PDH Inhibitor Achieves High Response Rate in Advanced Hematologic Malignancies

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NEW ORLEANS—The first-in-class pyruvate dehydrogenase complex (PDH) inhibitor, CPI-613, is associated with a 38% response rate among patients with advanced hematologic malignancies, according to a 26-patient, phase 1 safety, efficacy, and pharmacokinetics clinical trial. The results were presented at the 55th American Society of Hematology Annual Meeting and Exposition.

Cancer cells alter mitochondrial metabolism—offering a potential target for therapeutic intervention, explained lead study author Timothy Pardee, MD, PhD, from the Comprehensive Cancer Center of Wake Forest University in Winston-Salem, NC, and coauthors.

CPI-613, a lipoate derivative, targets the mitochondrial enzyme PDH and deplete tumor ATP.  Dr. Pardee and colleagues sought to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and efficacy of CPI-613 monotherapy among 26 heavily pretreated patients with advanced relapsed or refractory hematologic malignancies.

Patients had received a median of three previous anticancer therapies (range, 1-11 therapies).

“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 coauthors reported. “Dose was escalated in six cohorts to a final dose of 3,780 mg/m2.”

For patients experiencing a clinical benefit, treatment was continued.

“CPI-613 was well tolerated when infused over 2 hours, with no worsening of cytopenias at any dose level,” the researchers reported. “There were no cytopenias.”

Infusion times were therefore amended to 1 hour infusions once dose was escalated to 2,940 mg/m2—but the change resulted in “two of three patients” developing grade 3 renal failure, and the protocol was therefore changed back to 2-hour infusions, they reported.

At 3,780 mg/m2, one patient each suffered grade 3 nausea and grade 3 renal failure, thus defining this dose as exceeding the MTD.

“Renal failure resolved in all but one patient, who opted for hospice care,” the researchers noted. “A total of six patients were treated at a dose of 2,940 mg/m2 over 2 hours with no DLTs (dose-limiting toxicities) observed, establishing this as the MTD.”

There was no evidence of significant CPI-613 accumulation, the authors noted.

Of 21 evaluable patients, eight (38% response rate) achieved stable disease or better.

“All three MDS (myelodysplastic syndrome) 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,” the coauthors reported. “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.”

References

  1. Pardee T et al. Abstract #486. Presented at: American Society of Hematology Meeting 2013. Dec. 7-10, 2013; New Orleans. 

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