Clinical trial NCT01403948
Conditions: Lymphoma, Non-Hodgkin
Sponsor: Boehringer Ingelheim
Start date: 2011-08-01; Completion date: 2018-02-28
Enrollment: 48 participants; Allocation: ; Intervention model: SEQUENTIAL

Brief summary:
The purpose is to investigate the maximum tolerated dose (MTD), safety and tolerability, pharmacokinetics and efficacy of BI 836826 monotherapy in patients with relapsed or refractory non-Hodgkin lymphoma with at least prior treatments.

Detailed description:

Arms: arm 1: Adult patients with relapsed or refractory non-Hodgkin lymphoma of B cell origin after at least two prior treatments
Interventions: intervention 1: BI 836826
Intervention descriptions: intervention 1: Monotherapy with BI 836826 at escalating dose levels administered as an intravenous infusion

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106_RD-03 (10.0) / Saved on: 20 
Oct 2011
Clinical Trial Protocol
Doc. No.: c02158149-09
EudraCT No.:
BI Trial No.:
2010-024456-29
1270.2
BI Investigational
Product(s):
BI 836826
Title:
A Phase I, Open-Label, Dose-Escalation Trial with BI 836826 in 
Patients with Relapsed or Refractory non-Hodgkin Lymphoma of B cell 
Origin
Clinical Phase:
Phase I
Trial Clinical 
Monitor:
On behalf of
Phone:
Fax: 
Co-ordinating 
Investigator:
Phone:
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendment(s))
Version and Date:
Version: 6
Date: 13 Apr 2016
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not Applicable
Name of active ingredient:
BI 836826
Protocol date:
Trial number:
Revision date:
13 Apr 2016
25 Feb 2011
1270.2
Title of trial:
A Phase I, Open-Label, Dose-Escalation Trial with BI 836826 in Patients with 
Relapsed or Refractory non-Hodgkin Lymphoma of B cell Origin
Co-ordinating 
Investigator:
Trial sites:
Multi-centre trial
Clinical phase:
Phase I
Objectives:
To investigate the maximum tolerated dose (MTD), safety and tolerability, 
 and efficacy of BI 836826 monotherapy in patients with relapsed or 
refractory non-Hodgkin lymphoma
Methodology:
Open-label dose-escalation
No. of patients: 
Approximately 66
total entered:
Approximately 53
each treatment:
1 to 6 patients at each dose level, up to 4 patients treated at the 100 mg dose in 
expansion cohort,
additional cohort (up to 12) of Korean patients:3-6 patients at 50 mg, and 3-6 patients 
at 75 mg
Diagnosis :
Non-Hodgkin lymphoma of B cell origin
Main criteria
for inclusion:
Relapsed or refractory non-Hodgkin lymphoma of B cell origin not eligible for 
intensive anti-lymphoma treatment
Test product:
BI 836826
dose:
Starting dose will be 1 mg


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001-MCS-40-106_RD-03 (10.0) / Saved on: 20 Oct 2011
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not Applicable
Name of active ingredient:
BI 836826
Protocol date:
Trial number:
Revision date:
13 Apr 2016
25 Feb 2011
1270.2
mode of admin. :
BI 836826 administered intravenously as single agent treatment
Comparator products:
Not applicable
dose:
mode of admin. :
Duration of treatment: Patients are eligible for up to 3 courses with a total of 12 administrations of BI 
836826. Each course comprises of 4 administrations in weekly intervals followed by 
treatment free observation/rest. The duration of two first courses is each 7 weeks and
the duration of the third course is 12 weeks. The maximum duration of treatment and 
observation period/rest is 26 weeks before follow-up. 
Criteria for efficacy
and 
pharmacodynamics:
Reduction in tumour size, best overall response, progression free survival, failure free 
survival, plasma concentration time profiles
 
Criteria for safety:
Maximum tolerated dose, incidence and intensity of adverse events graded according 
to the common terminology criteria for adverse events (CTCAE, version 4.0), 
incidence of dose limiting toxicity, laboratory parameters.
Statistical methods:
Descriptive statistics


