A phase I, single-center, open label, dose de-escalation and expansion study of Ivosidenib + mFOLFIRINOX in patients with resectable pancreatic adenocarcinoma.

Abstract

TPS794 Background: Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis, with a 34% 5-year survival rate for patients with localized disease. Guidelines recommend consideration of neoadjuvant approaches in localized PDA with the goals of controlling microscopic metastatic disease and increasing rates of microscopically margin-negative resections. One of the hallmark characteristics of PDA is a micronutrient poor, highly stromal microenvironment. Surviving in this environment requires enhanced mitochondrial function, which utilizes isocitrate dehydrogenase 1 (IDH1). In pre-clinical studies, ivosidenib, an FDA approved medication for IDH1 mutant AML, induced high levels of reactive oxygen species in PDA cells with wild-type IDH1, and caused tumor regressions and extended survival in implanted KPC mouse models. Here, we investigate the addition of ivosidenib to standard of care neoadjuvant mFOLFIRINOX in patients with resectable PDA to determine safety, pharmacodynamics, and early efficacy signals. Methods: This is a phase I, single-center, open label, dose de-escalation and expansion study in patients with resectable PDA. Eligible patients must have histologically confirmed and resectable right-sided PDA based on CT or MRI imaging. Patients receive approximately 10 weeks of neoadjuvant treatment composed of 2 weeks of ivosidenib monotherapy, followed by 6 weeks (3 cycles) of mFOLFIRINOX with ivosidenib, followed by up to 4 weeks of ivosidenib monotherapy until the day of surgery. Ivosidenib is administered once daily at 500mg; it is to be de-escalated to 250mg based on Bayesian Optimal Interval Design with Informative Prior and a target dose limiting toxicity (DLT) rate of 30%. The primary endpoint is to determine the safety and tolerability of ivosidenib in combination with mFOLFIRINOX. Secondary endpoints include RECIST version 1.1 response rates, major pathologic response rates, and biochemical (CA19-9, CEA) response rates. Correlative studies will be performed on surgical samples to evaluate metabolomic profiles. At the time of submission, 10 out of 16 planned patients have been enrolled. There have been no DLT at 500mg of ivosidenib. Clinical trial information: NCT05209074 .