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Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer
Open accessAbstract
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.
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![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.](/paper-figures/1a65b8774a2c48bf9fb304d7a14b415a/randomized-phase-ib-ii-study-of-gemcitabine-plus-placebo-or-vismodegib-a-figure-3.jpg)
![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.](/paper-figures/a743673eb55d4afe92010381f297db65/randomized-phase-ib-ii-study-of-gemcitabine-plus-placebo-or-vismodegib-a-figure-5.jpg)
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“Many of the recent promising clinical signals in PDAC have arisen through rigorous preclinical analyses in syngeneic and autochthonous models that predated the trial and informed its design288.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [288]
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Metadata
- Authors
- Catenacci, D. V. T., Junttila, M. R., Karrison, T., Bahary, N., Horiba, M. N., Nattam, S. R., Marsh, R., Wallace, J., Kozloff, M., Rajdev, L., Cohen, D., Wade, J., Sleckman, B., Lenz, H.-J., Stiff, P., Kumar, P., Xu, P., Henderson, L., Takebe, N., Salgia, R., Wang, X., Stadler, W. M., de Sauvage, F. J., & Kindler, H. L.
- Affiliations
- Loyola University Medical Center (US)
- 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....
- Corresponding author
- Catenacci, Daniel V.T.
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2015-12-20
- Volume
- 33
- Issue
- 36
- Pages
- 4284-4292
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC4678179
- OpenAlex
- W2137357003
- Cited by
- 561
- References
- 55
- Citations by year
- 2026: 40 · 2025: 36 · 2024: 38 · 2023: 47 · 2022: 71 · 2021: 72 · 2020: 67 · 2019: 65 · 2018: 60 · 2017: 41 · 2016: 20 · 2015: 3
- FWCI
- 18.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of Clinical Oncology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- European Society for Medical Oncology
- National Institutes of Health (UL1TR000430, n01cm62201-16-0-1)
- Genentech
- National Cancer Institute (N01 CM062201, N01 CM-62201)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- metastatic pancreatic cancer, gemcitabine, vismodegib, sonic hedgehog pathway, Smoothened inhibition, Hedgehog pathway inhibitors, progression-free survival, overall survival, KRAS G12D, p53, drug safety, combination therapy
- MeSH terms
- Gemcitabine, Adult, Aged, Anilides, Animals, Antineoplastic Combined Chemotherapy Protocols, Deoxycytidine, Female, Humans, Male, Middle Aged, Neoplasm Staging, Pancreatic Neoplasms, Pyridines, Signal Transduction, Odds Ratio, Treatment Outcome, Karnofsky Performance Status, Disease-Free Survival, Mice, Kaplan-Meier Estimate, Hedgehog Proteins
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