A Cancer Research UK Phase I/IIa Clinical Trial of BI-1206; an Antibody to FcƔRIIB (CD32b), as a Single Agent and in Combination With an Anti-CD20 Antibody in Patients With CD32b Positive B-cell Malignancy
Phase: PHASE1
Conditions: B-cell Lymphoma, Chronic Lymphocytic Leukaemia, Waldenström Macroglobulinemia
Sponsor: Cancer Research UK



 
 
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CANCER RESEARCH UK 
Centre for Drug Development  
 
A CANCER RESEARCH UK PHASE I/IIA CLINICAL 
TRIAL OF BI-1206; AN ANTIBODY TO FCƔRIIB 
(CD32B), AS A SINGLE AGENT AND IN 
COMBINATION WITH AN ANTI-CD20 ANTIBODY IN 
PATIENTS WITH CD32B POSITIVE B-CELL 
MALIGNANCY. 
 
Sponsor protocol number: 
CRUKD/16/001 
EudraCT number: 
2015-004999-29 
 
Chief Investigator: 
Prof Andrew Davies 
Southampton General Hospital 
 
 
 
 
 
 
  
 
Sponsor: 
Cancer Research UK 
Centre for Drug Development  
 
 
 
 
 

 
 
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PARTICIPATING INVESTIGATORS AND CENTRES: 
Details of Principal Investigators and Investigational Sites are recorded on the Participating 
Investigators and Centres list in the Sponsor’s Trial Master File. 
VERSION HISTORY: 
Version No. 
Version Date 
Reason for update 
1 
07-Apr-2016 
Initial version submitted for Regulatory and Ethics approval 
2 
26-May-2016 
Sections 4.12, 5, 7.6.1, 9.6.3 and 11 updated in response to 
MHRA 
request 
including 
addition 
of 
Section 
5.3 
Communication Plan where dose escalation is to occur and 
extension of safety follow-up to 125 days. 
3 
04-Jul-2016 
Section 6.2.5 updated to amend shelf life of diluted drug to 
24 hours for first dose level. Other non-substantial changes 
made. 
4 
02-Feb-2017 
Sections 7.1.3 and 7.7 updated to include to oxygen 
saturation levels (SaO2) at baseline, prior to infusion during 
week 1-4 (induction period) and otherwise as clinically 
indicated. Eye examination to be performed within 4 weeks 
of first dose at screening. Patients in cohort will be seen on 
Day 25 (Week 4 day 4). 
 
Sections 7.7, 8.1.1, 8.4.1, 8.4.3 and 8.4.4 updated to include 
2 additional PD samples on days 2 and 4 of weeks 1-4. 
Emerging data will be reviewed at dose review meetings and 
a decision made for the following cohort as to whether or not 
these samples are required. PD sample 
  
 has been also reduced to 6mL.  
 
Other non-substantial changes made. 
5 
09-Jun-2017 
Non- substantial amendment  
- 
Clarification that Cohort 1 consists of a minimum of 
one patient and is consistent with other sections of 
the protocol. 
- 
Clarification that tumour assessment in the 
maintenance phase is every 16 weeks and is 
consistent with other sections of the protocol. 
 
Other non-substantial changes made. 
6 
25-Jan-2018 
Section 4.1.2 updated to reflect clarifications and changes to 
the eligibility criteria. 
 
Section 5.7.2 updated to clarify alternative pre-medication 
steroids for infusion related reactions may be used if 
deemed clinically appropriate by Investigator, CI, and 
Sponsor. 
 
Other non-substantial changes made. 
7 
(Not 
implemented) 
10-Jul-2018 
Change to the trial design to bring forward combination 
dose escalation (Arm 2) in Part A. 
 

 
 
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Change to the starting dose and dose increments of 
BI-1206 to be administered in combination with rituximab 
(Arm 2)  in Part A. 
 
Once the combination dose escalation arm (Part A, Arm 2) 
is opened, it will run in parallel to the single agent dose 
escalation arm (Part A, Arm1), dose decisions and cohort 
size decisions will be made independently from data within 
the arm, however available data from the other arm and 
any available data from other trials investigating BI-1206 
will be taken into consideration. 
 
Clarification that the RP2D of single agent BI-1206 
determined in Part A, Arm 1 and RP2D of combination 
dose of BI-1206 and rituximab determined in Part A, Arm 2 
may differ, but will not exceed 800 mg.  
 
Dose escalation cohorts in both Arm 1 and Arm 2 of Part A 
may include a minimum of one patient, if supported by 
emerging safety data and agreed in the dose decision 
meeting prior to next cohort opening. Any ≥ Grade 2 related 
toxicity in one patient will expand the cohorts to a 3+3 
patient cohort. 
 
All patients recruited to the combination arms of the trial will 
be given rituximab at a dose of 375 mg/m2 and follow the 
same dosing schedule. 
 
Rituximab biosimilars are permitted in the trial. 
 
PK/PD sampling schedule updated to reflect combination 
dose escalation (Arm 2) in Part A. 
 
Other non-substantial changes and corrections made. 
 
8 
20-Sep-2018 
CTA amendment 12 (incorporating Protocol version 7.0) 
was not approved by the MHRA.  
CTA amendment 13 (incorporating Protocol version 8.0) 
includes the changes from Protocol version 7.0 plus 
additional updates to Sections 5.3.2, 5.3.4, Table 1, 5.4.1, 
5.4.2, Figure 4, 5.4.3 and 4.2 to address the GNA (grounds 
for non-acceptance) raised: 
 
 - Clinically relevant Grade 2 or higher related toxicity will 
trigger cohort expansion from a minimum of one patient to 
3+3 cohorts; no option to revert back to single patient 
cohorts once expanded. 
- Statement added to clarify treatment arm allocation (in 
addition to dose level) will be confirmed and assigned by 
the Sponsor in the registration email. 
Section 4.1.2 , Exclusion criteria 7 corrected to clarify that 
certain ≤Grade 2 toxicities, which in the opinion of the 
Investigator and the Sponsor, should not exclude the 
patient from participation in the study. 
 
Other non-substantial changes and corrections made. 

 
 
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9 
20-Mar-2019  
Non-substantial amendment: 
 
 
  
The number and total volume of blood samples for 
pharmacodynamic analysis 
 
required during Week 1 – Week 4 has been reduced. 
A ± 5 minute time window has been added for the 
measurement of vital signs at the end of infusion.  
Clarification that drug-related SAEs after the 125-day 
period reporting is are required even if the patient has 
started another anti-cancer therapy. 
Other non-substantial changes made. 
10 
03-Sep-2019 
Substantial amendments: 
 
- Part A of the study: Remove eligibility requirement for 
CD32b positivity but continue to assess CD32b 
expression for information only.  
- Allow split dosing of BI-1206 +/- rituximab from Week 1 
if clinically indicated. 
- Additional assessments in Week 1 to monitor platelet 
counts and liver transaminases. 
- Clarification of dosing intervals, modifications and 
acceptable dose delays for logistical/ operational 
reasons. 
- Clarification of patient evaluability for dose escalation 
decisions. 
- Clarifications/revisions to inclusion/exclusion criteria. 
- Revision/addition of tertiary endpoints to align with the 
amendment and include additional biomarker work.  
- Other administrative/minor non-substantial changes. 
 

 
 
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TABLE OF CONTENTS 
 
 
 
TITLE PAGE 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
PROTOCOL SIGNATURES 
 
1 
PROTOCOL SYNOPSIS .................................................................................................... 14 
2 
INTRODUCTION ................................................................................................................. 16 
2.1 
Background .......................................................................................................................... 16 
2.1.1 
B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia. .................................. 16 
2.1.2 
CD32b and BI-1206 ............................................................................................................ 16 
2.2 
Investigational medicinal product ........................................................................................ 17 
2.2.1 
Structure of BI-1206 ............................................................................................................ 17 
2.2.2 
Mechanism of action of BI-1206 ......................................................................................... 17 
2.2.3 
Non-clinical anti-tumour activity .......................................................................................... 17 
2.2.4 
Safety considerations for the proposed trial ........................................................................ 18 
2.2.4.1 
BI-1206 Toxicology .......................................................................................................... 18 
2.2.5 
Clinical experience (other compounds targeting CD32b) ................................................... 19 
2.2.6 
Background on rituximab .................................................................................................... 20 
2.2.7 
Rituximab Biosimilars .......................................................................................................... 21 
2.2.8 
Expected safety profile for BI-1206 ± rituximab .................................................................. 21 
2.3 
Rationale for the proposed trial............................................................................................ 22 
2.3.1 
Rationale for BI-1206 starting dose .................................................................................... 23 
3 
TRIAL DESIGN ................................................................................................................... 25 
3.1 
Clinical trial objectives and endpoints .................................................................................. 25 
3.1.1 
Primary objectives and endpoints ....................................................................................... 25 
3.1.2 
Secondary objectives and endpoints .................................................................................. 26 
3.1.3 
Tertiary objectives and endpoints ....................................................................................... 26 
3.2 
Design of the clinical trial ..................................................................................................... 28 
3.3 
Definition of dose limiting toxicity ......................................................................................... 30 
3.4 
Definition of maximum tolerated dose ................................................................................. 31 
3.4.1 
Part A, Arm 1:Single-agent dose escalation ....................................................................... 31 
3.4.2 
Part A, Arm 2: Combination dose escalation ...................................................................... 31 
3.5 
Patient evaluability ............................................................................................................... 31 
3.5.1 
Response ............................................................................................................................ 31 
3.5.2 
Safety .................................................................................................................................. 31 
3.5.3 
Single Agent Dose escalation decisions (Part A, Arm 1) .................................................... 31 
3.5.4 
Combination dose escalation decisions (Part A, Arm 2) ..................................................... 32 
3.5.5 
Survival ................................................................................................................................ 32 
3.6 
Study duration ...................................................................................................................... 32 
4 
PATIENT SELECTION ....................................................................................................... 33 
4.1 
Eligibility criteria ................................................................................................................... 33 
4.1.1 
Inclusion criteria .................................................................................................................. 33 
4.1.2 
Exclusion Criteria ................................................................................................................ 34 
4.2 
Patient enrolment ................................................................................................................. 35 
5 
TREATMENT ...................................................................................................................... 36 
5.1 
Selection of the Phase I starting dose and schedule .......................................................... 36 
5.1.1 
Rationale for starting dose BI-1206 and rituximab .............................................................. 36 
5.2 
Dosing schedule/treatment schedule .................................................................................. 36 
5.2.1 
Dosing schedule/treatment schedule in BI-1206 single agent escalation phase (Part A, 
Arm 1) 36 
5.2.2 
Dosing schedule/treatment schedule in BI-1206/rituximab combination escalation phase 
(Part A, Arm 2) .................................................................................................................................. 37 

 
 
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5.2.3 
Dosing schedule/treatment schedule in BI-1206 single agent expansion phase (Part B, 
Arm 1) 37 
5.2.4 
Dosing schedule/treatment schedule in BI-1206/rituximab combination expansion phase 
(Part B, Arm 2) .................................................................................................................................. 37 
5.2.5 
Dosing schedule/treatment schedule, maintenance therapy (Part A and Part B) .............. 38 
5.3 
Communication Plan where dose escalation (Part A) is to occur ........................................ 38 
5.3.1 
Organisation and preparation for dose decision meetings. ................................................ 38 
5.3.2 
Areas to be discussed at dose decision meetings. ............................................................. 38 
5.3.3 
Follow-up of dose decision meetings .................................................................................. 39 
5.3.4 
Dissemination of Safety data between dose decision meetings ......................................... 39 
5.4 
BI-1206 single agent dose escalation scheme (Part A, Arm 1) ........................................... 39 
5.4.1 
Action if DLT observed in Cohort 1 (0.4mg to 50 mg), Part A Arm 1 .................................. 42 
5.4.2 
Dose escalation and action if clinically relevant ≥Grade 2 related toxicity observed at dose 
levels from Cohort 2 onwards, Part A Arm 1 .................................................................................... 42 
5.4.3 
Dose escalation and action if a DLT observed at dose levels from Cohort 2 onwards, 
Part A, Arm 1 .................................................................................................................................... 43 
5.5 
BI-1206 and rituximab escalation cohorts (Part A, Arm 2) .................................................. 43 
5.6 
Cohort expansion at maximum tolerated and/or maximum administered dose (Part A, Arm 
1 and Arm 2) ....................................................................................................................... 44 
5.7 
Single agent BI-1206 expansion cohort (Part B, Arm 1) ..................................................... 45 
5.8 
BI-1206 and rituximab combination expansion cohort (Part B, Arm 2) ............................... 45 
5.9 
Dose modifications .............................................................................................................. 45 
5.9.1 
Risk assessment for and management of tumour lysis syndrome ..................................... 45 
5.9.2 
Management of infusion related reactions .......................................................................... 45 
5.9.3 
Management of ocular toxicities ......................................................................................... 46 
5.9.4 
Management of thrombocytopenia (Grade 4) ..................................................................... 46 
5.9.5 
Dose reductions .................................................................................................................. 47 
5.9.6 
Dose delays and Treatment Discontinuation ...................................................................... 47 
5.9.7 
Duration of treatment .......................................................................................................... 48 
5.9.8 
Maintenance therapy ........................................................................................................... 48 
5.9.9 
Replacement of patients ..................................................................................................... 48 
5.10 
Concomitant medication and treatment ............................................................................... 48 
6 
PHARMACEUTICAL INFORMATION ................................................................................ 49 
6.1 
Supply of BI-1206 and rituximab ......................................................................................... 49 
6.1.1 
Supply of BI-1206 ................................................................................................................ 49 
6.1.2 
Supply of rituximab .............................................................................................................. 49 
6.2 
Pharmaceutical data ............................................................................................................ 50 
6.2.1 
Formulation of BI-1206 ........................................................................................................ 50 
6.2.2 
BI-1206 storage conditions ................................................................................................. 50 
6.2.3 
Method of preparation of BI-1206 for administration .......................................................... 50 
6.2.4 
Stability and labelling of the diluted BI-1206 ....................................................................... 50 
6.2.5 
BI-1206 administration ........................................................................................................ 50 
6.2.5.1 
BI-1206 administration for 0.4 mg dose level .................................................................. 50 
6.2.5.2 
BI-1206 administration for doses from 2 mg to 10 mg .................................................... 50 
6.2.5.3 
BI-1206 administration for  the 50mg dose level ............................................................. 51 
6.2.5.4 
BI-1206 administration at doses above 50mg ................................................................. 51 
6.2.5.5 
Pre-medications prior to antibody administration ............................................................ 51 
6.2.5.6 
Monitoring during infusion ............................................................................................... 51 
6.2.6 
BI-1206 Vein extravasation/accidental spillages ................................................................ 51 
6.2.7 
Formulation of rituximab ...................................................................................................... 52 
6.2.8 
Storage conditions of rituximab ........................................................................................... 52 
6.2.9 
Method of preparation of rituximab for administration ........................................................ 52 
6.2.10 
Stability and labelling of the diluted rituximab ................................................................. 52 
6.2.11 
Rituximab administration ................................................................................................. 52 
6.2.11.1 
Pre-medications prior to rituximab administration ........................................................... 53 
6.2.11.2 
Monitoring during infusion ............................................................................................... 53 
6.2.12 
Vein extravasation/accidental spillages .......................................................................... 53 
6.3 
Drug accountability .............................................................................................................. 53 

 
 
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6.3.1 
BI-1206 accountability ......................................................................................................... 53 
6.3.2 
Rituximab accountability ..................................................................................................... 53 
7 
INVESTIGATIONS SCHEDULE ......................................................................................... 54 
7.1 
Pre-treatment evaluations .................................................................................................... 54 
7.1.1 
Obtaining written informed consent .................................................................................... 54 
7.1.1.1 
CD32b and CD20 expression testing .............................................................................. 55 
7.1.2 
Pre-Screening – Part B only................................................................................................ 55 
7.1.3 
Baseline Evaluations ........................................................................................................... 55 
7.2 
Evaluations during Induction Therapy (Weeks 1-8) ............................................................ 57 
7.3 
Evaluations during maintenance therapy ............................................................................ 59 
7.4 
Evaluations at ‘off-study’ visit............................................................................................... 60 
7.5 
Follow-up ............................................................................................................................. 61 
7.5.1 
Safety follow-up ................................................................................................................... 61 
7.5.2 
Efficacy and survival follow-up ............................................................................................ 61 
7.6 
Schedule of events .............................................................................................................. 62 
8 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............................ 65 
8.1 
Summary of pharmacokinetic and pharmacodynamic assessments .................................. 65 
8.2 
Primary assessments .......................................................................................................... 71 
8.2.1 
CD32b expression for eligibility (Part B only) ...................................................................... 71 
8.2.2 
CD20 expression for eligibility (combination arm: Part A & B, Arm 2) ................................ 71 
8.3 
Secondary assessments ...................................................................................................... 71 
8.3.1 
BI-1206 Pharmacokinetics .................................................................................................. 71 
8.3.1.1 
Pharmacokinetic sampling, Part A, Arm 1 single agent BI-1206 .................................... 71 
8.3.1.2 
Pharmacokinetic sampling, Part B .................................................................................. 72 
8.3.1.3 
Pharmacokinetic sampling, Part A & B, Arm 2 (BI-1206 plus rituximab) ........................ 73 
8.3.2 
B-lymphocyte Levels - Pharmacodynamic .......................................................................... 73 
8.3.3 
Detection of anti-BI-1206 antibodies ................................................................................... 74 
8.4 
Tertiary/research assessments ........................................................................................... 76 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.5 
Storage and Shipment of Samples ...................................................................................... 77 
9 
ASSESSMENT OF SAFETY .............................................................................................. 78 
9.1 
Investigator Responsibilities ................................................................................................ 78 
9.2 
Medical Cover ...................................................................................................................... 78 
9.3 
Adverse event definitions ..................................................................................................... 78 
9.3.1 
Adverse event ..................................................................................................................... 78 
9.3.2 
Serious adverse events ....................................................................................................... 78 
9.3.3 
Suspected, unexpected, serious adverse reactions ........................................................... 79 
9.4 
Determining adverse event causality ................................................................................... 79 
9.5 
Expectedness ...................................................................................................................... 80 
9.6 
Collection of safety information............................................................................................ 80 
9.6.1 
Pre-Screening (Part B only) ................................................................................................ 80 
9.6.2 
Screening failures ............................................................................................................... 80 
9.6.3 
Eligible patients ................................................................................................................... 80 
9.6.4 
Follow-up of AEs and SAEs ................................................................................................ 81 
9.6.5 
Other safety information of interest ..................................................................................... 81 
9.7 
Reporting of SAEs to the Pharmacovigilance Department, CDD ........................................ 81 
9.7.1 
Events exempt from being reported as SAEs to the Pharmacovigilance Department ....... 81 
9.8 
Recording of adverse events and serious adverse events in eCRFs.................................. 82 
9.9 
Urgent safety measures ....................................................................................................... 82 
9.10 
Pregnancy ............................................................................................................................ 82 

 
 
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10 
ASSESSMENT OF EFFICACY .......................................................................................... 84 
10.1 
Measurement of disease ..................................................................................................... 84 
10.2 
Definition of clinical benefit .................................................................................................. 84 
10.3 
Timing and type of tumour assessments ............................................................................. 84 
10.3.1 
Tumour assessment for CLL patients ............................................................................. 84 
10.3.2 
Tumour assessments for patients with lymphomas (other than Waldenström’s 
macroglobulinemia)........................................................................................................................... 86 
10.3.3 
Tumour assessments for patients with Waldenström’s macroglobulinaemia ................... 87 
10.4 
Tumour response ................................................................................................................. 88 
10.4.1 
Response categories for CLL patients ............................................................................ 88 
10.4.2 
Response categories for lymphoma patients (except those with Waldenström’s 
macroglobulinaemia) ........................................................................................................................ 88 
10.4.3 
Response categories for Waldenström’s macroglobulinaemia patients ......................... 89 
10.4.4 
Recording of response in the eCRF ................................................................................ 89 
11 
PATIENT WITHDRAWAL BEFORE COMPLETION OF TREATMENT SCHEDULE ....... 90 
12 
DEFINING THE END OF TRIAL......................................................................................... 91 
13 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................................ 92 
13.1 
Presentation of data ............................................................................................................. 92 
13.2 
Safety ................................................................................................................................... 92 
13.3 
Pharmacokinetics ................................................................................................................ 92 
13.4 
Pharmacodynamics ............................................................................................................. 92 
13.5 
Anti-tumour activity .............................................................................................................. 93 
13.6 
Overall Survival and Progression-Free Survival .................................................................. 93 
13.6.1 
Overall Survival ............................................................................................................... 93 
13.6.2 
Progression-Free Survival ............................................................................................... 93 
14 
ADMINISTRATION ............................................................................................................. 94 
14.1 
Protocol deviations and amendments ................................................................................. 94 
14.2 
Serious breach of Good Clinical Practice ............................................................................ 94 
14.3 
Completion of the electronic case report form ..................................................................... 94 
14.4 
Trial performance, monitoring, auditing and inspection ....................................................... 95 
14.5 
Source document verification .............................................................................................. 95 
14.6 
Clinical study report ............................................................................................................. 96 
14.7 
Record retention .................................................................................................................. 96 
14.8 
Ethical considerations .......................................................................................................... 96 
14.9 
Indemnity ............................................................................................................................. 96 
14.10 
Publication policy and press releases ................................................................................. 97 
15 
REFERENCES .................................................................................................................... 98 
16 
APPENDICES ................................................................................................................... 102 
16.1 
APPENDIX 1: WHO PERFORMANCE SCALE ................................................................. 102 
16.2 
APPENDIX 2: DEAUVILLE CRITERIA FIVE POINT SCALE FOR FDG-PET REPORTING
 .......................................................................................................................................... 103 
16.3 
APPENDIX 3: NEW YORK HEART ASSOCIATION (NYHA) SCALE............................... 104 
16.4 
APPENDIX 4: MEASUREMENT OF DISEASE FOR PATIENTS WITH CHRONIC 
LYMPHOCYTIC LEUKAEMIA........................................................................................... 105 
16.5 
APPENDIX 5: Criteria for disease assessment for patients with lymphoma (other than 
Waldenström’s Macroglobulinaemia) ................................................................................ 110 
16.6 
APPENDIX 6: Criteria for disease assessment in patients with Waldenström’s 
Macroglobulinaemia .......................................................................................................... 113 

 
 
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PROTOCOL SIGNATURES 
Sponsor Signature: 
The Sponsor has read and agrees to the protocol, as detailed in this document.  I am aware of my 
responsibilities as the Sponsor under the UK Clinical Trials Regulations1, the guidelines of Good Clinical 
Practice (GCP)2, the Declaration of Helsinki3, the applicable regulations of UK law and the trial protocol.  
The Sponsor agrees to conduct the trial according to these regulations and guidelines and to 
appropriately direct and assist sponsor’s staff who will be involved in the trial, and ensure that all staff 
members are aware of their clinical trial responsibilities. 
 
Name: 
 
 
 
 
 
Title 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Guideline Integrated Addendum to ICH E6: Guideline for Good Clinical Practice E6(R2) Step 4 dated 
09 November 2016. 
3 WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA 
General Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 

 
 
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PROTOCOL SIGNATURES  
Investigator Signature: 
I have read and agree to the protocol, as detailed in this document.  I am aware of my responsibilities 
as an Investigator under the UK Clinical Trials Regulations1, the guidelines of Good Clinical Practice 
(GCP)2, the Declaration of Helsinki3, the applicable regulations of the relevant NHS Trusts and the trial 
protocol.  I agree to conduct the trial according to these regulations and guidelines and to appropriately 
direct and assist the staff under my control, who will be involved in the trial, and ensure that all staff 
members are aware of their clinical trial responsibilities. 
 
Investigator's Name: 
 
 
 
 
 
Name of site: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Guideline Integrated Addendum to ICH E6: Guideline for Good Clinical Practice E6(R2) Step 4 dated 
09 November 2016  
3 WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA 
General Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 

 
 
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Study Design: 
This is a multi-centre, dose escalation, first in human (FIH) Phase I/IIa trial in patients withB-cell 
malignancy. The clinical trial is in two parts (see Figure 2): 
 
Part A: The first part of the study will be a dose escalation stage conducted in two arms: 
• 
Arm 1 (single agent): Dose escalation phase to determine the MTD or MAD and 
recommended Phase II dose (RP2D) of BI-1206 administered as a single agent. 
 
• 
Arm 2 (combination): Dose escalation phase to determine the MTD or MAD and RP2D 
of BI-1206 administered in combination with an anti-CD20 antibody. Rituximab has been 
chosen as the most appropriate anti-CD20 antibody (see Sections 2.2.6 and 2.2.7). 
Part B: The second part of the study will be a dose expansion stage conducted in two arms, in patients 
with CD32b positive (CD32b+) B-cell malignancy:  
• Arm 1 (single agent): Expansion cohort of up to 25 patients administered single agent 
BI-1206 at the RP2D as determined in Part A, Arm 1. This expansion will include a 
minimum of 12 chronic lymphocytic leukaemia (CLL) and six mantle cell lymphoma (MCL) 
patients. Part B, Arm 1 will be able to open once a RP2D in Part A Arm 1 is established. 
 
