AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Dabrafenib mesilate Proprietary Product Name: Tafinlar Sponsor: GlaxoSmithKline Australia Pty Ltd Date of CER: 20 February 2013 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) · The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health, and is responsible for regulating medicines and medical devices. · The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary. · The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. · The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. · To report a problem with a medicine or medical device, please see the information on the TGA website <http://www.tga.gov.au>. About the Extract from the Clinical Evaluation Report · This document provides a more detailed evaluation of the clinical findings, extracted from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities. · The words [Information redacted], where they appear in this document, indicate that confidential information has been deleted. · For the most recent Product Information (PI), please refer to the TGA website <http://www.tga.gov.au/hp/information-medicines-pi.htm>. Copyright © Commonwealth of Australia 2013 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>. Submission PM-012-02231-3-4 Extract from the Clinical Evaluation Report for Tafinlar dabrafenib mesilate Page 2 of 91 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 4 1. Introduction _____________________________________________________________ 8 2. Clinical rationale _______________________________________________________ 8 3. Contents of the clinical dossier_______________________________________ 9 3.1. Scope of the clinical dossier ___________________________________________________ 9 3.2. Formulation __________________________________________________________________ 10 3.3. Guidance ______________________________________________________________________ 10 3.4. Paediatric data _______________________________________________________________ 10 3.5. Good clinical practice ________________________________________________________ 10 4. Pharmacokinetics ____________________________________________________ 11 4.1. Studies providing pharmacokinetic data ___________________________________ 11 4.2. Summary of pharmacokinetics _____________________________________________ 12 4.3. Evaluator’s overall conclusions on pharmacokinetics ____________________ 26 5. Pharmacodynamics __________________________________________________ 28 5.1. Studies providing pharmacodynamic data _________________________________ 28 5.2. Summary of pharmacodynamics ___________________________________________ 28 5.3. Evaluator’s overall conclusions on pharmacodynamics __________________ 33 6. Dosage selection for the pivotal studies __________________________ 34 7. Clinical efficacy _______________________________________________________ 35 7.1. Treatment of patients with BRAF V600 mutation positive unresectable or metastatic (Stage IV) melanoma ___________________________________________________ 35 7.2. Evaluator’s conclusions on clinical efficacy of dabrafenib for treatment of patients with BRAF V600 mutation positive unresectable or metastatic (Stage IV) melanoma ___________________________________________________________________________ 50 8. Clinical safety__________________________________________________________ 53 8.1. Studies providing evaluable safety data ____________________________________ 53 8.2. Pivotal studies that assessed safety as a primary outcome _______________ 55 8.3. Patient exposure _____________________________________________________________ 55 8.4. Adverse events _______________________________________________________________ 58 8.5. Laboratory tests ______________________________________________________________ 67 8.6. Post-marketing experience__________________________________________________ 72 8.7. Safety issues with the potential for major regulatory impact ____________ 72 8.8. Other safety issues ___________________________________________________________ 73 8.9. Evaluator’s overall conclusions on clinical safety _________________________ 75 9. First round benefit-risk assessment ______________________________ 78 Submission PM-012-02231-3-4 Extract from the Clinical Evaluation Report for Tafinlar dabrafenib mesilate Page 3 of 91 Therapeutic Goods Administration 9.1. First round assessment of benefits _________________________________________ 78 9.2. First round assessment of risks _____________________________________________ 78 9.3. First round assessment of benefit-risk balance ___________________________ 79 10. First round recommendation regarding authorisation ________ 79 11. Clinical questions _____________________________________________________ 80 11.1. Pharmacokinetics __________________________________________________________ 80 11.2. Efficacy ______________________________________________________________________ 80 11.3. Safety ________________________________________________________________________ 80 12. Second round evaluation of clinical data submitted in response to questions ______________________________________________________________________ 81 13. References _____________________________________________________________ 81 14. Appendix 1. Population PK of dabrafenib in subjects with solid tumours: ______________________________________________________________________ 82 14.1. Summary ____________________________________________________________________ 82 List of abbreviations Abbreviation Meaning a.k.a. Also known as AE Adverse event AML Acute myeloid leukaemia AMS Accelerator mass spectrometry ARF Acute renal failure ATP Adenosine triphosphate AUC Area under the plasma drug concentration-time curve AUC(0- Area under the concentration-time curve from zero to infinity ∞) AUC(0- Inter-dose interval area under the concentration-time curve BCC τ) Basal cell carcinoma Bcrp Breast cancer resistance protein BCS Biopharmaceutics Classification System Submission PM-012-02231-3-4 Extract from the Clinical Evaluation Report for Tafinlar dabrafenib mesilate Page 4 of 91 Therapeutic Goods Administration Abbreviation Meaning BID Twice a day BRAF A member of the RAF kinases Cavg Average concentration CL/F Apparent oral clearance (L/h) CL0 Initial (non-inducible) clearance (L/h) CLind Inducible clearance (L/h) Cmax Maximum observed concentration CPH Cox proportional hazards CR Complete response CSR Clinical Study Report Pre-dose (trough) concentration at the end of the dosing interval Cτ CT Computed tomography Ctrough Trough concentration CYP Cytochrome P450 DTIC dacarbazine ECG Electrocardiogram ECHO Echocardiogram ECOG Eastern Cooperative Oncology Group ED50 Daily dose resulting in 50% of maximum response EMA European Medicines Agency Emax Maximum response ERK Extracellular signal regulated kinase EU European Union F Absolute bioavailability FDG-PET Fluorodeoxyglucose-positron emission tomography Submission PM-012-02231-3-4 Extract from the Clinical Evaluation Report for Tafinlar dabrafenib mesilate Page 5 of 91 Therapeutic Goods Administration Abbreviation Meaning FTIH First time in humans GGT Gamma glutamyl transferase GI Gastrointestinal HPMC hydroxypropylmethylcellulose HR Hazard ratio HRQoL Health-related quality of life IIV Inter-individual variability IR Independent review ISS Integrated summary of safety ITT Intention-to-treat IUO Investigational use only IV Intravenous Ka Absorption rate constant (L/h) LDH Lactate dehydrogenase LLE Liquid-liquid extraction LLQ Lower limit of quantification LS Least squares LVEF Left ventricular ejection fraction MAPK pathway The RAS/RAF/MEK/ERK pathway (MAP kinase pathway) MEK Mitogen-activated ERK kinase MRI Magnetic resonance imaging OIRR Overall intracranial response rate ORR Overall response rate OS Overall survival pERK Phosphorylated ERK Submission PM-012-02231-3-4 Extract from the Clinical Evaluation Report for Tafinlar dabrafenib mesilate Page 6 of 91 Therapeutic