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A Prospective, Multicenter, Phase-II Trial of Ibrutinib Plus Venetoclax In BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open HOVON 141 CLL Version 4, 20 DEC 2018 A prospective, multicenter, phase-II trial of ibrutinib plus venetoclax in patients with creatinine clearance ≥ 30 ml/min who have relapsed or refractory chronic lymphocytic leukemia (RR-CLL) with or without TP53 aberrations HOVON 141 CLL / VIsion Trial of the HOVON and Nordic CLL study groups PROTOCOL Principal Investigator : Arnon P Kater (HOVON) Carsten U Niemann (Nordic CLL study Group)) Sponsor : HOVON EudraCT number : 2016-002599-29 ; Page 1 of 107 Levin M-D, et al. BMJ Open 2020; 10:e039168. doi: 10.1136/bmjopen-2020-039168 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open Levin M-D, et al. BMJ Open 2020; 10:e039168. doi: 10.1136/bmjopen-2020-039168 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open HOVON 141 CLL Version 4, 20 DEC 2018 LOCAL INVESTIGATOR SIGNATURE PAGE Local site name: Signature of Local Investigator Date Printed Name of Local Investigator By my signature, I agree to personally supervise the conduct of this study in my affiliation and to ensure its conduct in compliance with the protocol, informed consent, IRB/EC procedures, the Declaration of Helsinki, ICH Good Clinical Practices guideline, the EU directive Good Clinical Practice (2001-20-EG), and local regulations governing the conduct of clinical studies. Page 3 of 107 Levin M-D, et al. BMJ Open 2020; 10:e039168. doi: 10.1136/bmjopen-2020-039168 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open Levin M-D, et al. BMJ Open 2020; 10:e039168. doi: 10.1136/bmjopen-2020-039168 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open HOVON 141 CLL Version 4, 20 DEC 2018 2 Table of contents Page 1 SCHEME OF STUDY .................................................................................................................................... 4 2 TABLE OF CONTENTS ................................................................................................................................ 5 3 SYNOPSIS .................................................................................................................................................... 8 4 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .......................................................... 13 5 INTRODUCTION AND RATIONALE .......................................................................................................... 15 5.1 Description of disease and current treatment ................................................................................... 15 5.2 Investigational Medicinal Products .................................................................................................... 15 5.2.1 Venetoclax .......................................................................................................................... 15 5.2.2 Ibrutinib ............................................................................................................................... 16 5.3 Rationale of the study ....................................................................................................................... 16 6 STUDY OBJECTIVES ................................................................................................................................ 17 7 STUDY DESIGN .......................................................................................................................................... 18 8 STUDY POPULATION ................................................................................................................................ 18 8.1 Eligibility for registration .................................................................................................................... 18 8.1.1 Inclusion criteria .................................................................................................................. 19 8.1.2 Exclusion criteria ................................................................................................................. 20 8.2 Eligiblity for randomization ................................................................................................................ 20 8.3 Eligibility for Ibrutinib monotherapy in MRD-positive patients ........................................................... 20 9 TREATMENT .............................................................................................................................................. 21 9.1 Treatment with ibrutinib and venetoclax ........................................................................................... 21 9.1.1 Treatment schedule ............................................................................................................ 22 9.1.2 Administration of treatment ................................................................................................. 22 9.1.3 Dose adjustments for Ibrutinib and Venetoclax .................................................................. 23 9.2 Special precautions and supportive care .......................................................................................... 23 9.2.1 Prophylaxis and Management of Tumor Lysis Syndrome (TLS) ........................................ 23 9.2.2 Hematopoietic growth factors ............................................................................................. 24 9.2.3 Infections prophylaxis ......................................................................................................... 24 9.2.4 Management of Decrease in Spermatogenesis ................................................................. 24 9.2.5 Embryo-Fetal Toxicity ......................................................................................................... 25 9.2.6 Immunization ....................................................................................................................... 25 9.3 Ibrutinib maintenance treatment........................................................................................................ 25 9.4 Reinitiation of therapy for patients randomized to arm B .................................................................. 26 9.5 Co-intervention .................................................................................................................................. 26 9.5.1 Prohibited and cautionary Therapy ..................................................................................... 26 9.6 Investigational Medicinal Product Ibrutinib ........................................................................................ 28 9.6.1 Summary of known and potential risks ............................................................................... 28 9.6.2 Preparation and labeling ..................................................................................................... 30 9.6.3 Storage and handling .......................................................................................................... 30 9.6.4 Study drug supply ............................................................................................................... 30 9.6.5 Drug accountability ............................................................................................................. 30 9.6.6 Study drug return and destruction ...................................................................................... 31 9.7 Investigational Medicinal Product Venetoclax ................................................................................... 31 9.7.1 Summary of known and potential risks ............................................................................... 31 9.7.2 Preparation and labeling ..................................................................................................... 32 9.7.3 Storage and handling .......................................................................................................... 33 9.7.4 Study drug supply ............................................................................................................... 33 Page 5 of 107 Levin M-D, et al. BMJ Open 2020; 10:e039168. doi: 10.1136/bmjopen-2020-039168 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) BMJ Open HOVON 141 CLL Version 4, 20 DEC 2018 9.7.5 Drug accountability ............................................................................................................. 33 9.7.6 Study drug return and destruction ...................................................................................... 33 10 STUDY PROCEDURES .............................................................................................................................
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