Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer
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Published:2015-12-20
Issue:36
Volume:33
Page:4284-4292
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ISSN:0732-183X
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Container-title:Journal of Clinical Oncology
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language:en
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Short-container-title:JCO
Author:
Catenacci Daniel V.T.1, Junttila Melissa R.1, Karrison Theodore1, Bahary Nathan1, Horiba Margit N.1, Nattam Sreenivasa R.1, Marsh Robert1, Wallace James1, Kozloff Mark1, Rajdev Lakshmi1, Cohen Deirdre1, Wade James1, Sleckman Bethany1, Lenz Heinz-Josef1, Stiff Patrick1, Kumar Pankaj1, Xu Peng1, Henderson Les1, Takebe Naoko1, Salgia Ravi1, Wang Xi1, Stadler Walter M.1, de Sauvage Frederic J.1, Kindler Hedy L.1
Affiliation:
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....
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 (KrasG12D; p16/p19fl/fl; Pdx1-Cre and KrasG12D; p53R270H/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.
Publisher
American Society of Clinical Oncology (ASCO)
Subject
Cancer Research,Oncology
Cited by
427 articles.
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