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FLOWCHARTS
Flowchart for Course 1
Trial Periods
Screen
Treatment and observation/rest
EOT
FU
Course *
1
If no signs of 
progression 
and 
agreement on 
further 
treatment for 
the patient, 
please 
continue to 
Visit 1 on
Flowchart 
for Course 2
If the patient 
has disease 
progression 
or 
withdraws, 
please 
continue to 
EOT visit 
on 
Flowchart 
for Course 3
Week
1
2
3
4
5
6
7
Visit **
Screen
1
2
3
4
5
6
7
8
9
10
Days
-14 to
-1
1
2
3
+
2
8
9
10
+2
15
17
+2
22
29
±2
36
±
2
43
±2
Informed consent
x
Demographics
x
Medical history
x
Review of in-/exclusion 
criteria
x
x
1
Eligibility for trial
x
12-lead ECG
x
 
 
Height
x
Weight
x
x
x
x
x
x
x
x
Physical examination, 
incl. tumour size (lymph 
nodes, spleen, liver), 
x
x
x
x
Vital signs 2
x
x
x
x
x
x
x
x
x
x
x
x
x
Dose assignment
x3
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
General safety laboratory 
parameters 4
x
x
x
x
x
x
x
x
x
x
x
x
x
Administration of BI 
836826
x
x
x
x
Screening for Tumour 
Lysis Syndrome 5
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
Disease/response assessm. 
(clinical/imaging)
x
x
6
x6
x6
Serum pregnancy test 7
x
x
x
CMV monitoring 8
x
x
x
x
x
x
x
Lymphocyte typing 
(B/T/NK cells)
x
x
x
x
x
x
x
x
x
x
 
 
Virology screening 10
(HBV, HCV, HIV, CMV)
x
x
CT scan of neck, thorax, 
abdomen and pelvis
x11


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EOT: 
End of treatment visit, to be performed at withdrawal from further treatment (<12 administrations) or at the latest 8 
weeks after the last administration of BI 836826 (12 administrations)
FU: 
Follow-up visits (starts after EOT) at least every 6 weeks until 6 months after EOT visit, details see section 6.2.3.2
CMV:
Cytomegalovirus
HBV:
Hepatitis B virus
HCV:
Hepatitis C virus
HIV:
Human immunodeficiency virus
* the planned duration of course 1 is 7 weeks (49 days)
** the visit number follows the course number, i.e. visit 2 course 1 will read C1_V2 and visit 2 course 2 will read C2_V2 …
1
Review of eligibility
2
For details during and after infusion of BI 836826, refer to section 5.2.5.1
3
After informed consent, and review of in- and exclusion criteria, and before the first administration of the trial 
drug
4
For details refer to section 5.2.3.1
5
Screening for tumour lysis syndrome in between safety laboratory assessments (section 5.2.3.2)
6
Disease / response assessment will be based on clinical judgement when recent CT is not available
7
For women of childbearing potential only (please refer to sections 3.3.3 (exclusion criterion 20) and 5.2.3.1)
8
Quantitative CMV DNA PCR (section 5.2.3.3.2)
10
Please refer to section 5.2.3.3.1
11
CT scan may be performed up to 4 weeks prior to first infusion according to the standard of care in this patient 
population
.


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Flowchart for Course 2
Trial Periods
Treatment and observation/rest
EOT
FU
Course *
2
If clinical 
benefit and 
agreement 
on further 
treatment 
for the 
patient, 
please 
continue to 
Visit 1
Flowchart 
for Course 
3
If the 
patient has 
disease 
progression 
or 
withdraws, 
please 
continue to
EOT visit 
on 
Flowchart 
for Course 
3
Week
8
9
10
11
12
13
14
Visit **
1
2
3
4
5
6
7
8
9
10
Days 
1
2
3
+2
8
9
+4
15
17
+2
22
29
±2
36
±5
43
±2
Eligibility for course 2
x1
Vital signs 2
x
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
Physical examination, incl 
tumour size (lymph nodes, 
spleen, liver)  
 
x
x
x
Disease / response assessment 
(clinical/imaging)
x3
x3
x4
Serum pregnancy test 5
x
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x
General safety laboratory 
parameters 6
x
x
x
x
x
x
x
x
x
x
x
Administration of BI 836826
x
x
x
x
Screening for Tumour Lysis 
Syndrome 7
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
CMV monitoring 8
x
x
x
x
x
x
x
Lymphocyte typing (B/T/NK 
cells)
x
x
x
x
x
x
x
x
x
x
 
