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Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 5, pp 975–991 | Cite as

TGFβ receptor inhibitor galunisertib is linked to inflammation- and remodeling-related proteins in patients with pancreatic cancer

  • Davide MelisiEmail author
  • Rocio Garcia-Carbonero
  • Teresa Macarulla
  • Denis Pezet
  • Gael Deplanque
  • Martin Fuchs
  • Jorg Trojan
  • Mark Kozloff
  • Francesca Simionato
  • Ann Cleverly
  • Claire Smith
  • Shuaicheng Wang
  • Michael Man
  • Kyla E. Driscoll
  • Shawn T. Estrem
  • Michael M. F. Lahn
  • Karim A. Benhadji
  • Josep Tabernero
Original Article

Abstract

Purpose

Galunisertib, the first small molecule transforming growth factor beta (TGFβ) receptor inhibitor, plus gemcitabine resulted in the improvement of survival in patients with unresectable pancreatic cancer, but markers to identify patients likely to respond are lacking.

Methods

In the Phase 1b/2 JBAJ study, 156 patients were randomized 2:1 to galunisertib + gemcitabine (N = 104) or placebo + gemcitabine (N = 52). Clinical outcome data were integrated with baseline markers and pharmacodynamic markers while patients were on treatment, including circulating proteins using a multi-analyte panel, T cell subset evaluation, and miRNA profiling.

Results

Baseline biomarkers associated with overall prognosis regardless of treatment included CA19-9 and TGF-β1. In addition, IP-10, FSH, MIP-1α, and PAI-1 were potential predictive proteins. Baseline proteins that were changed during treatment included amphiregulin, CA15-3, cathepsin D, P-selectin, RAGE, sortilin, COMP, eotaxin-2, N-BNP, osteopontin, and thrombospondin-4. Plasma miRNA with potential prognostic value included miR-21-5p, miR-301a-3p, miR-210-3p, and miR-141-3p, while those with potential predictive value included miR-424-5p, miR-483-3p, and miR-10b-5p.

Conclusions

Galunisertib + gemcitabine resulted in improvement of overall survival, and 4 proteins (IP-10, FSH, MIP-1α, PAI-1) were potentially predictive for this combination treatment. Future studies should also include baseline evaluation of miR-424-5p, miR-483-3p, and miR-10b-5p.

Trial registration

Clinicaltrials.gov NCT01373164.

Keywords

Galunisertib TGF-β1 CA19-9 Pancreatic cancer 

Notes

Acknowledgements

The study team thanks patients and families for their willingness to participate in this study. We also thank all site staff and investigators at the institutions, and the trial personnel at Eli Lilly and Company and Covance. Work in the unit of the corresponding author was supported by the Investigator Grant no. 19111 through the Associazione Italiana per la Ricerca sul Cancro, Italy. Writing assistance was provided by Ananya Biswas (Eli Lilly Services India Pvt. Ltd., India).

Funding

This study was funded by Eli Lilly and Company, Indianapolis, Indiana, USA (Grant Number 230-0061-07472).

Compliance with ethical standards

Conflict of interest

Ann Cleverly, Ivelina Gueorguieva, Karim A. Benhadji, Shawn T. Estrem, Kyla Driscoll, and Michael Man are employees of Eli Lilly and Company, Indianapolis, Indiana, USA, and may hold company stock. Michael M. F. Lahn and Claire Smith are former employees of Eli Lilly and Company and hold company stock. Josep Tabernero has had an advisory role for Bayer, Boehringer Ingelheim, Genentech/Roche, Lilly, MSD, Merck Serono, Merrimack, Novartis, Peptomyc, Roche, Sanofi, Symphogen, and Taiho. Denis Pezet has had an advisory role for Sanofi, Novartis, and Roche.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

280_2019_3807_MOESM1_ESM.docx (21 mb)
Supplementary material 1 (DOCX 21524 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Davide Melisi
    • 1
    Email author
  • Rocio Garcia-Carbonero
    • 2
  • Teresa Macarulla
    • 3
  • Denis Pezet
    • 4
  • Gael Deplanque
    • 5
  • Martin Fuchs
    • 6
  • Jorg Trojan
    • 7
  • Mark Kozloff
    • 8
  • Francesca Simionato
    • 1
  • Ann Cleverly
    • 9
  • Claire Smith
    • 9
  • Shuaicheng Wang
    • 10
  • Michael Man
    • 11
  • Kyla E. Driscoll
    • 11
  • Shawn T. Estrem
    • 11
  • Michael M. F. Lahn
    • 11
  • Karim A. Benhadji
    • 11
  • Josep Tabernero
    • 3
  1. 1.Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Department of MedicineUniversità degli studi di VeronaVeronaItaly
  2. 2.University Hospital Doce de Octubre, Institute of Health Research Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONCMadridSpain
  3. 3.Vall d’Hebron University Hospital, Vall d’Hebron Institute of OncologyAutonomous University of Barcelona, CIBERONCBarcelonaSpain
  4. 4.Digestive Surgery Service, CHU Clermont-FerrandUniversity Clermont AuvergneClermont-FerrandFrance
  5. 5.Medical OncologySaint Joseph HospitalParisFrance
  6. 6.Hospital Bogenhausen, Municipal Hospital Munich GmbHMunichGermany
  7. 7.Goethe University Medical CenterFrankfurtGermany
  8. 8.Ingalls Memorial HospitalHarveyUSA
  9. 9.Eli Lilly and CompanyErl WoodUK
  10. 10.BioStat Solutions, IncFrederickUSA
  11. 11.Eli Lilly and CompanyIndianapolisUSA

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