CPI-613 Plus Modified FOLFIRINOX ‘Well Tolerated’ For Metastatic Pancreatic Cancer

CPI-613, given with a standard chemotherapy regimen, shows tolerability and possible activity for metastatic pancreatic cancer

medwireNews: A novel anticancer agent targeting tumour cell mitochondrial energy metabolism is well tolerated and has shown signs of activity when given alongside chemotherapy in a phase I study of patients with a new diagnosis of metastatic pancreatic adenocarcinoma.

“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”, the investigators comment in The Lancet Oncology.

The dose-escalation study identified the maximum tolerated dose (MTD) of CPI-613 to be 500 mg/m2 when given in conjunction with a modified FOLIFIRINOX regimen consisting of oxaliplatin 65 mg/m2, leucovorin 400 mg/m2, irinotecan 140 mg/m2 and fluorouracil 400 mg/m2 bolus plus 2400 mg/m2 over 46 hours.

In all, 18 patients were treated at this CPI-613 dose without dose-limiting toxicity, although grade 3–4 adverse events were common, report Angela Alistar, from Wake Forest University School of Medicine in Winston-Salem, North Carolina, USA, and co-authors.

These included hyperglycaemia (55%), hypokalaemia (33%), diarrhoea (28%), peripheral sensory neuropathy (28%), lymphopenia (28%), abdominal pain (22%) and anaemia (22%).

By contrast, two of three patients given CPI-613 at a dose of 1000 mg/m2 experienced dose-limiting toxicities, namely anaemia, lymphopenia, pulmonary embolus, hyponatraemia and dehydration in one individual, and hyponatraemia, hypotension and lymphopenia in the second.

While activity was not the primary study endpoint, the researchers report finding “an encouraging signal for possible synergy with standard of care chemotherapy without substantial additional toxicity.”

Exploratory analysis indicated that 17% of the patients given the MTD achieved a complete response to treatment, 44% had a partial response and 17% stable disease, giving a complete or partial response rate of 61%.

Of the three complete responses, two were maintained for 2 months after treatment discontinuation and one lasted for 6 months; these patients’ “excellent performance status” allowed rechallenge with the same regimen, resulting in stable disease in two patients and progressive disease after 2 months in the second.

And a patient with a partial response, who had “innumerable” liver and peritoneal lesions at diagnosis, chose to discontinue treatment after 32 cycles and has since maintained sub-cm residual disease for 12 months.

Median progression-free survival was 11.5 months. Two patients died on day 284 and 602, respectively, and nine patients were alive at time of writing. “This finding, coupled with the fact that all nine patients who are still alive have now survived longer than 374 days, means that the smallest median overall survival value was 374 days (12·4 months)”, the researchers write.

Angela Alistar et al say that a randomised phase II/III trial comparing FOLFIRINOX against modified FOLFIRINOX plus CPI-613 in this patient population will begin in mid-2017.

“Questions that remain unanswered at this point include the role of maintenance therapy for patients who achieve a radiological complete response, and how the combination of CPI-613 and [modified] FOLFIRINOX affects quality of life”, they write.

The authors add that the clinical observations noted in the trial suggest 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.”


Alistar A, Morris BB, Desnoyer R, et al. Safety and tolerability of the first-in-class agent CP-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol; Advance online publication 8 May 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30314-5

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