Targeting mitochondrial metabolism shows promise in pancreatic cancer
medwireNews: Researchers report promising results from a phase I trial evaluating CPI-613, which targets mitochondrial metabolism, in combination with modified FOLFIRINOX chemotherapy for the treatment of metastatic pancreatic cancer.
They say: “This study provides encouraging evidence for a novel, potentially effective combination chemotherapy regimen […] that was safe and well tolerated in patients with metastatic pancreatic cancer.”
Angela Alistar (Wake Forest School of Medicine, Winston-Salem, North Carolina, USA) and colleagues explain that “CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells.”
In the current study, they tested its safety and tolerability in combination with modified FOLFIRINOX (oxaliplatin 65 mg/m2, leucovorin 400 mg/m2, irinotecan 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 hours) in 20 adults with newly diagnosed metastatic pancreatic adenocarcinoma.
The patients all had good bone marrow, liver and kidney function, and a good ECOG performance status.
Using a two-stage dose-escalation scheme (single patient and traditional 3+3 design), the researchers found that the maximum tolerated dose of CPI-613 was 500 mg/m2.
Eighteen patients received this dose for a median 11 cycles. Two patients were enrolled at a higher dose of 1000 mg/m2, but both had dose-limiting toxicity, including anaemia, lymphopenia, pulmonary embolus, hyponatremia, hypotension, and dehydration, and discontinued treatment.
The most common grade 3 or 4 hematological adverse events occurring in the 18 patients who received the maximum tolerated dose were neutropenia (n=5), lymphopenia (n=5), anaemia (n=4), and thrombocytopenia (n=3).
The most common grade 3 or 4 non-hematological adverse events were hyperglycemia (n=10), hypokalemia (n=6), peripheral sensory neuropathy (n=5), diarrhea (n=5), and abdominal pain (n=4).
All but one patient experienced grade 1–3 sensory neuropathy, which was managed with dose de-escalation or discontinuation, and no patients died during active treatment.
Although efficacy was not a primary study endpoint, the researchers found that 11 (61%) of the 18 patients given the maximum tolerated dose had a complete or partial response.
The median progression-free survival was 11.5 months, and, at the time of analysis, median overall survival had not been reached but was at least 374 days, with nine patients surviving at least this long.
Writing in The Lancet Oncology, Alistar and co-authors conclude: “Although we recognise that the experience with this small cohort of patients is not reflective of what we might find in a phase 2 or 3 trial, we are encouraged to further explore this novel therapeutic combination.”
They add that the impact on quality of life needs to be assessed, but that experience from this trial “suggests that CPI-613 might have protective benefits (ie, increased tolerance to treatment) and could mitigate some of the chemotherapy-induced adverse events, which is highly relevant for patients with pancreatic cancer who typically have a high symptom burden.”
By Laura Cowen
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