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Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors

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Summary

Introduction This phase 1, open-label, multicenter, single-arm, dose-escalation study aimed to evaluate safety, pharmacokinetics (PK), and pharmacodynamics of erdafitinib (JNJ-42756493), an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, and to determine the recommended phase 2 dose in Japanese patients with advanced or refractory solid tumors. Methods Three to 6 patients were enrolled into sequentially escalating dose cohorts (erdafitinib 2, 4, or 6 mg) with a daily dosing schedule of 21-day cycles or a 7 days-on/7 days-off intermittent schedule (erdafitinib 10 mg or 12 mg) of 28-day cycles. Results Nineteen patients received escalating doses of erdafitinib with a daily or intermittent schedule. The most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (73.7%), nausea (36.8%), stomatitis (26.3%), dysgeusia (26.3%) and dry mouth (21.1%). The maximum tolerated dose was not reached in this study. No Grade 3 or higher TEAEs, or serious TEAEs were noted and no clinically significant changes in vital signs, laboratory parameters, and electrocardiogram readings were observed. However, one case of dose-limiting toxicity in the 12 mg intermittent dosing group was observed: Grade 2 detachment of retinal pigment epithelium (bilateral) with treatment discontinuation. The maximum plasma concentrations of erdafitinib exhibited a dose-dependent increase. The median tmax ranged from 2 to 3 h after the initial dose to 2–6 h following multiple daily dosing. Based on the safety and PK data, the 10 mg 7 days-on/7 days-off regimen was determined as the recommended phase 2 dose in this study. Conclusions Erdafitinib was well tolerated in Japanese patients with advanced or refractory solid tumors. Trial Registration: NCT01962532.

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Acknowledgments

Investigational compound erdafitinib (JNJ-42756493) was discovered in collaboration with Astex Pharmaceuticals. This study was supported by Janssen Pharmaceutical K.K. The authors thank all the patients for their participation in this study and acknowledge the collaboration and commitment of all investigators and their staff. The authors thank the safety monitoring committee members (Dr. I. Hyodo from the University of Tsukuba and Dr. F. Nagashima from Kyorin University). The authors thank Dr. Shivangi Gupta and Dr. Himabindu Gutha (both, SIRO Clinpharm Pvt. Ltd.) for providing writing assistance and Dr. Harry Ma (Janssen Research & Development, LLC.) for providing additional editorial support for this manuscript.

Funding

The study is sponsored by Janssen Pharmaceutical K.K.

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Authors and Affiliations

  1. National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan

    Tomohiro Nishina

  2. The Cancer Institute Hospital of Japanese Foundation of Cancer Research, Tokyo, Japan

    Shunji Takahashi

  3. Janssen Pharmaceutical K.K., Tokyo, Japan

    Ryota Iwasawa, Hidehisa Noguchi & Masayuki Aoki

  4. National Cancer Center Hospital East, Kashiwa, Japan

    Toshihiko Doi

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  1. Tomohiro Nishina
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  2. Shunji Takahashi
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  4. Hidehisa Noguchi
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  5. Masayuki Aoki
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Contributions

Drs. Nishina, Takahashi, and Doi were involved in study design, data interpretation, and involved as investigators. Ryota Iwasawa and Dr. Aoki had primary role in the study design, analysis, and data interpretation. Hidehisa Noguchi was responsible for the statistical analyses and design/interpretation of study results. All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors meet ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors provided direction and comments on the manuscript, made the final decision about where to publish these data, and approved submission to this journal.

Corresponding author

Correspondence to Toshihiko Doi.

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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.

Conflict of interest

Ryota Iwasawa, Hidehisa Noguchi, and Mayasuki Aoki are employees of Janssen Pharmaceutical K. K. (JPKK). Drs. Takahashi, Nishina and Doi received research grants from JPKK.

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

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Nishina, T., Takahashi, S., Iwasawa, R. et al. Safety, pharmacokinetic, and pharmacodynamics of erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in patients with advanced or refractory solid tumors. Invest New Drugs 36, 424–434 (2018). https://doi.org/10.1007/s10637-017-0514-4

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