AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Arsenic trioxide Proprietary Product Name: Phenasen Sponsor: Phebra Pty Ltd First Round CER report: 19 November 2014 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 2015 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-2014-02385-1-4 Extract from the Clinical Evaluation Report for Arsenic trioxide Page 2 of 104 Phenasen Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 1. Introduction _______________________________________________________________ 8 1.1. Submission type _____________________________________________________________ 8 1.2. Drug class and therapeutic indication _____________________________________ 8 1.3. Dosage forms and strengths ________________________________________________ 8 1.4. Dosage and administration _________________________________________________ 8 2. Clinical rationale _________________________________________________________ 9 3. Contents of the clinical dossier ______________________________________ 10 3.1. Scope of the clinical dossier _______________________________________________ 10 3.2. Paediatric data _____________________________________________________________ 12 3.3. Good clinical practice ______________________________________________________ 13 4. Pharmacokinetics ______________________________________________________ 13 4.1. Studies providing pharmacokinetic data ________________________________ 13 5. Pharmacodynamics ____________________________________________________ 13 5.1. Studies providing pharmacodynamic data ______________________________ 13 6. Dosage selection for the pivotal studies ___________________________ 13 7. Clinical efficacy _________________________________________________________ 13 7.1. For extended indication ___________________________________________________ 13 8. Clinical safety ___________________________________________________________ 69 8.1. Studies providing evaluable safety data _________________________________ 69 8.2. Pivotal studies that assessed safety as a primary outcome ____________ 70 8.3. Patient exposure ___________________________________________________________ 70 8.4. Safety results in the combination treatment studies____________________ 73 8.5. Safety results in the published single agent studies ____________________ 85 8.6. Post-marketing experience _______________________________________________ 89 8.7. Safety issues with the potential for major regulatory impact __________ 90 8.8. Other safety issues _________________________________________________________ 90 8.9. Evaluator’s overall conclusions on clinical safety _______________________ 92 9. First round benefit-risk assessment ________________________________ 96 9.1. First round assessment of benefits _______________________________________ 96 9.2. First round assessment of risks __________________________________________ 97 9.3. First round assessment of benefit-risk balance _________________________ 97 10. First round recommendation regarding authorisation _______ 99 11. Clinical questions ____________________________________________________ 99 Submission PM-2014-02385-1-4 Extract from the Clinical Evaluation Report for Arsenic trioxide Page 3 of 104 Phenasen Therapeutic Goods Administration 11.1. Pharmacokinetics __________________________________________________________ 99 11.2. Pharmacodynamics ________________________________________________________ 99 11.3. Efficacy ____________________________________________________________________ 100 11.4. Safety ______________________________________________________________________ 100 12. Second round evaluation of clinical data submitted in response to questions _____________________________________________________________________ 101 13. References ___________________________________________________________ 101 Submission PM-2014-02385-1-4 Extract from the Clinical Evaluation Report for Arsenic trioxide Page 4 of 104 Phenasen Therapeutic Goods Administration List of abbreviations Abbreviation Meaning 6MP 6-mercaptopurine ADR Adverse drug reaction AE Adverse event AIDA all trans retinoic and idarubicin ALLG Australasian Leukaemia and Lymphoma Group ALT Alanine amino transferase AML Acute myelogenous leukemia APL Acute promyelocytic leukaemia (also APML) APLDS APL differentiation syndrome APML3,APML4 ALLG APML trial codes, 3rd and 4th trials AST Aspartate amino transferase ATO Arsenic trioxide, As2O3 ATRA All-trans retinoic acid BaCT Centre for Biostatistics and Clinical Trials CI Confidence interval CNS Central nervous system CR Complete remission CSR Clinical study report CT chemotherapy CTCAE Common terminology criteria for adverse events D Daunorubicin DFS Disease free survival DMSC Data Management and Safety Committee EC Ethics committee Submission PM-2014-02385-1-4 Extract from the Clinical Evaluation Report for Arsenic trioxide Page 5 of 104 Phenasen Therapeutic Goods Administration Abbreviation Meaning ECG Electrocardiogram EFS Event-free survival FAB French-American-British, classification system FFS Failure Free Survival FLT3 FMS-like tyrosine kinase-3 GCP Good clinical practices GGT Gamma glutamine transferase GI Gastrointestinal H Homoharringtinone HCR Haematological complete remission IDA Idarubicin ITT Intention-to-treat iv Intravenous mRNA Messenger ribonucleic acid MTX Methotrexate NCCN National Comprehensive Cancer Network NCI National Cancer Institute ND Not done OS Overall survival PML- Promyelocytic leukaemia – retinoic acid receptor alpha fusion gene PP RARα Per protocol QTc QT interval RCT Randomised controlled trial RFS Relapse free survival RT-PCR Reverse transcriptase-polymerase chain reaction Submission PM-2014-02385-1-4 Extract from the Clinical Evaluation Report for Arsenic trioxide Page 6 of 104 Phenasen Therapeutic Goods Administration Abbreviation Meaning SAE Serious adverse event TE Thromboembolism TGA Therapeutic Goods Administration TTR Time to relapse VZV Varicella Zoster Virus WBC White blood count WCC White cell count Submission PM-2014-02385-1-4 Extract from the Clinical Evaluation Report for Arsenic trioxide Page 7 of 104 Phenasen Therapeutic Goods Administration 1. Introduction 1.1. Submission type This is a Category 1 Type-C submission for extension of indications. 1.2. Drug class and therapeutic indication Phenasen (ATO) is an antineoplastic agent (ATC code L01XX27: Antineoplastic and immunomodulating agents – Other antineoplastic agents). The approved indication is: ‘For the induction of remission and consolidation in patients with acute promyelocytic leukaemia (APL) who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose APL is characterised by the presence of the t(15:17) translocation or PML/RAR-alpha gene expression.’ The proposed {additional/replacement} indication is: ‘For the induction of remission and consolidation in patients with previously untreated Acute promyelocytic leukaemia (APL) in combination with all-trans retinoic acid (ATRA) and chemotherapy