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February 11, 2020
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Researchers hope to confirm ‘remarkable results’ of novel drug combination for advanced pancreatic cancer

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Minsig Choi, MD
Minsig Choi

Researchers at Stony Brook University’s Renaissance School of Medicine have developed an enzyme-targeting drug that could prolong survival for patients with metastatic pancreatic cancer.

Pancreatic cancer is a lethal disease for which incidence matches closely to all patient mortality,” Minsig Choi, MD, medical oncologist on the Stony Brook University Cancer Center gastroenterology oncology team at Renaissance School of Medicine, said in an interview with Healio. “Overall survival for advanced pancreatic cancer is 6 to 12 months for treated patients and less than 3 months for untreated patients.”

The new drug, CPI-613 (devimistat, Rafael Pharmaceuticals), will be evaluated in combination with modified FOLFIRINOX in an upcoming phase 3 clinical trial.

In a phase 1 study that included 18 patients, the CPI-613-chemotherapy combination conferred median OS of 20 months vs. 11 months with chemotherapy alone and an objective response rate of 61% vs. 32%.

Choi spoke with Healio about the mechanism of this drug combination and potential adverse events associated with it, as well as the future of pancreatic cancer treatment.

Question: What did you learn from your phase 1/phase 2 trial that might give hope to patients with metastatic pancreatic cancer?

A: In the study, 61% of patients had objective responses and 78% achieved clinical benefit. These are remarkable results compared with historical standard chemotherapy such as gemcitabine, which has a 10% response rate, and the best chemotherapy regimen now used, FOLFIRINOX, which has a response rate of about 31%. Such a remarkable clinical benefit led to AVENGER 500, a phase 3 clinical trial of CPI-613 in combination with modified FOLFIRINOX compared with modified FOLFIRINOX alone for patients with previously untreated metastatic adenocarcinoma of the pancreas.

Q: What is the mechanism of CPI-613?

A: CPI-613 is designed to target the mitochondrial tricarboxylic acid (TCA) cycle, an indispensable process essential to tumor cell multiplication and survival, selectively in cancer cells. Cancer requires considerable energy to continue on its daily course. This drug, which is a lipoate analog and enzyme cofactor in several central processes in metabolism, “tricks” the disease into believing it has sufficient energy. Interrupting this energy feedback mechanism causes the cancer cell to starve to death. Disruption of CPI-613 on the TCA cycle also substantially increases the sensitivity of cancer cells to a diverse range of chemotherapeutic agents, including FOLFIRINOX. This synergy allows for combinations of CPI-613 with lower doses of those generally toxic drugs to be highly effective, with fewer adverse events. Combinations with CPI-613 represent potential opportunities to substantially improve outcomes for patients with metastatic pancreatic cancer.

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Q: Are there any toxicities associated with the combination regimen?

A: Because the drug is given in combination with chemotherapy, it is hard to distinguish the toxicities of chemotherapy from those of CPI-613. In the clinical trial, investigators noted diarrhea, abdominal pain, hyperglycemia, numbness in the fingers and toes, and low potassium, as well as low white blood cells, anemia and thrombocytopenia. The hematologic toxicities are more likely from chemotherapy, whereas hyperglycemia is likely from CPI-613.

Q: Could this type of treatment improve metastatic pancreatic cancer survival rates?

A: There is no cure for advanced pancreatic cancer. The goal of chemotherapy is to prolong the patient’s survival and improve quality of life. When new drugs improve cancer shrinkage, as in this case, OS and better quality of life are expected. Although the initial trials included 20 patients who received the combination, we expect the phase 3 clinical trial to confirm the earlier finding.

Q: Do you foresee a future in which advanced pancreatic cancer is curable?

A: There has been a lot of progress in the treatment of pancreatic cancer based on use of better surgery, chemotherapy and radiation therapy. Better clinical trials, multidisciplinary care and improved translational application of preclinical data to the clinic would be needed to have a chance of curing pancreatic cancer. – by Jennifer Byrne

For more information:

Minsig Choi, MD, can be reached at 3 Edmund D. Pellegrino Road, Stony Brook, NY 11794.

Disclosure: Choi reports no relevant financial disclosures.