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 placed on this supplemental material which has been supplied by the author(s) Supplemental material BMJ Open <ul style="display: flex;"><li style="flex:1">HOVON 141 CLL </li><li style="flex:1">Version 4, 20 DEC 2018 </li></ul>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 <ul style="display: flex;"><li style="flex:1">Principal Investigator </li><li style="flex:1">:</li><li style="flex:1">Arnon P Kater (HOVON) </li></ul>Carsten U Niemann (Nordic CLL study Group)) <ul style="display: flex;"><li style="flex:1">Sponsor </li><li style="flex:1">:</li></ul>: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 placed on this supplemental material which has been supplied by the author(s) Supplemental material 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 placed on this supplemental material which has been supplied by the author(s) Supplemental material BMJ Open <ul style="display: flex;"><li style="flex:1">HOVON 141 CLL </li><li style="flex:1">Version 4, 20 DEC 2018 </li></ul>LOCAL INVESTIGATOR SIGNATURE PAGE Local site name: <ul style="display: flex;"><li style="flex:1">Signature of Local Investigator </li><li style="flex:1">Date </li></ul>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 placed on this supplemental material which has been supplied by the author(s) Supplemental material 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 placed on this supplemental material which has been supplied by the author(s) Supplemental material BMJ Open <ul style="display: flex;"><li style="flex:1">HOVON 141 CLL </li><li style="flex:1">Version 4, 20 DEC 2018 </li></ul><ul style="display: flex;"><li style="flex:1">2</li><li style="flex:1">Table of contents </li></ul>Page <a href="#4_0">1</a><a href="#5_0">2</a><a href="#8_0">3</a><a href="#13_0">4</a><a href="#15_0">5</a> <a href="#4_0">SCHEME OF STUD</a><a href="#4_0">Y</a><a href="#4_0">.</a><a href="#4_0">...................................................................................................................................4 </a><a href="#5_0">TABLE OF CONTENTS................................................................................................................................5 </a><a href="#8_0">SYNOPSIS ....................................................................................................................................................8 </a><a href="#13_0">INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE..........................................................13 </a><a href="#15_0">INTRODUCTION AND RATIONAL</a><a href="#15_0">E</a><a href="#15_0">.</a><a href="#15_0">.........................................................................................................15 </a><a href="#15_1">5.1 Description</a><a href="#15_1"> </a><a href="#15_1">of disease and current treatment ...................................................................................15 </a><a href="#15_2">5.2 Investigational</a><a href="#15_2"> </a><a href="#15_2">Medicinal Products....................................................................................................15 </a> <a href="#15_3">5.2.1 Venetoclax</a><a href="#15_3"> </a><a href="#15_3">..........................................................................................................................15 </a><a href="#16_0">5.2.2 Ibrutinib</a><a href="#16_0"> </a><a href="#16_0">...............................................................................................................................16 </a> <a href="#16_1">5.3 Rationale</a><a href="#16_1"> </a><a href="#16_1">of the study .......................................................................................................................16 </a><a href="#17_0">6</a><a href="#18_0">7</a><a href="#18_1">8</a> <a href="#17_0">STUDY OBJECTIVES ................................................................................................................................17 </a><a href="#18_0">STUDY DESIGN..........................................................................................................................................18 </a><a href="#18_1">STUDY POPULATION................................................................................................................................18 </a><a href="#18_2">8.1 Eligibility</a><a href="#18_2"> </a><a href="#18_2">for registration ....................................................................................................................18 </a> <a href="#19_0">Inclusion criteri</a><a href="#19_0">a</a><a href="#19_0">.</a><a href="#19_0">.................................................................................................................19 </a><a href="#20_0">Exclusion criteria.................................................................................................................20 </a> <a href="#19_0">8.1.1 </a><a href="#20_0">8.1.2 </a> <a href="#20_1">8.2 Eligiblity</a><a href="#20_1"> </a><a href="#20_1">for randomization ................................................................................................................20 </a><a href="#20_2">8.3 Eligibility</a><a href="#20_2"> </a><a href="#20_2">for Ibrutinib monotherapy in MRD-positive patient</a><a href="#20_2">s</a><a href="#20_2">.