Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436)

doi:10.1158/1078-0432.CCR-14-0887

Clinical Trial

. 2014 Sep 1;20(17):4449-58.

doi: 10.1158/1078-0432.CCR-14-0887. Epub 2014 Jun 23.

Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436)

Gerald S Falchook¹, Georgina V Long², Razelle Kurzrock³, Kevin B Kim⁴, H-Tobias Arkenau⁵, Michael P Brown⁶, Omid Hamid⁷, Jeffrey R Infante⁸, Michael Millward⁹, Anna Pavlick¹⁰, Melvin T Chin¹¹, Steven J O'Day⁷, Samuel C Blackman¹², C Martin Curtis¹², Peter Lebowitz¹², Bo Ma¹², Daniele Ouellet¹², Richard F Kefford¹³

Affiliations

¹ Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. gerald.falchook@scresearch.net georgina.long@sydney.edu.au.
² Melanoma Institute Australia and University of Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, and Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia. gerald.falchook@scresearch.net georgina.long@sydney.edu.au.
³ Moores Cancer Center, University of California San Diego, La Jolla, California.
⁴ Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁵ GlaxoSmithKline Medicines Research Unit, Prince of Wales Hospital, Randwick, New South Wales, Australia.
⁶ Cancer Clinical Trials Unit, Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia.
⁷ Experimental Therapeutics/Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles, California.
⁸ Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee.
⁹ Cancer Council Trials and Sir Charles Gairdner Hospital and University of Western Australia, Perth, Western Australia, Australia.
¹⁰ Division of Medical Oncology, New York University School of Medicine, New York, New York.
¹¹ Prince of Wales Clinical School, University of New South Wales, Randwick, Australia.
¹² GlaxoSmithKline Research and Development, Philadelphia, Pennsylvania and Research Triangle Park, North Carolina.
¹³ Melanoma Institute Australia and University of Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, and Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia.

PMID: 24958809
DOI: 10.1158/1078-0432.CCR-14-0887

Clinical Trial

Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436)

Gerald S Falchook et al. Clin Cancer Res. 2014.

. 2014 Sep 1;20(17):4449-58.

doi: 10.1158/1078-0432.CCR-14-0887. Epub 2014 Jun 23.

Authors

Affiliations

¹ Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. gerald.falchook@scresearch.net georgina.long@sydney.edu.au.
² Melanoma Institute Australia and University of Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, and Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia. gerald.falchook@scresearch.net georgina.long@sydney.edu.au.
³ Moores Cancer Center, University of California San Diego, La Jolla, California.
⁴ Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁵ GlaxoSmithKline Medicines Research Unit, Prince of Wales Hospital, Randwick, New South Wales, Australia.
⁶ Cancer Clinical Trials Unit, Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia.
⁷ Experimental Therapeutics/Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles, California.
⁸ Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee.
⁹ Cancer Council Trials and Sir Charles Gairdner Hospital and University of Western Australia, Perth, Western Australia, Australia.
¹⁰ Division of Medical Oncology, New York University School of Medicine, New York, New York.
¹¹ Prince of Wales Clinical School, University of New South Wales, Randwick, Australia.
¹² GlaxoSmithKline Research and Development, Philadelphia, Pennsylvania and Research Triangle Park, North Carolina.
¹³ Melanoma Institute Australia and University of Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, and Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia.

PMID: 24958809
DOI: 10.1158/1078-0432.CCR-14-0887

Abstract

Purpose: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship.

Experimental design: Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data.

Results: One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation-positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma.

Conclusion: The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose-response relationship. A maximum tolerated dose for dabrafenib was not determined.

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Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436)

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Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436)

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