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 Salgia, Xi Wang, Walter M Stadler, Frederic J de Sauvage, Hedy L Kindler, 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 Salgia, Xi Wang, Walter M Stadler, Frederic J de Sauvage, Hedy L Kindler

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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2015 by American Society of Clinical Oncology.

Figures

Fig 1.
Fig 1.
CONSORT diagram of clinical trial enrollment and treatment in phase II trial. gem, gemcitabine.
Fig 2.
Fig 2.
(A) Progression-free and (B) overall survival by treatment arm. Blue, gemcitabine plus vismodegib; gold, gemcitabine plus placebo. Hazard ratio (HR) after adjusting (adj) for Karnofsky performance score and disease status (newly diagnosed v recurrent).
Fig 3.
Fig 3.
Clinical trial translational correlatives. Serum SHH levels (A) comparing controls (n = 40) with patients with pancreatic cancer enrolled onto trial (n = 89), (B) by treatment group (gemcitabine plus vismodegib [GV] or gemcitabine plus placebo [GP]) with increasing treatment (TX) cycle, and association with age in (C) patients with cancer and (D) controls. (E) Radiologic correlatives evaluating association of baseline tumor perfusion with tumor response to therapy.
Fig 4.
Fig 4.
Effects of hedgehog pathway antagonism (HhAntag) on vasculature, stromal content, and intratumoral gemcitabine metabolites in KrasG12D; p16/p19fl/fl; Pdx1-Cre (KPP) tumors. (A) Quantitation of immunohistochemical staining for meca-32 expression in pancreatic tumors of KPP mice treated with vehicle (circles; n = 13) or smoothened (SMO) inhibitor (squares; n = 13) for 10 days. Data presented as percentages of meca-32–positive areas over analyzed tumor areas for each tumor (Mann-Whitney P = .54; scale bar, 200 um). (B) Quantitative analysis of stromal content by trichromatic stain in pancreatic tumors of KPP mice treated with vehicle or SMO inhibitor for 10 days. Data presented as percentages of positive stain areas over analyzed tissue areas (Mann-Whitney P = .29). (C) Mass spectromic quantitation of intratumoral concentration of 2′,2′-difluorodeoxycytidine triphosphate (dFdCTP; active form of gemcitabine) from each tumor after treatment for 10 consecutive days with vehicle or SMO inhibitor and gemcitabine 50 mg/kg 30 minutes before tumor collection (Mann-Whitney P = 1.000). (D) Ratios of 2′,2′-difluoro 2′-deoxycytidine (dFdC) to diflurodeoxyuridine (dFdU) in pancreatic tumors from each tumor (Mann-Whitney P = .48). NS, not significant.
Fig 5.
Fig 5.
Smoothened (SMO) inhibitor does not affect tumor progression or overall survival in Kras LSL-G12D; p16/p19 fl/fl; Pdx1-Cre (KPP) mice. (A) Individual tumor growth rates plotted by from serial ultrasound images as volumes depicted longitudinally by animal within each regimen. (B) Antilogged values of slopes in each longitudinal plot are graphed, and average tumor burden fold changes per day in each study group of KPP mice are shown, with approximate 95% CIs (vehicle v SMO inhibitor, P = .86; vehicle v combination, P = .0156; gemcitabine v combination, P = .18) (C) Kaplan-Meier plots of KPP mice treated with vehicle (blue, n = 15; median, 1.9 weeks), SMO inhibitor (gold, n = 16; median, 1.2 weeks), gemcitabine (gray, n = 14; median, 3.8 weeks), and gemcitabine plus SMO inhibitor combination (red, n = 12; median, 3.4 weeks; gemcitabine v vehicle, P = .0059; combination v vehicle, P = .0179; gemcitabine v combination, P = .10 [all P values from log-rank test]). HhAntag, hedgehog pathway antagonism.

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