TY - JOUR
T1 - Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer
AU - Catenacci, Daniel V.T.
AU - Junttila, Melissa R.
AU - Karrison, Theodore
AU - Bahary, Nathan
AU - Horiba, Margit N.
AU - Nattam, Sreenivasa R.
AU - Marsh, Robert
AU - Wallace, James
AU - Kozloff, Mark
AU - Rajdev, Lakshmi
AU - Cohen, Deirdre
AU - Wade, James
AU - Sleckman, Bethany
AU - Lenz, Heinz Josef
AU - Stiff, Patrick
AU - Kumar, Pankaj
AU - Xu, Peng
AU - Henderson, Les
AU - Takebe, Naoko
AU - Salgia, Ravi
AU - Wang, Xi
AU - Stadler, Walter M.
AU - De Sauvage, Frederic J.
AU - Kindler, Hedy L.
N1 - Funding Information:
Supported by National Cancer Institute Grant No. N01-CM-62201 under the American Recovery and Reinvestment Act of 2009. This protocol was developed at the ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research, Flims Switzerland. We thank Michael Vannier, MD, for his contributions to the radiologic correlative studies and Michelle Nannini, Janeko Bower, Vincent Javinal, Alfonso Arrazate, Lee Nguyen, Alfred Wong, Linda Rangell, Carmina Espiritu, and Jeff Eastham-Anderson for excellent technical assistance.We also received extensive and able technical support from the Genentech genotyping and murine reproductive technology core groups. We thank William Forrest for providing biostatistical guidance and Chunang Gu for developing the methodology to assess gemcitabine metabolites. We thank Stephen Gould and Frank Peale for engaging scientific discussions and critical input regarding this article.
Publisher Copyright:
© 2015 by American Society of Clinical Oncology.
PY - 2015/12/20
Y1 - 2015/12/20
N2 - 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.
AB - 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.
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U2 - 10.1200/JCO.2015.62.8719
DO - 10.1200/JCO.2015.62.8719
M3 - Article
C2 - 26527777
AN - SCOPUS:84957580046
VL - 33
SP - 4284
EP - 4292
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
SN - 0732-183X
IS - 36
ER -