 
CT scan of neck, thorax, 
abdomen and pelvis
x
EOT: 
End of treatment visit, to be performed at withdrawal from further treatment (<12 administrations) or at the latest 8 
weeks after the last administration of BI 836826 (12 administrations)
FU: 
Follow-up visits (starts after EOT) at least every 6 weeks until 6 months after EOT visit, details see section 6.2.3.2
CMV:
Cytomegalovirus
* the planned duration of course 2 is 7 weeks (49 days)
** the visit number follows the course number, i.e. visit 2 course 1 will read C1_V2 and visit 2 course 2 will read C2_V2 
1
Can be performed within 7±2 days prior to this visit
2
For details during and after infusion of BI 836826, refer to section 5.2.5.1
3
Disease / response assessment will be based on clinical judgement when recent CT is not available. Radiological 
assessments will be performed following the local standard of care.
4
Assessment can be performed prior to visit 10, if CT scan from visit 9 is available.
5
For women of childbearing potential only (please refer to sections 3.3.3 (exclusion criterion 20) and 5.2.3.1)
6
For details refer to section 5.2.3.1
7
Screening for tumour lysis syndrome in between safety laboratory assessments (section 5.2.3.2)
8
Quantitative CMV DNA PCR (section 5.2.3.3.2)


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Flowchart for Course 3, End of Treatment visit and Follow-up
Trial Periods
Treatment and observation/rest
EOT
FU
Course *
3
Week
15
16
17
18
19
20
21
23
25
see12
Visit **
1
2
3
4
5
6
7
8
9
Days 
1
8
15
22
29
(+2)
36
(+5)
43
(+5)
57
(±5)
71
(±5)
Eligibility for course 3
x1
Vital signs 2
x
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
x
x
x
x
x
Physical examination, incl.
tumour size (lymph nodes, 
spleen, liver), 
x
x
x
x
x
Disease / response assessment 
(clinical/imaging)
x
x3
x
x3
Serum pregnancy test 4
x
x
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x5
General safety laboratory 
parameters 6
x
x
x
x
x
x
x
x
x
x
x
Administration of BI 836826
x
x
x
x
Screening for Tumour Lysis 
Syndrome 7
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x8
CMV monitoring 9
x
x
x
x
x
x
x
x
x
x
x
Lymphocyte typing (B/T/NK 
cells)
x
x
x
x
x
x
x
x
x
x
 
 
CT scan of neck, thorax, 
abdomen and pelvis
x
x11
12-lead ECG
x
Completion of active trial 
treatment
x
Status (remission, progression, 
death)
x
x
Other therapy for lymphoma
x
x
EOT: 
End of treatment visit, to be performed at withdrawal from further treatment (<12 administrations) or at the latest 8 
weeks after the last administration of BI 836826 (12 administrations)
FU: 
Follow-up visits (starts after EOT) at least every 6 weeks until 6 months after EOT visit, details see section 6.2.3.2
CMV:
Cytomegalovirus
* the planned duration of course 3 is 12 weeks (84 days)
** the visit number follows the course number, i.e. visit 2 course 1 will read C1_V2 and visit 2 course 2 will read C2_V2 …
1
Can be performed within 7±2 days prior to this visit
2
For details during and after infusion of BI 836826, refer to section 5.2.5.1
3
Disease / response assessment will be based on clinical judgement when recent CT is not available
4
For women of childbearing potential only (please refer to sections 3.3.3 (exclusion criterion 20) and 5.2.3.1)
5
Concomitant therapy during FU only in case indicated for treatment of an AE (section 4.2.1)
6
For details refer to section 5.2.3.1
7
Screening for tumour lysis syndrome in between safety laboratory assessments (section 5.2.3.2)
8
For AE assessment during FU refer to sections 5.2.1 and 6.2.3.2


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9
Quantitative CMV DNA PCR (section 5.2.3.3.2)
11
In case end of treatment occurs before week 26, a CT scan can be performed at the EOT visit if clinically indicated 
for response assessment (e.g. progression) 
12
If 12 infusions has been administered the EOT should be performed at the latest in week 26 (day 77±5 of course 3)  