• 
Arm 2 (combination): Expansion cohort of up to 25 patients at the identified RP2D as 
determined in Part A, Arm 2 that can be given with an anti-CD20 antibody. Rituximab has 
been chosen as the most appropriate anti-CD20 antibody (see Sections 2.2.6 and 2.2.7). 
This expansion will include a minimum of 12 CLL and six MCL patients. Part B, Arm 2 will 
be able to open once a RP2D in Part A Arm 2 is established. 
Study treatment: 
BI-1206 will be administered by (intravenous) IV infusion to all patients once weekly for a period of four 
weeks, which  will be classified as induction therapy.  The starting dose of BI-1206 will be 0.4 mg 
(Week 1).  
When BI-1206 and rituximab are given in combination (Arm 2 in Parts A and B), the rituximab infusion 
will be given after the BI-1206 infusion at a dose consistent with the Summary of Product Characteristics 
(SmPC) of rituximab (375 mg/m2).  
For patients who show clinical benefit at Week 8 (as defined in Section 10.2), a period of maintenance 
therapy may be given. A patient’s maintenance therapy will be given at the same dose (single agent 
BI-1206 or combination) as their induction therapy and will be given once every eight weeks for a period 
of up to one year, following their first dose of BI-1206 or combination treatment on the trial.   
Patient Population:  
Up to 81 evaluable patients with B-cell malignancies will be entered into this trial.   
In Part A, Arm 1 (single agent dose escalation), it is estimated that up to 19 patients will be required to 
establish the BI-1206  single agent RP2D.  In Part A, Arm 2 (combination dose escalation), it is 
estimated that up to 15 patients will be required to establish the BI-1206 combination RP2D. 
In Part B, approximately 40-50 patients will be recruited in the expansion arms (to include a minimum 
of 24 CLL and 12 MCL patients). The final number of patients in the trial overall will depend upon the 
number of dose escalations required to identify the single agent RP2D (Part A, Arm 1) and the RP2D 
combination dose (Part A, Arm 2) [1]. 

 
 
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2 
INTRODUCTION 
2.1 
Background 
2.1.1 
B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia. 
The B-cell malignancies B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) 
are the most common types of haematological malignancy.  NHL is the sixth most common cancer in 
the UK, with B-cell lymphomas (including follicular lymphoma [FL], diffuse large B-cell lymphoma 
[DLBCL] and mantle cell lymphoma [MCL] among others) accounting for 85% of all NHLs [2]. In the 
United Kingdom this equates to over 10,000 cases in 2012 [3].  
The most substantial advancement in the treatment of B-cell malignancies, since the advent of 
combination chemotherapy, has been the addition of the monoclonal anti-CD20 antibody rituximab 
(Rituxan™). Since its initially reported single-agent activity in indolent lymphomas in 1997, the role of 
rituximab has expanded to cover both indolent and aggressive lymphomas.  Rituximab has become 
firmly incorporated in the therapy of patients with follicular and other indolent lymphomas in combination 
with chemotherapy.  Furthermore, maintenance therapy with rituximab is being employed to delay time 
to disease progression [4]. Undoubtedly, the advent of rituximab has contributed to the observed 
improved survival in FL [5-7]. Many patients will however demonstrate resistance to therapies that 
include rituximab or will relapse following rituximab exposure.  For these patients, effective options are 
limited.  The median survival period for patients with  relapsed and refractory B-cell lymphoma treated 
with rituximab is approximately 13 months [8, 9].  
Chronic lymphocytic leukaemia is a B-cell malignancy characterised by a progressive accumulation of 
functionally incompetent lymphocytes in the peripheral blood.  It is the most common form of leukaemia 
found in adults in the Western World, with an annual incidence of approximately six cases per 100,000, 
mainly affecting the elderly population [10]. The onset of the disease may be insidious and the clinical 
course variable. Fludarabine based combination regimens are increasingly used as initial treatment in 
a limited population of fit patients [11] and the addition of rituximab to combination chemotherapy has 
resulted in improved outcomes [12]. Despite recent developments in the treatment of CLL, challenges 
remain for those patients refractory to fludarabine regimens or to those who are not suitable for this 
treatment, where the median survival is approximately 12 months [13]. 
Despite recent therapeutic advances, CLL remains incurable and there is a clinical need for new 
treatment options, in the management of advanced disease. 
2.1.2 
CD32b and BI-1206 
CD32b (also known as FcγRIIB) is a cell surface receptor whose expression in adults is restricted to 
myeloid (e.g. macrophages, dendritic, Langerhan and mast cells) and lymphoid cells (B cells); but not 
natural killer (NK) cells [14-17]. CD32b is a physiological regulator  of humoral immunity and plays a 
role in maintaining B-cell tolerance in the periphery [18, 19]. As the sole inhibitory hFcγR, CD32b 
negatively regulates immune cell responses to endogenous and therapeutic antibodies by 
counteracting signals from the activating FcγRs (CD64, CD32a, CD32c, and CD16) [20, 21]. 
Preclinical studies have shown that loss of CD32b increases the efficacy of therapeutic antibodies [16, 
17, 22]. This observation has been corroborated in the clinic where multiple studies have demonstrated 
that high CD32b expression levels correlate positively with poor prognosis and inversely with success 
of rituximab therapy in FL and MCL [23, 24]. 
 
 
 
  
 
 
 
 
  
BI-1206 is a fully human IgG1 antibody, developed by BioInvent International AB. The target antigen, 
FcγRIIB (also known as CD32b), is a single transmembrane receptor expressed on immune cells [25, 
26]. CD32b is expressed at high levels by lymphomas and leukaemias of B cell origin including MCL, 

 
 
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• 
 
 
 
 
   
 
 
 
 
 
 
  
 
2.2.4 
Safety considerations for the proposed trial 
2.2.4.1 
BI-1206 Toxicology 
BI-1206 demonstrates extremely specific binding to human FcγRIIB (hFcγRIIB, also known as CD32b) 
and does not cross react with even closely related human proteins such as FcγRIIA or FcγRIIB from 
other animal species; consequently there are no relevant animal toxicology test species available to 
evaluate the safety of this antibody.  
Studies have been performed to assess the potential for cytokine release syndrome (CRS) with BI-1206 
and despite CD32b expression being restricted to myeloid and lymphoid cells there is no evidence that 
BI-1206 is capable of inducing cytokine release from whole blood in vitro. 
 
   
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 

 
 
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A summary of the safety considerations and mitigation strategies for this trial is provided in 
Section 2.2.8. 
For additional information concerning BI-1206, please refer to the Investigator Brochure. The non-
clinical package and proposed approach for setting the starting dose for this study was discussed with 
the MHRA at a scientific advice meeting 
 
 
 
 
2.2.5 
Clinical experience (other compounds targeting CD32b) 
This proposed clinical trial is a first in human (FIH) study of BI-1206 a human IgG1 anti CD32b 
monoclonal antibody and as such there is no existing clinical experience with this product.   
In 2015 Xencor commenced evaluation of XmAb5871 a monoclonal antibody that targets CD19 with its 
variable domain and an immune inhibitory Fc domain to target FcγRIIb in patients with rheumatoid  
arthritis (RA). Initial results of a Phase Ib/II, randomised, double-blinded, placebo-controlled study in 
patients with RA have been reported [33]. Patients received six IV infusions of XmAb5871 or placebo 

 
 
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on an every 14 day schedule.  In Part A, 30 RA patients were randomised to placebo or XmAb5871 in 
four consecutive dose cohorts of 0.3, 1, 3, or 10 mg/kg.  After completion of Part A, 27 patients with 
active RA were enrolled in an extension cohort, Part B, to receive either 10 mg/kg XmAb5871 or placebo 
in a 2:1 ratio. A total of 57 patients were randomised; 40 patients received at least 1 dose of XmAb5871. 
The peripheral B cell count decreased ~40% from baseline after the first dose in all XmAb5871 cohorts 
and did not decrease further with subsequent doses. XmAb5871 was generally well tolerated, with two 
serious adverse events (SAEs) reported in the XmAb5871 group (infusion-related reaction, venous 
thrombosis). The most common treatment-related adverse events in the XmAb5871 group were 
nausea, vomiting or diarrhoea which occurred only during the first infusion in 25% of patients. Two 
subjects experienced infusion reactions with hypotension (both at 10 mg/kg) and were discontinued. 
The nature and severity of these infusion reactions were consistent with those reported for other 
monoclonal antibody therapies.  The researchers concluded XmAb5871 administered over 12 weeks 
was  generally well tolerated.  Although the trial was not powered to show a significant difference in 
efficacy results between XmAb5871 and placebo, sufficient efficacy trends were seen to warrant 
continued clinical development of XmAb5871 in autoimmune diseases. 
The only other CD32b targeted antibody currently being evaluated in clinical trials at the time of writing 
this protocol appears to be the CD32b x CD79b Dual Affinity Re-Targeting (DART®) Bi-specific 
Antibody-Based Molecule: MGD010 being developed by MacroGenics. In February 2015, MacroGenics 
initiated a Phase I study in healthy volunteers with  this agent (Clinical trials.gov identifier 
NCT023760360).   
No other trials have been conducted using a CD32b targeted monoclonal antibody, however the use of 
monoclonal antibodies (such as rituximab) in the treatment of B-cell malignancies is routine practice 
and a number of trials have been performed or are ongoing using fully human or humanised IgG1 
antibodies similar to BI-1206.  
For further details on other compounds targeting CD32b or any other trials that have been developed 
to investigate BI-1206, refer to BI-1206 Investigators Brochure (IB). At the start of the clinical trial, the 
information referenced from the IB was current. Updates to the IB will not be reflected in this section so 
refer to the current version of the IB for up to date information. 
2.2.6 
Background on rituximab 
The choice of rituximab (and approved biosimilars,  see Section 2.2.7) as the combination agent for this 
study has been made in the context of a clinical landscape for treatment of B-cell malignancies that is 
rapidly evolving. Notably the third generation anti-CD20 antibody, obinutuzumab, has shown promising 
results in clinical trials [34, 35].  Obinutuzumab has received EMA approval for use as a first line 
treatment for CLL in combination with chlorambucil [36, 37] but it is not currently available in the UK for 
treatment of relapsed/refractory CLL or for the treatment of other  B-cell malignancies. Additionally, the 
mechanisms by which the efficacy of rituximab is reduced have been much better elucidated than for 
obinutuzumab[38]. Rituximab has therefore been chosen as the most appropriate anti-CD20 antibody 
for use in combination at the start of this study.  
 
The human anti-CD20 monoclonal antibody (mAb) rituximab was the first mAb approved for cancer 
immunotherapy, and has been widely administered to patients with B-cell cancers including FL, DLBCL, 
CLL, and MCL. Currently, rituximab is approved in Europe as induction therapy in combination with 
chemotherapy for patients with Stage III-IV FL who are previously untreated, as well as maintenance 
therapy in those responding to induction therapy; it is also approved as monotherapy for patients who 
are chemoresistant or are in their second or subsequent relapse after chemotherapy.  Rituximab is also 
approved for the treatment of patients with CD20 positive diffuse large B-cell non-Hodgkin’s lymphoma 
in combination with CHOP (cyclophosphamide, vincristine and doxorubicin) chemotherapy. In 
lymphoma the standard rituximab dose is 375 mg/m2.  In CLL, rituximab is approved for the treatment 
of patients with previously untreated and relapsed/refractory CLL at a standard dose of 500 mg/m2.  
 
For the purposes of this clinical trial, rituximab will be classed as an investigational medicinal product 
(IMP) and all patients recruited in Arm 2, including CLL patients, will be treated with a standard rituximab 
dose of 375 mg/m2. 

 
 
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The toxicities associated with rituximab are described in the SmPC for this agent (included in the IB 
Package). Based on data for patients with NHL and CLL from clinical trials and from post-marketing 
surveillance, the most frequently observed adverse events in patients receiving rituximab are infusion-
related reactions (such as infusion reaction, cytokine release syndrome [CRS] and tumour-lysis 
syndrome [TLS] ) which occur in >50% of patients, and are predominantly seen during the first infusion, 
usually in the first one to two hours following the start of administration.  The incidence of infusion-
related symptoms decreases substantially with subsequent infusions and is less than 1% after eight 
doses of the drug.  Infectious events (predominantly bacterial and viral) occurred in 30 to 55 % of 
patients during clinical trials in patients with NHL and in 30 to 50 % of patients with CLL.  The most 
frequently reported or observed serious adverse drug reactions were, infusion-related reactions 
(including CRS and TLS), infections and cardiovascular events. Other common undesirable effects 
associated with rituximab include: neutropenia, leucopenia, plus febrile neutropenia and 
thrombocytopenia, angioedema, pruritus, rash and alopecia, nausea, fever, chills, asthenia, headache 
and decreased IgG levels. Of note, results of the PRIMA trial examining long term maintenance therapy 
with rituximab did not demonstrate a significant decrease in IgG levels with long-term maintenance 
therapy of rituximab. 
2.2.7 
Rituximab Biosimilars 
Rituximab was first marketed in Europe under the brand name MabThera®. More recently, rituximab 
biosimilars have been launched (e.g. Rixathon® and Truxima®). It should be noted rituximab biosimilars 
may be used in this clinical trial (Sponsor must be notified prior to use) since they are licensed for 
use in the same indications and have the same expected safety profile as the originator product 
MabThera®. Therefore, any reference to rituximab throughout this protocol refers to both the originator 
product, MabThera® or an approved rituximab biosimilar. 
For additional information concerning rituximab (or rituximab biosimilar), please refer to the SmPC 
specific to the brand used. 
The rituximab SmPC included in the IB Package supplied for use in this trial is defined as the reference 
safety information (RSI) for all brands of rituximab used in this trial. 
2.2.8 
Expected safety profile for BI-1206 ± rituximab 
Based on preclinical experience with BI-1206 alone and in combination with anti-CD20 antibodies (such 
as rituximab), emerging clinical data from the ongoing CRUKD/16/001 trial, reported clinical data 
regarding XmAb5871 and clinical experience of rituximab therapy, the potential toxicities associated 
with BI-1206 ± rituximab therapy could include the following: 
• 
Infusion related reactions including CRS are a known, common side-effect of rituximab 
treatment and are an expected side effect of BI-1206 treatment. Symptoms could include rash, 
fever, rigors, bronchospasm, and hypotension. All patients will receive supportive care including 
pre-medication (see Section 5.9.2) and will be monitored before during and after infusion.  
• 
Side effects resulting from lymphodepletion and/or depletion of immune effector cells, 
notably infections related to neutropenia and/or lymphopenia. Neutropenia is considered 
unlikely based upon the results of preclinical studies undertaken in two murine models that 
expressed hCD32b and hCD20 under the control of human promoters and on a mCD32b null 
background. These models demonstrated that BI-1206 ± rituximab selectively depleted B cells 
preferentially to other lymphoid or myeloid lineage cells. In the event these AE do manifest it is 
anticipated they will be readily manageable in the context of advanced B-cell malignancies. 
Haematology assessments conducted during the trial will include assessment of white blood 
cells (WBC) with differential count (eosinophils, basophils, neutrophils and lymphocytes) and B 
cell levels. Furthermore, patients who are Hepatitis (Hep) B, C or Human Immunodeficiency 
Virus (HIV) positive, or who have an active, ongoing infection or an active, known or suspected 
autoimmune disease will not be eligible for trial participation.  
• 
Effects on blood pressure, Blockade of CD32b by BI-1206 could theoretically lead to 
treatment related changes in blood pressure. Blood pressure will be regularly monitored during 
the course of the trial and will be managed as required in line with local practice. 

 
 
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• 
Thrombocytopenia/platelet count decreased. 
Included due to reported clinical data for the CRUKD/16/001 study. Laboratory test results are 
regularly monitored during the course of the trial and will be managed in line with local practice. 
Please see current version of IB for rate of occurrence. 
 
• 
Elevated transaminases. 
Included due to reported clinical data for the CRUKD/16/001 study. Laboratory test results are 
regularly monitored during the course of the trial and will be managed in line with local practice. 
Please see current version of IB for rate of occurrence. 
• 
Ocular toxicity BI-1206 binding to the eye or spinal cord is unlikely given the limited potential 
that antibodies have to cross the blood brain barrier. However given their, albeit remote, 
potential to occur eye examinations have been included in the schedule of events to allow for 
assessment throughout study treatment. See Section 5.9.3 . 
• 
Tumour-lysis syndrome (TLS) is a known, side effect of mAb therapy. Patients will be 
risk-assessed for TLS and receive supportive care as described in Section 5.9.1  
• 
Autoimmune disease. From the observational studies in a murine CD32b-/- transgenic model 
it has also been noted that CD32b inhibition is tolerated but there are certain, as yet 
unelucidated, genetic factors that can give rise to a profound autoimmune state in susceptible 
animals. The relevance of these factors to the proposed trial is expected to be limited by virtue 
of the short duration of CD32b inhibition by BI-1206 in vivo as compared to the life-long and 
total absence of CD32b in CD32b-/- mice.  Patients with active autoimmune disease (as defined 
in the protocol) will be excluded from the trial. Autoimmune assessments will be performed as 
clinically indicated.   
• 
Potential for an anti-drug antibody (ADA) response. Despite the reported occurrence of 
MAHA in the murine toxicology studies the potential for neutralising antibodies directed against 
BI-1206 in trial patients is expected to be minimal by virtue of the fact that BI-1206 is a fully 
human antibody. Experience with other approved humanised therapeutic antibodies suggest 
an incidence of ADA ranging from <1% to over 30% [39, 40]. Neither the frequency nor the 
impact of these ADA (if observed) on the efficacy or tolerability of BI-1206 can be predicted 
ahead of the trial but will be monitored during the trial. 
• 
Combination effects. The undesirable effects of rituximab are generally manageable when 
used as monotherapy or in combination with cytotoxic chemotherapy.  In combination with BI 
1206 these effects may be present and could be exacerbated.  Patients will be monitored 
closely for exacerbation of known or suspected toxicities and for unexpected combination 
adverse effects 
2.3 
Rationale for the proposed trial 
For the majority of patients, B-cell NHL and CLL are incurable using existing therapeutic approaches.  
Although anti-CD20 directed therapy has improved outcomes, very many patients still relapse following 
treatment or are refractory to it and therefore additional novel non-cross resistant therapies are required. 
The human CD20 mAb rituximab was the first mAb approved for cancer immunotherapy, and has been 
widely administered to patients with B-cell cancers including FL, DLBCL, CLL and MCL [41] in addition 
to an expanding number of autoimmune conditions. While rituximab is efficacious in FL and DLBCL, 
improving overall survival, only modest responses are seen in CLL and MCL. Furthermore, even in 
rituximab-responsive lymphoma sub-types some individuals show initial resistance or subsequently 
develop it. 
 
BI-1206 is a fully-human anti-CD32b (FcγRIIB) antagonistic antibody that, in addition to directly killing 
tumour cells, is thought to work by prolonging anti-CD20 antibody residence on the cell membrane of 
cancer cells, preventing them from becoming resistant to treatments such as rituximab.  It is anticipated 
that BI-1206 will have appreciable single agent activity but that the main likely clinical use will be in 
combination with rituximab and other sensitive antibodies preventing their internalisation by FcγRIIB 
and thereby augmenting their activity. Consequently, the clinical trial has been designed to allow 

 
 
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A starting dose of 0.4 mg provides a safety margin of more than 3,000-fold in relation to the GLP 
toxicology study and a 10-fold margin of safety over the ED10 value established in the in vivo PKPD 
study. BI-1206 has been shown to have no agonistic activity and at low doses BI-1206 is likely to 
undergo rapid clearance due to target mediated drug disposition. Therefore the selected starting dose 
is believed to be justifiable based on the large multiple of safety it offers over the animal studies; 
receptor occupancy not being sufficiently high to impede physiological function and B cell depletion  
being minimised by virtue of rapid clearance of the drug product at low doses. 

 
 
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3.2 
Design of the clinical trial 
This is a multicentre, first in human (FIH), open label dose escalation trial, Phase I/IIa study in patients 
with B-cell malignancies. The clinical trial is in two parts (see Figure 2); 
 
Part A: The first part of the study will be a dose escalation stage conducted in two arms: 
 
• 
Arm 1 (single agent): Dose escalation phase to determine the MTD or MAD and 
recommended Phase II dose (RP2D) for evaluation of BI-1206 as a single agent.  
 
• 
Arm 2 (combination): Dose escalation phase to determine the MTD or MAD and RP2D of 
BI-1206 administered in combination with an anti-CD20 antibody. Rituximab has been chosen 
as the most appropriate anti-CD20 antibody (see Sections 2.2.6 and 2.2.7). 
 
Part B: The second part of the study will be a dose expansion stage conducted in two arms:   
• 
Arm 1 (single agent):  Expansion cohort of up to 25 patients with CD32b+ B-cell malignancies 
administered single agent BI-1206 at the RP2D as determined in Part A, Arm 1. This expansion 
will include a minimum of 12 chronic lymphocytic leukaemia (CLL) and 6 mantle cell lymphoma 
(MCL) patients.  
Part B, Arm 1 will be able to open once a RP2D in Part A Arm 1 is established.  
 
• 
Arm 2 (combination): Expansion cohort of up to 25 patients with CD32b+ and CD20+ B-cell 
malignancies at the RP2D that can be given with an anti-CD20 antibody as determined in Part 
A. This expansion will include a minimum of 12 CLL and 6 MCL patients.  
Part B, Arm 2 will be able to open once a RP2D in Part A Arm 2 is established.  
In both Parts A and B, if a patient shows evidence of clinical benefit (as defined in Section 10.2), they 
will be eligible to continue on maintenance therapy.  Maintenance therapy will consist of a single dose 
of BI-1206 ± rituximab every eight weeks for up to one year after Week 1 of induction therapy. 
It is expected that up to 81 evaluable patients will be required to complete this trial, with the final number 
depending on the number of dose levels explored.   
 
 

 
 
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Figure 2: Schematic of trial design 
Boxes outlined in red are those to which the DLT definition described in Section 3.3 applies.  
 
 
 
 

 
 
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3.3 
Definition of dose limiting toxicity 
Some of the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) definitions are derived 
from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.02.  Please note that not all of the events described as DLTs are fully supported by NCI 
CTCAE but are formed by amalgams of different events in order to assist with assessments of adverse 
events. 
The definition of DLT applies to both the single agent and combination dose escalation arms (Part A of 
the study [boxes outlined in red in Figure 2]). 
A DLT is defined as a highly probably or probably BI-1206 or rituximab-related AE occurring during 
the four weeks of induction treatment and up to one week post the fourth infusion of BI-1206 (i.e. by 
Day 28/Week 5) which fulfils one or more of the following criteria: 
• 
Neutropenia or neutrophil count decrease Grade 4 (ANC < 0.5 x 109/L) for >10 days duration 
*see note despite growth factor support 
• 
Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented 
infection) with Grade 3 or 4 neutropenia (absolute neutrophil count [ANC] <1.0 x 109/L) and fever 
≥38.5ºC).  
• 
 Infection (documented clinically or microbiologically) with Grade 3 or 4 neutropenia (ANC <1.0 x 
109/L) 
• 
Thrombocytopenia or platelet count decrease Grade 4: a) for 5 days*see note, or b) associated 
with active bleeding, or c) requiring platelet infusion 
• 
Grade 3 or 4 non-haematological toxicity.  This includes Grade 3 and 4 biochemical AEs as 
DLTs.   
 
EXCLUDING: 
o Grade 3 or 4 nausea or vomiting in patients who have not received optimal treatment with 
anti-emetics 
o Grade 3 or 4 diarrhoea in patients who have not received optimal treatment with anti-
diarrhoeals 
o Alopecia 
o Grade 3 infusion related reactions 
o Transient, asymptomatic Grade 3 biochemical abnormalities if agreed by the Sponsor and 
the study team, including the Chief Investigator 
• 
Event with a fatal outcome. 
*Note: In the event of a Grade 4 neutropenia or Grade 4 thrombocytopenia, a full blood count 
must be performed at least on Day 10 (Day 5 for thrombocytopenia) after the onset of the event 
to determine if a DLT has occurred.  The investigator must continue to monitor the patient 
closely until resolution to Grade 3 or less. Please See Section 5.9.4 ‘Management of 
thrombocytopenia (Grade 4)’ for further details. 
Refer to Section 5.3 for detail concerning intra-patient dose escalation and DLT. 
DLTs defined above will be considered for the purposes of dose escalation decisions; however, should 
cumulative toxicity become apparent this will also be taken into consideration when determining either 
the next dose level or the RP2D 
Should any change be made to the grade or causality of an AE during the trial that may alter its DLT 
status, the Sponsor must be informed immediately as this may affect dose escalation decisions. 
 

