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

Abstract

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.

Conflict of interest statement

Conflicts of Interest:

There are no other conflicts to report.

©2014 American Association for Cancer Research.

Figures

Figure 1

Overview of carbon metabolism. Shown is a simplified schematic of carbon metabolism with the CPI-613 targets PDH and KDH shown in grey.

Figure 2

CPI-613 inhibits mitochondrial respiration. A) Oxygen consumption rates (OCR) are shown for K562 and OCI-AML3 cells treated with CPI-613. Cells were incubated with the indicated concentration of CPI-613 for 2 hours prior to the assay. The electron transport chain uncoupler FCCP was added and OCR was measured in triplicate from 3 separate measurements, repeated in 3 independent experiments. Error bars are the standard deviation. *=p value

Figure 3

Response in a Burkitt's lymphoma patient. PET/CT images are shown for patient #14 just prior to enrollment and after 3 and 5 cycles as labeled.

Figure 4

Response in a CTCL patient. Photographs of representative lesions from patient #20 after 1, 4, or 7 cycles of CPI-613.

Figure 5

Pharmacokinetics of CPI-613. A) Plasma CPI-613 levels following 2 hour infusion shown in log scale to highlight the triphasic clearance. B) Comparison of day 1 and day 6 plasma levels shown on a linear scale.