Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer

Daniel V T Catenacci, Melissa R. Junttila, Theodore Karrison, Nathan Bahary, Margit N. Horiba, Sreenivasa R. Nattam, Robert Marsh, James Wallace, Mark Kozloff, Lakshmi Rajdev, Deirdre Cohen, James Wade, Bethany Sleckman, Heinz Josef Lenz, Patrick Stiff, Pankaj Kumar, Peng Xu, Les Henderson, Naoko Takebe, Ravi SalgiaXi Wang, Walter M. Stadler, Frederic J. De Sauvage, Hedy L. Kindler

Research output: Contribution to journalArticle

157 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4284-4292
Number of pages9
JournalJournal of Clinical Oncology
Volume33
Issue number36
DOIs
StatePublished - Dec 20 2015

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gemcitabine
HhAntag691
Pancreatic Neoplasms
Placebos
Disease-Free Survival
Survival
Pharmaceutical Preparations
Perfusion
Tomography
Ligands
Safety

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Catenacci, D. V. T., Junttila, M. R., Karrison, T., Bahary, N., Horiba, M. N., Nattam, S. R., ... Kindler, H. L. (2015). Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. Journal of Clinical Oncology, 33(36), 4284-4292. https://doi.org/10.1200/JCO.2015.62.8719

Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. / Catenacci, Daniel V T; Junttila, Melissa R.; Karrison, Theodore; Bahary, Nathan; Horiba, Margit N.; Nattam, Sreenivasa R.; Marsh, Robert; Wallace, James; Kozloff, Mark; Rajdev, Lakshmi; Cohen, Deirdre; Wade, James; Sleckman, Bethany; Lenz, Heinz Josef; Stiff, Patrick; Kumar, Pankaj; Xu, Peng; Henderson, Les; Takebe, Naoko; Salgia, Ravi; Wang, Xi; Stadler, Walter M.; De Sauvage, Frederic J.; Kindler, Hedy L.

In: Journal of Clinical Oncology, Vol. 33, No. 36, 20.12.2015, p. 4284-4292.

Research output: Contribution to journalArticle

Catenacci, DVT, Junttila, MR, Karrison, T, Bahary, N, Horiba, MN, Nattam, SR, Marsh, R, Wallace, J, Kozloff, M, Rajdev, L, Cohen, D, Wade, J, Sleckman, B, Lenz, HJ, Stiff, P, Kumar, P, Xu, P, Henderson, L, Takebe, N, Salgia, R, Wang, X, Stadler, WM, De Sauvage, FJ & Kindler, HL 2015, 'Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer', Journal of Clinical Oncology, vol. 33, no. 36, pp. 4284-4292. https://doi.org/10.1200/JCO.2015.62.8719
Catenacci, Daniel V T ; Junttila, Melissa R. ; Karrison, Theodore ; Bahary, Nathan ; Horiba, Margit N. ; Nattam, Sreenivasa R. ; Marsh, Robert ; Wallace, James ; Kozloff, Mark ; Rajdev, Lakshmi ; Cohen, Deirdre ; Wade, James ; Sleckman, Bethany ; Lenz, Heinz Josef ; Stiff, Patrick ; Kumar, Pankaj ; Xu, Peng ; Henderson, Les ; Takebe, Naoko ; Salgia, Ravi ; Wang, Xi ; Stadler, Walter M. ; De Sauvage, Frederic J. ; Kindler, Hedy L. / Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer. In: Journal of Clinical Oncology. 2015 ; Vol. 33, No. 36. pp. 4284-4292.
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title = "Randomized phase Ib/II study of gemcitabine plus placebo or vismodegib, a hedgehog pathway inhibitor, in patients with metastatic pancreatic cancer",
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.",
author = "Catenacci, {Daniel V T} and Junttila, {Melissa R.} and Theodore Karrison and Nathan Bahary and Horiba, {Margit N.} and Nattam, {Sreenivasa R.} and Robert Marsh and James Wallace and Mark Kozloff and Lakshmi Rajdev and Deirdre Cohen and James Wade and Bethany Sleckman and Lenz, {Heinz Josef} and Patrick Stiff and Pankaj Kumar and Peng Xu and Les Henderson and Naoko Takebe and Ravi Salgia and Xi Wang and Stadler, {Walter M.} and {De Sauvage}, {Frederic J.} and Kindler, {Hedy L.}",
year = "2015",
month = "12",
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doi = "10.1200/JCO.2015.62.8719",
language = "English (US)",
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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.

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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