</a><a href="#20_2">..........................................................20 </a><ul style="display: flex;"><li style="flex:1"><a href="#0_0">9</a></li><li style="flex:1"><a href="#0_0">TREATMENT ..............................................................................................................................................21 </a></li></ul><a href="#0_1">9.1 Treatment</a><a href="#0_1"> </a><a href="#0_1">with ibrutinib and venetoclax ...........................................................................................21 </a> <a href="#0_2">9.1.1 </a><a href="#0_3">9.1.2 </a><a href="#0_4">9.1.3 </a> <a href="#0_2">Treatment schedule ............................................................................................................22 </a><a href="#0_3">Administration of treatmen</a><a href="#0_3">t</a><a href="#0_3">.</a><a href="#0_3">................................................................................................22 </a><a href="#0_4">Dose adjustments for Ibrutinib and Venetoclax ..................................................................23 </a> <a href="#0_5">9.2 Special</a><a href="#0_5"> </a><a href="#0_5">precautions and supportive car</a><a href="#0_5">e</a><a href="#0_5">.</a><a href="#0_5">.........................................................................................23 </a> <a href="#0_6">9.2.1 </a><a href="#0_7">9.2.2 </a><a href="#0_8">9.2.3 </a><a href="#0_9">9.2.4 </a><a href="#0_10">9.2.5 </a><a href="#0_11">9.2.6 </a> <a href="#0_6">Prophylaxis and Management of Tumor Lysis Syndrome (TLS</a><a href="#0_6">)</a><a href="#0_6">.</a><a href="#0_6">.......................................23 </a><a href="#0_7">Hematopoietic growth factors .............................................................................................24 </a><a href="#0_8">Infections prophylaxis .........................................................................................................24 </a><a href="#0_9">Management of Decrease in Spermatogenesis .................................................................24 </a><a href="#0_10">Embryo-Fetal Toxicity .........................................................................................................25 </a><a href="#0_11">Immunization.......................................................................................................................25 </a> <a href="#0_12">9.3 Ibrutinib</a><a href="#0_12"> </a><a href="#0_12">maintenance treatment........................................................................................................25 </a><a href="#0_13">9.4 Reinitiation</a><a href="#0_13"> </a><a href="#0_13">of therapy for patients randomized to arm </a><a href="#0_13">B</a><a href="#0_13">.</a><a href="#0_13">.................................................................26 </a><a href="#0_14">9.5 Co-interventio</a><a href="#0_14">n</a><a href="#0_14">.</a><a href="#0_14">.................................................................................................................................26 </a> <a href="#0_15">9.5.1 Prohibited</a><a href="#0_15"> </a><a href="#0_15">and cautionary Therapy.....................................................................................26 </a> <a href="#0_16">9.6 Investigational</a><a href="#0_16"> </a><a href="#0_16">Medicinal Product Ibrutinib........................................................................................28 </a> <a href="#0_17">9.6.1 </a><a href="#0_18">9.6.2 </a><a href="#0_19">9.6.3 </a><a href="#0_20">9.6.4 </a><a href="#0_21">9.6.5 </a><a href="#0_22">9.6.6 </a> <a href="#0_17">Summary of known and potential risk</a><a href="#0_17">s</a><a href="#0_17">.</a><a href="#0_17">..............................................................................28 </a><a href="#0_18">Preparation and labelin</a><a href="#0_18">g</a><a href="#0_18">.</a><a href="#0_18">....................................................................................................30 </a><a href="#0_19">Storage and handling..........................................................................................................30 </a><a href="#0_20">Study drug supply ...............................................................................................................30 </a><a href="#0_21">Drug accountability .............................................................................................................30 </a><a href="#0_22">Study drug return and destruction ......................................................................................31 </a> <a href="#0_23">9.7 Investigational</a><a href="#0_23"> </a><a href="#0_23">Medicinal Product Venetoclax...................................................................................31 </a> <a href="#0_6">9.7.1 </a><a href="#0_24">9.7.2 </a><a href="#0_25">9.7.3 </a><a href="#0_26">9.7.4 </a> <a href="#0_6">Summary of known and potential risk</a><a href="#0_6">s</a><a href="#0_6">.</a><a href="#0_6">..............................................................................31 </a><a href="#0_24">Preparation and labelin</a><a href="#0_24">g</a><a href="#0_24">.</a><a href="#0_24">....................................................................................................32 </a><a href="#0_25">Storage and handling..........................................................................................................33 </a><a href="#0_26">Study drug supply ...............................................................................................................33 </a>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 placed on this supplemental material which has been supplied by the author(s) Supplemental material BMJ Open <ul style="display: flex;"><li style="flex:1">HOVON 141 CLL </li><li style="flex:1">Version 4, 20 DEC 2018 </li></ul><a href="#0_27">9.7.5 </a><a href="#0_28">9.7.6 </a> <a href="#0_27">Drug accountability .............................................................................................................33 </a><a href="#0_28">Study drug return and destruction ......................................................................................33 </a><ul style="display: flex;"><li style="flex:1"><a href="#0_10">10 </a></li><li style="flex:1"><a href="#0_10">STUDY PROCEDURE</a><a href="#0_10">S</a><a href="#0_10">.