A Phase I Study Of The Safety, Efficacy and Pharmacokinetics Of The First In Class Pyruvate Dehydrogenase Complex Inhibitor Cpi-613 In Patients With Advanced Hematologic Malignancies

Altered metabolism is a hallmark of cancer, including hematologic malignancies. Cancer cells alter the normally catabolic role of their mitochondria to produce biosynthetic precursors to more efficiently generate additional cancer cells. This altered metabolism is a possible therapeutic target. The lipoate derivative CPI-613 is a first in class agent that targets the mitochondrial enzyme pyruvate dehydrogenase complex (PDH). This trial was designed to determine the maximally tolerated dose (MTD), pharmacokinetics, safety, and efficacy of CPI-613 given as a single agent.

CPI-613 was given over a 2 hour infusion on days 1 and 4 for 3 weeks every 28 days with a starting dose of 420 mg/m². The dose was escalated in 6 cohorts to a final dose of 3780 mg/m². Treatment was continued if the patient experienced clinical benefit. Pharmacokinetic samples were analyzed to determine the half-life of CPI-613.

A total of 26 patients with advanced relapsed or refractory hematologic malignancies were enrolled. Patients were heavily pretreated with a median of 3 previous therapies (range 1-11). CPI-613 was well tolerated when infused over 2 hours, with no worsening of cytopenias at any dose level. After the dose was escalated to 2940 mg/m² the protocol was amended to a 1 hour infusion. When infused over 1 hour, 2 of 3 patients developed grade 3 renal failure. Infusion time was then returned to 2 hours and dose escalation resumed. At a dose of 3780 mg/m², one patient experienced prolonged grade 3 nausea and one patient grade 3 renal failure, defining this dose as above the MTD. Renal failure resolved in all but one patient who opted for hospice care. A total of 6 patients were treated at a dose of 2940 mg/m² over 2 hours with no DLTs observed, establishing this as the MTD. CPI-613 was eliminated from the plasma in a triphasic pattern. The α-phase occurred during the first 6-8 hrs post-administration and was associated with a relatively rapid decline in the mean plasma CPI-613 concentrations with a T_1/2 of ∼1.3 hrs. The β-phase occurred from 6-8 hrs to 24 hrs post-administration and was associated with a modest increase in CPI-613 concentration, from ∼0.5 to 4 μM when averaged across all dose levels. The γ- or final phase started from 24 hrs until 72 hrs post-administration and was associated with a very slow decline in mean plasma CPI-613 values consistent with high plasma protein binding. Upon repeat dosing there was no evidence of significant accumulation of CPI-613. Of the 21 patients evaluable for a response, eight achieved a response of stable disease or better for a response rate of 38%. All three MDS patients had a response, including one therapy-related MDS patient with deletion 7q who achieved a complete remission and continues on therapy for over 31 cycles. One refractory AML patient had clearance of marrow blasts, allowing for a subsequent allogeneic stem cell transplant. A Burkitt's and a cutaneous T cell lymphoma patient each achieved a partial response, maintained over 17 and 14 cycles respectively. The Burkitt’s patient had her only site of disease resected, and currently has no evidence of disease more than 6 months post resection.

CPI-613 is a non-myelosuppressive PDH inhibitor with activity against aggressive hematological malignancies. The therapeutic index appears high, warranting further studies of CPI-613 in phase II trials.

Pardee:Cornerstone Pharmaceuticals: Honoraria. Lee:Cornerstone Pharmaceuticals: Employment. Luddy:Cornerstone Pharmaceuticals: Employment. Maturo:Cornerstone Pharmaceuticals: Employment. Rodriguez:Cornerstone Pharmaceuticals: Employment.