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Supplemental material
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
;
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Levin M-D, et al. BMJ Open 2020; 10:e039168. doi: 10.1136/bmjopen-2020-039168
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- 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.
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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)
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- HOVON 141 CLL
- Version 4, 20 DEC 2018
- 2
- Table of contents
Page
12345
SCHEME OF STUDY....................................................................................................................................4 TABLE OF CONTENTS................................................................................................................................5 SYNOPSIS ....................................................................................................................................................8 INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE..........................................................13 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
678
STUDY OBJECTIVES ................................................................................................................................17 STUDY DESIGN..........................................................................................................................................18 STUDY POPULATION................................................................................................................................18
8.1 Eligibility for registration ....................................................................................................................18
Inclusion criteria..................................................................................................................19 Exclusion criteria.................................................................................................................20
8.1.1 8.1.2
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 9.1.2 9.1.3
Treatment schedule ............................................................................................................22 Administration of treatment.................................................................................................22 Dose adjustments for Ibrutinib and Venetoclax ..................................................................23
9.2 Special precautions and supportive care..........................................................................................23
9.2.1 9.2.2 9.2.3 9.2.4 9.2.5 9.2.6
Prophylaxis and Management of Tumor Lysis Syndrome (TLS)........................................23 Hematopoietic growth factors .............................................................................................24 Infections prophylaxis .........................................................................................................24 Management of Decrease in Spermatogenesis .................................................................24 Embryo-Fetal Toxicity .........................................................................................................25 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 9.6.2 9.6.3 9.6.4 9.6.5 9.6.6
Summary of known and potential risks...............................................................................28 Preparation and labeling.....................................................................................................30 Storage and handling..........................................................................................................30 Study drug supply ...............................................................................................................30 Drug accountability .............................................................................................................30 Study drug return and destruction ......................................................................................31
9.7 Investigational Medicinal Product Venetoclax...................................................................................31
9.7.1 9.7.2 9.7.3 9.7.4
Summary of known and potential risks...............................................................................31 Preparation and labeling.....................................................................................................32 Storage and handling..........................................................................................................33 Study drug supply ...............................................................................................................33
Page 5 of 107
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- HOVON 141 CLL
- Version 4, 20 DEC 2018
9.7.5 9.7.6
Drug accountability .............................................................................................................33 Study drug return and destruction ......................................................................................33
- 10
- STUDY PROCEDURES..............................................................................................................................34
10.1 Time of clinical evaluations ...............................................................................................................34
10.1.1 Follow up.............................................................................................................................34
10.2 Required investigations.....................................................................................................................34 10.3 Storage for future studies..................................................................................................................39 10.4 Response evaluation.........................................................................................................................39 10.5 Quality of Life assessment................................................................................................................39 10.6 Minimal Residual Disease.................................................................................................................40 10.7 Central review ...................................................................................................................................41
10.7.1 Cytological and immunophenotype review .........................................................................41
10.8 Side studies.......................................................................................................................................41
11 12
WITHDRAWAL OF PATIENTS OR PREMATURE TERMINATION OF THE STUDY ..............................41
11.1 Withdrawal of individual patients from protocol treatment ................................................................41 11.2 Follow up of patients withdrawn from protocol treatment .................................................................42 11.3 Withdrawal of informed consent........................................................................................................42 11.4 Premature termination of the study...................................................................................................43
12.1 Definitions..........................................................................................................................................44 12.2 Adverse event ...................................................................................................................................45
12.2.1 Reporting of adverse events...............................................................................................45 12.2.2 Follow up of adverse events...............................................................................................45
12.3 Serious Adverse Events....................................................................................................................46
12.3.1 Reporting of serious adverse events ..................................................................................46 12.3.2 Causality assessment of Serious Adverse Events .............................................................47 12.3.3 Follow up of Serious Adverse Events.................................................................................47 12.3.4 Processing of serious adverse event reports .....................................................................47
12.4 Reporting Suspected Unexpected Serious Adverse Reactions........................................................48 12.5 Pregnancies ......................................................................................................................................48 12.6 Second Primary Malignancies...........................................................................................................49 12.7 Reporting of safety issues.................................................................................................................49 12.8 Annual safety report..........................................................................................................................49 12.9 Data Safety and Monitoring Board (DSMB)......................................................................................50 12.10 Safety monitoring ..............................................................................................................................50 12.11 Product Complaints...........................................................................................................................51
13 14
ENDPOINTS................................................................................................................................................51
13.1 Primary endpoint ...............................................................................................................................51 13.2 Secondary endpoints ........................................................................................................................52
14.1 Patient numbers and power considerations......................................................................................53 14.2 Study population definitions ..............................................................................................................53 14.3 Alerting rules .....................................................................................................................................54 14.4 Statistical analysis.............................................................................................................................54
14.4.1 Efficacy analysis .................................................................................................................54 14.4.2 Toxicity analysis..................................................................................................................55 14.4.3 Additional analyses.............................................................................................................55 14.4.4 Interim analysis...................................................................................................................55 14.4.5 Statistical analysis of the quality of life assessment (QoL).................................................57 14.4.6 Statistical analysis plan (SAP) ............................................................................................57 14.4.7 Data and Safety monitoring board......................................................................................57