</a><a href="#0_10">.............................................................................................................................34 </a></li></ul><a href="#0_29">10.1 Time</a><a href="#0_29"> </a><a href="#0_29">of clinical evaluations ...............................................................................................................34 </a> <a href="#0_30">10.1.1 Follow</a><a href="#0_30"> </a><a href="#0_30">up.............................................................................................................................34 </a> <a href="#0_31">10.2 Required</a><a href="#0_31"> </a><a href="#0_31">investigation</a><a href="#0_31">s</a><a href="#0_31">.</a><a href="#0_31">....................................................................................................................34 </a><a href="#0_32">10.3 Storage</a><a href="#0_32"> </a><a href="#0_32">for future studie</a><a href="#0_32">s</a><a href="#0_32">.</a><a href="#0_32">.................................................................................................................39 </a><a href="#0_33">10.4 Response</a><a href="#0_33"> </a><a href="#0_33">evaluation.........................................................................................................................39 </a><a href="#0_34">10.5 Quality</a><a href="#0_34"> </a><a href="#0_34">of Life assessmen</a><a href="#0_34">t</a><a href="#0_34">.</a><a href="#0_34">...............................................................................................................39 </a><a href="#0_18">10.6 Minimal</a><a href="#0_18"> </a><a href="#0_18">Residual Disease.................................................................................................................40 </a><a href="#0_35">10.7 Central</a><a href="#0_35"> </a><a href="#0_35">review ...................................................................................................................................41 </a> <a href="#0_36">10.7.1 Cytological</a><a href="#0_36"> </a><a href="#0_36">and immunophenotype review .........................................................................41 </a> <a href="#0_37">10.8 Side</a><a href="#0_37"> </a><a href="#0_37">studies.......................................................................................................................................41 </a><a href="#0_38">11 </a><a href="#0_10">12 </a> <a href="#0_38">WITHDRAWAL OF PATIENTS OR PREMATURE TERMINATION OF THE STUDY ..............................41 </a><a href="#0_39">11.1 Withdrawal</a><a href="#0_39"> </a><a href="#0_39">of individual patients from protocol treatment ................................................................41 </a><a href="#0_40">11.2 Follow</a><a href="#0_40"> </a><a href="#0_40">up of patients withdrawn from protocol treatment .................................................................42 </a><a href="#0_41">11.3 Withdrawal</a><a href="#0_41"> </a><a href="#0_41">of informed consent........................................................................................................42 </a><a href="#0_42">11.4 Premature</a><a href="#0_42"> </a><a href="#0_42">termination of the stud</a><a href="#0_42">y</a><a href="#0_42">.</a><a href="#0_42">..................................................................................................43 </a><a href="#0_10">SAFETY ......................................................................................................................................................44 </a><a href="#0_29">12.1 Definitions..........................................................................................................................................44 </a><a href="#0_25">12.2 Adverse</a><a href="#0_25"> </a><a href="#0_25">event ...................................................................................................................................45 </a> <a href="#0_43">12.2.1 Reporting</a><a href="#0_43"> </a><a href="#0_43">of adverse event</a><a href="#0_43">s</a><a href="#0_43">.</a><a href="#0_43">..............................................................................................45 </a><a href="#0_44">12.2.2 Follow</a><a href="#0_44"> </a><a href="#0_44">up of adverse event</a><a href="#0_44">s</a><a href="#0_44">.</a><a href="#0_44">..............................................................................................45 </a> <a href="#0_45">12.3 Serious</a><a href="#0_45"> </a><a href="#0_45">Adverse Event</a><a href="#0_45">s</a><a href="#0_45">.</a><a href="#0_45">...................................................................................................................46 </a> <a href="#0_46">12.3.1 Reporting</a><a href="#0_46"> </a><a href="#0_46">of serious adverse events ..................................................................................46 </a><a href="#0_0">12.3.2 Causality</a><a href="#0_0"> </a><a href="#0_0">assessment of Serious Adverse Events .............................................................47 </a><a href="#0_47">12.3.3 Follow</a><a href="#0_47"> </a><a href="#0_47">up of Serious Adverse Event</a><a href="#0_47">s</a><a href="#0_47">.