 
 
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3.4 
Definition of maximum tolerated dose  
3.4.1 
Part A, Arm 1:Single-agent dose escalation 
If two out of up to six patients at the same dose level experience a DLT as defined in Section 3.3, this 
dose level of BI-1206 will be considered the maximum administered dose level (MAD) and no further 
patients will be treated at this dose level. In this case, the maximum tolerated dose (MTD) will be 
determined as a dose level below the MAD, which could be a dose previously administered or an 
intermediate dose between a dose already administered and the MAD. This MTD will be agreed 
following the review of all the relevant toxicity data between the Sponsor and the study team, including 
the Chief Investigator.   
The MAD could also equal the MTD in the event that dose escalation is stopped before two DLTs are 
observed at a given dose level due to the expectation that higher dose levels would be too toxic to 
administer to patients, or if the 800 mg dose level is reached. 
The RP2D in Part A, Arm 1 which will be used in Part B, Arm 1 of the clinical trial, will be determined 
by the Sponsor, Chief Investigator and Principal Investigators, following review of all relevant 
pharmacokinetic/pharmacodynamic (PK/PD) and clinically relevant toxicity data for all patients entered 
onto the trial in Part A Arm 1, and the identified MTD or MAD. All significant toxicities and available data 
from Part A, Arm 2 and data from any other trials investigating BI-1206 will also be considered in the 
determination of the RP2D. 
3.4.2 
Part A, Arm 2: Combination dose escalation  
The MTD and MAD of BI-1206, when given in combination with rituximab and will be defined as above 
(Section 3.4.1).  
The MAD could also equal the MTD in the event that dose escalation is stopped before two DLTs are 
observed at a given dose level due to the expectation that higher dose levels would be too toxic to 
administer to patients, or if the 800 mg BI-1206 dose level is reached. The MTD and MAD of BI-1206 
in combination with rituximab (at a fixed dose 375mg/m2) may be different to that of the single agent 
BI-1206 in Part A, Arm 1. 
The RP2D from Part A, Arm 2 which will be used in Part B (Arm 2) of the clinical trial, will be determined 
by the Sponsor, Chief Investigator and Principal Investigators, following review of all relevant PK/PD 
and clinically relevant toxicity data for all patients entered onto the trial in Part A Arm 2, and the identified 
MTD or MAD.  All significant toxicities and available data from the Part A Arm 1 and data from any other 
trials investigating BI-1206 will also be considered in the determination of the RP2D. 
 
3.5 
Patient evaluability 
3.5.1 
Response 
All patients who meet the eligibility criteria, receive at least one administration of mAb (BI-1206 
with/without rituximab) as part of this trial, have a baseline assessment of disease and at least one 
repeat disease assessment will be evaluable for response. 
3.5.2 
Safety 
All patients receiving at least one administration of mAb (BI-1206 with/without rituximab) as part of this 
trial will be evaluable for safety.  
3.5.3 
Single Agent Dose escalation decisions (Part A, Arm 1) 
Patients treated during the Part A, Arm 1 dose escalation phase of the trial who either receive four 
administrations of BI-1206 or experience a DLT will be evaluable for dose escalation and/or cohort 
expansion decisions in Part A, Arm 1.  

 
 
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Patients who receive less than 80% of their total planned induction doses (total across the four 
administrations) but complete the DLT period (Week 5) are not evaluable for dose escalation decisions 
(unless they have experienced a DLT).   
Data from all patients who receive less than 4 doses of BI-1206 (single agent) and any available data 
from Part A, Arm 2 (if opened) will also be reviewed and taken into consideration at dose decision 
meetings. Data from any other trials investigating BI-1206 will also be considered in the dose escalation 
decisions. 
For patients who do not receive the total full dose, please see Section 6.2.5.6 for decision making on 
continuation of treatment. Section 5.9.6 ‘Dose delays/treatment discontinuation’ also offers guidance 
for re-challenging patients post related AE observation.  
3.5.4 
Combination dose escalation decisions (Part A, Arm 2) 
The starting dose for BI-1206 in Part A, Arm 2 will not exceed the highest dose of single agent of 
BI-1206 that has been safely administered in Part A, Arm 1 (at the time of opening Part A, Arm 2), and 
which is deemed clinically appropriate to combine with rituximab. The starting dose in Part A, Arm 2 will 
be determined at a dose decision meeting following review of a completed cohort in Part A, Arm 1. 
Once Arm 2 is opened, patients treated in the combination dose escalation cohorts who either receive 
four administrations of BI-1206 in combination with rituximab or experience a DLT will be evaluable for 
dose escalation and/or cohort expansion decisions in Part A, Arm 2.  
Patients who receive less than 80% of their total planned induction doses (total across the four 
administrations) but complete the DLT period (Week 5) are not evaluable for dose escalation decisions 
(unless they have experienced a DLT).   
Data from all patients who receive less than 4 doses of BI-1206 in combination with rituximab and 
available data from Part A, Arm 1 will also be reviewed and taken into consideration for subsequent 
dose escalations in the combination arm. Data from any other trials investigating BI-1206 will also be 
considered in the dose escalation decisions.  
For patients who do not receive the total full dose, please see Section 5.9.6 ‘Dose delays/treatment 
discontinuation’ which also offers guidance on the thresholds for re-challenging patients post related 
AE observation. 
3.5.5 
Survival 
All patients receiving at least one administration of mAb (BI-1206 with/without rituximab) as part of this 
trial will be evaluable for survival (OS and PFS) regardless of whether they subsequently receive other 
anti-cancer treatments. Please see Section 7.5.2. 
3.6 
Study duration 
Following completion of recruitment to each escalation arm (single agent or combination) in Part A, the 
data will undergo review and assessment by the Sponsor. The Sponsor will confirm the decision to  
progress to Part B of trial and the respective expansion arm (Arm 1 single agent or Arm 2 combination) 
will open to recruitment. The single agent (Arm 1) and combination (Arm 2) expansion cohorts in Part 
B may open and progress independently of each other. The Sponsor will confirm when recruitment to  
each of the expansion cohort is complete.   
The number of patients recruited to the dose escalation arms of the study could increase in the event 
that additional cohorts are required to investigate intermediate doses of BI-1206.   

 
 
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4.1.2 
Exclusion Criteria 
1.  
Allogenic bone marrow transplant within 12 months prior to the first dose of BI-1206 or presence 
of chronic graft versus host disease. 
2.  
Patients with clinically active leptomeningeal or central nervous system lymphoma/leukaemia. 
3.  
Patients who receive doses of prednisolone >10 mg daily (or equipotent doses of other 
corticosteroids) are not eligible for the study unless administered as pre-medication.  
During the screening period, doses of up to 20 mg per day may be given but the dose must be 
reduced to 10 mg/day by Week 1 Day 1.  See Sections 5.9.2 and Section 5.10 regarding allowable 
pre-medication and conditions for steroid use 
4.  
Known or suspected hypersensitivity to study drugs. 
5.  
Cardiac or renal amyloid light-chain (AL) amyloidosis. 
6.  
Patients who have received radiotherapy, endocrine therapy*, immunotherapy, chemotherapy or 
investigational medicinal products during the previous 4 weeks before treatment, must discuss 
with the CI and Sponsor to agree the appropriate interval (if required) between prior therapy and 
commencement of BI-1206. The wash out duration will be compatible with the clinical context 
within which previous medication had been used. Patient must also have recovered from therapy 
related toxicity.  
* exceptions to endocrine therapy are noted in exclusion criteria #13 and #19. 
7.  
Ongoing toxic manifestations of previous treatments.  Exceptions to this are alopecia or certain 
≤Grade 2 toxicities, which in the opinion of the Investigator and the Sponsor should not exclude 
the patient. 
8.  
Ability to become pregnant (or already pregnant or lactating). However, those female patients 
who have a negative serum or urine pregnancy test before enrolment and agree to use two forms 
of contraception (one highly effective form plus a barrier method) [oral, injected or implanted 
hormonal contraception and condom; intra-uterine device and condom; diaphragm with 
spermicidal gel and condom] or agree to sexual abstinence4, for four weeks before entering the 
trial, during the trial and for twelve months after completing treatment are considered eligible.  
9.  
Male patients with partners of child-bearing potential (unless they agree to take measures not to 
father children by using a barrier method of contraception [condom plus spermicide] or to sexual 
abstinence effective from the first administration of BI-1206 or rituximab on the study, throughout 
the trial and for twelve months afterwards. Men with partners of child-bearing potential must also 
be willing to ensure that their partner uses an effective method of contraception for the same 
duration for example, hormonal contraception, intrauterine device, diaphragm with spermicidal 
gel or sexual abstinence4). Men with pregnant or lactating partners should be advised to use 
barrier method contraception (e.g. condom plus spermicidal gel) to prevent exposure to the foetus 
or neonate. 
10.  
Major thoracic or abdominal surgery from which the patient has not yet recovered. 
11.  
At high medical risk because of non-malignant systemic disease including infection. 
12.  
Known to be serologically positive for hepatitis B, hepatitis C (hepatitis C antibody positive 
patients are eligible providing PCR for viral RNA is negative) or human immunodeficiency virus 
(HIV).   
 
 
 
4 Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
 

 
 
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13.  
Patients with an active5 autoimmune disease (not including CLL auto-immune disease).  Patients 
with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger will be permitted to participate. 
14.  
Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart 
Association [NYHA] Section 16.3 Appendix 3), history of clinically significant cardiac ischaemia 
or clinically significant history of cardiac arrhythmia in the past 6 months.  
For events that are deemed to be not clinically significant and have occurred in the last 6 months, 
Investigator must discuss with CI and Sponsor to confirm eligibility. 
15.  
Patients for whom rituximab is contraindicated due to severe previous hypersensitivity or any 
other reason (Arm 2 in Parts A & B [combination arms] only). 
16.  
Ongoing infection requiring treatment with antibiotics, antifungals or antivirals. Prophylactic use 
of antibiotics, antifungals or antivirals will not exclude patients. 
17.  
Any other condition which in the Investigator’s opinion would not make the patient a good 
candidate for the clinical trial. 
18.  
Is a participant or plans to participate in another interventional clinical study, whilst taking part in 
this Phase I/IIa study of BI-1206.  Participation in an observational study would be acceptable. 
19.  
Current malignancies of other types, with the following exceptions: 
- 
Adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or 
squamous cell carcinoma of the skin.  
 
- 
Asymptomatic prostate cancer without known metastatic disease, with no requirement 
for therapy or requiring only hormonal therapy (either past or continuing) and with normal 
prostate-specific antigen for >1 year prior to start of study therapy are eligible for the trial.  
 
- 
Current or prior malignancy which could affect compliance with the protocol or 
interpretation of results. Patients with curatively-treated non-melanoma skin cancer, non-
muscle-invasive bladder cancer, or carcinomas-in-situ are generally eligible. 
 
4.2 
Patient enrolment 
Before enrolling the patient in the trial, the Investigator or designated representative should determine 
the eligibility of the patient during the trial screening period.   
Eligible patients must be enrolled in the electronic data capture (EDC) system by site staff and then 
registered by the CDD before they start treatment with BI-1206 ±rituximab. Eligible patients will be 
allocated a study number by the EDC system during the enrolment process. The CDD will send 
confirmation of the patient registration, including the assigned dose level and assigned treatment arm 
(single agent or combination), to the Investigator following enrolment of the patient. Study treatment 
may only be administered after this confirmation has been received. 
 
5 History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid 
syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or 
glomerulonephritis (Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement 
hormone will be eligible as will be patients with controlled Type I diabetes mellitus on a stable dose of insulin). Patients with 
eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis 
are excluded) are eligible for the study provided all of following conditions are met: 
• Rash must cover < 10% of body surface area 
• Disease is well controlled at baseline and requires only low-potency topical corticosteroids 
• No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months 
 

 
 
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5 
TREATMENT 
5.1 
Selection of the Phase I starting dose and schedule 
5.1.1 
Rationale for starting dose BI-1206 and rituximab 
BI-1206 (single agent) will be given at a starting dose of 0.4 mg, please refer to Section 2.3.1 for 
rationale.  
The BI-1206 dose levels are flat doses given in units of mg for each cohort, whereas the rituximab 
doses are adjusted for the body surface area (BSA) of each patient and given in units of mg/m2.  
The dose(s) of rituximab used in Part A & B of the study will be a fixed dose of 375 mg/m2 based upon 
the approved dose of rituximab.  
For the purpose of this trial, all patients including CLL will receive 375 mg/m2 for every rituximab infusion 
for consistency. The proposed weekly dosing schedule with BI-1206 and rituximab is in line with the 
rituximab SmPC standard of care for patients who receive rituximab alone.  The 8 weekly maintenance 
therapy schedule is at a frequency in line with rituximab administration post chemotherapy and will only 
be given if patients are showing clinical benefit as defined in Section 10.2. 
Single agent BI-1206 (Arm 1) will be initiated first in Part A and BI-1206 in combination with rituximab 
(Arm 2) may start once the intrapatient dose escalation cohort (Cohort 1) in Arm 1 has been completed.   
The starting dose level for BI-1206 in Part A, Arm 2 will not exceed the highest dose of BI-1206 that 
has been safely given as a single agent in Part A, Arm 1 and deemed safe to be given in combination, 
following review in the Dose Decision Meeting (see Section 5.3). This will allow assesment of any single 
agent BI-1206 toxicity at the specified dose level to decide if it would be clinically appropriate to start 
the combination arm (Part A, Arm 2)  
Once the combination dose escalation arm (Arm 2) is opened, both arms will run in parallel but 
independently, to determine RP2D of single agent BI-1206 in Part A, Arm 1 and RP2D of BI-1206 in 
combination with rituximab in Part A, Arm 2 (see Sections 5.4 and 5.5).  
The RP2D of BI-1206 in the relevant arm (single agent or combination) needs to be established in Part 
A before the respective expansion cohort in Part B of the trial opens to recruitment (single agent 
expansion cohort, Arm 1 and combination expansion cohort, Arm 2, see Sections 5.7 and 5.8). Arm 1 
and Arm 2 in Part B may open and progress independently of each other. 
 
5.2 
Dosing schedule/treatment schedule 
5.2.1 
Dosing schedule/treatment schedule in BI-1206 single agent escalation phase (Part A, 
Arm 1) 
BI-1206 will be administered once weekly for four weeks, this will be classified as induction therapy.  
The starting dose of BI-1206 will be 0.4 mg given as a 30 minute (min) intravenous (IV) infusion.  
Intra-patient dose escalation will be performed in the first cohort which will consist of a minimum of 
one patient. In Cohort 1, if a patient withdraws before completing induction therapy for reasons other 
than DLT they will be replaced, following a dose review meeting at which the planned dose level for the 
replacement patient will be decided (the starting dose for this patient will be at or below a level already 
received on the study, see Section 5.4).  
Subsequent cohorts will be at doses that are approximately comparable to or above the expected 
pharmacologically active dose (PAD) determined based on the preclinical toxicology data (>60 mg).  
These cohorts will include a minimum of one patient cohorts as described in Section 5.4.  The maximum 
weekly dose of BI-1206 to be administered will be 800 mg, infusion times will vary dependent on the 

 
 
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5.2.5 
Dosing schedule/treatment schedule, maintenance therapy (Part A and Part B) 
For all patients completing induction therapy in Parts A and B, and who are deriving clinical benefit at 
Week 8 (as defined in Section 10.2), maintenance therapy may be given. A patient’s maintenance 
therapy will be the same as their induction therapy and will be given every eight weeks for up to one year 
after their first BI-1206 dose on the study (Week 1 of induction therapy).   
• 
For patients in Arm 1 in Parts A and B (single agent arms) who continue on maintenance 
therapy, the dose of BI-1206 will be continued at the level of the last dose received in their 
induction therapy. 
• 
For those patients in Arm 2 in Parts A and B (combination arms) who continue on maintenance 
therapy, these patients will continue to receive BI-1206 and rituximab at the level of the last 
dose received in their induction therapy. 
 
5.3 
Communication Plan where dose escalation (Part A) is to occur 
5.3.1 
Organisation and preparation for dose decision meetings. 
Dose decision meetings will be organised by the Sponsor for weekly review of patient data during the 
first three weeks of the intra-patient dose escalation cohort in Arm 1 only, and subsequently during or 
following Week 5 of the last patient recruited to each cohort in Arm 1 or in Arm 2. Dose decision 
meetings will be triggered and occur independently for each treatment arm. 
 
Required attendees/functional groups are as defined in the Sponsor’s SOP: Sponsor 
Pharmacovigilance (PV) representative, Sponsor Medical Sciences representative (MS), Sponsor 
Clinical Study Manager or appropriate delegate, CI and PIs with patients at their sites undergoing review 
(a nominated sub- or co-investigator may attend in the PI’s place if necessary). Optional attendees are 
Research Nurses or other relevant site staff and the following Sponsor representatives; Clinical 
Research Associates (CRAs), Clinical Study Co-ordinator (CSC), Clinical Data Manager (CDM) and, 
Project Leader (PL). PI’s who do not have patients in the cohort under review are encouraged to attend 
but not required.  
 
Prior to the dose decision meeting, the Sponsor will distribute the agenda and all necessary data to the 
meeting attendees and all study PIs if they are not available to attend the meeting, specifying which 
patients and data will form part of the review. The essential data to be reviewed to make decisions 
concerning changes in dose will be defined in the monitoring guidelines for the study. These will consist 
primarily of clinical data listings from Data Management (DM), safety data listings from PV and available 
pharmacokinetic and pharmacodynamic (PK/PD) assay data.  
 
For intra-patient dose escalation, in order to ensure that the most recent trial data is under review data 
listings will be reviewed alongside anonymised safety data signed off by the site Investigator and faxed 
or emailed from site directly.  
 
The dose decision for treatment of subsequent patients will be based upon safety data from all patients 
in a cohort after the last patient in the existing cohort completes their induction therapy and has been 
followed up for a minimum of 7 days following their fourth dose.  Data from any previous cohorts in the 
same arm and data from complete/incomplete cohorts in the other arm will also be taken into account 
in dose decision meetings. Any available data from any other trials investigating BI-1206 will also be 
considered in the dose decision meetings. 
 
5.3.2 
Areas to be discussed at dose decision meetings. 
Areas which should be discussed  at the dose decision meeting include:  
• 
Outline any relevant criteria specified by the protocol relating to changes in dose levels to the 
attendees e.g. study dose escalation scheme, dose limiting toxicity (DLT) criteria, criteria for 
expansion of cohorts (including any ≥Grade 2 related toxicity considered to be clinically relevant 
as defined in Section 5.4.2)  etc. Patients treated since the last dose review meeting including 
IMP related adverse events noted and duration of treatment.  

 
 
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• 
Assessment and agreement on any dose limiting toxicities that may have occurred and 
resulting actions.  
• 
Relevant PK and/or PD data available since the last dose decision meeting and any proposals 
to amend PK/PD scheduling based on emerging data (Section 8). In event of any changes to 
the sampling schedule, it should be noted the total blood volume and burden of the patient will 
not increase. 
• 
Any available data from any other trials investigating BI-1206.  
• 
Any additional relevant information relating to adverse events or patient safety which may have 
arisen following distribution of listings for the meeting and will therefore not be documented in 
the listings.  
• 
Any possible concern after the review of cumulative data.  
• 
Assessment and agreement on the appropriate next dose level or other action such as dose 
expansion, dose reduction or halt to recruitment.  
• 
If the next cohort should be a minimum of one patient cohort or 3+3 cohort based on the 
emerging safety data.  
• 
If it is appropriate to open the combination arm (Arm 2)  and agreement of starting dose and 
size of cohort for the first cohort based on available data from Arm 1. 
5.3.3 
Follow-up of dose decision meetings 
Following the meeting the Sponsor will prepare and disseminate minutes documenting the data 
reviewed per patient and any outcomes or decisions made. Dose limiting toxicities, SAEs, medically 
important events (as specified by the protocol) and suspected unexpected serious adverse reactions 
(SUSARs) discussed will be documented in the minutes and listed by patient. If changes to these 
emerge as part of the review and discussion the minutes will reflect these and any actions to be taken 
as a result. Dose decision meeting minutes will be distributed by the Sponsor to the CI, all study PIs 
and any other relevant site staff. 
If due to exceptional circumstances, the CI is not able to attend the dose review meeting, the meeting 
minutes will be sent to the CI by email who will respond to confirm agreement with the dose decision 
and cohort size prior to recruitment of the next patient to the relevant cohort.  
The outcome of the dose review will also be approved by the Sponsor’s Head of Medical Sciences 
before recruitment of the next patient to the relevant cohort. Patients can only be registered and treated 
on the study following email confirmation from the Sponsor to the site of the agreed dose level and 
assigned treatment arm (single agent or combination) for the specific patient.  
5.3.4 
Dissemination of Safety data between dose decision meetings 
Safety information relating to SUSARs will be collected and provided to the MHRA and Ethics 
Committee as outlined in Section 9. Where the Sponsor becomes aware of significant relevant safety 
information (such as a DLT or clinicially relevant ≥Grade 2 related toxicity to expand a cohort from a 
minimum of one patient to 3+3 cohorts) during treatment of patients on the study, this will be 
communicated to all PIs and relevant site staff by email as soon as is reasonably possible. Updates 
regarding the DLT assessment and actions to be taken will also be provided by email where needed 
with follow-up phone-calls where required. 
 
5.4 
BI-1206 single agent dose escalation scheme (Part A, Arm 1) 
The weekly doses to be administered to each cohort are shown below (Table 1). Intermediate doses 
may be examined, e.g. a dose between 400 mg and 800 mg could be chosen for further investigation 
based on a review of the emerging safety data but in any event, dose increases will not exceed those 
described below.  Intermediate dose levels will only be explored if deemed clinically appropriate after 
review of a completed cohort in Arm 1 and agreed in a dose decision meeting (see Section 5.3). The 
maximum weekly dose to be administered will be 800 mg. 
An accelerated dose escalation scheme will be used in the initial dose levels which will occur in a 
minimum of one patient.  Intra-patient dose escalation will be permitted until either a DLT is reported or 
the dose reaches 100 mg, which is above the expected PAD determined based on the preclinical 
toxicology data (>60 mg).   

 
 
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Please refer to Section 5.3 for details of the communication plan and process for dose escalation review 
and dissemination of information. In Cohort 1, if a patient withdraws before completing induction therapy 
for reasons other than DLT they will be replaced, following a dose review meeting with the Sponsor and 
CI at which the planned dose level for the replacement patient will be decided. The replacement patient 
would start treatment at a dose level that the previous patient has already received and the dose level 
at subsequent weeks would increase to a maximum of 50 mg in line with the dose escalations described 
in Table 1, so they may receive a dose of 50 mg for more than one week.  
 
The decision to dose escalate between cohorts will be based on the four weeks (one week after the 
Induction Therapy Week 4 dose) safety data from patients in the current cohort and all available safety 
data from previous cohorts. 
 
 

 
 
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Table 1: Proposed single agent dose escalation schedule (subject to revision based upon 
emerging safety data; Part A, Arm 1) 
Cohort Number 
Total 
BI-1206  
Dose 
(mg)  
Cohort 
sizeb 
Notes 
1  
(pt1 wk 1) 
0.4 
1 
 
 
 
 
 
1  
(pt1 wk 2) 
2 
 
 
 
 
 
1  
(pt1 wk 3) 
10 
 
 
 
 
 
 
 
1  
(pt1 wk 4) 
50 
 
 
 
 
 
 
Assess patient for safety for 7 days post Week 4 infusion before next cohort or before each patient if Cohort 1 
consists of more than one patient 
Follow the last patient for safety in each cohort to 7 days post Week 4 infusion before the next cohort is opened to 
recruitment (all cohorts going forward) 
2 
100 
1a - 3 
 
 
 
3 
200 
1a - 3 
 
 
 
4 
400 
1a - 3 
 
 
 
 
 
 
5 
800 
3 + 3 
 
 
 
a Assumes that no clinically relevant ≥Grade 2 related toxcity has occurred 
bAssumes that no DLTs are encountered and is also dependant on number of patients that need to be replaced (if patient 
withdraws for reasons other than DLT). 
 
 

 
 
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5.4.1 
Action if DLT observed in Cohort 1 (0.4mg to 50 mg), Part A Arm 1  
Cohort 1 will consist of a minimum of a single patient, with intra patient dose escalation permitted up to 
a maximum weekly dose of 50 mg. Safety data will be reviewed on a weekly basis prior to the next 
planned dose and a decision to dose-escalate will be made based on this data. 
If a DLT is observed at or below a dose of 50 mg the cohort will be expanded to up to six patients at 
the dose level at which the DLT is first identified (the most recent dose prior to onset of the event 
identified as a DLT).  If one out of the six patients experiences DLT, intra-patient dose escalation will 
cease but standard dose escalation will continue; subsequent cohorts will be expanded to three 
patients. If two or more out of the six patients experiences a DLT, decisions about future patients will 
be made in accordance with Figure 4. 
 