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOWCHARTS..................................................................................................4
Flowchart for Course 1 ...............................................................................................4
Flowchart for Course 2 ...............................................................................................6
Flowchart for Course 3, End of Treatment visit and Follow-up.................................7
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION................................................................................ 19
1.1
MEDICAL BACKGROUND ............................................................................19
1.2
DRUG PROFILE ...............................................................................................21
2.
RATIONALE, OBJECTIVES, AND BENEFIT – RISK 
ASSESSMENT...................................................................................... 24
2.1
RATIONALE FOR PERFORMING THE TRIAL ........................................24
2.2
TRIAL OBJECTIVES.......................................................................................24
2.3
BENEFIT - RISK ASSESSMENT....................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.......... 28
3.1
OVERALL TRIAL DESIGN AND PLAN.......................................................28
3.1.1
Administrative structure of the trial .........................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP ..........................................................................................30
3.3
SELECTION OF TRIAL POPULATION.......................................................31
3.3.1
Main diagnosis for study entry....................................................................31
3.3.2
Inclusion criteria...........................................................................................31
3.3.3
Exclusion criteria..........................................................................................32
3.3.4
Removal of patients from therapy or assessments ....................................33
3.3.4.1
Removal of individual patients.................................................................33
3.3.4.2 
Discontinuation of the trial by the sponsor ..............................................34
4.
TREATMENTS.................................................................................... 35
4.1
TREATMENTS TO BE ADMINISTERED ....................................................35
4.1.1
Identity of BI investigational product and comparator product .............36
4.1.2
Method of assigning patients to treatment groups....................................36
4.1.3
Selection of doses in the trial .......................................................................36
4.1.4
Drug assignment and administration of doses for each patient...............37
4.1.4.1
Prophylactic measures..............................................................................37
4.1.4.1.1
Premedication..........................................................................................37
4.1.4.1.2
Monitoring for infusion-related reactions ...............................................38
4.1.4.1.3 Tumour lysis syndrome............................................................................38
4.1.4.2
Handling of infusion-related reactions.....................................................39
4.1.4.3
Management of infections:.......................................................................39


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4.1.4.4
Continuation of Treatment during a Course, or beginning a new 
course........................................................................................................39
4.1.5
Blinding and procedures for unblinding....................................................41
4.1.5.1
Blinding....................................................................................................41
4.1.5.2
Procedures for emergency unblinding......................................................41
4.1.6
Packaging, labelling, and re-supply............................................................41
4.1.7
Storage conditions ........................................................................................41
4.1.8
Drug accountability......................................................................................41
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT ....................................................................................................42
4.2.1
Rescue medication, emergency procedures, and additional 
treatment .......................................................................................................42
4.2.1.1 Rescue medication ........................................................................................42
4.2.1.2 Supportive care .............................................................................................42
4.2.1.2.1 Antibiotics and Antivirals..........................................................................42
4.2.1.2.2 Growth factors ...........................................................................................43
4.2.1.3 Concomitant medication...............................................................................43
4.2.2
Restrictions....................................................................................................43
4.2.2.1
Restrictions regarding concomitant treatment..........................................43
4.2.2.2 
Restrictions on diet and life style .............................................................44
4.3
TREATMENT COMPLIANCE .......................................................................44
5.
VARIABLES AND THEIR ASSESSMENT ..................................... 45
5.1
EFFICACY .........................................................................................................45
5.1.1
Endpoints of efficacy....................................................................................45
5.1.2
Assessment of efficacy..................................................................................45
5.1.2.1
Tumour size..............................................................................................45
5.1.2.2
Assessment and definition of overall best response.................................46
5.1.2.2.1 Complete remission..................................................................................46
5.1.2.2.2 Complete remission unconfirmed ............................................................46
5.1.2.2.3 Partial remission.......................................................................................46
5.1.2.2.4 Stable disease ...........................................................................................47
5.1.2.2.5 Relapsed disease (after CR, CRu)/ Progressive disease (after PR, 
SD)............................................................................................................47
5.1.2.3
Progression free survival..........................................................................47
5.1.2.4
Failure free survival..................................................................................47
5.2
SAFETY ..............................................................................................................48
5.2.1
Endpoints of safety.......................................................................................48
5.2.1.1
Dose limiting toxicity...............................................................................49