</a><a href="#0_47">................................................................................47 </a><a href="#0_48">12.3.4 Processing</a><a href="#0_48"> </a><a href="#0_48">of serious adverse event reports .....................................................................47 </a> <a href="#0_49">12.4 Reporting</a><a href="#0_49"> </a><a href="#0_49">Suspected Unexpected Serious Adverse Reactions........................................................48 </a><a href="#0_50">12.5 Pregnancies</a><a href="#0_50"> </a><a href="#0_50">......................................................................................................................................48 </a><a href="#0_45">12.6 Second</a><a href="#0_45"> </a><a href="#0_45">Primary Malignancies...........................................................................................................49 </a><a href="#0_51">12.7 Reporting</a><a href="#0_51"> </a><a href="#0_51">of safety issues.................................................................................................................49 </a><a href="#0_52">12.8 Annual</a><a href="#0_52"> </a><a href="#0_52">safety repor</a><a href="#0_52">t</a><a href="#0_52">.</a><a href="#0_52">.........................................................................................................................49 </a><a href="#0_0">12.9 Data</a><a href="#0_0"> </a><a href="#0_0">Safety and Monitoring Board (DSMB</a><a href="#0_0">)</a><a href="#0_0">.</a><a href="#0_0">.....................................................................................50 </a><a href="#0_53">12.10 Safety monitoring ..............................................................................................................................50 </a><a href="#0_25">12.11 Product Complaint</a><a href="#0_25">s</a><a href="#0_25">.</a><a href="#0_25">..........................................................................................................................51 </a><a href="#0_54">13 </a><a href="#0_38">14 </a> <a href="#0_54">ENDPOINTS................................................................................................................................................51 </a><a href="#0_55">13.1 Primary</a><a href="#0_55"> </a><a href="#0_55">endpoint ...............................................................................................................................51 </a><a href="#0_10">13.2 Secondary</a><a href="#0_10"> </a><a href="#0_10">endpoints ........................................................................................................................52 </a><a href="#0_38">STATISTICAL CONSIDERATIONS ...........................................................................................................52 </a><a href="#0_10">14.1 Patient</a><a href="#0_10"> </a><a href="#0_10">numbers and power consideration</a><a href="#0_10">s</a><a href="#0_10">.</a><a href="#0_10">.....................................................................................53 </a><a href="#0_56">14.2 Study</a><a href="#0_56"> </a><a href="#0_56">population definitions ..............................................................................................................53 </a><a href="#0_25">14.3 Alerting</a><a href="#0_25"> </a><a href="#0_25">rules .....................................................................................................................................54 </a><a href="#0_57">14.4 Statistical</a><a href="#0_57"> </a><a href="#0_57">analysi</a><a href="#0_57">s</a><a href="#0_57">.</a><a href="#0_57">............................................................................................................................54 </a> <a href="#0_58">14.4.1 Efficacy</a><a href="#0_58"> </a><a href="#0_58">analysis .................................................................................................................54 </a><a href="#0_25">14.4.2 Toxicity</a><a href="#0_25"> </a><a href="#0_25">analysis..................................................................................................................55 </a><a href="#0_59">14.4.3 Additional</a><a href="#0_59"> </a><a href="#0_59">analyse</a><a href="#0_59">s</a><a href="#0_59">.</a><a href="#0_59">............................................................................................................55 </a><a href="#0_27">14.4.4 Interim</a><a href="#0_27"> </a><a href="#0_27">analysi</a><a href="#0_27">s</a><a href="#0_27">.</a><a href="#0_27">..................................................................................................................55 </a><a href="#0_10">14.4.5 Statistical</a><a href="#0_10"> </a><a href="#0_10">analysis of the quality of life assessment (QoL).................................................57 </a><a href="#0_60">14.4.6 Statistical</a><a href="#0_60"> </a><a href="#0_60">analysis plan (SAP) ............................................................................................57 </a><a href="#0_61">14.4.7 Data</a><a href="#0_61"> </a><a href="#0_61">and Safety monitoring boar</a><a href="#0_61">d</a><a href="#0_61">.</a><a href="#0_61">.....................................................................................57 </a>

A Prospective, Multicenter, Phase-II Trial of Ibrutinib Plus Venetoclax In

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