5.4.2 
Dose escalation and action if clinically relevant ≥Grade 2 related toxicity observed at 
dose levels from Cohort 2 onwards, Part A Arm 1 
From Cohort 2 onwards, all cohorts will include a minimum of one patient (see Figure 4) 
 
• 
In the first patient recruited, any episode of clinically relevant ≥Grade 2 related toxicity would 
trigger cohort expansion to a minimum of 3 patients. 
 
• 
Clinical relevance of the related toxicity will be determined by review and agreement between 
the relevant Investigator, Chief Investigator and Sponsor according to the following definition:  
The test of clinical relevance is that the adverse event in question would cause the Investigator 
to re-evaluate the risk-benefit assessment of continuing therapy for the patient experiencing 
the event and to conclude that on a balance of probabilities, the risk-benefit ratio could be 
materially worsening 
• 
The decision to expand a minimum of one patient cohort to a 3+3 cohort following a clinically 
relevant ≥Grade 2 related toxicity will be documented and distributed by the Sponsor to all 
Investigators as per Section 5.3.4. The decision may occur outside the dose decision meetings 
as it is dependent on when the event/s occurs. The assessment of a clinically relevant toxicity 
will end at Week 5 (same as the DLT period i.e.one week post fourth infusion). 
• 
As per Section 9.4, related toxicity will be highly probably, probably and possibly related to 
BI-1206 (or rituximab in Arm 2). 
It should be noted that dose escalation and cohort size decisions will be made based on data from 
completed cohorts in the single agent arm (Arm 1); available data from the combination arm (Arm 2) 
will be also be reviewed and considered in the Arm 1 dose decision meetings. Please refer to 
Section 5.3 for details of the communication plan, the process for dose escalation review and decision 
making and the dissemination of information. 
All patients in a cohort must have completed induction therapy and 7 days post the fourth infusion for 
dose-escalation to the next cohort to occur. The second patient in any cohort will not commence 
treatment until after the first patient in that cohort has completed two infusions of BI-1206; the third 
patient in any cohort will not commence treatment until after the second patient in that cohort has 
completed one infusion of BI-1206. 
 
 
 

 
 
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Figure 4: Dose escalation decision-making and action if clinically relevant ≥Grade 2 related 
toxicity and/ or DLT observed at dose levels from Cohort 2 (Part A, Arm 1)  
  
5.4.3 
Dose escalation and action if a DLT observed at dose levels from Cohort 2 onwards, 
Part A, Arm 1 
If one instance of DLT is observed in any cohort, the cohort will be expanded to include up to six 
patients. If one out of the six patients experience a DLT then dose escalation will continue, and the next 
cohort will consist of a minimum of 3 patients as decribed in Figure 4. If no DLTs are seen in 3 patients, 
further escalations will continue as 3+3 cohorts. 
No additional patients will be added to a cohort after a second DLT is observed. Should DLT occur in 
more than two out of three or two out of six patients in a cohort, the previous dose level may not be the 
most appropriate RP2D. Intermediate dose levels may be explored if deemed clinically appropriate after 
review of a completed cohort, see Section 3.4. 
Please refer to Section 5.3 for details of the communication plan and process for dose escalation review 
and dissemination of information. The proposed dose escalation scheme in Table 1 may be modified 
in light of emerging safety data following consultation between the Sponsor and the CI.  
  
5.5 
BI-1206 and rituximab escalation cohorts (Part A, Arm 2) 
The combination escalation arm (Part A, Arm 2) will open to recruitment following review of a completed 
single agent dose level in Arm 1. The starting dose for BI-1206 in combination with rituximab will be 
agreed at a dose decision meeting based on data from completed cohorts in the single agent arm. The 
combination dose will not exceed the highest dose of BI-1206 safely given (≤1 DLT in up to six patients) 
as a single agent to date and must be deemed clinically appropriate to combine with rituximab. 

 
 
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The dose(s) of rituximab will be 375 mg/m2 based upon the approved dose of rituximab. For the purpose 
of this trial, all patients including CLL patients will receive 375 mg/m2 for every rituximab infusion for 
consistency. 
Once the combination escalation arm (Part A, Arm 2) is opened, it will run in parallel to the single agent 
escalation arm (Part A, Arm1) but dose decisions and cohort size decisions will be made independently 
for each arm. Combination cohorts will also be a minimum of one patient and dose escalation/cohort 
expansion decision-making as described in Sections 5.4.2 and 5.4.3 will also apply to the combination 
escalation cohorts. 
It should be noted that dose escalation decisions will be based on data from the combination arm 
(Arm 2) with available data from the single agent arm (Arm 1) and any other ongoing trials with BI-1206 
also being reviewed and considered. Please refer to Section 5.3 for details of the communication plan 
and process for dose escalation review and dissemination of information. 
All patients in a cohort must have completed induction therapy and 7 days post the fourth infusion 
without DLT for dose-escalation to the next cohort to occur. The second patient in any cohort will not 
commence treatment until after the first patient in that cohort has completed two infusions of BI-1206 
in combination with rituximab; the third patient in any cohort will not commence treatment until after the 
second patient in that cohort has completed one infusion of BI-1206 and rituximab. 
In Part A, Arm 2 the dose level of rituximab will be fixed and the dose level of BI-1206 will be explored 
in the escalation phase in order to establish the BI-1206 MAD or MTD and RP2D in combination with 
rituximab, see Section 3.4. 
The BI-1206 doses explored in Part A, Arm 2 may follow the dose levels outlined in Table 1 but will be 
dependent on emerging data. Intermediate BI-1206 doses may be examined, e.g. a dose between 
400 mg and 800 mg could be chosen for further investigation based on a review of the emerging safety 
data but in any event, dose increases will not exceed those described in Table 1. Intermediate dose 
levels will only be explored if deemed clinically appropriate after review of a completed cohort in Arm 2 
and agreed in dose decision meeting (see Section 5.3).  
The maximum weekly BI-1206 dose to be administered will be 800 mg in both Arm 1 and Arm 2. 
 
5.6 
Cohort expansion at maximum tolerated and/or maximum administered dose 
(Part A, Arm 1 and Arm 2) 
Cohorts may be expanded to six patients as described in Sections 5.4.1 and 5.4.2. If only one out of 
six patients experiences a DLT, dose escalation will continue. If two out of up to six (i.e. between two 
and six) patients experience a DLT dose escalation will stop and this dose will be defined as the 
maximum administered dose (MAD). At least six patients will be treated at a dose below the MAD to 
define the MTD. 
The MAD could also equal the MTD in the event that dose escalation is stopped before two DLTs are 
observed at a given dose level due to the expectation that higher dose levels would be too toxic to 
administer to patients, or if the 800 mg dose level is reached. 
The single agent RP2D in Part B, Arm 1 of the proposed clinical trial will be determined by the Sponsor, 
CI and PIs, following review of all available PK/PD and clinically relevant toxicity data for all patients 
entered onto the trial in Part A (Arm 1 and Arm 2), and the identified MTD or MAD.   
The combination RP2D in Part B, Arm 2 of the proposed clinical trial will be determined by the Sponsor, 
CI and PIs, following review of all available PK/PD and clinically relevant toxicity data for all patients 
entered onto the trial in Part A (Arm 1 and Arm 2), and the identified MTD or MAD.   

 
 
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Any available data from other trials investigating BI-1206 will also be considered in defining the RP2D 
in Arm 1 and Arm 2. The RP2D for each arm may be the same or different but it will not exceed 800 mg 
as per Table 1. 
 
5.7 
Single agent BI-1206 expansion cohort (Part B, Arm 1) 
On determining the RP2D of single agent BI-1206 in Part A, Arm 1, up to 25 further patients will be 
enrolled into an expanded single agent cohort (Part B, Arm 1) at that dose level for further evaluation 
of toxicity and efficacy. This cohort will include a minimum of 12 chronic lymphocytic leukaemia (CLL) 
and six mantle cell lymphoma (MCL) patients.   
 
5.8 
BI-1206 and rituximab combination expansion cohort (Part B, Arm 2) 
On determining the RP2D of BI-1206 in combination with rituximab in Part A, Arm 2, up to 25 further 
patients will be enrolled into an expanded combination cohort (Part B, Arm 2) at that dose level for 
further evaluation of toxicity and efficacy. This cohort will include a minimum of 12 CLL and six MCL 
patients.   
5.9 
Dose modifications  
Protocol defined dose modification criteria for treatment in Part B will be reviewed and updated if 
required based on the emerging clinical data from Part A of the trial. 
For the combination arms in Parts 1 and 2, BI-1206 and ritxumab should be administered independently 
of any dose delay to the other agent. The decision to continue with either agent alone, if the other has 
to be withdrawn, should be at the discretion of the investigator depending on whether there is clinical 
advantage to continuing with treatment. 
5.9.1 
Risk assessment for and management of tumour lysis syndrome 
Prior to each infusion (BI-1206 or rituximab), patients should be risk assessed for tumour lysis syndrome 
(TLS) and treated with adequate hydration and administration of uricostatics starting 48 hours prior to 
the start of the infusion as well as prednisolone if appropriate. This may require a delay in the patient 
receiving treatment. 
5.9.2 
Management of infusion related reactions 
Pre-medications as specified of oral paracetamol 1 gram and IV chlorphenamine 10 mg will be 
administered as standard at least 30 minutes prior to each BI-1206 or rituximab infusion. Hydrocortisone 
100 mg IV or dexamethasone 8 mg IV may also be administered prior to administration of BI-1206 or 
rituximab infusion, at the same time as the chlorphenamine and paracetamol at the Investigator's 
discretion. Alternative premedication steroids, antihistamine and analgesics (painkillers) may be used 
if clinically indicated according to Investigator’s judgement, after discussion and approval from the CI 
and Sponsor. 
Patients should be carefully monitored for signs of CRS or acute infusion reaction during each infusion, 
e.g. signs such as urticaria, wheeze, hypotension, tachycardia, dyspnoea (shortness of breath), etc. 
This monitoring period will last up to at least 4 hours after the first BI-1206 infusion and at least 30 
minutes after every subsequent BI-1206 infusion. For rituximab infusions, this monitoring period will last 
up to at least 30 minutes after the end of each infusion.   
Should patients develop any of the symptoms described above despite pre-medication (with or without 
steroids), the infusion must be stopped immediately and IV hydrocortisone 100 mg or IV 
dexamethasone 8 mg administered. Alternative steroid treatment may be used if clinically indicated 
according to Investigator’s judgement. Once the reaction has stopped, infusion of BI-1206 or rituximab 
may restart with a 50% reduction in the rate of infusion. If IV hydrocortisone/dexamethasone is 

 
 
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insufficient, the reaction may be further managed with antipyretics, anti-histamines, intra-venous 
sodium chloride (NaCl), bronchodilators and additional glucocorticoids as required and as per local 
protocols. 
Patients who are to receive rituximab (Arm 2 in Parts A and B): For those patients whose 
lymphocyte counts are >25 x 109/L it is recommended to administer prednisone/prednisolone 100 mg 
IV shortly before rituximab infusion to decrease the rate and severity of acute infusion reactions and/or 
CRS. A reduced infusion rate should be considered for these patients for the first infusion and a split 
dosing over two days during the first week, i.e. rituximab 100mg IV Day 1 (Week 1 only) followed 
by rituximab 375mg/m2 minus 100mg IV Day 2 (Week 1 only). The rate of infusion and confirmation of 
split dosing in subsequent weeks must be agreed with the Sponsor and CI prior to commencement of 
treatment. 
Patients who are to receive BI-1206 (All patients): If IRRs are seen following Week 1 infusion, the 
Investigator may consider spilt dosing over 2 days for subsequent infusions (from Week 2 onwards) to 
decrease severity of reactions in subsequent doses.The rate of infusion and confirmation of split dosing 
must be agreed with the Sponsor and CI prior to commencement of treatment. 
Patients with severe, life threatening reactions to BI-1206 or rituximab must not receive further infusions 
and should be withdrawn from the trial. 
Investigators have the option to split the dose of BI-1206 at any point from (and including) Week 1 
onwards based on clinical presentation of the patient at study entry and the Investigator’s clinical 
judgement of what is likely to be most appropriate for an individual patient and collective study 
experience with giving BI-1206 to date. Once the decision to split a dose is taken, the patient must 
continue to receive split dosing for the duration of their study participation. 
For rituximab, as per normal clinical practice, Investigators have the option to revert back to single 
dosing after splitting the dose.  
 
5.9.3 
Management of ocular toxicities 
As described in Section 2.2.8, preclinical studies noted evidence of FcγRIIB expression on the eye. Eye 
examinations have therefore been included in the schedule of events to allow for assessment 
throughout study treatment. 
If any grade of toxicity affecting the macula and/or affecting patient’s vision is observed then study 
treatment must be stopped and intensified monitoring implemented as per the site ophthalmologist’s 
recommendation.  Restarting treatment will be considered on discussion with the PI, CI, ophthalmologist 
and Sponsor. 
If NCI-CTCAE v4.02 Grade 1 ocular toxicity is observed which does not affect the macula or patient’s 
vision, study treatment may continue with intensive monitoring as per site ophthalmologist’s 
recommendation. 
If Grade 2 or above ocular toxicity is observed, not affecting the macula or patient’s vision, treatment 
must be stopped and intensified monitoring should be implemented as per site ophthalmologist’s 
recommendation.  Restarting treatment will be considered on discussion with the PI/CI, ophthalmologist 
and Sponsor 
 
5.9.4 
Management of thrombocytopenia (Grade 4) 
If Grade 4 thrombocytopenia is noted post infusion: 
• 
Perform daily (or as frequent as possible) full blood count (FBC) monitoring until resolution to 
Grade 3 or less.  

 
 
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• 
If this is not possible, then the patient should be monitored closely until resolution to Grade 3 
or less AND as a minimum a FBC must be performed on the 5th day from when Grade 4 
thrombocytopenia was first noted (unless there is documented resolution to Grade 3 before 
that point). 
• 
Toxicity must be resolved to at least Grade 2 or lower before the next dose can commence; 
therefore a delay in treatment may be required. 
 
5.9.5 
Dose reductions 
Patients who experience a DLT (as defined in Section 3.3) that resolves to Grade ≤1 or recovers to 
baseline within 7 days of the start of the DLT may recommence treatment (with BI-1206 ± rituximab), 
with the agreement of the PI, CI and Sponsor. The dose should be reduced to the previous dose level 
and rate of infusion may be reduced and agreed with the Sponsor and Investigator prior to treatment.  
If the AE has not resolved to Grade ≤1 or recovered to baseline within 7 days, the patient will be taken 
off-study and treatment shoud be discontinued. If the patient experiences another DLT, either the same 
or different toxicity, further treatment is not permitted. 
 
5.9.6 
Dose delays and Treatment Discontinuation 
In this trial, if a patient experiences one or more of the following toxicities related (highly probably, 
probably or possibly) to BI-1206 or rituximab treatment, the treatment for that patient should be 
delayed/modified as described.  Please refer to Section 5.9.2 for actions to be taken in event of a 
reaction during the infusion. 
Grade 1 or 2 toxicity (haematological or non-haematological) other than ocular toxicity or 
infusion related reaction. 
No dose modifications or delays are necessary; refer to Section 5.9.3 for guidance on management of 
ocular toxicity, Section 5.9.2 for guidance on management of infusion related reactions.  
Grade 3 or 4 Haematological toxicity that does not meet DLT definition as described in 
Section 3.3 
Treatment with BI-1206 and rituximab, if applicable should be delayed until recovery of the patient’s full 
blood count to Grade ≤ 2. Treatment may be delayed for a maximum of three weeks.  Patients 
experiencing ≥Grade 3 haematological toxicity lasting longer than three weeks must not receive further 
treatment with BI-1206 or rituximab. Growth factor support is permissible during this period. 
Grade 3 or 4 Non-haematological toxicity that does not meet DLT definition as described in 
Section 3.3 
Refer to Section 5.9.3 for guidance on management of ocular toxicity, Section 5.9.2 for guidance on 
management of infusion related reactions.  For other events, treatment with BI-1206 and rituximab, if 
applicable, should be delayed until recovery of the AE(s) to Grade ≤ 2.  Treatment may be delayed for 
a maximum of three weeks.  Patients experiencing ≥Grade 3 toxicity lasting longer than three weeks 
must not receive further treatment with BI-1206 or rituximab.   
Please see Sections 6.2.5.6 and 6.2.11.2 for further information relating to patient withdrawal from 
treatment. 
 
Modifications for logistical reasons i.e. Bank Holidays 
For logistical reasons (i.e. bank holidays), treatment may be delayed by a maximum of one week or 
treatment may be given one day earlier (decrease time between dosing to six days during induction 
therapy) following agreement by CI and Sponsor, prior to commencing treatment. 
 

 
 
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5.9.7 
Duration of treatment 
In the induction phase, treatment should continue for four weeks unless (a) the patient asks to be 
withdrawn, (b) there is evidence of disease progression, (c) the patient is experiencing unacceptable 
toxicity or (d) the Investigator feels the patient should be withdrawn for any other reason.  Other reasons 
are listed in Section 11.  
The duration of treatment may be extended if dose interruptions/ delays result in an extended induction 
period. 
5.9.8 
Maintenance therapy 
Patients who are deriving clinical benefit (as defined in Section 10.2) may continue at the end of the 
induction therapy onto maintenance therapy for up to 1 year following their first dose of BI-1206 
treatment on the study. Maintenance therapy will cease if (a) the patient asks to be withdrawn, (b) there 
is evidence of disease progression, (c) the patient is experiencing unacceptable toxicity or (d) the 
investigator feels the patient should be withdrawn for any other reason. Other reasons are listed in 
Section 11. As BI-1206 is at an early stage of development, the long term side-effects are unknown. 
Treatment will therefore not continue beyond the one year maintenance period of this study. 
5.9.9 
Replacement of patients 
Patients who come off study due to dose limiting toxicity prior to completing four weeks of induction 
therapy will not be replaced. Patients who come off study prior to completing four weeks of induction 
therapy for any other reason will be replaced for purposes of DLT evaluation during the single and 
combination dose escalation cohorts. Once a RP2D dose has been established (BI-1206 monotherapy 
and BI-1206 + rituximab combination) patients who withdraw due to disease progression and/or 
unacceptable toxicity will not be replaced. Other withdrawn patients may be replaced, if considered 
appropriate, after discussion between the PI, CI and Sponsor. 
There may be circumstances based on the emerging data from the trial or IMP availability which result 
in a patient not being replaced. This will be documented by the Sponsor.   
5.10 Concomitant medication and treatment 
Concomitant medication may be given as medically indicated.  Details of the concomitant medication 
given must be recorded in the patient’s medical records and the electronic case report form (eCRF). 
Radiotherapy may be given concomitantly for the symptomatic control of lymphadenopathy; however 
these irradiated lesions will not be evaluable for response.  
Refer to Section 5.9.2 for details of pre-medications to be administered prior to BI-1206 and/or rituximab 
infusions. Live vaccinations are not permitted whilst on the trial; other immunisations are permitted.  
Doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) are not permitted 
whilst on the trial, other than as pre-medication where the patient is at risk of tumour lysis due to high 
tumour burden,  where it has been approved by the CI and Sponsor as an alternative pre-medication 
or if alternative steroids are required, if clinically indicated to treat infusion related reactions as per 
Section 5.9.2. During the screening period, doses of up to 20mg per day may be given but the dose 
must be reduced to 10mg/day by Week 1 Day 1 (other than as pre-medication).  
The patient must not receive any other anti-cancer therapy or investigational drugs while on the trial.  
Participation in an observational study is allowed. 

 
 
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6 
PHARMACEUTICAL INFORMATION 
6.1 
Supply of BI-1206 and rituximab 
6.1.1 
Supply of BI-1206 
A complete certificate of analysis and a Qualified Person (QP) certification must be provided with each 
batch of the investigational medicinal product (IMP): BI-1206 and be retained in the Pharmacy File. 
For information on BI-1206 and re-ordering of supplies, contact the Clinical Research Associate 
(CRA)/Clinical Study Manager (CSM) responsible for the trial who will arrange further supplies.  
BI-1206 will be manufactured by: 
Nova Laboratories Limited 
 
 
 
 
 
BI-1206 will be stored, labelled and distributed by: 
Cancer Research UK Formulation Unit 
 
 
 
 
 
 
 
 
 
The distributor (Cancer Research UK Formulation Unit) must provide confirmation of the shipment to 
the CSM/CRA on despatch of the IMP. 
The primary and secondary packaging for the IMP will be labelled according to Eudralex Volume 4: 
Annex 13 ‘Investigational Medicinal Products’ of the European Union guide to Good Manufacturing 
Practice (GMP).   
Prior to despatch of BI-1206 to the clinical trial site a label detailing the Investigator’s name and site 
name and address will be added by the Manufacturing Authorisation Holder in accordance with GMP 
to the secondary packaging (box).  
An example of the approved label(s) can be found in the TMF and site Pharmacy File.  
6.1.2 
Supply of rituximab 
Rituximab will be considered an IMP as patients will not be taking the drug before enrolment on this 
trial. Rituximab is licensed for clinical use in the UK and EU and is marketed under several different 
brand names and will be used in accordance with the respective SmPC. The investigators will be 
responsible for their own supply of rituximab. Prior to dispensing rituximab will be labelled by the 
Pharmacy according to Eudralex Volume 4: Annex 13 ‘Investigational Medicinal Products’ of the EU 
Guide to Good Manufacturing Practice. The label applied by Pharmacy will be approved by CR-UK and 
an example of the approved label for rituximab will be filed in the Pharmacy Folder. Sufficient quantities 
of rituximab will be dispensed to cover the prescribed dose (as per Section 6.2). 
Rituximab will be dispensed from the hospital pharmacy on a per patient basis. 

 
 
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As per Section 2.2.7, it should be noted rituximab biosimilars may be used in this clinical trial (Sponsor 
must be notified prior use). For additional information concerning rituximab, please refer to the SmPC 
specific to the brand used. Note the rituximab SmPC included in the IB Package supplied to the support 
the current clinical trial will be used as the RSI for rituximab in this trial. 
6.2 
Pharmaceutical data 
6.2.1 
Formulation of BI-1206 
BI-1206 will be supplied as a concentrate for solution for infusion (5mL fill volume) in 5 mL Type 1 clear 
glass vials with a concentration of 10 mg/mL. 
 
 
6.2.2 
BI-1206 storage conditions 
All supplies must be stored in a secure, limited access storage area. 
BI-1206 must be stored in its original packaging at 2-8°C, protected from light. 
6.2.3 
Method of preparation of BI-1206 for administration 
Good aseptic practice must be employed when preparing solutions of BI-1206 for infusion. 
 
 
 
 
 
 
 
Please refer to the Pharmacy and Drug Administration guidelines located in the Pharmacy File for 
additional guidance. 
Each vial of BI-1206 is for single use only. Any unused contents and/or vials dispensed for patient use 
must be destroyed as per local policies and accounted for as described in Section 6.3.1. 
6.2.4 
Stability and labelling of the diluted BI-1206 
After removal from the refrigerator and dilution 
, BI-1206 solution can be kept at ambient 
temperature. From a microbiological point of view, the administration should be performed as close as 
possible to the preparation of the diluted drug. For the 0.4mg dose level the diluted drug must be 
administered within 24 hours of dilution. For all other dose levels (2mg upwards) the diluted drug must 
be used within 48 hours of dilution.  Refer to the handling instructions in the Pharmacy File for further 
details. Labelling requirements for the reconstituted BI-1206 for infusion can be found in the Pharmacy 
File.  
6.2.5 
BI-1206 administration 
Before administration, the exact dosage must always be double-checked by a second suitably qualified 
person. All checks and double-checks must be documented (signed and dated) and the documentation 
must be available for the CRA/CSM to verify. 
6.2.5.1 
BI-1206 administration for 0.4 mg dose level  
BI-1206 will be administered as a slow IV infusion using a syringe driver over a fixed interval of 
30  minutes.  
6.2.5.2 
BI-1206 administration for doses from 2 mg to 10 mg  
BI-1206 will be administered as a slow IV infusion using an infusion pump over a fixed interval of 
30  minutes.  
 

 
 
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6.2.5.3 
BI-1206 administration for  the 50mg dose level 
BI-1206 will be administered as a slow IV infusion using an infusion pump at an initial rate of 50 mg/hr.  
If no adverse effects are seen the rate of infusion may be increased at 30 minute intervals, as specified 
in the Pharmacy and Drug Administration Guidelines.  
 
6.2.5.4 
BI-1206 administration at doses above 50mg  
First infusion (Week 1) 
 
BI-1206 will be administered as a slow intravenous infusion at an initial rate of 50 mg/hr.  If no adverse 
effects are seen the rate of infusion may be increased at 30 minute intervals, up to a maximum rate of 
400 mg/hr, as specified in the Pharmacy and Drug Administration Guidelines.  
 
