A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma

  • Pancreas. 2016 Mar;45(3):370-5. doi: 10.1097/MPA.0000000000000458.
Andrew H Ko  1 ,  Noelle LoConte ,  Margaret A Tempero ,  Evan J Walker ,  R Kate Kelley ,  Stephanie Lewis ,  Wei-Chou Chang ,  Emily Kantoff ,  Michael W Vannier ,  Daniel V Catenacci ,  Alan P Venook ,  Hedy L Kindler
Affiliations
  • 1. From the *Division of Hematology/Oncology, University of California San Francisco, San Francisco, CA; †Division of Hematology/Oncology, University of Wisconsin, Madison, WI; ‡Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; and §Department of Radiology and ∥Division of Hematology/Oncology, University of Chicago, Chicago, IL.
PMID: 26390428 DOI: 10.1097/MPA.0000000000000458
Abstract

Objectives: In 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.

Methods: Patients 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.

Results: The 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.

Conclusions: This 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.

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