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Population pharmacokinetics and exposure–overall survival analysis of the transforming growth factor-β inhibitor galunisertib in patients with pancreatic cancer

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Abstract

Purpose

To evaluate the exposure–overall survival (OS) relationship in patients with advanced pancreatic cancer treated with galunisertib plus gemcitabine (GG) or gemcitabine plus placebo (GP).

Methods

Galunisertib 300 mg/day was given orally as intermittent dosing and gemcitabine as per label. Galunisertib exposure metrics for each patient in the GG arm (n = 99) of a phase 2 study of pancreatic cancer were calculated. Parametric survival models were used to identify influential baseline and response covariates on OS.

Results

The population pharmacokinetics dataset included data from 297 patients/healthy subjects (age: 22–84 years, weight: 39–126 kg) across multiple studies, including this pancreatic cancer study. Galunisertib was rapidly absorbed with peak concentrations attained within 0.5–2 h and had an elimination half-life of 8 h. Between-subject variance on apparent clearance was estimated to be 47%. Age was the only characteristic to have a statistically significant effect on apparent clearance. A parametric Weibull survival model with treatment effect (dose) estimated a hazard ratio of 0.796, after adjusting for patient baseline factors that were significantly associated with OS. There was also a flat daily exposure–OS relationship within the observed exposure range, once all significant baseline covariates were included. Response covariates, such as reduction in CA19-9, time on treatment, and cumulative exposure over treatment cycles were also identified as significant factors for OS for patients with pancreatic cancer.

Conclusions

This analysis suggests that 300 mg/day galunisertib administered as 150 mg twice daily for 14 days on/14 days off treatment is an appropriate dosing regimen for patients with pancreatic cancer.

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Acknowledgements

The authors would like to thank all investigators who participated in the study.

Funding

This study was sponsored by Eli Lilly and Company, manufacturer of galunisertib. Work in the unit of DM was supported by the Investigator Grant no.19111 through the Associazione Italiana per la Ricerca sul Cancro (AIRC). Medical writing assistance was provided by Samantha Forster, PhD, CMPP, of ProScribe—part of the Envision Pharma Group, and was funded by Eli Lilly and Company. ProScribe’s services complied with international guidelines for Good Publication Practice (GPP3).

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Authors and Affiliations

  1. Global PK/PD, Eli Lilly and Company, Sunninghill Road, Erl Wood Manor, ROB building, Windlesham, Surrey, GU20 6PH, UK

    Ivelina Gueorguieva, Colin Miles & Ann Cleverly

  2. Vall d’Hebron University Hospital and Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain

    Josep Tabernero & Teresa Macarulla

  3. Digestive Molecular Clinical Oncology, University of Verona, Verona, Italy

    Davide Melisi & Valeria Merz

  4. Eli Lilly and Company, Indianapolis, IN, USA

    Timothy H. Waterhouse & Michael M. Lahn

  5. Eli Lilly and Company, Bridgewater, NJ, USA

    Karim A. Benhadji

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  1. Ivelina Gueorguieva
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Contributions

All authors participated in the interpretation of the study results, and in the drafting, critical revision, and approval of the final version of the manuscript. Ivelina Gueorguieva, Josep Tabernero, Michael M. Lahn, Ann Cleverly, and Karim A. Benhadji were involved in the study design. All authors were involved in data collection and interpretation. Josep Tabernero and Davide Melisi were investigators in the study. Ivelina Gueorguieva, Timothy H. Waterhouse, Colin Miles, and Ann Cleverly conducted the statistical analysis. The authors confirm that the principal investigators for this paper were Dr Josep Tabernero and Dr Davide Melisi, and that they had direct clinical responsibility for patients.

Corresponding author

Correspondence to Ivelina Gueorguieva.

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Conflict of interest

Ivelina Gueorguieva, Ann Cleverly, Timothy H. Waterhouse, Colin Miles, and Karim A. Benhadji are current employees of and own shares in Eli Lilly and Company. Michael M. Lahn was an employee of Eli Lilly and Company during the design and conduct of the study and currently owns shares in Eli Lilly and Company. Josep Tabernero has had consultant/advisory roles for Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly and Company, Imclone, MSD, Merck Serono, Millennium, Novartis, Roche, Sanofi, Symphogen, and Taiho. Davide Melisi has received research funding from Celgene, Incyte, and Shire, and has a consulting role with Baxter, Eli Lilly and Company, Incyte, and Shire. Teresa Macarulla received honoraria for consultancy from Baxalta, Baxter, Celgene, Genzyme, Roche, Sanofi, Shire Pharmaceuticals, Tesaro, and QED Therapeutics, and has received travel/accommodation compensation from Bayer, H3 Biomedicine, Merck, and Sanofi. Valeria Merz has no conflicts of interest to disclose.

Role of the sponsor

Eli Lilly and Company was involved in the study design, data collection, data analysis, and preparation of the manuscript.

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.

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Gueorguieva, I., Tabernero, J., Melisi, D. et al. Population pharmacokinetics and exposure–overall survival analysis of the transforming growth factor-β inhibitor galunisertib in patients with pancreatic cancer. Cancer Chemother Pharmacol 84, 1003–1015 (2019). https://doi.org/10.1007/s00280-019-03931-1

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