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Blood smear showing MDS

The US Food and Drug Administration (FDA) has granted orphan designation to an investigational drug for the treatment of myelodysplastic syndromes (MDS).

The drug, CPI-613, targets metabolic changes that are thought to occur in many cancer cells.

It has demonstrated activity and tolerability in a phase 1 trial of patients with advanced, relapsed/refractory hematologic malignancies.

CPI-613 previously received orphan designation for acute myeloid leukemia (AML) and pancreatic carcinoma.

Orphan designation is granted for drugs intended to treat diseases that affect fewer than 200,000 individuals in the US. This designation gives the makers of CPI-613, Cornerstone Pharmaceuticals, 7 years of US marketing exclusivity once the drug is approved.

The designation also allows the company to apply for government funding to defray trial costs, tax credits for clinical research expenses, and a potential waiver of the FDA’s application user fee.

CPI-613: Mechanism and phase 1 results

CPI-613 induces cancer-specific inhibition of the mitochondrial enzymes pyruvate dehydrogenase (PDH) and alpha ketoglutarate dehydrogenase (KGDH).

Disrupting the function of PDH and KGDH disrupts tumor mitochondrial metabolism. As a result, tumor cells are starved of energy and biosynthetic intermediates, which leads to cell death.

Researchers evaluated CPI-613 in a phase 1 study of patients with advanced, relapsed/refractory hematologic malignancies.

The team, led by Timothy S. Pardee, MD, of Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, presented the results at the 2013 ASCO Annual Meeting as abstract 2516. (Information in the abstract differs slightly from that presented at the meeting.)

The trial was designed to determine the maximum tolerated dose, safety, and anticancer activity of CPI-613 as a single agent.

Twenty-one evaluable patients received CPI-613 on days 1 and 4 for 3 weeks every 28 days. Ten patients received more than 1 cycle of therapy.

The starting dose was 420 mg/m2. Treatment could be continued if the patient experienced clinical benefit. Doses were escalated to a final dose of 3780 mg/m2.

CPI-613 was generally well-tolerated when infused over 2 hours. Patients did not experience worsening cytopenias at any dose level. However, 1-hour infusions led to grade 3 renal failure in 2 patients.

At a dose of 3780 mg/m2, 1 patient had prolonged grade 3 nausea, and 1 patient had grade 3 renal failure. Six patients received a 2-hour infusion of 2940 mg/m2 without dose-limiting toxicities, so the researchers considered this the maximum tolerated dose.

Of the 21 patients, 9 achieved a response of stable disease or better. One MDS patient achieved a complete remission and maintained it over 23 cycles. One AML patient achieved a morphologic leukemia-free state. 

A Burkitt lymphoma patient and a cutaneous T-cell lymphoma patient maintained partial responses over 16 and 15 cycles, respectively. Two multiple myeloma patients, 2 MDS patients, and 1 AML patient had stable disease.

“We are very encouraged by the tolerability and signals of activity seen in several patients in this phase 1 study for whom there is no available therapy shown to provide clinical benefit,” Dr Pardee said.

“We look forward to further evaluating CPI-613 in the early relapsed/refractory AML patient setting when administered in combination with a standard chemotherapeutic regimen, as well as in early relapsed or refractory MDS patients, with the hope of improving the outcomes and the quality of life for these patients through the combined use of this mechanistically novel agent.”

The AML study is a phase 1 trial investigating CPI-613 in combination with high-dose cytarabine and mitoxantrone, and the MDS study is a phase 2 trial investigating single-agent CPI-613. ht-logo-end


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