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 maximally tolerated dose (MTD), pharmacokinetics (PKs), 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 3780 mg/m2, there were 2 dose-limiting toxicities (DLTs). At a dose of 2940 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 ~1.34 hours. Of 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.

Temperature induces significant changes in both glycolytic reserve and mitochondrial spare respiratory capacity in colorectal cancer cell lines

“…The cancer literature reports use of different protocols involving exposure of cell lines to hyperthermia from 1 hour 13 up to 3 days 3 , and some cases up for 2 weeks 14 (in most cases 12–36 h) which makes difficult to draw direct parallels between possible molecular mechanisms underlying the in vitro results and the outcomes of the human hyperthermia clinical studies. The Seahorse extracellular flux analyzer has been reported to produce valuable data measuring cancer metabolism under different experimental conditions including, but not limited to the following: testing effects on novel therapies 15–17 , changes in cancer cell substrate preferences 18–20 , effects of gene overexpression or knockdown in cancer cells 21–23 , effects of hypoxia 20, 24 and cell environmental factors 25–27 .…”

Targeting Metabolism for Cancer Therapy

“…Consistent with this notion, other complex I inhibitors have shown efficacy as anti-tumor agents (Appleyard et al, 2012; Schockel et al, 2015) and may show selective toxicity against oncogene-ablation resistant cells (Viale et al, 2014) and cancer stem cells (Sancho et al, 2015). Additional complex I inhibitors are under development (Bastian et al, 2017), and other inhibitors of respiration or mitochondrial metabolism, including the lipoic acid derivative CPI-613 (Table 1), are currently being assessed in clinical trials (Lycan et al, 2016; Pardee et al, 2014). …”

Mitochondria in cancer metabolism, an organelle whose time has come?

“…In preclinical studies CPI-613 has shown extensive anticancer effects. In a phase one study, CPI-613 has shown to be well tolerated and active in several patients with advanced myeloid malignancies [31]. In combination with chemotherapy it had encouraging activity in patients with relapsed or refractory AML especially in patients 60 years of age or older (Pardee et al in press).…”