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Clinical Trial
. 2016 Mar;45(3):370-5.
doi: 10.1097/MPA.0000000000000458.

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

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
Clinical Trial

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

Andrew H Ko et al. Pancreas. 2016 Mar.

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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Conflict of interest statement

The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Waterfall plot demonstrating maximum change in target lesions from baseline in evaluable patients. Black bars indicate dose level 1; white bars, dose level 2.
Figure 2
Figure 2
Computed tomographic images (upper panels, pancreatic tumor marked by arrow) with corresponding perfusion images (lower panels) in 1 patient, demonstrating increased blood flow after 2 months of study treatment.
See this image and copyright information in PMC

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References

    1. Ingham PW. Signalling by hedgehog family proteins in Drosophila and vertebrate development. Curr Opin Genet Dev. 1995;5:492–498. - PubMed
    1. Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001;411:349–354. - PubMed
    1. Oro AE, Higgins KM, Hu Z, et al. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science. 1997;276:817–821. - PubMed
    1. Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29:1408–1414. - PMC - PubMed
    1. Rodriguez-Blanco J, Schilling NS, Tokhunts R, et al. The hedgehog processing pathway is required for NSCLC growth and survival. Oncogene. 2013;32:2335–2345. - PMC - PubMed

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