Attachment: Extract from Clinical Evaluation: Cabozantinib
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AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Cabozantinib Proprietary Product Name: Cabometyx Sponsor: Ipsen Pty Ltd Date of first round report: 21 April 2017 Date of second round report: 26 September 2017 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 <https://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 <https://www.tga.gov.au/product-information-pi>. Copyright © Commonwealth of Australia 2018 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-2016-04459-1-4 Extract from the Clinical Evaluation Report for Cabometyx Final 18 Page 2 of 110 October 2018 Therapeutic Goods Administration Contents List of common abbreviations_______________________________________________ 5 1. Submission details _______________________________________________________ 9 1.1. Identifying information _____________________________________________________ 9 1.2. Submission type _____________________________________________________________ 9 1.3. Drug class and therapeutic indication _____________________________________ 9 1.4. Dosage forms and strengths ________________________________________________ 9 1.5. Dosage and administration _________________________________________________ 9 2. Background _____________________________________________________________ 10 2.1. Information on the condition being treated _____________________________ 10 2.2. Current treatment options ________________________________________________ 11 2.3. Clinical rationale ___________________________________________________________ 11 2.4. Formulation ________________________________________________________________ 11 2.5. Guidance ____________________________________________________________________ 12 2.6. Evaluator’s commentary on the background information______________ 12 3. Contents of the clinical dossier ______________________________________ 12 3.1. Scope of the clinical dossier _______________________________________________ 12 3.2. Paediatric data _____________________________________________________________ 12 3.3. Good clinical practice ______________________________________________________ 12 3.4. Evaluator’s commentary on the clinical dossier ________________________ 12 4. Pharmacokinetics ______________________________________________________ 12 4.1. Studies providing pharmacokinetic information ________________________ 12 4.2. Summary of pharmacokinetics ___________________________________________ 14 4.3. Evaluator’s overall conclusions on pharmacokinetics __________________ 21 5. Pharmacodynamics ____________________________________________________ 21 5.1. Studies providing pharmacodynamic information ______________________ 21 5.2. Summary of pharmacodynamics _________________________________________ 21 5.3. Evaluator’s overall conclusions on pharmacodynamics ________________ 22 6. Dosage selection for the pivotal studies ___________________________ 22 6.1. Pharmacokinetics and pharmacodynamics: dose finding studies _____ 22 6.2. Phase II dose finding studies______________________________________________ 22 6.3. Phase III pivotal studies investigating more than one dose regimen __ 22 6.4. Evaluator’s conclusions on dose finding for the pivotal studies _______ 23 7. Clinical efficacy _________________________________________________________ 24 7.1. Studies providing evaluable efficacy data _______________________________ 24 Submission PM-2016-04459-1-4 Extract from the Clinical Evaluation Report for Cabometyx Final 18 Page 3 of 110 October 2018 Therapeutic Goods Administration 7.2. Pivotal or main efficacy studies___________________________________________ 24 7.3. Other efficacy studies _____________________________________________________ 52 7.4. Analyses performed across trials: pooled and meta analyses __________ 52 7.5. Evaluator’s conclusions on clinical efficacy ______________________________ 52 8. Clinical safety ___________________________________________________________ 52 8.1. Studies providing evaluable safety data _________________________________ 52 8.2. Patient exposure ___________________________________________________________ 54 8.3. Adverse events _____________________________________________________________ 56 8.4. Evaluation of issues with possible regulatory impact __________________ 69 8.5. Other safety issues _________________________________________________________ 91 8.6. Post marketing experience________________________________________________ 93 8.7. Evaluator’s overall conclusions on clinical safety _______________________ 94 9. First round benefit-risk assessment ________________________________ 95 9.1. First round assessment of benefits _______________________________________ 95 9.2. First round assessment of risks __________________________________________ 96 9.3. First round assessment of benefit-risk balance _________________________ 97 10. First round recommendation regarding authorisation _______ 97 11. Clinical questions ____________________________________________________ 97 11.1. Pharmacokinetics __________________________________________________________ 97 11.2. Pharmacodynamics ________________________________________________________ 98 11.3. Efficacy _____________________________________________________________________ 98 11.4. Safety _______________________________________________________________________ 98 12. Second round evaluation ___________________________________________ 98 12.1. Response to questions_____________________________________________________ 98 12.2. Clinical study report (CSR) Addendum 2 for Study XL184-308 _______ 106 13. Second round benefit-risk assessment _________________________ 108 13.1. Second round assessment of benefits ___________________________________ 108 13.2. Second round assessment of risks_______________________________________ 109 13.3. Second round assessment of benefit-risk balance _____________________ 109 14. Second round recommendation regarding authorisation ___ 109 Submission PM-2016-04459-1-4 Extract from the Clinical Evaluation Report for Cabometyx Final 18 Page 4 of 110 October 2018 Therapeutic Goods Administration List of common abbreviations Abbreviation Meaning AE Adverse event ALT Alanine aminotransferase AST Aspartate aminotransferase AUC0-24 Area under the plasma concentration-time curve from time 0 to 24- hours AUC0-t Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration AUC0-inf Area under the plasma concentration-time curve from time 0 extrapolated to infinity Bid Twice daily BMI Body Mass Index BP Blood Pressure 14C Carbon-14 isotope Cmax Observed maximum plasma concentration Micro Curies CIμCi Confidence Interval CL/F Apparent total body clearance CP Childs-Pugh CRF Case report form CT Computed tomography CV coefficient of variation CTCAE Common toxicity criteria for adverse events dL Decilitre ECOG Eastern Cooperative Oncology Group g Grams Submission PM-2016-04459-1-4 Extract from the Clinical Evaluation Report for Cabometyx Final 18 Page 5 of 110 October 2018 Therapeutic Goods Administration Abbreviation Meaning GLS Geometric least square ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group FBE Free Base Equivalent FDA Food and Drug Administration (US) FT4 Free T4 h