GA CPI 613: A single-arm, open-label phase I study of CPI-613 in combination with gemcitabine and nab-paclitaxel for patients with locally advanced or metastatic pancreatic cancer

Pancreatic cancer is the third leading cause of cancer death in the USA with current standard of care treatments that have moderate toxicity and median overall survival of less than 12 months. Safer and more effective treatments are needed. The glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species such as Nab-Paclitaxel. CPI- 613 is a novel antimitocondrial developed by Rafael Pharmaceuticals. Preclinical data suggests possible synergy of CPI- 613 with nab-paclitaxel. This is a single-arm, open-label, nonblinded phase I study of CPI-613 in combination with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer. Key eligibility criteria include: histologically or cytologically documented and measurable locally advanced and metastatic pancreatic adenocarcinoma, ECOG performance status 0-2, first-line systemic treatment. CPI-613 infused intravenously with a starting dose of 500 mg/m2 followed by modified dose nab-paclitaxel and gemcitabine on day 1, 8, 15 of a 28-day cycle. The study is comprised of a two-stage dose-escalation schema to evaluate the MTD of CPI-613. At least six months of treatment was planned for patients who have a response. Primary endpoint of the study is MTD of CPI 613 when combined with gemcitabine and nab-paclitaxel and secondary endpoints of the study are treatment related adverse events and clinical response to treatment. This study was initiated in February 2018 at Atlantic Health System and has completed accrual in December 2019. Clinical trial information: NCT03435289. 26 patients were screened, and 23 patients were enrolled, with 22 patients evaluable. The MTD of CPI- 613 was determined at 1500mg/m2; all patients are off treatment. The median OS for patients treated at 500 mg/m2 was 20.8 mo and PFS was 6.4 mo, the median OS for patients treated at 1000 mg /m2 was 10.3 mo and PFS was 5.0 mo and the median OS for 1500 mg/m2 was 9.2 mo and PFS was 3.5 mo. The treatment was well tolerated overall with expected toxicity mainly related to chemotherapy (such as fatigue, neuropathy, hematologic toxicity). The results prove that the treatment is feasible, and CPI 613 shows clinical synergy with chemotherapy. Further expansion of the combination in a multisite setting is being evaluated.