Subsequent infusions (Week 2 onwards) 
 
BI-1206 will be administered as a slow intravenous infusion at an initial rate of 100 mg/hr.  If no adverse 
effects are seen the rate of infusion may be increased at 30 minute intervals, up to a maximum rate of 
400 mg/hr, as specified in the Pharmacy and Drug Administration guidelines.  
 
The Sponsor and Investigators will review and revise the infusion rates and may adjust these 
for subsequent cohorts in Part A and Part B.  
 
In any event, the maximum rate of infusion for BI-1206 administration on this trial is 400 mg/hr. 
  
6.2.5.5 
Pre-medications prior to antibody administration  
Refer to Section 5.9.2 for details of pre-medications to be administered prior to BI-1206 infusions.  Pre-
medications will be supplied by the hospital pharmacy. 
 
6.2.5.6 
Monitoring during infusion  
Refer to Section 5.9.2 or details of monitoring requirements during the infusion.  
If no reactions are observed, the total infusion time should be no more than 10% shorter than the 
expected time when given according to the infusion rates detailed above.  
If a BI-1206 infusion is interrupted due to an adverse event (AE) and a full dose is not given, the Sponsor 
and CI should be informed. The case should be discussed and agreement from the Sponsor and CI 
obtained regarding continuation of treatment in subsequent weeks.  
Please see Section 5.9.6 ‘Dose delays/treatment discontinuation’ which also offers guidance for re-
challenging patients post related AE observation. 
Patients with severe, life threatening reactions to BI-1206 must not receive further infusions and should 
be withdrawn from the trial. 
Following an IRR event, if the patient is unable to receive the next full dose of BI-1206 due to a 
subsequent IRR event, the Investigator should consider withdrawing the patient from further BI-1206 
treatment – this should be discussed with the Sponsor and CI. 
6.2.6 
BI-1206 Vein extravasation/accidental spillages  
BI-1206 is not a vesicant.  Vein extravasation and accidental spillages should be dealt with according 
to hospital policy.   

 
 
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6.2.7 
Formulation of rituximab 
The following text is an excerpt from the SmPC for rituximab (MabThera®). For further information 
please refer to the full text in the rituximab SmPC specific to the brand being used.  
Rituximab will be supplied as vials of 10 mL or 50mL with a 10 mg/mL concentration, for intravenous 
use after dilution. Rituximab is provided in sterile, preservative-free, non-pyrogenic, single use vials. 
6.2.8 
Storage conditions of rituximab 
All supplies must be stored in a secure, limited access storage area. 
Rituximab must be stored in its original packaging in a refrigerator (2-8ºC). Keep the container in the 
outer carton, in order to protect from light. 
Each vial of rituximab is for single use only. Any unused contents and/or vials dispensed for patient use 
must be destroyed as per local policies and accounted for as described in Section 6.3.2. 
6.2.9 
Method of preparation of rituximab for administration 
Good aseptic practice must be employed when preparing solutions of rituximab for infusion. 
The approved diluents for dilution of rituximab are sterile, pyrogen-free NaCl 9 mg/mL (0.9%) solution 
for injection or 5% D-glucose in water.   
Please refer to the SmPC specific to the brand of rituximab being used for detailed instructions on how 
to reconstitute rituximab. 
6.2.10 Stability and labelling of the diluted rituximab 
The prepared infusion solution of rituximab is physically and chemically stable for 24 hours at 2 -8°C 
and subsequently for 12 hours at room temperature, provided dilution has taken place in controlled and 
validated aseptic conditions. 
6.2.11 Rituximab administration 
Before administration, the exact dosage must always be double-checked by a second suitably qualified 
person.  All checks and double-checks must be documented (signed and dated) and the documentation 
must be available for the CRA/CSM to verify. 
Rituximab will be administered at the following rates (as per the SmPC specifc to the brand being used).  
 
First infusion 
The initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated in 50 mg/h 
increments every 30 minutes, to a maximum of 400 mg/h. 
For those patients whose lymphocyte counts are >25 x 109/L, a reduced infusion rate should be 
considered for the first infusion and dosing may be split over two days during the first week, i.e. rituximab 
100mg  IV Day 1 (Week 1 only) followed by  rituximab 375mg/m2 minus 100mg IV  Day 2 (Week 1 only). 
The Sponsor and CI must agree the required infusion rate and any split dosing requirements and 
communicate these to the investigator site before the start of treatment. 
 
 
Subsequent infusions 
Subsequent doses can be infused at an initial rate of 100 mg/h, and increased by 100 mg/h increments 
at 30 minute intervals, to a maximum of 400 mg/h. 

 
 
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Patients with severe, life threatening reactions to rituximab must not receive further infusions and should 
be withdrawn from the study. 
 
6.2.11.1 Pre-medications prior to rituximab administration  
Refer to Section 5.9.2 for details of pre-medications to be administered prior to rituximab infusions. 
Pre-medications will be supplied by the hospital pharmacy. 
 
6.2.11.2 Monitoring during infusion  
Refer to Section 5.9.2 for details of monitoring requirements during the infusion. 
If a rituximab infusion is interrupted due to an AE and a full dose is not given, the Sponsor and CI should 
be informed. The case should be discussed and agreement from the Sponsor and CI obtained regarding 
continuation of treatment in subsequent weeks. 
Patients with severe, life threatening reactions to rituximab must not receive further infusions and should 
be withdrawn from the trial. 
Following an IRR event, if the patient is unable to receive the the next full dose of rituximab due to a 
subsequent IRR event, the Investigator should consider withdrawing the patient from further rituximab 
treatment – this should be discussed with the Sponsor and CI. 
 
6.2.12  Vein extravasation/accidental spillages  
Rituximab is not a vesicant.  Vein extravasation and accidental spillages should be dealt with according 
to hospital policy.   
 
6.3 
Drug accountability 
6.3.1 
BI-1206 accountability 
Accurate records of all BI-1206 shipments, vials dispensed, and all BI-1206 returned must be 
maintained. This inventory record must be available for inspection at any time by CRAs or CSM of 
Cancer Research UK’s Centre for Drug Development (CDD). All IMP supplies are to be used only in 
accordance with this protocol and under the supervision of the Investigator. 
The Investigator undertakes not to destroy any unused or returned IMP unless authorised to do so by 
the CDD.  Any unused IMP must be destroyed according to hospital procedures and properly accounted 
for using the IMP Destruction Form and also on the IMP Accountability Record. During the course of 
the trial the CRA will check the numbers of vials of BI-1206 shipped to the centre, the number used and 
the number destroyed or returned. The pharmacy will give an account of any discrepancy. 
6.3.2 
Rituximab accountability 
Accurate records of all rituximab doses dispensed, including the brand used, expiry date and batch 
number should be recorded.  These records must be available for inspection at any time by CRAs or 
CSM.   
During the course of the trial the CRA will check the doses of rituximab prepared and administered to 
patients on this trial.  The pharmacy will give an account of any discrepancy. 
 

 
 
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7 
INVESTIGATIONS SCHEDULE 
In cases where a patient has investigations at a different hospital, for example weekly blood samples, 
then it is the Investigator’s responsibility to ensure he/she receives and reviews the reported results.  
These results must be available for source data verification (SDV). Laboratory reference ranges, 
including effective dates, and evidence of laboratory accreditation must be obtained from all laboratories 
used. 
The Investigator or delegate must inform Cancer Research UK’s CDD of any changes to the laboratory 
normal ranges or to any laboratory accreditation and provide any new documentation. 
7.1 
Pre-treatment evaluations 
Details of all evaluations/investigations for enrolled patients, including relevant dates, required by the 
protocol must be recorded in the medical records.  
Please also refer to the tabulated Schedule of Assessments in Section 7.6. 
7.1.1 
Obtaining written informed consent 
Written informed consent must be obtained from the patient before any protocol-specific procedures 
are carried out.  
The patient must be given adequate time to think about their commitment to the study.  If more than 28 
days has passed since informed consent was obtained before the start of BI-1206 dosing then the 
Investigator should consider whether repeat consent should be obtained from a patient.   
Only the PI and those Sub-Investigator(s) with delegated responsibility by the PI, and who have signed 
the Delegation Log, are permitted to obtain informed consent from patients and sign the consent form. 
All signatures must be obtained before the occurrence of any medical intervention required by the 
protocol (ICH GCP 4.8.8 and 8.3.1.2).  The date of the signatures of both the patient and the 
PI/Sub- Investigator obtaining informed consent should be the same. 
The PI or the Sub-Investigator must inform the patient about the background to the study, and present 
knowledge of the normal management of their disease and BI-1206 and rituximab (if applicable). They 
must also ensure that the patient is aware of the following points:  
• 
That treatment with BI-1206 (or, if applicable BI-1206 in combination with rituximab) is new and 
that the exact degree of activity is at present unknown, but that treating him/her will contribute 
to further knowledge. 
• 
The known toxicity of BI-1206 and rituximab, if applicable and the possibility of experiencing 
side-effects. 
• 
The potential dangers of becoming pregnant (or the patient’s partner becoming pregnant) and 
he/she has been given information about appropriate medically approved contraception. (refer 
to Section 9.10). 
• 
That he/she may refuse treatment either before or at any time during the trial and that refusal 
to participate will involve no penalty or loss of benefits to which they are otherwise entitled. 
• 
Whom to contact for answers to pertinent questions about the research and their rights, and 
also who to contact in the event of a research-related injury. 
A copy of the Informed Consent Document (ICD) must be given to the patient to keep and the original 
ICD, must be filed in the Investigator Trial File (ITF) (unless otherwise agreed that the original document 
will be filed in the medical records and a copy kept in the ITF). 
 

 
 
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7.1.1.1 
CD32b and CD20 expression testing 
Part A (CD32b testing): 
• 
As part of the main screening and consent process, the patient will be asked to provide an 
initial blood sample or historical (or routine care) biopsy sample for CD32b analysis.  
• 
The blood sample wil be taken and the archival tumour requested, post consent to the main 
study.  There is no limit on the date of  the archival tumour being tested. 
• 
Testing may also be performed on any available bone marrow or lymph node sample which is 
taken during the screening process. 
The results of this analysis is for information only.  
Part B (CD32b and CD20 testing): 
• 
Pre screening consent, as per Section 7.1.2, must be given by the patient before analysis can 
take place.  
• 
For CD32b testing, the available tissue or blood must be taken and tested with 6 months of 
main study consent. 
For CD20 testing, for patients that are refractory to rituximab, i.e either progressing whilst on 
rituximab based therapy (induction or maintenance) or progressing within 6 months of their 
last dose of rituximab, a biopsy should be performed prior to study entry to ensure that there 
is continued expression of CD20. 
The results of this analysis will inform the patient’s eligibility for the main trial.  
 
To note: For CD32b testing, patients with follicular lymphoma and any other patient group where  B 
cells are not present in the circulation, blood samples should not be provided, only tissue e.g. lymph 
node, bone marrow or any other secondary tumour sample.   
 
7.1.2 
Pre-Screening – Part B only 
Patients must give separate written informed consent before analysis of a historical biopsy sample (or 
a new blood sample, taken for CD32b (CD20 if required) positivity by immunohistochemistry or flow 
cytometry, if not previously performed. This Pre-Screening test may be performed at any point prior to 
the patient providing written informed consent for the full trial. For CD32b testing in Part B, the available 
tissue or blood must be taken and tested with 6 months of main study consent.  
CD20 expression is required for all patients receiving BI1206 and rituximab in combination.  
7.1.3 
Baseline Evaluations  
The following must be performed/obtained before the patient receives their first dose of BI-1206 or 
rituximab. Existing results such as radiological measurements may be used even where these 
investigations were performed prior to the patient’s provision of information consent for the study if they 
were performed within the required time window.  
• 
Written informed consent (as detailed in Section 7.1.1) before any protocol-specific procedures 
are carried out. Note for eligible patients, all adverse events (AEs), including serious adverse 
events (SAEs), must be monitored and recorded in the eCRF from the time the patient consents 
to any protocol-specific procedure (see Section 9 for further details).  
For Part B patients: following pre-screening consent, safety reporting is applicable as per 
Section 9.6. 
• 
Bone marrow aspirate and/or lymph node biopsy.  This can be performed for disease 
assessment purposes at the patient’s local hospital as part of their routine care. If performed 
solely for purposes of the trial, the patient must first consent to the main study. This must be 
performed/obtained within eight weeks before the patient receives their first dose. Aspirate 

 
 
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will be taken for flow cytometry analysis as detailed in Section 8.3.2 and CD32b/CD20 
confirmation of disease as described in Sections 8.2.1 and 8.2.2.  
• 
Demographic details (within four weeks before the patient receives their first dose of BI-1206 
or rituximab on study.) 
• 
Medical history including prior diagnosis, prior treatment, concomitant conditions/diseases and 
baseline symptoms, concomitant treatment (within four weeks before the patient receives 
their first dose of BI-1206 or rituximab on study).  
• 
For patients recruited in Part A: CD32b expression assessed centrally by blood, bone 
marrow sample and/or lymph node sample sent during screening assessments. 
• 
For patients recruited in Part B: Confirmation of CD32b+ disease.  Confirmed centrally by 
blood, bone marrow or lymph node biopsy sample taken within 6 months of study entry as 
described in Section 8.2.1. Note: testing of any archival sample for the sole purpose of 
determining trial eligibility should only take place once the patient has provided 
informed consent for this analysis either by signing the screening consent form or the 
main consent form for the study. If CD32b status has already been assessed at the trial 
approved laboratory according to the trial agreed method in the 6 months prior to main study 
consent, these results can be used for inclusion and there is no requirement for retest. If surgery 
is required to obtain a new lymph node biopsy sample, then tissue should be retained for 
analysis of tissue markers as described in Section 8.4.4. 
• 
For patients receiving rituximab: Confirmation of CD20+ disease; confirmed by blood, bone 
marrow or lymph node biopsy sample. In patients that are refractory to rituximab, i.e either 
progressing whilst on rituximab based therapy (induction or maintenance) or progressing 
within 6 months of their last dose of rituximab, a biopsy should be performed prior to study 
entry to ensure that there is continued expression of CD20.. Please note: if no B cells are 
present in circulation, do not send a blood sample for CD20 disease assessment. 
• 
Serum Immunoglobulins – IgA, IgM & IgG (within four weeks before the patient receives their 
first dose of BI-1206 or rituximab on study).  
• 
Beta-2-microglobulin (within four weeks before the patient receives their first dose of BI-1206 
or rituximab on study). 
• 
Radiological Disease Assessments (within four weeks before the patient receives their first 
dose of BI-1206 or rituximab on study).   
o 
Patients with CLL: Computerised tomography (CT) scan of neck, chest, abdomen and 
pelvis must be performed within four weeks before the patient receives their first dose 
of BI-1206 or rituximab on study.  
o 
Patients with Lymphoma (other than Waldenström’s macroglobulinemia): CT 
scan of neck, chest, abdomen and pelvis and a fluorodeoxyglucose positron emission 
tomography ([18F]FDG-PET) scan must be performed for those Patients with PET-avid 
disease within four weeks before the patient receives their first dose of BI-1206 or 
rituximab on study. 
o 
Patients with Waldenström’s macroglobulinemia: CT scan of neck, chest, 
abdomen and pelvis must be performed within four weeks before the patient receives 
the first dose of BI-1206 or rituximab on study.  If there is a concern regarding high 
grade transformation then a [18F]FDG-PET scan should also be performed within four 
weeks before the patient receives their first dose of BI-1206 or rituximab on study. 
o 
Patients with Waldenström’s macroglobulinemia: (within four weeks before the 
patient receives their first dose of BI-1206 or rituximab on study): a blood sample 
should be taken for assessment of serum paraprotein electrophoresis and 
immunofixation.  Please note, this serum paraprotein is also sometimes referred to as 
serum monoclonal protein IgM, but should not be confused with IgM assessed as part 
of the immunoglobulin sample described above as this is a different assessment or 
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• 
Assessment of Hepatitis B and C and HIV positivity (within four weeks before the patient 
receives their first dose of BI-1206 or rituximab on study).  
• 
Electrocardiogram (ECG) (within four weeks before the patient receives their first dose of 
BI-1206 or rituximab on study);  
• 
Female patients able to have children must have a negative result on a human chorionic 
gonadotropin (HCG) pregnancy test (serum or urine test is acceptable) within two weeks 
before the patient receives their first dose of BI-1206 or rituximab on study. 
• 
Clinical disease measurements, if applicable (i.e. patients with clinically assessable disease). 
This must be performed within one week before the patient receives their first dose of 
BI-1206 or rituximab on study.  
• 
Complete physical examination (within one week before the patient receives their first dose 
of BI-1206 or rituximab on study); 
• 
Height, weight, body surface area (BSA) (within one week before the patient receives their 
first dose of BI-1206 or rituximab on study.) 
• 
WHO performance status, temperature, seated blood pressure (BP), pulse rate and oxygen 
saturation levels (Sa02) (within one week before the patient receives their first dose of 
BI-1206 or rituximab on study);  
• 
Laboratory tests (blood/urine samples) to confirm eligibility (to be repeated, if not performed 
within one week before the patient receives their first dose of BI-1206 or rituximab on study).  
o 
Haematology – haemoglobin (Hb), platelets, white blood cells (WBC) with differential 
count (eosinophils, basophils, neutrophils and lymphocytes), CD3 T Lymphocytes, 
CD19 B lymphocytes (usually as part of TBNK or lymphocyte subset panel). 
o 
Biochemistry – lactate dehydrogenase (LDH), sodium, potassium, calcium (adjusted), 
phosphate, urea, creatinine, total protein, albumin, bilirubin, alanine aminotransferase 
(ALT) and/or aspartate aminotransferase (AST) 
o 
Urinalysis – protein and blood 
o 
Coagulation–partial thromboplastin time (PTT/APTT) and either prothrombin time (PT) 
or international normalised ratio (INR).  
• 
Eye examination performed by appropriately trained member of site staff including: slit lamp 
assessment, retinal examination and measurement of visual acuity (within four weeks before 
the patient receives their first dose of BI-1206 or rituximab on study). 
7.2 
Evaluations during Induction Therapy (Weeks 1-8) 
• Symptom-directed physical examination: if clinically indicated, a symptom-directed physical 
examination is to be performed within 24 hours prior to each BI-1206 administration and at 
Week 5. Patients in Cohort 1, Arm 1 only will also attend for this assessment at 72 hours post 
infusion at Weeks 1 to 4 (on Days 4, 11, 18 and 25). 
• WHO performance status, to be recorded within 24 hours prior to each dose of BI-1206 or 
rituximab and at Week 5.  This will also be assessed for patients in Cohort 1, Arm 1 only, 72 
hours post infusion at Weeks 1 to 4 (on Days 4, 11, 18 and 25) for dose escalation 
purposes.Temperature, pulse rate, seated BP, to be recorded within 2 hours prior to each dose 
of BI-1206 or rituximab and at Week 5.  These will also be assessed for patients in Cohort 1 at 
Day 4 of Weeks 1 to 4 (Days 4, 11, 18 and 25) for dose escalation purposes. 
• During the first BI-1206 infusion for each patient: Pulse rate, temperature and seated BP must 
be measured every 15 minutes for the first hour and then within every 30 minutes until the end 
of the infusion. Where the infusion lasts less than an hour these should be measured every 
15  minutes.  
• During second and subsequent BI-1206 infusions and all rituximab infusions for each patient: 
Pulse rate, temperature and seated BP must be measured within every 30 minutes until the 
end of the infusion.  

 
 
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• After the BI-1206 or rituximab infusions for each patient: Pulse rate, temperature and seated 
BP must be measured at 30 minutes (± 5 minutes) after the end of the infusion and, in Part A,  
Week 1 at 2 and 4 hours after the end of the BI-1206 infusion.   
In Arm 2, where BI-1206 and rituximab are given on the same day, the pulse, temperature and 
seated BP should be measured within 2 hours prior to the BI-1206 infusion, at the end of the 
BI-1206 infusion, within every 30 minutes between the infusions prior to the start of the rituximab 
infusion and at the end of the rituximab infusion. 
• For patients receiving rituximab treatment: Weight measured during screening should be 
used for BSA calculation for induction therapy.  
• Adverse events and concomitant treatments: At each visit, before each BI-1206 or rituximab 
administration, an assessment of any AE experienced since the previous visit must be made 
by the Investigator or Research Nurse and the start and stop dates of the AE together with the 
relationship of the event to treatment with BI-1206 and/or rituximab must be recorded in the 
medical records.   
All AEs must be graded according to NCI CTCAE Version 4.02. (See Section 9 for further details 
regarding AE reporting requirements).  
Any concomitant treatment must be recorded in the medical records (See Section 9 for further 
details regarding AE reporting requirements). 
• Laboratory tests: 
Haematology, biochemistry and urinalysis: must be repeated before each BI-1206  
administration (and before each rituximab administration if given on a different day to BI-1206), 
Week 1, Day 4 and at Weeks 5 and 8.  Laboratory tests can be performed up to 24 h prior to 
each infusion but results must be available and reviewed by the investigator before BI-1206 or 
rituximab is given. These will also be repeated for patients treated in Cohort 1, Arm 1 only at 
Day 4 of Weeks 1 to 4 for dose escalation purposes (Days 4, 11, 18 and 25). 
• 
Haematology: detailed in Section 7.1.3. 
• 
Biochemistry: detailed in Section 7.1.3.  
• 
Urinalysis: detailed in Section 7.1.3. 
• If split dosing is implemented, laboratory tests will be relative to the first infusion administered 
each week then as clinically indicated on the second day. 
• Beta-2-microglobulin levels will be assessed at Week 8. 
• ECG: performed if clinically indicated. 
• Eye exam: performed as described in Section 7.1.3 at Week 8 and otherwise if clinically 
indicated. 
• Serum Immunoglobulins – IgA, IgM & IgG levels will be assessed at Week 8. 
• Patients with Waldenström’s macroglobulinemia: a blood sample should be taken for 
assessment of serum paraprotein at Week 8 (electrophoresis and immunofixation) 
• Radiological disease assessments:  
• CLL Patients: CT scan of neck, chest, abdomen and pelvis will be performed at Week 8. 
• Patients with lymphomas: CT scan of neck, chest, abdomen and pelvis and for non 
Waldenströms Macroglobulinaemia patients, an [18F] FDG-PET scan if positive at baseline will 
be performed at Week 8. 
• Bone marrow aspirate and lymph node biopsy:  
• 
CLL Patients: Those patients who had positive test at baseline and who show a complete 
response on Week 8 assessments will have a sample taken for disease assessment. If a 
sample is being taken for disease assessment, then aspirate will also be taken for flow 
cytometry analysis as detailed in Section 8.3.2.  

 
 
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• 
Patients with lymphomas: Those patients who had positive test at baseline and who 
show a complete response on Week 8 assessments will have a sample taken for disease 
assessment. If a sample is being taken for disease assessment, then aspirate will also be 
taken for flow cytometry analysis as detailed in Section 8.3.2. 
• 
 
 
 
 
• Blood samples for PK analysis, will be taken at each of the time points specified in Section 8.3.   
• Pharmacodynamic blood samples for assessment of CD32b B-lymphocyte levels, 
 
 and anti-drug 
antibody levels, should be taken pre- and post treatment as described in Sections 8.3 and 8.4. 
• Oxygen Saturation levels (Sa02) to be performed pre-dose during Week 1 – 4 (induction 
therapy only) and otherwise as clinically indicated. 
7.3 
Evaluations during maintenance therapy 
For patients who demonstrate clinical benefit  (as defined in Section 10.2) at Week 8 following their 
induction therapy, further treatment with BI-1206 (± rituximab) may continue. The patient will receive the 
same dose of BI-1206 ± rituximab as they received during their induction therapy.  Starting from Week 8 
onwards (post scan results) maintenance therapy will continue every eight weeks (± 2 weeks) from the first 
maintenance dose for up to one year after the first dose of BI-1206 on the study. 
• Symptom-directed physical examination: If clinically indicated, a symptom-directed physical 
examination will be performed prior to BI-1206 administration. 
• WHO performance status to be recorded prior to BI-1206 or rituximab. 
• For patients receiving rituximab: For maintenance treatment, weight should be measured 
prior to each dose and BSA recalculated if the patient’s weight has changed by more than 10% 
from the weight used for the current BSA (i.e. weight at 1st maintenance will be compared to 
from weight measured at screening). 
• Pulse rate, temperature and seated BP must be measured within 2 hours prior to each infusion, 
within every 30 minutes during the infusion and at 30 minutes (± 5 minutes) after the end of the 
infusion  
Where BI-1206 and rituximab are given on the same day, the pulse, temperature and seated 
BP should be measured within 2 hours prior to the BI-1206 infusion at the end of the BI-1206 
infusion, within every 30 minutes between the infusions, prior to the start of the rituximab 
infusion and at the end of the rituximab infusion. 
• Adverse events and concomitant treatments: At each visit, before each BI-1206 administration, 
an assessment of any AE experienced since the previous visit must be made by the Investigator 
or Research Nurse and the start and stop dates of the AE together with the relationship of the 
event to treatment with BI-1206 and/or rituximab must be recorded in the medical records.  All 
AEs must be graded according to NCI-CTCAE Version 4.02.  Any concomitant treatment must 
also be recorded in the medical records and electronic case report form (eCRF).  
• Haematology, biochemistry and urinalysis: must be repeated before each BI-1206 
administration (and before each rituximab administration if given on a different day to BI-1206).   
• 
Haematology: See Section 7.1.3. 
• 
Biochemistry: See Section 7.1.3. 
• 
Urinalysis: See Section 7.1.3. 
• 
ECG: performed if clinically indicated. 
• 
Eye exam: performed if clinically indicated. 

