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Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors

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Abstract

Purpose

Inhibition of transforming growth factor-beta receptor I (TGF-beta RI)-mediated signaling pathways blocks tumor growth and metastases in nonclinical studies. Galunisertib (LY2157299), a small molecule inhibitor of TGF-beta RI serine/threonine kinase, had antitumor effects with acceptable safety/tolerability in a first-in-human dose (FHD) study conducted mainly in Caucasian patients with glioma. In this nonrandomized, open-label, dose-escalation study, we assessed safety/tolerability, pharmacokinetics (PK), and tumor response in Japanese patients.

Methods

Patients with advanced and/or metastatic disease refractory were assigned sequentially to Cohort-1 (80 mg) or Cohort-2 (150 mg) of galunisertib, administered twice daily and treated using 2-week on, 2-week off treatment cycles. Dose escalation was guided by predefined PK criteria and dose-limiting toxicities (DLT). Safety assessments included treatment-emergent adverse events (TEAEs) and cardiac safety (ultrasound cardiography/Doppler imaging, electrocardiogram, chest computed tomography, and cardiotoxicity serum biomarkers).

Results

Twelve patients (Cohort-1, n = 3; Cohort-2, n = 9) were enrolled and the most common types of cancer were pancreatic (n = 5) and lung cancer (n = 3). Seven patients (Cohort-1, n = 2; Cohort-2, n = 5) experienced possibly galunisertib-related TEAEs. The most frequent related TEAEs were brain natriuretic peptide increased (n = 2), leukopenia (n = 2), and rash (n = 2). No cardiovascular toxicities or other DLTs were reported. PK profile of galunisertib was consistent with the FHD study. Maximum plasma concentration was reached within 2 h post-dose, and the mean elimination half-life was 9 h.

Conclusions

Galunisertib had an acceptable tolerability and safety profile in Japanese patients with advanced cancers.

ClinicaTrials.gov. Identifier

NCT01722825.

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Acknowledgments

We thank all the patients who participated in this study, their families, and all the study site staff who assisted with this study.

Funding

This study was sponsored by Eli Lilly and Company. Medical writing assistance was provided by Julie A. Ely, PhD, CMPP, and Serina Stretton, PhD, CMPP, of ProScribe—Envision Pharma Group, and was funded by Eli Lilly Japan K.K.

Role of the sponsor

Eli Lilly and Company provided study drug (galunisertib) and was also involved in the study design, data collection, data analysis, and preparation of the manuscript.

Role of contributors

All authors participated in the interpretation of study results and in the drafting, critical revision, and approval of the final version of the manuscript. HA, OT, IG, and TT were involved in the study design and HA, OT, KO, IG, and TT were involved in the data analyses. YF, NY, HN, KS, YY, HU, and TT were investigators in the study. All authors had full access to the data in the study and the final responsibility for the decision to submit for publication.

Author information

Author notes

  1. Hirofumi Utsumi

    Present address: Respiratory Medicine, The Jikei University School of Medicine, Tokyo, Japan

  2. Tomohide Tamura

    Present address: St Luke’s International Hospital, Tokyo, Japan

Authors and Affiliations

  1. Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan

    Yutaka Fujiwara, Hiroshi Nokihara, Noboru Yamamoto, Kuniko Sunami, Hirofumi Utsumi & Tomohide Tamura

  2. Gastrointestinal Oncology, National Cancer Center Hospital, Tokyo, Japan

    Yasuhide Yamada

  3. Medical Science, Eli Lilly Japan K.K., Kobe, Japan

    Hiroya Asou & Osamu TakahashI

  4. Japan PK/PD, Eli Lilly Japan K.K., Kobe, Japan

    Ken Ogasawara

  5. Global PK/PD, Lilly Research Laboratories, Windlesham, Surrey, UK

    Ivelina Gueorguieva

Authors
  1. Yutaka Fujiwara
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Corresponding author

Correspondence to Yutaka Fujiwara.

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Human and animal rights

All procedures performed in this study involving human participants were in accordance with the ethical standards of the Institutional Review Board and with the 1964 Declaration of Helsinki and its later amendments.

Informed consent

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

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Fujiwara, Y., Nokihara, H., Yamada, Y. et al. Phase 1 study of galunisertib, a TGF-beta receptor I kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 76, 1143–1152 (2015). https://doi.org/10.1007/s00280-015-2895-4

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  • DOI: https://doi.org/10.1007/s00280-015-2895-4

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