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Updated: Apr 25, 2026
An Automated Differential Nuclear Staining Assay for Accurate Determination of Mitocan Cytotoxicity
Published on: May 12, 2020
A phase I study of the first-in-class antimitochondrial metabolism agent, CPI-613, in patients with advanced
Timothy S Pardee1, King Lee2, John Luddy2
1Internal Medicine, Section on Hematology and Oncology, Wake Forest Baptist Health, Winston-Salem, North Carolina. Cancer Biology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, North Carolina. tspardee@wakehealth.edu.
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.
Insights
CPI-613, a novel agent targeting mitochondrial metabolism, showed activity in patients with hematologic malignancies. The maximum tolerated dose was established, and the drug was generally well-tolerated, with some renal events observed.
Area of Science:
- Oncology
- Mitochondrial Metabolism
- Pharmacology
Background:
- CPI-613 is a novel lipoate derivative targeting mitochondrial metabolism.
- Hematologic malignancies represent a significant unmet need, particularly in relapsed or refractory settings.
Purpose of the Study:
- To determine the effects of CPI-613 on mitochondrial function.
- To define the maximum tolerated dose (MTD), pharmacokinetics, and safety of CPI-613.
- To evaluate the clinical activity of CPI-613 in patients with relapsed or refractory hematologic malignancies.
Main Methods:
- CPI-613 was tested on human leukemia cell lines to assess mitochondrial function.
- A Phase I clinical trial administered CPI-613 as a 2-hour infusion on days 1 and 4 every 28 days.
- Pharmacokinetic and safety assessments were conducted, including dose-limiting toxicity (DLT) evaluation.
Main Results:
- CPI-613 inhibited mitochondrial respiration in leukemia cells.
- The MTD was determined to be 2,940 mg/m(2) given over 2 hours, with no DLTs observed at this dose.
- In heavily pretreated patients, CPI-613 showed a 29% clinical benefit rate, with responders exhibiting immune activation.
Conclusions:
- CPI-613 effectively inhibits mitochondrial function.
- CPI-613 demonstrates clinical activity in a heavily pretreated patient cohort with hematologic malignancies.
- Further investigation into CPI-613 for hematologic malignancies is warranted.
