Australian Public Assessment Report for Arsenic trioxide Proprietary Product Name: Phenasen Sponsor: Phebra Pty Ltd December 2015 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 AusPARs · An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. · AusPARs are prepared and published by the TGA. · An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. · An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. · A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. 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]>. AusPAR Phenasen Arsenic trioxide Phebra Pty Ltd PM-2014-02385-1-4 Final 16 December 2015 Page 2 of 56 Therapeutic Goods Administration Contents I. Introduction to product submission _____________________________________ 6 Submission details ____________________________________________________________________ 6 Product background __________________________________________________________________ 7 Regulatory status _____________________________________________________________________ 8 Product Information__________________________________________________________________ 9 II. Quality findings _____________________________________________________________ 9 Introduction ___________________________________________________________________________ 9 III. Nonclinical findings _______________________________________________________ 9 IV. Clinical findings ____________________________________________________________ 9 Introduction ___________________________________________________________________________ 9 Clinical rationale _____________________________________________________________________ 10 Pharmacokinetics ____________________________________________________________________ 13 Pharmacodynamics__________________________________________________________________ 13 Dosage selection for the pivotal studies ___________________________________________ 13 Efficacy _______________________________________________________________________________ 14 Evaluator’s conclusions on clinical efficacy _______________________________________ 14 Safety _________________________________________________________________________________ 18 First round benefit-risk assessment _______________________________________________ 29 First round recommendation regarding authorisation ___________________________ 32 Clinical questions ____________________________________________________________________ 33 Second round evaluation of clinical data submitted in response to questions _ 33 V. Pharmacovigilance findings ____________________________________________ 34 Risk management plan ______________________________________________________________ 34 VI. Overall conclusion and risk/benefit assessment __________________ 41 Quality ________________________________________________________________________________ 41 Nonclinical ___________________________________________________________________________ 41 Clinical ________________________________________________________________________________ 41 Risk management plan ______________________________________________________________ 44 Risk-benefit analysis ________________________________________________________________ 44 Outcome ______________________________________________________________________________ 54 Attachment 1. Product Information ______________________________________ 55 Attachment 2. Extract from the Clinical Evaluation Report __________ 55 AusPAR Phenasen Arsenic trioxide Phebra Pty Ltd PM-2014-02385-1-4 Final 16 December 2015 Page 3 of 56 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning 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 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 AusPAR Phenasen Arsenic trioxide Phebra Pty Ltd PM-2014-02385-1-4 Final 16 December 2015 Page 4 of 56 Therapeutic Goods Administration Abbreviation Meaning 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 Corrected QT interval RCT Randomised controlled trial RFS Relapse free survival RT-PCR Reverse transcriptase-polymerase chain reaction SAE Serious adverse event TE Thromboembolism TGA Therapeutic Goods Administration TTR Time to relapse VZV Varicella Zoster Virus WBC White blood cell count AusPAR Phenasen Arsenic trioxide Phebra Pty Ltd PM-2014-02385-1-4 Final 16 December 2015 Page 5 of 56 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: Extension of indications Decision: Approved Date of decision: 24 August 2015 Date of entry onto ARTG 26 August 2015 Active ingredient(s): Arsenic trioxide Product name(s): Phenasen® Sponsor’s name and address: Phebra Ply Ltd 19 Orion Road, Lane Cove West, NSW 2066 Dose form(s): Concentrated injection Strength(s): 10 mg / 10 mL Container(s): Glass Type I Clear Pack size(s): 10 x 10 mL vials Approved therapeutic use: 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. Route(s) of administration: Intravenous infusion (IVI). Dosage: Cycles of treatment are given to achieve complete remission, defined as the complete disappearance of all Ieukaemic myeloblasts and promyelocytes and < 5% overall myeloblasts by morphological examination of the marrow. After induction of remission, consolidation cycles may be given, and maintenance therapy considered. Phenasen may be given in combination with all-trans retinoic acid (ATRA) and/or chemotherapy. ARTG number (s): 152760 AusPAR Phenasen Arsenic trioxide Phebra Pty Ltd PM-2014-02385-1-4 Final 16 December 2015 Page 6 of 56 Therapeutic Goods Administration Product background This AusPAR describes the application by the sponsor to extend the indications for Phenasen (arsenic trioxide (ATO)) to include use alongside idarubicin and/or ATRA (all- trans retinoic acid), in newly diagnosed acute promyelocytic leukaemia (APL) as follows1 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/or chemotherapy and whose APL is characterised by the presence of the t(15:17) translocation or PML/RAR-alpha