 
 
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• 
Assessment of disease: 
A CT scan will be performed every 16 weeks (± 2 weeks but must be performed and reported  
before the patient’s BI-1206 infusion) and at off-study where a scan has not been performed in 
the previous 8 weeks.   
Should the Investigator assess that the patient is no longer deriving clinical benefit (as defined 
in Section 10.2) from continued maintenance therapy, the patient will be withdrawn from the 
trial.  
Patients with lymphomas: For patients who have [18F]FDG PET-avid disease at baseline 
whose CT scans show a complete response, an [18F]FDG-PET scan should be performed 
within 4 weeks of receipt of the CT scan results.  
Patients with Waldenström’s macroglobulinemia: a blood sample should be taken for 
assessment of serum paraprotein. Normal serum IgM levels should also be measured. 
• Bone marrow aspirate:  
o 
CLL Patients: Those patients who had positive test at baseline and who show a 
complete response for the first time at a disease assessment during the maintenance 
period will have a bone marrow sample taken. 
 
 
 
 
o 
Patients with lymphomas: Only those patients who had positive test at baseline and 
who show a complete response for the first time at a disease assessment during the 
maintenance period will have a bone marrow sample taken. 
 
 
 
• Pharmacodynamic blood sample for assessment of anti-drug antibody levels, should be taken 
as described in Section 8.3. 
• Blood samples for PK analysis, will be taken at each of the time points specified in Section 8.3.  
  
7.4 
Evaluations at ‘off-study’ visit 
The off-study visit will occur when a patient will no longer continue on the treatment portion of the trial 
(either induction or maintenance treatment).  This may be because of any of the reasons outlined in 
Section 11 or for patients who have completed a year of maintenance therapy.  If a patient comes off-
study following the Week 8 assessments and prior to commencing maintenance therapy the Week 8 
assessments will be considered the “off-study” assessments.  At this visit the following investigations 
where possible will be performed: 
• A symptom-directed physical examination including WHO performance status, temperature, 
pulse rate and seated BP. 
• Haematology (see Section 7.1.3). 
• Biochemistry (see Section 7.1.3). 
• Urinalysis (see Section 7.1.3). 
• Serum Immunoglobulins – IgA, IgM & IgG levels will be assessed. 
• Beta-2-microglobulin. 
• Eye examination as described in Section 7.1.3 within ± 2 weeks of the off-study visit date.  
• ECG: performed if clinically indicated. 

 
 
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• Assessment of disease (unless disease progression has been noted at an earlier assessment 
or, if the patient has gone on to maintenance therapy and an assessment has been performed 
within the previous eight weeks (56 days)):  
CT scan to assess tumour burden within ± 2 weeks of the off-study visit date; 
o Patients with lymphomas: For patients who have FDG PET-avid disease at baseline 
whose CT scans show a complete response, an FDG-PET scan should be performed 
within ± 2 weeks of the off-study visit date.   
 
o Patients with Waldenström’s macroglobulinemia: a blood sample should be taken 
for assessment of serum paraprotein. 
• Bone marrow aspirate:  
o 
CLL Patients: Those patients who had positive test at baseline and who show a 
complete response for the first time at a disease assessment at the off-study visit will 
have a bone marrow sample taken. 
 
 
  
 
o 
Patients with lymphomas: Only those patients who had positive test at baseline and 
who show a complete response for the first time at a disease assessment at the off-
study visit will have a bone marrow sample taken. 
 
 
 
• Pharmacodynamic blood sample for assessment of ADA levels, should be taken as described 
in Section 8.3. 
• Assessment of AEs. 
• Review of concomitant treatments. 
 
7.5 
Follow-up 
7.5.1 
Safety follow-up 
For eligible patients, SAE and AE monitoring will continue until 125 days after the last administration of 
BI-1206 and or rituximab on study (whichever is later) or until the patient starts another anti-cancer 
therapy (see Section 9.6). Any drug-related AEs still ongoing after this period will be followed up monthly 
until resolution to baseline or stabilisation, unless the patient starts another anti-cancer therapy. 
Should an Investigator become aware of any drug-related SAEs after this period (even if the patient 
has started another anti-cancer therapy) these must also be reported to the CDD within the expedited 
timelines in Section 9.7. 
7.5.2 
Efficacy and survival follow-up 
All patients will be followed up for survival at one year (to be calculated from the date of their first 
BI-1206 treatment) and subsequently until the last patient has completed one year of follow-up from the 
date of their first BI-1206 treatment.  
Contact will be made at  routine follow-up appointments (approximately every 16 weeks) to assess 
survival status. Information on disease status will also be captured for any patients who have not shown 
progressive disease at the time of their off-study visit.  
Survival (and if applicable, disease status) will be captured every approximately every 16 weeks from 
the off study visit, up to 1 year after the patient started study treatment and then every 6 months until 
the last patient has completed one year of follow-up from the date of their first BI-1206 treatment.

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(e) Clinical laboratory assessments should be performed prior to each BI-1206 infusion (and before each rituximab administration if given on a different day to BI-1206).  Laboratory tests can be 
performed up to 24 h prior to each infusion but results must be available and reviewed by the investigator before BI-1206/rituximab is given.  In the event of a Grade 4 neutropenia or Grade 4 
thrombocytopenia a full blood count must be performed at least on Day 5 (Day 10 for neutropenia) after the onset of the event to determine if a dose limiting toxicity has occurred.  Monitoring must 
continue until resolution to Grade 3 or less. At screening, GFR measurement may be required if there is a concern regarding the calculated creatinine clearance measurement). 
If split dosing is implemented, laboratory tests will be relative to the first infusion administered each week then as clinically indicated on the second day. 
(f) Eye exam, performed by ophthalmologist to be performed at screening, week 8 and off-study and otherwise as clinically indicated. 
(g) ECG to be performed pre-study and otherwise as clinically indicated.  
(h) For patients recruited to Part A & B, Arm 2, rituximab to be given on Day 2 post BI-1206 at Week 1. If infusion time permits, then subsequent doses of rituximab will be given on the same day 
as BI-1206. Maintenance treatment (from Week 8) will only be given if a patient is deemed eligible to continue on to maintenance treatment following Week 8 assessments. 
If split dosing is implemented, laboratory tests will be relative to the first infusion administered each week then as clinically indicated on the second day. 
(i) Maintenance therapy will only be given to those patients who demonstrate stable or responding disease and will start after the Week 8 scan results following induction therapy confirming patient 
is eligible for maintenance treatment.  Patients will receive the same dose of BI-1206 (and rituximab if received) as in their induction therapy from week 8 onwards (i.e. Week 9 or 10) and every 8 
weeks (± 2 weeks) from the first maintenance dose, for up to one year from first induction dose. 
(j) A CT scan to assess the patient’s tumour burden to be performed at Week 8 (prior to commencing maintenance therapy) and then every 16 weeks (± 2 weeks) during maintenance therapy and 
at off-study.  Patients with Waldenstrom’s macroglobulinaemia will also have serum paraprotein samples taken at these time points. If a complete response is noted, a bone marrow biopsy may 
be performed and in a lymphoma patient with PET-avid disease a FDG-PET scan will also be performed. A scan is only required at Off-study if no appropriate disease assessment has been 
performed recently (at week 8 or as required on maintenance).  
(k) Monthly follow-up required ONLY for those AEs and SAEs considered drug-related (highly probable, probable or possible) and present at off-study.  Monthly follow-up for AEs to continue until 
resolution, return to baseline, stabilisation or patient starts another anti-cancer treatment. 
(l) Day 11, 18, 25 assessments performed for patients in Cohort 1, Arm 1 only. 
(m) Bone marrow aspirate samples are used for pharmacodynamic analysis, trephine samples are to be taken where required for disease assessment, if a sample is taken as part of routine care 
within 8 weeks prior to starting on the study a repeat baseline sample is not required. After baseline, a bone marrow sample is only required for disease assessment to confirm at complete 
response. 
(n) Follow-up will continue until the last patient has completed one year of follow-up from the date of their first BI-1206 treatment. 
(o) Samples may also be taken on Day 2 and/or Day 4 after each weekly dose during weeks 1-4, emerging data will be reviewed at dose review meetings and a decision will be made for the 
following cohort as to whether or not these samples are required. Schedule may also differ between arms due to logistical reasons, refer to Study Laboratory Manual for details 
(p)  Oxygen saturation levels (SaO2) to be performed pre-study, prior to each dose during Week 1- 4 (induction therapy) and otherwise as clinically indicated 
(q)  Part A: CD32b expression assessed centrally by blood, bone marrow sample and/or lymph node sample and to be sent during screening assessments.  For Part B: CD32b positivity to be 
confirmed during pre-screening.

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8.2 
Primary assessments 
8.2.1 
CD32b expression for eligibility (Part B only) 
In order to be eligible for treatment on this study, patients in Part B must have confirmed CD32b positive 
malignancy (Table 6). Analysis of CD32b expression will be performed centrally according to agreed 
standard operating procedures (SOPs) and validated methods as follows; 
A. For all patients:  
a. If an archival lymph node biopsy is available that has been taken within 6 months of 
study entry this can be used for assessment of CD32b expression. Or if a lymph node 
biopsy is to be taken as part of routine care (not for trial purposes) within 6 months of 
study entry and patient consents to screen CD32b on this sample, this can be used for 
assessment of CD32b expression 
b. Alongside this assessment, 2mL of blood may also collected within 6 months of study 
entry. Flow cytometry analysis will be performed for CD32b expression on B cells. 
B. If no CD32b expression is noted in the blood or archival sample, 
a. A bone marrow sample will be collected within 6 months of study entry (consent to main 
study required). A flow cytometry analysis will be performed to confirm CD32b 
expression on B cells.  If no expression seen then and if appropriate ; 
b. A lymph node biopsy may be taken within 6 months of study entry (consent to main 
study required, if for trial purposes only). Immunohistochemistry (IHC) will be performed 
for CD32b and CD20.   
If no CD32b expression is noted in any of the methods above, the patient is not eligible for the trial and 
should be documented as a screen failure.   
8.2.2 
CD20 expression for eligibility (combination arm: Part A & B, Arm 2) 
In order to be eligible for treatment on the combination arm of the study, patients must have confirmed 
CD20 positive malignancy.  Analysis of CD20 expression will be performed by IHC or flow cytometry as 
per routine assessment at each site or confirmed centrally if the local assessment is not available.  
In patients that are refractory to rituximab, i.e either progressing whilst on rituximab based therapy 
(induction or maintenance) or progressing within 6 months of their last dose of rituximab, a biopsy should 
be performed prior to study entry to ensure that there is continued expression of CD20.  (Table 6). 
8.3 
Secondary assessments 
8.3.1 
BI-1206 Pharmacokinetics 
BI-1206 levels will be measured in serum by enzyme-linked immunosorbent assay (ELISA) according 
to agreed SOPs and validated methods. 
The serum concentration/time data will be analysed using non-compartmental methods. The 
pharmacokinetic (PK) parameters to be determined for BI-1206 include the maximum observed serum 
concentration (Cmax), time to reach Cmax (Tmax), and the area under the serum  concentration time curve 
(AUC), and the terminal elimination half-life (T1/2), mean residence time (MRT), total body clearance 
(CLT) and steady/state volume of distribution (VSS).  
Please refer to the Study Laboratory Manual for guidance on the handling, storage and shipment of 
samples. 
8.3.1.1 
Pharmacokinetic sampling, Part A, Arm 1 single agent BI-1206 
During intra-patient dose escalation (one patient): a 6 mL blood sample will be taken pre-infusion, at 
end of infusion (EOI) (+5 mins) and at 4 hours (±15 mins), 24 hours (±1 hour), 48 hours (±1 hour) and 
72 hours (±5 hours) post the end of infusion for every BI-1206 administration during induction therapy. 

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From Cohort 2 onwards (Part A, Arm 1): a 6 mL blood sample will be taken pre- infusion, at end of 
infusion (+5 mins) and at 4 hours (±15 mins), 24 hours (±1 hour), 48 hours (±1 hour) and 72 hours 
(±5 hours) post end of infusion following dose 1 (Week 1) and then again at the same time points prior 
to and following the patient’s fourth dose (Week 4). A 6 mL blood sample will also be taken prior to the 
BI-1206 infusions at Weeks 2 and 3 (Table 3). 
The approximate volume of blood withdrawn from each patient receiving BI-1206 alone for 
pharmacokinetic analysis will be 84-144 mL during the induction period (8 weeks) with an additional 
36 mL withdrawn over the subsequent maintenance treatment period. 
All patients who receive maintenance therapy will have 6 mL blood samples taken prior to each infusion 
(every 8 weeks). 
Table 3: Part A, Arm 1 PK sampling schedule  
Time  
Part A: Cohort 1  
(Intra-patient dose escalation) 
Part A : From Cohort 2 onwards 
Induction  
Maintenance  
Induction  
Maintenance  
Week 
1  
Week 
2  
Week 
3  
Week 
4  
Every 
8 
weeks  
Week 
1  
Week 
2  
Week 
3  
Week 
4  
Every 8 weeks  
Pre 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
EOI  
X  
X  
X  
X  
 
X  
 
 
X  
 
+4hrs 
X  
X  
X  
X  
 
X  
 
 
X  
 
+ 24hrs 
X  
X  
X  
X  
 
X  
 
 
X  
 
+48hrs 
X 
X 
X 
X 
 
X 
 
 
X 
 
+ 72hrs 
X  
X  
X  
X  
 
X  
 
 
X  
 
Total per 
patient 
(mL)  
144 
(up to 36) 
84 
(up to 36) 
For split dosing administration of single agent BI-1206: 
• 
Part A: Cohort 2 onwards: up to 18 PK time points may be taken  during the induction period 
(8 weeks) with an additional 6 PK timepoints thereafter (to include pre-infusion sampling during 
the maintenance phase). This will be approximately 108 mLs taken over the first eight weeks 
with approximately 36mLs taken post the induction phase, throughout the maintenance phase. 
• 
If split dosing is implemented, the blood volume requested will not exceed the maximum volume 
noted above i.e. 144 mL.   
• 
Please refer to the study laboratory manual for handling, adjusted sample times, sample volume 
per time point, storage and shipment of samples. 
 
8.3.1.2 
Pharmacokinetic sampling, Part B 
For patients in Part B Arm 1 (single agent expansion): a 6 mL blood sample will be taken each week 
prior to the BI-1206 infusion (every 8 weeks during the maintenance period).  The approximate volume 
of blood withdrawn from each patient in the Part B expansion (BI-1206 analysis) will be 24 mL during 
the induction period with an additional 36 mL withdrawn over the subsequent maintenance treatment 
period (Table 4). 
Table 4: Part B Arm 1, single agent expansion PK sampling schedule  
Time  
Induction Phase 
Maintenance Phase 

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8.3.3 
Detection of anti-BI-1206 antibodies 
Pre-treatment, on-treatment, and post-treatment blood samples will be analysed for anti-drug antibodies 
(ADAs) as a batch at the end of Part A, or earlier if clinically indicated. Samples from Part B will be 
analysed if clinically indicated or for publication purposes (samples may not be analysed, for example if 
the study terminates early for safety or other reasons).  
Measurement of anti-BI-1206 antibodies in serum will be performed to highlight any potential for 
immunogenicity and to understand the underlying reasons for any potential atypical PK. Analysis will be 
performed by ELISA, according to agreed SOPs and validated methods.   
A 6 mL sample of blood will be collected from all patients (Parts A & B) at the following time points: Prior 
to first dose of BI-1206 at Week 1, Week 5, Week 8, every 8 weeks during the maintenance phase and 
at the off-study visit. 
The approximate volume of blood withdrawn from each patient for this analysis will be 60 mL, 36 mL of 
which would be taken in the 1 year maintenance period (plus one 6 mL off study sample).  
 
 

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* Also pre each infusion during maintenance phase, and at off study. Decision to analyse or not to be made based 
on PK data. 
# These blood samples need to be taken prior to the first dose of BI-1206, they may be taken either during the 
screening period or prior to the BI-1206 dose at Week 1 of treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 
Tertiary/research assessments 
 
  
 
 
   
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

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8.5 
Storage and Shipment of Samples 
Blood, bone marrow and tumour samples will be taken at the local participating clinical site for either 
local storage (until the Sponsor confirms shipping requirements and receiving laboratory) or will be 
shipped to a central analysing laboratory. The Sponsor will define the local storage requirements prior 
to shipment or will coordinate the shipment of the sample to the central laboratory. Thereafter, storage 
of remaining samples will be as per Sponsor agreements with the relevant laboratories. 
Refer to Study Laboratory Manual for further details. 

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9 
ASSESSMENT OF SAFETY 
9.1 
Investigator Responsibilities 
The investigator is responsible for monitoring the safety of patients who have enrolled in the trial and for 
accurately documenting and reporting information as described in the following sections.   
9.2 
Medical Cover 
The Chief/Principal Investigator (CI/PI) is also responsible for ensuring patients have access to 24 hour 
advice and/or care.  Patients will be provided with the necessary contact numbers for both normal 
working and out of hours care. A copy of the protocol must be made available out of hours to ward staff 
and clinicians on call so that the appropriate advice may be given to the patient, the patient’s relative or 
other care giver (for example GP).  The CI/PI must ensure that should the on call clinician or ward staff 
require more advice than is in this protocol, that they have access to the Investigator or delegated 
members of the investigator’s team who can answer any questions.   
9.3 
Adverse event definitions 
9.3.1 
Adverse event 
An adverse event (AE) is any untoward, undesired or unplanned medical occurrence in a patient 
administered an investigational medicinal product (IMP), a comparator product or an approved drug.   
An AE can be a sign, symptom, disease, and/or laboratory or physiological observation that may or may 
not be related to the IMP or comparator.   
An AE includes but is not limited to those in the following list.  
• 
A clinically significant worsening of a pre-existing condition. This includes conditions that may 
resolve completely and then become abnormal again.  
• 
AEs occurring from an overdose of an IMP, whether accidental or intentional. 
• 
AEs occurring from lack of efficacy of an IMP, for example, if the Investigator suspects that a 
drug batch is not efficacious or if the Investigator suspects that the IMP has contributed to 
disease progression. 
9.3.2 
Serious adverse events 
A serious adverse event (SAE) is any AE, regardless of dose, causality or expectedness, that: 
• 
results in death; 
• 
is life-threatening*; 
• 
requires in-patient hospitalisation or prolongs existing in-patient hospitalisation (some 
hospitalisations are exempt from SAE reporting – e.g. hospital admissions planned prior to the 
patient entering the trial; overnight stays for planned procedures such a blood transfusions 
(Section 9.7.1); 
• 
results in persistent or significant incapacity or disability; 
• 
is a congenital anomaly or birth defect; 
• 
is any other medically important event.** 
*A life-threatening event is defined as an event when the patient was at substantial risk of dying 
at the time of the adverse event, or use or continued use of the device or other medical product 
might have resulted in the death of the patient. 
**A medically important event is defined as any event that may jeopardise the patient or may 
require intervention to prevent one of the outcomes listed above. Examples include allergic 
brochospasm (a serious problem with breathing) requiring treatment in an emergency room, 

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serious blood dyscrasias (blood disorders) or seizures/convulsions that do not result in 
hospitalisation. The development of drug dependence or drug abuse would also be examples 
of important medical events. 
For fatal SAEs, wherever possible report the cause of death as an SAE with a fatal outcome rather than 
reporting death as the SAE term. When available the autopsy report will be provided to the Sponsor. 
If during the course of the study, other medically important events are identified and there is a 
requirement to report specific events outside of the standard criteria, this will be communicated to site 
and the protocol will be updated to reflect this.  
Any dose limiting toxicity (DLT) must be reported to the CDD Clinical Study Manager (CSM) and CRA 
within 24 hours of site staff becoming aware of the DLT.  The CDD Pharmacovigilance Department must 
be copied into any initial email notification.  
Other reportable events that must be treated as SAEs are listed below.   
• 
Pregnancy exposure to the IMP.  Any pregnancy occurring in a patient or a patient’s partner 
during treatment with an IMP or occurring within six months of the last IMP administration, must 
be reported to the Pharmacovigilance Department in the same timelines as an SAE.  These 
should be reported even if the patient is withdrawn from the trial. 
• 
Overdose (any dose above that specified in the protocol, not necessarily intentional), with or 
without an AE. 
• 
Inadvertent or accidental exposure to an IMP with or without an AE, including for example, 
spillage of the IMP that contaminates staff.   
• 
Any AE that could be related to the protocol procedures, and which could modify the conduct of 
the trial. 
9.3.3 
Suspected, unexpected, serious adverse reactions 
A SUSAR is a suspected, unexpected, serious adverse reaction.  All AEs and SAEs will be assessed 
by Cancer Research UK’s Centre for Drug Development (CDD) for seriousness, causality and 
expectedness.  The Pharmacovigilance Department will expedite all SUSARs to the relevant Competent 
Authority/Authorities and the relevant Ethics Committee(s) within the timelines specified in legislation 
(SI 2004/1031 as amended).  
9.4 
Determining adverse event causality 
The relationship of an AE to BI-1206 and/or rituximab is determined as follows. 
Highly probable 
• 
Starts within a time related to the IMP administration and 
• 
No obvious alternative medical explanation. 
Probable 
• 
Starts within a time related to the IMP administration and 
• 
Cannot be reasonably explained by known characteristics of the patient’s clinical state. 
Possible 
• 
Starts within a time related to the IMP administration and 
• 
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
Unlikely 
• 
The time association or the patient’s clinical state is such that the trial drug is not likely 
to have had an association with the observed effect. 

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Not related 
• 
The AE is definitely not associated with the IMP administered. 
Note: Drug-related refers to events assessed as possible, probable or highly probable. 
The Investigator must endeavour to obtain sufficient information to determine the causality of the AE 
(i.e. IMP, other illness, progressive malignancy etc) and must provide his/her opinion of the causal 
relationship between each AE and IMP.  This may require instituting supplementary investigations of 
significant AEs based on their clinical judgement of the likely causative factors and/or include seeking a 
further opinion from a specialist in the field of the AE. 
The following guidance should be taken in to account when assessing the causality of an AE: 
• 
Previous experience with the IMP and whether the AE is known to have occurred with the IMP. 
• 
Alternative explanations for the AE such as concomitant medications, concurrent illness, non-
medicinal therapies, diagnostic tests, procedures or other confounding effects. 
• 
Timing of the events between administration of the IMP and the AE. 
• 
IMP blood levels and evidence, if any, of overdose. 
• 
De-challenge, that is, if the IMP was discontinued or the dosage reduced, what happened to the 
adverse reaction? 
• 
Re-challenge, that is, what happened if the IMP was restarted after the AE had resolved? 
9.5 
Expectedness 
Assessment of expectedness for BI-1206 will be made by the Pharmacovigilance Department against 
the current version of the Investigator’s Brochure (IB).  
Assessment of expectedness for rituximab will be made by the Pharmacovigilance Department against 
the current version of the SmPC submitted as part of the IB Package. 
 
9.6 
Collection of safety information 
9.6.1 
Pre-Screening (Part B only) 
Following pre-screening informed consent, any SAEs that are considered by the Investigator to be 
related to pre-screening must be reported to the Pharmacovigilance Department, CDD. 
9.6.2 
Screening failures 
For patients who fail screening, SAEs must be reported to the Pharmacovigilance Department from the 
date of main study consent until the date the patient is confirmed as ineligible. 
9.6.3 
Eligible patients 
For eligible patients, SAE and AE collection and monitoring will commence at the time the patient gives 
their written consent to participate in the trial by signing the main study consent form and will continue 
until 125 days after the last administration of BI-1206 and/or rituximab on study (whichever is later) or 
until the patient starts another anti-cancer therapy.   
Should an Investigator become aware of any drug-related SAEs after this 125 day period (even if the 
patient has started another anti-cancer therapy), these must also be reported to the CDD within the 
expedited timelines in Section 9.7. 

