). At a dose of 2,940 mg/m(2) 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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Caprylates / pharmacology
  • Caprylates / therapeutic use*
  • Cell Line, Tumor
  • Drug Administration Schedule
  • Female
  • Hematologic Neoplasms / diagnosis
  • Hematologic Neoplasms / drug therapy*
  • Hematologic Neoplasms / metabolism
  • Hematologic Neoplasms / mortality
  • Hematologic Neoplasms / pathology*
  • Humans
  • Leukemia / drug therapy
  • Leukemia / metabolism
  • Leukemia / pathology
  • Male
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Neoplasm Staging
  • Positron-Emission Tomography
  • Sulfides / pharmacology
  • Sulfides / therapeutic use*
  • Tomography, X-Ray Computed
  • Treatment Outcome
  • Young Adult


  • Antineoplastic Agents
  • CPI 613
  • Caprylates
  • Sulfides