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J Clin Oncol. 2015 Dec 20;33(36):4284-92. doi: 10.1200/JCO.2015.62.8719. Epub 2015 Nov 2.

Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer.

Author information

1
Daniel V.T. Catenacci, Theodore Karrison, James Wallace, Mark Kozloff, Peng Xu, Les Henderson, Ravi Salgia, Walter M. Stadler, Hedy L. Kindler, University of Chicago Medical Center; Patrick Stiff, Loyola University Medical Center, Chicago; Robert Marsh, Northshore University Health System, Evanston; James Wallace, Mark Kozloff, Ingalls Hospital, Harvey; James Wade, Decatur Memorial Hospital, Decatur; Pankaj Kumar, Oncology/Hematology Associates, Peoria, IL; Melissa R. Junttila, Xi Wang, and Frederic J. de Sauvage, Genentech, South San Francisco; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Nathan Bahary, University of Pittsburgh Cancer Institute, Pittsburgh, PA; Margit N. Horiba, University of Maryland Greenebaum Cancer Center, Baltimore, MD; Sreenivasa R. Nattam, Ft Wayne Medical Oncology/Hematology, Ft Wayne, IN; Lakshmi Rajdev, Montefiore Medical Center, Bronx; Deirdre Cohen, New York University Cancer Center, New York, NY; Bethany Sleckman, St John's Mercy Medical Center, St Louis, MO; and Naoko Takebe, National Cancer Institute, National Institutes of Health, Bethesda, MD. dcatenac@medicine.bsd.uchicago.edu.
2
Daniel V.T. Catenacci, Theodore Karrison, James Wallace, Mark Kozloff, Peng Xu, Les Henderson, Ravi Salgia, Walter M. Stadler, Hedy L. Kindler, University of Chicago Medical Center; Patrick Stiff, Loyola University Medical Center, Chicago; Robert Marsh, Northshore University Health System, Evanston; James Wallace, Mark Kozloff, Ingalls Hospital, Harvey; James Wade, Decatur Memorial Hospital, Decatur; Pankaj Kumar, Oncology/Hematology Associates, Peoria, IL; Melissa R. Junttila, Xi Wang, and Frederic J. de Sauvage, Genentech, South San Francisco; Heinz-Josef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; Nathan Bahary, University of Pittsburgh Cancer Institute, Pittsburgh, PA; Margit N. Horiba, University of Maryland Greenebaum Cancer Center, Baltimore, MD; Sreenivasa R. Nattam, Ft Wayne Medical Oncology/Hematology, Ft Wayne, IN; Lakshmi Rajdev, Montefiore Medical Center, Bronx; Deirdre Cohen, New York University Cancer Center, New York, NY; Bethany Sleckman, St John's Mercy Medical Center, St Louis, MO; and Naoko Takebe, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Abstract

PURPOSE:

Sonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models.

PATIENTS AND METHODS:

Patients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (Kras(G12D); p16/p19(fl/fl); Pdx1-Cre and Kras(G12D); p53(R270H/wt); Pdx1-Cre) were studied.

RESULTS:

No safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model.

CONCLUSION:

The addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01064622.

PMID:
26527777
PMCID:
PMC4678179
DOI:
10.1200/JCO.2015.62.8719
[Indexed for MEDLINE]
Free PMC Article

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