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A phase I and pharmacokinetic study of taladegib, a Smoothened inhibitor, in Japanese patients with advanced solid tumors

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Summary

Background This phase I dose-escalation study investigated the safety of the Smoothened inhibitor taladegib in Japanese patients with advanced solid tumors. Methods Patients received taladegib orally once daily for 28-day cycles, using a 3 + 3 dose-escalation method. The primary objective was the safety and tolerability of taladegib at doses up to the global recommended dose (400 mg). Secondary objectives included pharmacokinetics, changes in skin glioma-associated oncogene homolog 1 (Gli1) transcript levels, and antitumor activity. Results Nineteen patients received treatment (100 mg: 3; 200 mg: 3; 400 mg: 13). No dose-limiting toxicities (DLTs) were observed at doses of 100 mg or 200 mg; 3 of the 9 patients evaluable for DLTs at the 400 mg dose level experienced DLTs (thrombocytopenia: 1; decreased appetite: 2). The most commonly reported treatment-related adverse events were dysgeusia (13/19, 68.4%), decreased appetite (12/19, 63.2%), nausea (9/19, 47.4%), fatigue (9/19, 47.4%), and vomiting (6/19, 31.6%). The pharmacokinetic profile suggested that exposure to taladegib was higher in Japanese than non-Japanese patients, possibly related to differences in body weight and/or drug formulation. At all dose levels, a high level of inhibition of skin Gli1 transcript levels was observed after 15 and 30 days of exposure to taladegib. Partial response was achieved by 1 patient (basal cell carcinoma of the skin) and stable disease by 4 patients. Conclusions Taladegib doses of 100 mg and 200 mg, but not the global recommended dose of 400 mg, were well tolerated in this population of Japanese patients with advanced solid tumors.

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Acknowledgments

The authors would like to thank all study participants.

Funding support

This study was sponsored by Eli Lilly Japan K.K.; the manufacturer of taladegib is Eli Lilly and Company. Medical writing assistance was provided by Justine Southby, PhD, CMPP, and Tania Dickson, PhD, CMPP, of ProScribe – Envision Pharma Group, and was funded by Eli Lilly Japan K.K. ProScribe’s services complied with international guidelines for Good Publication Practice (GPP3).

Author information

Authors and Affiliations

  1. Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan

    Hideki Ueno & Shunsuke Kondo

  2. Division of Dermatology, Shizuoka Cancer Center, Shizuoka, Japan

    Shusuke Yoshikawa

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

    Koichi Inoue & Masaomi Tajimi

  4. Eli Lilly and Company, Paris, France

    Valérie Andre

  5. Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan

    Haruyasu Murakami

Authors
  1. Hideki Ueno
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  2. Shunsuke Kondo
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  3. Shusuke Yoshikawa
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  4. Koichi Inoue
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  5. Valérie Andre
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  6. Masaomi Tajimi
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  7. Haruyasu Murakami
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Contributions

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

All authors participated in the interpretation of study results, and in the drafting, critical revision, and approval of the final version of the manuscript. VA and MT were involved in the study design and statistical analysis. KI was involved in the pharmacokinetic and pharmacodynamic analyses. SK, HM, and SY were involved in the data collection. HU, SK, HM, and SY were investigators in the study.

Corresponding author

Correspondence to Hideki Ueno.

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Conflicts of interest

KI and MT are employees of Eli Lilly Japan K.K. and VA is an employee of Eli Lilly and Company. VA and MT own stock in Eli Lilly and Company. HU has received research funding from Eli Lilly, Baxalta, NanoCarrier, and Taiho Pharmaceutical and has served on a Speaker’s Bureau for Taiho Pharmaceutical. HM has received honoraria from Eli Lilly Japan K.K., AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb Japan, Chugai Pharmaceutical Co., Ltd., Clovis Oncology, Nippon Kayaku, Novartis, Ono Pharmaceutical Co., Ltd., Pfizer, Taiho Pharmaceutical, and Teijin Pharma Limited.

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.

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Ueno, H., Kondo, S., Yoshikawa, S. et al. A phase I and pharmacokinetic study of taladegib, a Smoothened inhibitor, in Japanese patients with advanced solid tumors. Invest New Drugs 36, 647–656 (2018). https://doi.org/10.1007/s10637-017-0544-y

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  • DOI: https://doi.org/10.1007/s10637-017-0544-y

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