Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial

Abstract

BackgroundPancreatic cancer statistics are dismal, with a five-year survival of less than 10%, and over 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma, including aerobic glycolysis, oxidative phosphorylation, glutaminolysis, lipogenesis and lipolysis, autophagic status, and anti-oxidative stress. CPI-613 is a novel anti-cancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumor cells, causing changes in mitochondrial enzyme activities and redox status which lead to apoptosis, necrosis and autophagy of tumor cells.MethodsThis is a phase 1 study to determine the maximum-tolerated dose (MTD) of CPI-613 when used in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2 and irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus and 2400 mg/m2 over 46 h) in combination with CPI-613 in patients with newly diagnosed metastatic pancreatic adenocarcinoma with good bone marrow, liver and kidney function and good performance status (NCT01835041 – closed to recruitment). A two-stage dose-escalation scheme (single patient and traditional 3+3 design) was applied. In the single patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2/day; the dose level was then escalated by doubling the previous dose if there was no toxicity greater than Grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxicity attributed as probably or definitely related to CPI-613 was ≥ Grade 2. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as used in the last cohort of the single patient dose-escalation stage. Secondary objectives were safety, preliminary efficacy, and tissue collection for future analyses. Response rates, progression-free survival and overall survival data were assessed in the patients treated at the MTD.FindingsTwenty patients were enrolled April 22, 2013 – January 8, 2016. The MTD of CPI-613 was 500 mg/m2. The median number of treatment cycles administered at the MTD was 11 (interquartile range, 4–19). Two patients enrolled at a higher dose (1000 mg/m2) both experienced a DLT (dose limiting toxicity). There were 2 unexpected serious adverse events (SAEs), both for the first patient enrolled: 1) possible leaching due to infusion of CPI-613 via non-PVC tubing, and 2) the patient re- accessed her port at home after accidental de-access. Neither incident resulted in a negative clinical outcome. Expected SAEs were: thrombocytopenia, anemia and lymphopenia (all for Patient #2, with anemia and lymphopenia being a DLT); hyperglycemia (Patient #7); hypokalemia, hypoalbuminemia and sepsis (Patient #11); and neutropenia (Patient #20). There was no grade 5 toxicity. For the 18 patients treated at the MTD, the most common Grade 3–4 toxicities were hypokalemia (6/18, 33%), diarrhea (5/18, 28%) and abdominal pain (4/18, 22%). Sensorial neu...

Metabolomic profiling of mouse mammary tumor derived cell lines reveals targeted therapy options for cancer subtypes

“…35,36 Finally, CPI-613 is being investigated as a component in combination therapies for several malignancies including colorectal cancer, 37 small cell lung cancer, 38 and pancreatic cancer. 39 Our findings support investigating these compounds to treat specific subtypes of breast cancer, as each tested compound demonstrates some degree of inhibition regardless of subtype. Moreover, our findings provide an additional rationale for subtype-specific drug selection based on the underlying metabolism of the cancer cells in question, as the drug sensitivity for the EMT and papillary cells directly correlates with the metabolic profile of each subtype.…”

Mitochondria in cancer metabolism, an organelle whose time has come?

“…In combination with chemotherapy it had encouraging activity in patients with relapsed or refractory AML especially in patients 60 years of age or older (Pardee et al in press). CPI-613 in combination with chemotherapy roughly doubled the objective response rate for patients with metastatic pancreatic cancer and showed encouraging median survival [32]. CPI-613 is currently being evaluated in several additional clinical trials (ClinicalTrials.gov Identifiers: NCT02168140, NCT02232152, NCT02484391).…”

Recent advances in the treatment of pancreatic cancer

“…AVENGER 500 (ClinicalTrials.gov Identifier: NCT03504423) is a phase III RCT investigating modified FOLFIRINOX with or without CPI-613 15 , a tricarboxylic acid cycle inhibitor. Accrual should be complete by mid-2020, and results are highly anticipated after showing promise in the phase I setting (ORR 61%, CRR 17%) 16 .…”