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9.6.4 
Follow-up of AEs and SAEs 
Follow-up of AEs with a causality of possible, probable or highly probable will continue until the events 
resolve, stabilise or the patient starts another anti-cancer therapy.   
The Pharmacovigilance Department will make requests for further information on SAEs to the trial site 
at regular intervals.  Requested follow-up information should be reported to the Pharmacovigilance 
Department in a timely manner and as soon as possible after receipt of the follow-up request.  For fatal 
or life-threatening cases, follow-up information must be reported to the Pharmacovigilance Department 
as soon as possible. 
9.6.5 
Other safety information of interest 
We will also collect information on the following situations, whether they are associated with an AE or 
not: 
• 
Abuse or misuse 
• 
Occupational exposure (to a person other than the patient, for example spilling of IMP on hands 
of nurse or splashing in the eye) 
Any occurrences of these should be reported in the same manner as SAEs (Section 9.7). 
9.7 
Reporting of SAEs to the Pharmacovigilance Department, CDD 
All SAEs and safety information of interest as defined in Section 9.6.5, regardless of causality, must be 
reported to the Pharmacovigilance Department in an expedited manner. 
SAEs should be documented on an SAE report form, using the completion guidelines provided.  
The SAE report form should be e-mailed to Pharmacovigilance Department within 24 hours of 
site staff becoming aware of the SAE. 
 
Each episode of an SAE must be recorded on a separate SAE report form. The NCI CTCAE 
Version 4.02 must be used to grade the severity of each SAE, and the worst grade recorded.  If new or 
amended information on a previously reported SAE becomes available, the Investigator should report 
this to the Pharmacovigilance Department on a new SAE report form.  
If the SAE has not been reported within the specified timeframes, a reason for lateness must be added 
on the form when sending the SAE report to the Pharmacovigilance Department. 
Should the Investigator become aware of any drug-related SAEs after the patient goes “off-study”, these 
must also be reported to the PV Department within the specified timelines specified above. 
9.7.1 
Events exempt from being reported as SAEs to the Pharmacovigilance Department 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is 
prolonged for any reason and then an SAE form must be completed.  The events must still be recorded 
in the appropriate section of the electronic case report form (eCRF). 
Prolongation of hospitalisation - Prolongation of hospitalisation without an associated adverse event 
(for example, prolonged hospitalisation while appropriate social care is set up for elderly patients). 
Admission for monitoring in patients at risk of tumour lysis syndrome - Where a patient has a high 
disease burden and is at greater risk of tumour lysis syndrome it may be appropriate to admit them for 
additional monitoring following IMP administration. Where this additional monitoring is planned prior to 
starting the infusion, this is exempt from being reported as an SAE. 

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Elective admissions – Elective admissions to hospital for procedures which were planned prior to 
entering the trial are not SAEs.  Hospitalisation for administration of the IMP according to the trial 
protocol is also exempt from being reported as an SAE, unless the patient experiences an event during 
the admission which would normally qualify as an SAE. 
Death due to disease progression- Cases of death due to disease progression do not require SAE 
reporting, unless considered related to the IMP.  
9.8 
Recording of adverse events and serious adverse events in eCRFs 
All AEs, including SAEs, must be recorded in the eCRF for eligible patients. All concomitant medications, 
including herbal medications and supplements must be recorded. Any therapy used to treat the event 
must be recorded. The eCRF will be reconciled with the safety database during and at the end of the 
trial. Therefore, the sites should ensure the data entered on the SAE report form and the data entered 
into the eCRF are consistent. The CDD Medical Advisor and the Investigator(s) will regularly review the 
safety data from both the safety and the clinical database. 
9.9 
Urgent safety measures 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect 
the patient of a clinical trial against any immediate hazard to their health or safety.  This includes 
procedures taken to protect patients from pandemics or infections that pose serious risk to human 
health.  
USMs may be taken without prior authorisation from the competent authority. The Medicines and 
Healthcare products Regulatory Agency (MHRA) and the Research Ethics Committee (REC) must be 
notified within three days of such measures being taken. 
Should the site initiate a USM, the Investigator must inform the Sponsor immediately either by: 
• 
 
  
The notification must include:  
• 
the date of the USM;  
• 
who took the decision; and  
• 
why action was taken. 
The Sponsor will then notify the MHRA and the REC within three calendar days of USM initiation.   
9.10 Pregnancy 
Female patients who become pregnant during the treatment period must be withdrawn from study 
treatment immediately. 
The Investigator must make every effort to try and ensure that a clinical trial patient or a partner of a 
clinical trial patient does not become pregnant during the trial or for twelve months afterwards. This 
should be done as part of the consent process by explaining clearly to the patient the potential dangers 
of becoming pregnant and also providing each patient with information about appropriate medically 
approved contraception. Two forms of medically approved contraception should be used, such as:   
• 
oral contraceptives and condom; 
• 
intra-uterine device (IUD) and condom; 
• 
diaphragms with spermicidal gel and condom. 

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Contraception should be effective before the patient is enrolled on the trial, throughout the trial and for 
twelve months after completing the trial. 
Alternatively the patient may agree to sexual abstinence, effective from main study consent throughout 
the trial and for twelve months afterwards. Abstinence is only considered to be an acceptable method 
of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception.  
It should be explained to the patient that if his partner is pregnant or breast-feeding when he is enrolled 
on the trial, the patient should use barrier method contraception (condom plus spermicidal gel) to prevent 
the unborn baby or the baby being exposed to the BI-1206 and in Arm 2, rituximab.  
However, if a patient or a partner of a patient does become pregnant, the reporting procedures below 
must be followed. 
Any pregnancy occurring in a patient or a patient’s partner during treatment with an IMP or occurring 
within twelve months of last IMP administration must be reported to the Pharmacovigilance Department 
within 24 hours of the site staff becoming aware of it using a Pregnancy Notification Form (provided in 
the ITF). It is the Investigator’s responsibility to obtain consent for follow-up from the patient or patient’s 
partner. In addition, the Investigator must be made aware of the need to obtain contact details for the 
patient’s partner’s General Practitioner. The Pharmacovigilance Department will follow-up all 
pregnancies for the pregnancy outcome via the Investigator, using a Pregnancy Report Form.  
The Investigator should document within the patient notes, the patient confirming consent for the 
Sponsor to collect pregnancy follow-up information. In the case that the partner of a patient becomes 
pregnant, a consent form should be provided to the patient’s partner in order to obtain consent for 
collecting privacy data, in accordance with the general data protection regulation. 
The Investigator must ensure that all patients are aware at the start of a clinical trial of the importance 
of reporting all pregnancies (in themselves and their partners) that occur whilst being treated with the 
IMP and occurring up to twelve months after the last IMP administration.  The Investigator should offer 
counselling to the patient and/or the partner, and discuss the risks of continuing with the pregnancy and 
the possible effects on the foetus.  Monitoring of the patient or partner should continue until the 
conclusion of the pregnancy, if the patient or patient’s partner has consented to this. Monitoring of the 
baby should continue until 12 months after birth, if the patient or patient’s partner has consented to this. 
 

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10 ASSESSMENT OF EFFICACY 
10.1 Measurement of disease 
Disease in patients with CLL must be measured according to the Hallek, 2008 criteria given in 
Appendix 4 [42]. For patients with lymphomas, disease must be measured according to the Cheson 
2014 criteria given in Appendix 5 [43] and for those with Waldenström's macroglobulinemia, disease 
must be assessable by the criteria stated in Appendix 6 [44] 
10.2 Definition of clinical benefit 
The determination of clinical benefit will normally require the patient to have achieved a minimum 
response of stable disease according to the response criteria defined in Appendices 4, 5 and 6 ([42], 
[43], [44]). In the exceptional event of an investigator considering that a patient is deriving clinical benefit 
despite failure to achieve stable disease or better, the case must be discussed with the CI and Sponsor 
who must agree to continuation of maintenance treatment before any such treatment will commence. 
10.3 Timing and type of tumour assessments 
A thorough evaluation of malignancy, as judged appropriate by the Investigator, and in line with the 
protocol, must be performed before a patient receives their first dose of BI-1206 or rituximab. The same 
methods that detect evaluable lesions at baseline must be used to follow these lesions throughout the 
trial. To ensure compatibility, radiological assessments used to assess response must be performed 
using identical techniques.  Imaging based evaluation is preferred to evaluation by clinical examination 
when both methods have been used to assess the anti-tumour effect of a treatment. 
All radiological assessments must be performed within four weeks before starting treatment with BI-1206 
or rituximab. The interval between the last anti-cancer therapy and these measurements must be at 
least four weeks (28 days). All clinical measurements to assess response must be performed within one 
week prior to a patient’s first dose of BI-1206.  
Copies of the scans must be available for external independent review if requested by Cancer Research 
UK’s Centre for Drug Development (CDD). 
All patients will be evaluated at baseline, four weeks after the last dose of BI-1206 or rituximab on study, 
every 16 weeks (± 2 weeks) during their maintenance phase and at off-study, unless progression occurs 
at an earlier time point, at which the patient will be evaluated instead. 
10.3.1 Tumour assessment for CLL patients 
For patients with CLL, tumour assessments will include:  
Baseline (within 28 days prior to induction therapy Week 1)  
• 
Physical examination and measurement of clinical/palpable lesions.  
• 
CT scan of neck, chest, abdomen and pelvis. 
• 
Peripheral blood sample for measurement of B lymphocytes, neutrophils, platelets and 
haemoglobin. 
• 
Bone marrow aspirate (can be performed within eight weeks of induction therapy, Week 1 and 
may have been performed as part of standard care – see Section 7.1.2). 
• 
 All areas of disease present must be documented (even if specific lesions are not going to be 
followed for response) and the measurements of all measurable lesions must be recorded 
clearly on the scan reports. Any non-measurable lesions must be stated as being present.  
 

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Evaluations at Week 8 (4 Weeks post last BI-1206 induction therapy administration)  
• 
Physical examination and measurement of clinical/palpable lesions. 
• 
CT scan of neck, chest, abdomen and pelvis.  
• 
Peripheral blood sample for measurement of B lymphocytes, neutrophils, platelets and 
haemoglobin. 
• 
Bone marrow aspirate for patients who had a positive test at baseline and who have shown a 
complete response (at least two months after last dose of study medication). 
± one week window may be acceptable for the Week 8 scans due to logistical reasons however every 
effort should be made to keep to the 8 week specified time point. Please notify CI and Sponsor if scans 
cannot be performed at Week 8. 
Evaluations every 16 weeks (± 2 weeks) during maintenance phase  
Patients who have not shown disease progression at an earlier assessment will have the following 
assessments performed:  
• 
Physical examination and measurement of palpable lesions. 
• 
CT scan of neck chest, abdomen and pelvis. 
• 
Peripheral blood sample for measurement of B lymphocytes, neutrophils, platelets and 
haemoglobin. 
• 
Bone marrow aspirate for patients who have shown a complete response and who have not 
had prior bone marrow confirmation of response. 
Evaluations at off-study 
Patients who have not shown disease progression at an earlier assessment (or if in the maintenance 
phase have not had an assessment within the previous 8 weeks) will have the following assessments 
performed:  
• 
Physical examination and measurement of palpable lesions. 
• 
CT scan of neck, chest, abdomen and pelvis. 
• 
Peripheral blood sample for measurement of B lymphocytes, neutrophils, platelets and 
haemoglobin. 
• 
Bone marrow aspirate and biopsy for patients who had a positive test at baseline and who have 
shown a complete response and who have not had prior bone marrow confirmation of response. 
All lesions measured at baseline must be measured at every subsequent disease assessment, and 
recorded clearly on the scan reports.  All non-measurable lesions noted at baseline must be noted on 
the scan report as present or absent.  
All patients, who are removed from the trial for reasons other than progressive disease, must be 
re- evaluated at the time of treatment discontinuation, unless a tumour assessment was performed 
within the previous four weeks.  
It is the responsibility of the Principal Investigator to ensure that the radiologists are aware of the 
requirement to follow-up and measure every target lesion mentioned at baseline and comment on the 
non-target lesions in accordance with Hallek criteria (Appendix 5).  
 

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10.3.2 Tumour assessments for patients with lymphomas (other than Waldenström’s 
macroglobulinemia)  
For patients with lymphomas, tumour assessments will include:  
Baseline (within 28 days of induction therapy Week 1)  
• 
Physical examination and measurement of clinical/palpable lesions. 
• 
CT scan of neck, chest, abdomen and pelvis. 
• 
[18F]FDG-PET scan (for PET-avid lymphomas only) according to the Deauville scale criteria as 
described in Appendix 2. Bone marrow aspirate (can be performed within eight weeks of 
induction therapy Week 1 and may have been performed as part of standard care – see Section 
7.1.2).  
All areas of disease present must be documented (even if specific lesions are not going to be followed 
for response) and the measurements of all measurable lesions must be recorded clearly on the scan 
reports. Any non-measurable lesions must be stated as being present.  
Evaluations at Week 8 (4 Weeks post last BI-1206 administration)  
• 
Physical examination and measurement of clinical/palpable lesions. 
• 
CT scan of neck, chest, abdomen and pelvis. 
• 
[18F]FDG-PET scan (if positive at baseline according to the Deauville scale criteria set out 
below). 
• 
Bone marrow aspirate for patients who had a positive test at baseline and who have shown a 
complete response.  
± one week window may be acceptable for the Week 8 scans due to logistical reasons however every 
effort should be made to keep to the 8 week specified time point. Please notify CI and Sponsor if scans 
cannot be performed at Week 8. 
Evaluations every 16 weeks (± 2 weeks) during maintenance phase  
Patients who have not shown disease progression at an earlier assessment will have the following 
assessments performed:  
• 
Physical examination and measurement of clinical/palpable lesions. 
• 
CT scan of neck, chest, abdomen and pelvis. 
• 
If a complete response is noted on the above assessments, then [18F]FDG-PET scan should be 
performed (if positive at baseline).  
• 
Bone marrow aspirate for patients who had a positive test at baseline and who have shown a 
complete response and who have not had prior bone marrow confirmation of response.  
Evaluations at off-study 
Patients who have not shown disease progression at an earlier assessment (or if in the maintenance 
phase have not had an assessment within the previous 8 weeks) will have the following assessments 
performed:  
• 
Physical examination and measurement of palpable lesions. 
• 
CT scan of neck, chest, abdomen and pelvis. 
• 
If a complete response is noted on the above assessments, then [18F]FDG-PET scan should be 
performed (if positive at baseline). 

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• 
Bone marrow aspirate for patients who had a positive test at baseline, who have shown a 
complete response and who have not had prior bone marrow confirmation of response.  
10.3.3 Tumour assessments for patients with Waldenström’s macroglobulinaemia  
For patients with Waldenström’s macroglobulinaemia (WM), tumour assessments will include: 
Baseline (within 28 days of induction therapy Week 1)  
• 
Physical examination and measurement of clinical/palpable lesions. 
• 
CT scan of neck, chest, abdomen and pelvis. 
• 
[18F]FDG-PET scan where there is a concern regarding high grade transformation 
• 
Bone marrow aspirate (can be performed within eight weeks of induction therapy Week 1 and 
may have been performed as part of standard care – see Section 7.1.2).  
• 
A blood sample should be taken for assessment of serum paraprotein by electrophoresis and 
immunofixation.  Please note, this serum paraprotein is also sometimes referred to as serum 
monoclonal protein IgM, but should not be confused with IgM assessed as part of the 
immunoglobulin sample also described in Section 7.1.2 as this is a different assessment. 
Normal serum IgM levels should also be measured. 
All areas of disease present must be documented (even if specific lesions are not going to be followed 
for response) and the measurements of all measurable lesions must be recorded clearly on the scan 
reports.  Any non-measurable lesions must be stated as being present. 
Evaluations at Week 8 (4 Weeks post last BI-1206 administration)  
• 
Physical examination and measurement of clinical/palpable lesions. 
• 
CT scan of neck, chest, abdomen and pelvis. 
• 
Bone marrow aspirate for patients who had a positive test at baseline and who have shown a 
complete response.   
• 
A blood sample should be taken for assessment of serum paraprotein. Normal serum IgM levels 
should also be measured. 
± one week window may be acceptable for the Week 8 scans due to logistical reasons however every 
effort should be made to keep to the 8 week specified time point. Please notify CI and Sponsor if scans 
cannot be performed at Week 8. 
Evaluations every 16 weeks (± 2 weeks) during maintenance phase  
Patients who have not shown disease progression at an earlier assessment will have the following 
assessments performed: 
• 
Physical examination and measurement of clinical/palpable lesions. 
• 
CT scan of neck, chest, abdomen and pelvis. 
• 
Bone marrow aspirate for patients who had a positive test at baseline and who have shown a 
complete response and who have not had prior bone marrow confirmation of response. 
• 
A blood sample should be taken for assessment of serum paraprotein. Normal serum IgM levels 
should also be measured. 
Evaluations at off-study 
Patients who have not shown disease progression at an earlier assessment (or if in the maintenance 
phase have not had an assessment within the previous 8 weeks) will have the following assessments 
performed:  
• 
Physical examination and measurement of palpable lesions 

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• 
CT scan of neck, chest, abdomen and pelvis 
• 
Bone marrow aspirate for patients who had a positive test at baseline, who have shown a 
complete response and who have not had prior bone marrow confirmation of response 
• 
A blood sample should be taken for assessment of serum paraprotein. Normal serum IgM levels 
should also be measured. 
All lesions measured at baseline must be measured at every subsequent disease assessment, and 
recorded clearly on the scan reports.  All non-measurable lesions noted at baseline must be noted on 
the scan report as present or absent.  
[18F]FDG-PET scans will be assessed according to the Deauville criteria five point scale [45], as detailed 
in Appendix 2 (Section 16.2).  Lesions which correspond to 1 to 3 on the Deauville scale will be 
considered PET negative for this study, lesions which correspond to 4 to 5 on the Deauville scale will 
be considered as PET positive.  
All patients, who are removed from the trial for reasons other than progressive disease, must be re-
evaluated at the time of treatment discontinuation, unless a tumour assessment was performed within 
the previous four weeks.  
It is the responsibility of the Principal Investigator to ensure that the radiologists are aware of the 
requirement to follow-up and measure every target lesion mentioned at baseline and comment on the 
non-target lesions in accordance with Cheson criteria (Appendix 5). 
10.4 Tumour response 
All patients who meet the eligibility criteria receive at least one dose of mAb (BI-1206 with/without 
rituximab) as part of this trial and who have a baseline assessment of disease and at least one repeat 
assessment will be evaluable for response. Best tumour response will be assessed and reported in line 
with the efficacy endpoints for the trial. 
Expert reviewers appointed by CDD may undertake an independent review of Investigator assessed 
tumour responses. The expert reviewers will include at least one specialist who is not an Investigator in 
the trial. In case of disagreement between the Investigator and the expert reviewers’ assessment, the 
Investigator will be informed of the expert reviewers’ assessment and both assessments reported in the 
clinical study report (CSR). The eCRF will reflect the Investigator’s opinion. 
The following categories of response will be defined, in accordance with the categories outlined in 
Appendices 4, 5 and 6 respectively 
10.4.1 Response categories for CLL patients 
Complete Response (CR) 
Complete Response (with incomplete marrow recovery) (CRi) 
Partial Remission (PR) 
Stable Disease (SD) 
Progressive Disease (PD) 
 
10.4.2 Response categories for lymphoma patients (except those with Waldenström’s 
macroglobulinaemia) 
Complete Remission (CR) 
Partial Remission (PR) 
Stable Disease (SD) 
Progressive Disease (PD) 
 
 

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10.4.3 Response categories for Waldenström’s macroglobulinaemia patients  
Complete Response (CR) 
Very Good Partial Response (VGPR) 
Partial Response (PR) 
Minor Response (MR) 
Stable Disease (SD) 
Progressive Disease (PD) 
 
10.4.4 Recording of response in the eCRF 
The applicable overall response category for each visit that includes disease assessment must be 
recorded in the eCRF. 

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11 PATIENT 
WITHDRAWAL 
BEFORE 
COMPLETION 
OF 
TREATMENT 
SCHEDULE 
The Investigator must make every reasonable effort to keep each patient on trial for the whole duration 
of the trial (i.e. until 4 weeks post the last BI-1206 administration in the induction phase). However, if 
the Investigator removes a patient from the trial or if the patient declines further participation, final 
‘off-study’ assessments should be performed ideally before any subsequent therapeutic intervention.  
All the results of the evaluations and observations, together with a description of the reasons for 
withdrawal from the trial, must be recorded in the medical records and in the electronic case report form 
(eCRF). 
Patients who are removed from the trial due to adverse events (clinical or laboratory) will be treated and 
followed according to accepted medical practice. All pertinent information concerning the outcome of 
such treatment must be recorded in the eCRF and on the serious adverse event (SAE) report form 
where necessary. 
The following are justifiable reasons for the Investigator to withdraw a patient from study treatment. 
Every effort will be made to complete safety follow-up activities unless consent to safety follow-up has 
been withdrawn by the patient. 
• 
Adverse event/serious adverse event (AE/SAE); 
• 
Withdrawal of consent; 
• 
Serious deviation from the trial protocol (including persistent patient attendance failure and 
persistent non-compliance); 
• 
Sponsor’s decision to terminate the trial; 
• 
Withdrawal by the Investigator for clinical reasons not related to BI-1206 or rituximab. 
• 
Evidence of disease progression; 
• 
Pregnancy (for female patients during the study).  
 

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12 DEFINING THE END OF TRIAL  
The ‘end of trial’ is defined as the date when: 
 
The last patient has received their last maintenance treatment, completed their off study visit, 
and follow up period for related AEs (if appliciable) and 1 year survival follow up has been 
completed for all patients. 
It is the responsibility of the CDD to inform the Medicines and Healthcare products Regulatory Agency 
(MHRA) and the Research Ethics Committee (REC) within 90 days of the ‘end of the trial’ that the trial 
has closed. 
In cases of early termination of the trial (for example, due to toxicity) or a temporary halt by the CDD, 
the CDD will notify the MHRA and the REC within 15 days of the decision and a detailed, written 
explanation for the termination/halt will be given. 
Recruitment will cease when: 
• 
The study drug (s) is/are considered too toxic to continue treatment before the required number 
of patients have been recruited.   
• 
The stated number of patients to be recruited has been reached. 
• 
The stated objectives of the trial are achieved. 
Regardless of the reason for termination, all data available for patients at the time of discontinuation of 
follow-up must be recorded in the eCRF. All reasons for discontinuation of treatment must be 
documented.   
In terminating the trial, CDD and the Investigators must ensure that adequate consideration is given to 
the protection of the patient’s interest. 
 

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13 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
The final analysis will be conducted after one of the following conditions is met: 
• 
The trial is terminated early 
• 
The end of trial as defined in Section 12 has been reached.    
13.1 Presentation of data 
Data will be presented in a descriptive fashion. Variables will be analysed to determine whether the 
criteria for the trial conduct are met.  This will include a description of patients who did not meet all the 
eligibility criteria, an assessment of protocol deviations, IMP accountability and other data that impact 
on the general conduct of the trial. 
Baseline characteristics will be summarised for all enrolled patients. Patients who died or withdrew 
before treatment started or did not complete the required safety observations will be described and 
evaluated separately. 
Treatment administration will be described for all cycles. Dose administration, dose modifications or 
delays and the duration of therapy will be described. 
13.2 Safety 
Safety data will be collected from the date of written consent.  Safety variables will be summarised by 
descriptive statistics. Laboratory variables will be described using the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.02. 
Adverse events (AEs) will be reported for each dose level and presented as tables of frequency of AEs 
by body system and by worst severity grade observed. Tables should indicate related and unrelated 
events.   
13.3 Pharmacokinetics 
The serum concentration/time data will be analysed using non-compartmental methods.  The 
pharmacokinetic (PK) parameters to be determined for BI-1206 include the maximum observed serum 
concentration (Cmax), time to reach Cmax (Tmax), and the area under the serum concentration time curve 
(AUC), and the terminal elimination half-life (T1/2), total body clearance (CLT) and steady/state volume 
of distribution (VSS).   
13.4 Pharmacodynamics 
The pharmacodynamic analyses to be performed are described below.  Reports will undergo a quality 
control (QC) step prior to finalisation and will be signed by the person responsible for performing the 
assays and the laboratory Quality Assurance (QA) manager once final.  
Anti-drug antibody (ADA) 
The presence of anti-BI-1206-antibody responses will be assessed using ELISA and reported per 
patient. 
B-lymphocyte levels: CD19, CD20 and CD32b 
CD19 B-lymphocyte levels will be assessed and reported at each site as part of the regular haematology 
assessment to determine the level of peripheral blood B-lymphocyte depletion. Results will be entered 
onto the clinical database and provided to the analysing pharmacodynamic laboratory for comment.   
CD32b and CD20/CD19 B-lymphocyte expression levels in blood will be measured using flow cytometry. 
Results will be reported and analysed longitudinally for each patient. 

