title: A Phase I Study of FOLFIRINOX Plus IPI-926, a Hedgehog Pathway Inhibitor, for Advanced Pancreatic Adenocarcinoma.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Ko
authors.forename: Noelle
authors.initials: N
authors.lastname: LoConte
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tempero
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Walker
authors.forename: R
authors.initials: R
authors.lastname: Kate Kelley
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lewis
authors.forename: Wei-Chou
authors.initials: WC
authors.lastname: Chang
authors.forename: Emily
authors.initials: E
authors.lastname: Kantoff
authors.forename: Michael W
authors.initials: MW
authors.lastname: Vannier
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Catenacci
authors.forename: Alan P
authors.initials: AP
authors.lastname: Venook
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018395:CA-19-9 Antigen / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009422:Nervous System Diseases / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D014704:Veratrum Alkaloids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D014839:Vomiting / Q000139:chemically induced
chemical_list: D018395:CA-19-9 Antigen; D053823:Hedgehog Proteins; C541444:IPI-926; D009944:Organoplatinum Compounds; D014704:Veratrum Alkaloids; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin