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Extract from the Clinical Evaluation Report for Trifluridine/Tipiracil

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Extract from the Clinical Evaluation Report for Trifluridine/Tipiracil AusPAR Attachment 2 Extract from the Clinical Evaluation Report for trifluridine / tipiracil Proprietary Product Name: Lonsurf and Orcantas Sponsor: Servier Laboratories Australia Pty Ltd First round report: July 2016 Second round report: January 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]>. AusPAR Attachment 2 Lonsurf and Orcantas PM-2016-00929-1-4 Extract from the Clinical Evaluation Report 2 of 136 List of abbreviations Abbreviations Meaning AE Adverse event AT As treated (population) AUC Area under the curve BCS Biopharmaceutics Classification System BD Twice daily BSA Body surface area BSC Best supportive care CER Clinical evaluation report CI Confidence interval CL/F Apparent oral clearance Cmax Maximum plasma concentration CR Complete response CRC Colorectal Cancer CSR Clinical study report CTCAE Common Terminology Criteria for Adverse Events CV Coefficient of variation CYP Cytochrome P450 DCR Disease control rate DR Duration of response ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group eCRF Electronic case report form EGFR Epidermal growth factor receptor EMA European Medicines Agency AusPAR Attachment 2 Lonsurf and Orcantas PM-2016-00929-1-4 Extract from the Clinical Evaluation Report 3 of 136 Abbreviations Meaning FAS Full analysis set FDA Food and Drug Administration FTD Trifluridine FTY 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione GCP Good clinical Practice G-CSF Granulocyte colony stimulating factor HPLC High performance liquid chromatography HR Hazard ratio ICH International Conference on Harmonisation ITT Intent-to-treat LC/MS/MS Liquid chromatography-tandem mass spectrometry mCRC Metastatic colorectal cancer MedDRA Medical Dictionary for Regulatory Activities NCCN National Comprehensive Cancer Network NCI National Cancer Institute OCT2 Organic cation transporter-2 ORR Overall response rate OS Overall survival PFS Progression-free survival PD Pharmacodynamics PK Pharmacokinetics PS Performance status PT Preferred term QC Quality Control QD Once daily QTc QT interval corrected for heart rate AusPAR Attachment 2 Lonsurf and Orcantas PM-2016-00929-1-4 Extract from the Clinical Evaluation Report 4 of 136 Abbreviations Meaning QTcB QT interval corrected for heart rate using Bazett’s correction QTcF QT interval corrected for heart rate using Fridericia’s correction RECIST Response Evaluation Criteria in Solid Tumours SAE Serious adverse event SmPC Summary of Product Characteristics SOC System organ class TDS Three times daily T1/2 Terminal elimination half-life TK1 Thymidine kinase 1 Tmax Time of maximum observed plasma concentration Tpase Thymidine phosphorylase TPI Tipiracil hydrochloride TR Tumour response (evaluable population) TTF Time to treatment failure VEGF Vascular endothelial growth factor AusPAR Attachment 2 Lonsurf and Orcantas PM-2016-00929-1-4 Extract from the Clinical Evaluation Report 5 of 136 1. Introduction This is a submission to register a new chemical entity (NCE) fixed-dose combination tablet consisting of trifluridine and tipiracil (trade names Lonsurf and Orcantas) for the treatment of metastatic colorectal carcinoma (mCRC). 1.1. Drug class and therapeutic indication 1.1.1. Drug class Pharmacotherapeutic group: antineoplastic agents, antimetabolites. ATC code: L01BC59. Trifluridine is an antineoplastic thymidine-based nucleoside analog which is incorporated into deoxyribonucleic acid (DNA) in tumour cells following phosphorylation. Tipiracil inhibits degradation of trifluridine by inhibiting thymidine phosphorylase (TPase), resulting in increased systemic exposure to trifluridine when trifluridine and tipiracil are given together. 1.1.2. Proposed indication The proposed indication is the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti- VEGF agents, and anti-EGFR agents. 1.2. Dosage forms and strengths The submission proposes registration of the following dosage forms and strengths: • Lonsurf/Orcantas 15/6.14: white, round, biconvex, immediate-release, film-coated tablet consisting of the fixed-dose combination of trifluridine 15 mg and tipiracil hydrochloride 7.065 mg (equivalent to tipiracil 6.14 mg) imprinted with ‘15’ on one side and ‘102’ and ‘15 mg’ on the other side in grey ink. To be taken orally. • Lonsurf/Orcantas 20/8.19: pale red, round, biconvex, immediate-release, film-coated tablet consisting of the fixed-dose combination of trifluridine 20 mg and tipiracil hydrochloride 9.420 mg (equivalent to tipiracil 8.19 mg) imprinted with ‘20’ on one side and ‘102’ and ‘20 mg on the other side in grey ink. To be taken orally. 1.3. Dosage and administration The proposed Product Information (PI) states that the recommended starting dose of Lonsurf/Orcantas in adults is 35 mg/m2/dose administered orally twice daily on Days 1 to 5 and Days 8 to 12 of each 28 day cycle as long as benefit is observed or until unacceptable toxicity occurs. The dose is calculated according to body surface area (BSA), rounded to the nearest 5 mg increment. The dosage should not exceed 80 mg/dose. If doses are missed or held, the patient should not make up for missed doses. The PI provides guidelines for dose modification based on individual safety and tolerability relating to both haematologic and non-haematologic toxicities. The PI also includes recommendations for dosage in special populations. The PI specifies that Lonsurf/Orcantas should be taken with a glass of water, within 1 hour after completion of the morning and evening meals. Comment: The dosage of 35 mg/m2/dose is based on the trifluridine component of the fixed-dose combination. AusPAR Attachment 2 Lonsurf and Orcantas PM-2016-00929-1-4 Extract from the Clinical Evaluation Report 6 of 136 2. Clinical rationale The submission included a clinical rationale (justification) for the proposed fixed-dose combination tablet. The key aspects of the clinical rationale provided by the sponsor are provided below. Servier is the Australian sponsor of a new fixed dose combination product (FDC) containing a combination of trifluridine (FTD) and tipiracil hydrochloride (TPI) at a molar ratio 1:0.5 (weight ratio, 1:0.471) to be used in the treatment of metastatic colorectal cancer (mCRC). FTD is an antineoplastic thymidine-based nucleoside analog which is incorporated into deoxyribonucleic acid (DNA) in tumour cells following phosphorylation. TPI inhibits degradation of FTD by inhibiting thymidine phosphorylase (TPase), thus increasing systemic exposure to FTD when FTD and TPI are given together. Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide. In Australia, there were 17,070 projected new cases diagnosed in 2014, with CRC comprising 13.5% of all new cancer cases diagnosed in 2015. In Australia, patients with unresectable mCRC usually die from the disease, with five year overall survival of about 15%. The primary chemotherapy
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