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Levels of B lymphocytes will be measured in bone marrow aspirate to determine the level of bone 
marrow B lymphocyte depletion.  Cell surface markers will be assessed using flow cytometry and results 
analysed longitudinally for each patient.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.5 Anti-tumour activity 
Documenting anti-tumour activity is a secondary objective of this trial.  Patients must receive at least 
one dose of BI-1206 and/or rituximab on as part of this trial; have a baseline disease assessment and 
at least one follow-up disease assessment to be evaluable for response.  Patients who experience clear 
clinical disease progression without formal post-treatment disease assessment will be included and will 
be considered to have progressive disease.  Objective responses, the best tumour response achieved 
by each patient while on trial and the time to progression will be presented in the data listings. 
13.6 Overall Survival and Progression-Free Survival 
13.6.1 Overall Survival  
All patients who receive BI-1206 and/or rituximab on as part of this trial will be evaluable for overall 
survival, regardless of whether they subsequently receive other anti-cancer treatments.  Overall survival 
will be measured from the date of administration of the first dose of BI-1206 on this trial. Subgroup 
analyses of per protocol patients may be performed.  Median overall survival will be reported. Patients 
who are lost to follow-up will be censored at the time of last contact, patients who start a new treatment 
will not be censored.  
 
13.6.2 Progression-Free Survival  
All patients who receive BI-1206 and/or rituximab as part of this study and who complete a baseline and 
at least one post-treatment disease assessment (or experience clear disease progression without a 
formal post-treatment disease assessment) will be evaluable for progression-free survival (PFS), 
regardless of whether they subsequently receive other anti-cancer treatments. PFS will be measured 
from the date of administration of the first dose of BI-1206. Subgroup analyses of per protocol patients 
may be performed. Median progression free survival will be reported. Patients who are lost to follow-up 
will be censored at the time of last recorded disease assessment, patients who start a new treatment 
will not be censored. 
 

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14 ADMINISTRATION 
This trial is conducted under a clinical trial authorisation (CTA) and approval from the Medicines and 
Healthcare products Regulatory Agency (MHRA) and the relevant Research Ethics Committee(s) (REC) 
will be obtained before the start of this trial.  This trial is sponsored and monitored by Cancer Research 
UK‘s Centre for Drug Development (CDD). Applicable regulatory requirements are described in this 
section. 
14.1 Protocol deviations and amendments 
The protocol should be adhered to throughout the conduct of the study, if a situation arises where the 
conduct of the study may not be in line with the protocol, then site should contact the CDD to discuss 
this. 
Amendments to the protocol may only be made with the approval of the CDD. A protocol amendment 
may be subject to review by the assigned Ethics Committee, Health Research Authority (HRA) and the 
MHRA. Written documentation of the Ethics Committee and HRA (and if appropriate the MHRA) 
‘favourable opinion’ (i.e. approval) must be received before the amendment can be implemented and 
incorporated into the protocol if necessary. 
14.2 Serious breach of Good Clinical Practice  
A serious breach is a breach which is likely to effect to a significant degree: the safety or physical or 
mental integrity of the subjects of the trial, or the scientific value of the trial. 
In order that the Sponsor can fulfil their obligations in terms of reporting serious breaches of Good 
Clinical Practice (GCP) to the MHRA within seven calendar days of identification, site staff must inform 
the Sponsor of any unplanned deviations to the trial protocol (or GCP principles) as soon as possible 
after the deviation occurs to allow prompt evaluation by the Sponsor. 
14.3 Completion of the electronic case report form  
Electronic case report forms (eCRFs) approved and maintained by the CDD will be used to collect the 
data. The Investigator is responsible for ensuring the accuracy, completeness, clarity and timeliness of 
the data reported in the eCRFs. 
Only the Investigator and those personnel who have signed the Delegation Log provided by the CDD 
and have been authorised by the Investigator should enter or change data in the eCRFs. Authorised 
users will be included on a user list in order to be provided access to the eCRF.  All protocol required 
investigations must be reported in the eCRF. The Investigators must retain all original reports, traces 
and images from these investigations for future reference.   
The collection and processing of personal data from the patients enrolled in this clinical trial will be 
limited to those data that are necessary to investigate the efficacy, safety, quality and usefulness of the 
study drug used in this trial. The data must be collected and processed with adequate precautions to 
ensure patient confidentiality and compliance with applicable data privacy protection according to the 
applicable regulations.The data collected will comply with Directive 95/46/EC of the European 
Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the 
processing of personal data. 
Data will be entered directly into electronic screens by authorised site personnel.  Amendments to eCRF 
data will be made directly to the system and the system audit trail will retain details of the original 
value(s), who made the change, a date and time, and a reason for the change. 
Once an eCRF form has been entered by the site personnel, the data are cleaned using manual and 
automated checks. Queries will be issued electronically to the site. Authorised personnel must answer 
the queries by making relevant amendments to data or providing a response.  Answered queries will be 
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Once the patient is ‘off study’ and the eCRF has been fully completed, the Investigator must provide an 
electronic signature to authorise the complete subject casebook. 
At the end of the trial all eCRFs are retained and archived by the CDD and a PDF copy provided to the 
Investigator who is responsible for archiving at site. 
14.4 Trial performance, monitoring, auditing and inspection 
Before the trial can be initiated, the prerequisites for conducting the trial must be clarified and the 
organisational preparations made with the trial centre. The CDD must be informed immediately of any 
change in the personnel involved in the conduct of the trial. 
During the trial the CDD Clinical Research Associate (CRA) will be responsible for monitoring data 
quality in accordance with CDD’s standard operating procedures (SOPs). A strategic monitoring 
approach, including targeted source data verification, will be implemented where appropriate. 
Before the study start, the Investigator will be advised of the anticipated frequency of the monitoring 
visits.  The Investigator will receive reasonable notification before each monitoring visit. 
It is the responsibility of the CRA to: 
• 
review trial records and compare them with source documents; 
• 
check pharmacokinetic and pharmacodynamic samples and storage; 
• 
discuss the conduct of the trial and the emerging problems with the Investigator; 
• 
check that the drug storage, dispensing and retrieval are reliable and appropriate; and 
• 
verify that the available facilities remain acceptable. 
At the end of the trial all unused BI-1206 supplied must be destroyed at site (only once authorised to do 
so by the CRA or CSM) or if authorised by Cancer Research UK returned to the supplier.  
It is the responsibility of the Sponsor to notify the REC of the ‘end of the trial’. (see definition in 
Section 12). 
During the course of the trial, the Quality Assurance Department of the CDD, or external auditors 
contracted by the CDD, may conduct an on-site audit visit (ICH Topic E6 (R2) Guideline for Good Clinical 
Practice Sections 1.6). 
Principal Investigators conducting this trial will accept the potential for inspection by the MHRA. 
 
14.5 Source document verification 
Unless agreed in writing, all data collected in the eCRF must be verifiable by the source data. Therefore 
it is the Investigator’s responsibility to ensure that both he/she and his/her study team records all relevant 
data in the medical records. The Investigator must allow the CRA direct access to relevant source 
documentation for verification of data entered into the eCRF, taking into account data protection 
regulations. Entries in the eCRF will be compared with patients’ medical records and the verification will 
be recorded in the eCRF.   
Some source data may exist only electronically and be entered, or loaded directly into the eCRF.   
The patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the CDD appointed to audit the trial, NHS Trust staff and by regulatory 
authorities. Details will remain confidential and patients’ names will not be recorded outside the hospital. 

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14.6 Clinical study report 
At appropriate intervals, interim data listings will be prepared to give the Investigator the possibility to 
review the data and check the completeness of information collected. All clinical data will be presented 
at the end of the trial on final data listings. The Sponsor will prepare a clinical study report (CSR) based 
on the final data listings. The CSR will be submitted to the Investigator(s) for review and confirmation it 
accurately represents the data collected during the course of the trial. Summary results of the trial will 
be provided by the CDD to the MHRA and to the Research Ethics Committee. 
14.7 Record retention 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate 
records to enable both the conduct of a clinical trial and the quality of the data produced to be evaluated 
and verified.  These essential documents (as detailed in Chapter V of Volume 10 (Clinical Trials) of The 
Rules Governing Medicinal Products in the European Union based upon Section 8 of the ICH GCP 
Guidelines), including source documents such as scans, trial related documents and copies of the 
eCRFs, associated audit trail and serious adverse event (SAE) report forms, shall show whether the 
Investigator has complied with the principles and guidelines of Good Clinical Practice (GCP). 
All essential documents required to be held by the Investigator must be stored in such a way that 
ensures that they are readily available, upon request, to the Regulatory Agency or Sponsor, for the 
minimum period required by national legislation or for longer if needed by CDD.  Records must not be 
destroyed without prior written approval from CDD. 
The medical files of trial subjects shall be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private practice. 
14.8 Ethical considerations 
Before starting the trial, the protocol and patient informed consent document(s) (ICD) must go through the 
CDD’s external review process, and be approved by the CDD’s Protocol and Safety Review Board (PSRB) 
and receive the favourable opinion of the assigned REC. 
It is the Chief/Principal Investigator’s responsibility to update patients (or their authorised 
representatives, if applicable) whenever new information (in nature or severity) becomes available that 
might affect the patient’s willingness to continue in the trial.  The Chief/Principal Investigator must ensure 
this is documented in the patient’s medical notes and the patient is re-consented. 
The Sponsor and Chief/Principal Investigator must ensure that the trial is carried out in accordance with 
the GCP principles and requirements of the UK Clinical Trials regulations (SI 2004/1031 and SI 
2006/1928 as amended), the ICH GCP guidelines and the WMA Declaration of Helsinki - Ethical 
Principles for Medical Research Involving Human Subjects adopted by the 18th WMA General 
Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 
14.9 Indemnity 
This trial is sponsored by Cancer Research UK and therefore injury to a patient caused by the 
compounds under trial will not carry with it the right to seek compensation from the pharmaceutical 
industry.  Cancer Research UK will provide patients with compensation for adverse side effects, in 
accordance with the principles set out in the Association of the British Pharmaceutical Industry (ABPI) 
guidelines on compensation for medicine-induced injury. 
 
 

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14.10   Publication policy and press releases 
Results of this trial must be submitted for publication.  The CDD must be involved in reviewing all drafts 
of the manuscripts, abstracts, press releases and any other publications. Manuscripts must be submitted 
to the CDD at least 42 days in advance of being submitted for publication to allow time for the CDD to 
schedule a review and resolve any outstanding issues. Abstracts, presentations and press releases 
must be submitted to the CDD at least 14 days in advance of being released.   
Authors must acknowledge that the trial was sponsored by and performed with the support of CDD. The 
Chief Investigator should be the principal author of the paper reporting the trial results, and any 
Investigator recruiting ≥ 10% of patients should be listed as an author - in order of numbers of patients 
recruited. 
The contribution of the CDD should be recognised by at least one member of staff being included as an 
author on the publication.   

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15 REFERENCES 
Note for Guidance on Good Clinical Practice.  ICH Topic E6.  CSMP/ICH/135/95.  EMEA, May 1996, 
updated September 1997 with post Step 4 errata included  
Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 on the approximation 
of the laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal products for human 
use. Official Journal of the European Communities L121/34-44 
Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human 
use to the competent authorities, notification of substantial amendments and declaration of the end of 
the trial. October 2005.  ENTR/F2/BL D(2003) CT 1 (Revision 2) 
Detailed guidance on the application format and documentation to be submitted in an application for an 
Ethics Committee opinion on the clinical trial on medicinal products for human use. February 2006. 
ENTR/CT 2 (Revision 1) 
Detailed guidance on the collection, verification and presentation of adverse reaction reports arising 
from clinical trials on medicinal products for human use. April 2006.  ENTR/CT 3 (Revision 2) 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument 1031) 
Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for 
good clinical practice as regards investigational medicinal products for human use, as well as the 
requirements for authorisation of the manufacturing or importation of such products.  Official Journal of 
the European Union L 91/13 
The Medicines for Human use (Clinical Trials) Amendment Regulations 2006 (Statutory Instrument 
2006/1928).  
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Kelley, S.K., et al., Preclinical pharmacokinetics, pharmacodynamics, and activity of a 
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Armitage JO, W.D., New approach to classifying non-Hodgkin’s lymphomas: Clinical features 
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Cancer Research UK. CancerStats report - Non-Hodgkin's Lymphoma UK. 2012; Available 
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van Oers, M.H., et al., Rituximab maintenance improves clinical outcome of relapsed/resistant 
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Swenson, W.T., et al., Improved survival of follicular lymphoma patients in the United States. J 
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Fisher, R.I., et al., New treatment options have changed the survival of patients with follicular 
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Plosker, G. and D. Figgitt, Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic 
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Johnston, A., et al., Retreatment with rituximab in 178 patients with relapsed and refractory B-
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10. 
Morton, L.M., et al., Lymphoma incidence patterns by WHO subtype in the United States, 1992-
2001. Blood, 2006. 107(1): p. 265-76. 
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Brown, J.R., The treatment of relapsed refractory chronic lymphocytic leukemia. Hematology 
Am Soc Hematol Educ Program, 2011. 2011: p. 110-8. 
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Faderl, S., et al., Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) in 
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28. 
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6(5): p. 380-3. 

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45. 
Meignan, M., A. Gallamini, and C. Haioun, Report on the First International Workshop on 
Interim-PET-Scan in Lymphoma. Leuk Lymphoma, 2009. 50(8): p. 1257-60. 
 
 

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16.2 APPENDIX 2: DEAUVILLE CRITERIA FIVE POINT SCALE FOR FDG-PET 
REPORTING 
Below is an extract from M. Meignan, A. Gallamini, and C. Haioun, “Report on the first 
international workshop on interim-PET-scan in lymphoma,” Leukemia & Lymphoma, vol. 50, 
no. 8, pp. 1257–1260, 2009. 
 
Five points scale 
1. No uptake 
2. Uptake less than mediastinum 
3. Uptake more than mediastinum but less than liver 
4. Uptake moderately increased above liver at any site 
5. Markedly increased uptake at any site including new sites of disease 

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16.3  APPENDIX 3: NEW YORK HEART ASSOCIATION (NYHA) SCALE 
 
Class I – 
patients with cardiac disease but without resulting limitation of physical activity; 
ordinary physical activity does not cause undue dyspnoea (or fatigue, palpitation or 
anginal pain) 
Class II – 
patients with cardiac disease resulting in slight limitation of physical activity; they are 
comfortable at rest; ordinary physical activity results in dyspnoea (or fatigue, 
palpitation or anginal pain) 
Class III – 
patients with cardiac disease resulting in marked limitations of physical activity; they 
are comfortable at rest; less than ordinary physical activity causes dyspnoea (or 
fatigue, palpitation or anginal pain) 
Class IV – 
patients with cardiac disease resulting in inability to carry out physical activity without 
discomfort; symptoms of dyspnoea (or of angina) may be present even at rest; if any 
physical activity is undertaken, discomfort is increased. 
 
 
 

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5.1.4. Absence of constitutional symptoms. 
5.1.5. Blood counts above the following values: 
5.1.5.1.Neutrophils more than 1.5 x 109/L (1500/µL) without need for exogenous growth factors. 
5.1.5.2. Platelets more than 100 x 109/L (100 000/µL) without need for exogenous growth factors. 
5.1.5.3. Haemoglobin more than 110 g/L (11.0 g/dL) without red blood cell transfusion or need for 
exogenous erythropoietin. 
5.1.6. For patients in clinical trials (Table 3), a marrow aspirate and biopsy should be performed 
at least 2 months after the last treatment and if clinical and laboratory results listed in sections 
5.1.1 through 5.1.5 demonstrate that a CR has been achieved. 
To define a CR, the marrow sample must be at least normocellular for age, with less than 30% of 
nucleated cells being lymphocytes. Lymphoid nodules should be absent. In some cases, lymphoid 
nodules can be found, which often reflect residual disease. These nodules should be recorded as 
“nodular PR.” Moreover, immunohistochemistry should be performed to define whether these nodules 
are composed primarily of T cells or lymphocytes other than CLL cells or of CLL cells. If the marrow is 
hypocellular, a repeat determination should be performed after 4 weeks, or until peripheral blood counts 
have recovered. However, this time interval should not exceed 6 months after the last treatment. A 
marrow biopsy should be compared with that of pre-treatment marrow. In general practice, the use of a 
marrow biopsy for evaluating a CR is at the discretion of the physician. In clinical trials aiming at 
maximizing the CR rate, the quality of the CR should be assessed for MRD by flow cytometry (see 
Section 5.9) or by immunohistochemistry (IHC). 
5.1.7. A controversial issue is how best to categorize the response of patients who fulfil all the 
criteria for a CR (including the marrow examinations described in Section 5.16) but who have a 
persistent anaemia or thrombocytopenia or neutropenia apparently unrelated to CLL but related 
to drug toxicity.  
We recommend that these patients be considered as a different category of remission: CR with 
incomplete marrow recovery (CRi). For the definition of this category, CRi, the marrow evaluation (see 
Section 5.1.6) should be performed with scrutiny and not show any clonal infiltrate. In clinical trials, CRi 
patients should be monitored prospectively to determine whether their outcome differs from that of 
patients with detectable residual disease or with noncytopenic CR. 
5.2. Partial remission (PR) 
PR is defined by the criteria described in Sections 5.2.1, 5.2.2, or 5.2.3 (if abnormal before therapy), as 
well as one or more of the features listed in Section 5.2.4. To define a PR, these parameters need to be 
documented for a minimal duration of 2 months (Table 4). Constitutional symptoms persisting for more 
than 1 month should be recorded. 
5.2.1. A decrease in the number of blood lymphocytes by 50% or more from the value before 
therapy. 
5.2.2. Reduction in lymphadenopathy (by CT scans in clinical trials or by palpation in general 
practice) as defined by the following: 
5.2.2.1. A decrease in lymph node size by 50% or more either in the sum products of up to 6 lymph 
nodes, or in the largest diameter of the enlarged lymph node(s) detected prior to therapy. 
5.2.2.2. No increase in any lymph node, and no new enlarged lymph node. In small lymph nodes (< 2 
cm), an increase of less than 25% is not considered to be significant.  

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5.2.3. A reduction in the noted pre-treatment enlargement of the spleen or liver by 50% or more, 
as detected by CT scan (in clinical trials) or palpation (in general practice).  
5.2.4. The blood count should show one of the following results: 
5.2.4.1. Neutrophils more than 1.5 x 109/L (1500/µL) without need for exogenous growth factors. 
5.2.4.2. Platelet counts greater than 100 x109/L (100,000/µL) or 50% improvement over baseline without 
need for exogenous growth factors. 
5.2.4.3. Hemoglobin greater than 110 g/L (11.0 g/dL) or 50% improvement over baseline without 
requiring red blood cell transfusions or exogenous erythropoietin. 
5.3. Progressive disease 
Progressive disease during or after therapy is characterized by at least one of the following: 
5.3.1. Lymphadenopathy. Progression of lymphadenopathy is often discovered by physical 
examination and should be recorded. In CLL, the use of CT scans usually does not add much 
information for the detection of progression or relapse. Therefore, the use of imaging methods to follow 
CLL progression is at the discretion of the treating physician. Disease progression occurs if one of the 
following events is observed: 
Appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, hepatomegaly, 
or other organ infiltrates. An increase by 50% or more in greatest determined diameter of any previous 
site. 
5.3.2. An increase in the previously noted enlargement of the liver or spleen by 50% or more or 
the de novo appearance of hepatomegaly or splenomegaly.  
5.3.3. An increase in the number of blood lymphocytes by 50% or more with at least 5000 B 
lymphocytes per microliter. 
5.3.4. Transformation to a more aggressive histology (e.g., Richter syndrome). Whenever 
possible, this diagnosis should be established by lymph node biopsy. 
5.3.5. Occurrence of cytopenia (neutropenia, anaemia, or thrombocytopenia) attributable to CLL. 
5.3.5.1. During therapy. Cytopenias may occur as a side effect of many therapies and should be 
assessed according to Table 5. During therapy, cytopenias cannot be used to define disease 
progression. Each protocol should define the amount of drug(s) to be administered with such cytopenias. 
5.3.5.2. After treatment. The progression of any cytopenia (unrelated to autoimmune cytopenia), as 
documented by a decrease of Hb levels by more than 20 g/L (2 g/dL) or to less than 100 g/L (10 g/dL), 
or by a decrease of platelet counts by more than 50% or to less than 100 x 109/L (100 000cells/_L), 
which occurs at least 3 months after treatment, defines disease progression, if the marrow biopsy 
demonstrates an infiltrate of clonal CLL cells. 
5.4. Stable disease 
Patients who have not achieved a CR or a PR, and who have not exhibited progressive disease, will be 
considered to have stable disease (which is equivalent to a non response). 
5.5. Treatment failure 
Responses that should be considered clinically beneficial include CR and PR; all others (e.g., stable 
disease, non response, progressive disease, or death from any cause) should be rated as a treatment 
failure. 
5.6. Time to progression, progression-free survival, and overall survival 
Time to progression (TTP) is defined as the time from study entry until objective disease progression 
(see Section 5.3). Progression free survival (PFS) is defined as the time from study entry until objective 
disease progression or death. Overall survival is defined as the time from study entry until death from 
any cause, and is measured in the intent-to-treat population. 

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5.7. Relapse 
Relapse is defined as a patient who has previously achieved the above criteria (Sections 5.1 and 5.2) 
of a CR or PR, but after a period of 6 or more months, demonstrates evidence of disease progression 
(see Section 5.3). 
5.8. Refractory disease 
Refractory disease is defined as treatment failure (as defined in Section 5.5) or disease progression 
within 6 months to the lastantileukemic therapy. For the definition of “high-risk CLL” justifying the use of 
allogeneic stem cell transplantation, the disease should be refractory to a purine analog-based therapy 
or to autologous hematopoietic stem cell transplantation. 
5.9. Minimal residual disease 
The complete eradication of the leukemia is an obvious desired endpoint. New detection technologies, 
such as multicolour flow cytometry and real-time quantitative PCR, have determined that many patients 
who achieved a CR by the 1996 NCI-WG guidelines have detectable MRD. Although eradication of 
MRD may improve prognosis, prospective clinical trials are needed to define whether additional 
treatment intended solely to eradicate MRD provides a significant benefit to clinical outcome. The 
techniques for assessing MRD have undergone a critical evaluation and have become fairly standard.60 
Either 4-color flow cytometry (MRD flow) or allele-specific oligonucleotide PCR is reliably sensitive down 
to a level of approximately one CLL cell in 10 000 leukocytes. As such, patients will be defined as having 
a clinical remission in the absence of MRD when they have blood or marrow with less than one CLL cell 
per 10 000 leukocytes. The blood generally can be used for making this assessment except during the 
period within 3 months of completing therapy, particularly for patients treated with alemtuzumab, 
rituximab, and other antibodies targeting CLL. In such cases, it is essential to assess the marrow for 
MRD. Therefore, future clinical trials that aim toward achieving long-lasting CRs should include at least 
one test to assess MRD because the lack of leukemia persistence using these sensitive tests seems to 
have a strong, positive prognostic impact. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 4: Response definition after treatment for patients with CLL, using the parameters of 
Tables 1 and and 3 
 
 
 

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16.6 APPENDIX 6: Criteria for disease assessment in patients with Waldenström’s 
Macroglobulinaemia 
Below is an extract from Owen et al (British Journal of Haematology, 2013, 160, 171-176) this should 
be used in conjunction with the previous update from Kimby et al (Clinical Lymphoma and Myeloma, Vol 
6, Issue 5, pages  380–383, Mar 2006)to assess disease response in patients with WM.   
 
Response (abbreviation) 
Criteria 
Complete response (CR) 
 Absence of serum monoclonal IgM protein by immunofixation 
Normal serum IgM level 
Complete resolution of extramedullary disease, i.e., lymphadenopathy and splenomegaly 
if present at baseline 
Morphologically normal bone marrow aspirate and trephine biopsy 
Very 
good 
partial 
response 
(VGPR) 
Monoclonal IgM protein is detectable 
≥90% reduction in serum IgM level from baselinea 
Complete resolution of extramedullary disease, i.e., lymphadenopathy/splenomegaly if 
present at baseline 
No new signs or symptoms of active disease 
Partial response (PR) 
Monoclonal IgM protein is detectable 
≥50% but<90% reduction in serum IgM level from baselinea 
Reduction in extramedullary disease, i.e., lymphadenopathy/splenomegaly if present at 
baseline 
No new signs or symptoms of active disease 
Minor response (MR)  
Monoclonal IgM protein is detectable 
≥25% but<50% reduction in serum IgM level from baselinea 
No new signs or symptoms of active disease 
Stable disease (SD) 
Monoclonal IgM protein is detectable 
<25% reduction and <25% increase in serum IgM level from baselinea 
No progression in extramedullary disease, i.e.,lymphadenopathy/splenomegaly 
No new signs or symptoms of active disease 
Progressive disease (PD) 
≥25% increase in serum IgM levela from lowest nadir (requires confirmation) and/or 
progression in clinical features attributable the disease 
a Sequential changes in IgM levels may be determined either by M protein quantitation by densitometry or total serum IgM 
quantitation by nephelometry.