1. A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma
- Author
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Ko, Andrew H, LoConte, Noelle, Tempero, Margaret A, Walker, Evan J, Kelley, R Kate, Lewis, Stephanie, Chang, Wei-Chou, Kantoff, Emily, Vannier, Michael W, Catenacci, Daniel V, Venook, Alan P, and Kindler, Hedy L
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Digestive Diseases ,Pancreatic Cancer ,Rare Diseases ,Orphan Drug ,Clinical Research ,Clinical Trials and Supportive Activities ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adenocarcinoma ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,CA-19-9 Antigen ,Camptothecin ,Diarrhea ,Dose-Response Relationship ,Drug ,Feasibility Studies ,Female ,Fluorouracil ,Hedgehog Proteins ,Humans ,Irinotecan ,Kaplan-Meier Estimate ,Leucovorin ,Male ,Middle Aged ,Nausea ,Nervous System Diseases ,Organoplatinum Compounds ,Oxaliplatin ,Pancreatic Neoplasms ,Signal Transduction ,Treatment Outcome ,Veratrum Alkaloids ,Vomiting ,phase I ,Hedgehog ,FOLFIRINOX ,pancreatic cancer ,stroma ,Gastroenterology & Hepatology ,Clinical sciences - Abstract
ObjectivesIn mouse models of pancreatic cancer, IPI-926, an oral Hedgehog inhibitor, increases chemotherapy delivery by depleting tumor-associated stroma. This multicenter phase Ib study evaluated IPI-926 in combination with FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) in patients with advanced pancreatic cancer.MethodsPatients were treated with once-daily IPI-926 plus FOLFIRINOX. A 3 + 3 dose escalation design was used, with cohort expansion at the maximum tolerated dose. A subset of patients underwent perfusion computed tomography to assess changes in tumor perfusion.ResultsThe maximum tolerated dose was identified 1 dose level below standard FOLFIRINOX. Common treatment-related adverse events included liver function test abnormalities, neuropathy, nausea/vomiting, and diarrhea. Objective response rate was high (67%), and patients receiving IPI-926 maintenance showed further declines in CA19-9 levels even after FOLFIRINOX discontinuation. Treatment did not result in consistent increases in tumor perfusion. The study closed early when a separate phase II trial of IPI-926 plus gemcitabine indicated detrimental effects of this combination.ConclusionsThis is the first study to demonstrate the feasibility of using FOLFIRINOX as the chemotherapeutic backbone in a clinical trial design. Although robust antitumor activity and acceptable safety were observed with the addition of IPI-926 to this regimen, future development of Hedgehog inhibitors in pancreatic cancer seems unlikely.
- Published
- 2016