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Investigational New Drugs

, Volume 36, Issue 2, pp 259–268 | Cite as

Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF V600 mutation-positive solid tumors: a phase 1 study

  • Yutaka Fujiwara
  • Naoya Yamazaki
  • Yoshio Kiyohara
  • Shusuke Yoshikawa
  • Noboru Yamamoto
  • Arata Tsutsumida
  • Hiroshi Nokihara
  • Kenjiro Namikawa
  • Akihira Mukaiyama
  • Fanghong Zhang
  • Tomohide Tamura
PHASE I STUDIES

Summary

Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF V600E mutated metastatic melanoma. This study evaluated the safety and tolerability, pharmacokinetics and preliminary efficacy of dabrafenib in Japanese patients. Methods This phase I, open-label, dose escalation study was conducted in 12 Japanese patients with BRAF V600 mutation positive solid tumours. Primary endpoint was safety, assessed by monitoring and recording of all adverse events (AEs), serious AEs, drug-related AEs; secondary endpoints were pharmacokinetic profiles and efficacy measured by tumour response. This study is registered with ClinicalTrials.gov, number NCT01582997. Results Of the 12 patients enrolled, 3 each received 75 mg and 100 mg dabrafenib while 6 received 150 mg dabrafenib twice daily orally. Melanoma and thyroid cancer were the primary tumours reported in 11 (92%) and 1 (8%) patients respectively. Most AEs were grade 1 or 2 and considered related to study treatment. Most common AEs reported in the 12 patients were alopecia in 7 (58%); pyrexia, arthralgia and leukopenia in 6 (50%) each, hyperkeratosis and nausea in 4 (33%) each. Partial response as best overall response was reported in 7 of 12 (58%) patients and in 6 (55%) with malignant melanoma. No dose-limiting toxicity (DLTs) were reported during the DLT evaluation periods. Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients with BRAF mutated malignant melanoma.

Keywords

BRAF V600 Dabrafenib Japanese Malignant melanoma Mutation Solid tumor 

Notes

Acknowledgements

The study was funded by GlaxoSmithKline. Dabrafenib is an asset of Novartis AG as of March 2, 2015. We thank all the investigators and patients who participated in the study, their families as well as staff at the study centers. We also thank Dr. Krishna Swetha Gummuluri, Novartis Healthcare Pvt. Ltd., India, for medical writing support.

Author contributions

All of the authors had full access to data in the study, discussed the results, critically reviewed the draft manuscript, and approved the final manuscript for submission

Funding

GlaxoSmithkline

Compliance with ethical standards

Conflict of interest

Y Fujiwara reports grants from AstraZeneca, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Merck Serono, MSD and Novartis; and honoraria and personal fees from Bristol-Myers Squibb and ONO. N Yamazaki reports personal fees from ONO, Takeda, Bristol-Myers Squibb, Chugai, Boehringer Ingelheim and research funding from ONO, Bristol-Myers Squibb and Novartis Pharma K.K. Y Kiyohara reports personal fees from ONO, Chugai, Bristol-Myers Squibb and grants from Chugai and MSD. N Yamamoto reports grants from Chugai,Taiho, Eisai, Eli Lilly, Quintiles, Astellas, BMS, Novartis, Daiichi-Sankyo, Pfizer,Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, ONO and Takeda and other support from Chugai, Astrazeneca, Eli Lilly and BMS. H Nokihara reports grants from Merck Serono, Pfizer, Novartis, Daiichi Sankyo, GlaxoSmithKline and Quintiles and personal fees from Taiho Pharmaceuticals, Eisai, Chugai, Eli Lilly, AstraZeneca, Boehringer-Ingelheim,ONO, Sanofi and Bristol-Myers Squibb. K Namikawa reports personal fees from ONO, Bristol-Myers Squibb, Merck Sharp and Dohme, Toray Industries, Chugai and Novartis Pharmaceuticals. T Tamura reports personal fees from Chugai, Taiho, Eisai, Yakult, Eli Lilly, Boehringer-Ingelheim, Bristol-Myers Squibb, ONO and Kyowa Kirin. A Mukaiyama and F Zhang are employees of Novartis Pharma K.K., Japan. S Yoshikawa, and A Tsutsumida have nothing to disclose.

Ethical approval

All procedures performed in the study were conducted in accordance with the International Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP) and the Declaration of Helsinki. All protocols and amendments were approved by the independent ethics committee or institutional review board for each study center. All patients provided written informed consent before participating in any study procedures.

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Yutaka Fujiwara
    • 1
  • Naoya Yamazaki
    • 2
  • Yoshio Kiyohara
    • 3
  • Shusuke Yoshikawa
    • 3
  • Noboru Yamamoto
    • 1
  • Arata Tsutsumida
    • 2
  • Hiroshi Nokihara
    • 1
  • Kenjiro Namikawa
    • 2
  • Akihira Mukaiyama
    • 4
  • Fanghong Zhang
    • 4
  • Tomohide Tamura
    • 5
  1. 1.Department of Experimental TherapeuticsNational Cancer Center HospitalTokyoJapan
  2. 2.Department of Dermatologic OncologyNational Cancer Center HospitalTokyoJapan
  3. 3.Dermatology DivisionShizuoka Cancer Center HospitalShizuokaJapan
  4. 4.Development DepartmentNovartis Pharma K.KTokyoJapan
  5. 5.Thoracic CenterSt. Luke’s International HospitalTokyoJapan

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