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5.2.2
Assessment of adverse events ......................................................................49
5.2.2.1
Definitions of adverse events ...................................................................49
5.2.2.2
Adverse event and serious adverse event reporting .................................51
5.2.3
Assessment of safety laboratory parameters .............................................53
5.2.3.1
General safety laboratory parameters.......................................................53
5.2.3.2
Screening for laboratory evidence of tumour lysis syndrome..................54
5.2.3.3
Virology....................................................................................................55
5.2.3.3.1 Screening for hepatitis B, hepatitis C, cytomegalovirus and human 
immunodeficiency virus...........................................................................55
5.2.3.3.2 CMV monitoring......................................................................................55
5.2.3.4
Lymphocyte typing...................................................................................55
5.2.4
Electrocardiogram........................................................................................55
5.2.5
Assessment of other safety parameters ......................................................56
5.2.5.1
Vital signs.................................................................................................56
5.2.5.2
Physical examination................................................................................56
5.3
OTHER................................................................................................................56
5.3.1
Other endpoints............................................................................................56
5.3.2
Other assessments.........................................................................................57
5.3.2.1
Demographics and history........................................................................57
5.3.2.2
Concomitant diagnoses.............................................................................57
 
5.4
APPROPRIATENESS OF MEASUREMENTS .............................................59
 
 
6.
INVESTIGATIONAL PLAN.............................................................. 62
6.1
VISIT SCHEDULE............................................................................................62
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS.................62
6.2.1
Screening and run-in period(s) ...................................................................62


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6.2.2
Treatment periods ........................................................................................63
6.2.2.1 Course 1 ........................................................................................................63
6.2.2.2 Course 2 ........................................................................................................63
6.2.2.3 Course 3 ........................................................................................................63
6.2.3
End of treatment and follow-up period......................................................64
6.2.3.1 
End of treatment .......................................................................................64
6.2.3.2 
Follow-up .................................................................................................64
6.2.3.3
End of the whole trial ...............................................................................65
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE ..................................................................................... 66
7.1
STATISTICAL DESIGN - MODEL ................................................................66
7.2
NULL AND ALTERNATIVE HYPOTHESES...............................................66
7.3
PLANNED ANALYSES ....................................................................................66
7.3.1
Primary analyses ..........................................................................................66
7.3.2
Secondary analyses.......................................................................................66
7.3.2.1
Tumour size..............................................................................................66
7.3.2.3
Best overall response................................................................................67
7.3.2.4 
Progression free survival, 
, failure free survival, 
...............................67
 
 
7.3.3
Safety analyses..............................................................................................67
7.3.4
Interim analyses............................................................................................68
7.4
HANDLING OF MISSING DATA...................................................................70
7.5
RANDOMISATION...........................................................................................70
7.6
DETERMINATION OF SAMPLE SIZE.........................................................70
8.
INFORMED CONSENT, DATA PROTECTION; TRIAL 
RECORDS ............................................................................................ 71
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND
INFORMED CONSENT ...................................................................................71
8.2
DATA QUALITY ASSURANCE......................................................................72
8.3
RECORDS ..........................................................................................................72
8.3.1
Source documents.........................................................................................72
8.3.2
Direct access to source data and documents..............................................73
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................73
8.4.1
Listedness ......................................................................................................73
8.4.2
Expedited reporting to health authorities and IECs/IRBs.......................73


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8.5
STATEMENT OF CONFIDENTIALITY.......................................................73
8.6
COMPLETION OF TRIAL..............................................................................73
9.
REFERENCES ..................................................................................... 74
9.1
PUBLISHED REFERENCES...........................................................................74
9.2
UNPUBLISHED REFERENCES .....................................................................80
10.
APPENDICES ...................................................................................... 81
10.2
AGGRESSIVE AND INDOLENT LYMPHOMA..........................................82
10.3
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE SCORE................................................................................82
10.4
ANN ARBOR STAGING ..................................................................................83
10.5
CALCULATION OF GLOMERULAR FILTRATION RATE ....................83
10.6
CLINICAL EVALUATION OF LIVER INJURY..........................................84
10.6.1
Introduction ..................................................................................................84
10.6.2
Procedures.....................................................................................................84
10.7 
FLOWCHART 
 FOR THE SPLIT 
FIRST DOSE  ADMINISTRATION (LOW DOSE AND FULL 
DOSE)..................................................................................................................86
10.7.1 
Flowchart for Course 1 ................................................................................86
11.
DESCRIPTION OF GLOBAL AMENDMENTS............................. 88


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ABBREVIATIONS
ADCC
Antibody dependent cellular cytotoxicity
AE
Adverse event
ALT
Alanine amino transferase
anti-HBs
Hepatitis B surface antibody
anti-HBc
Hepatitis B core antibody
anti-HCV
Hepatitis C antibody
AP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time
AST
Aspartate amino transferase
 
 
 
B-NHL
B cell Non-Hodgkin lymphoma
CD
Cluster of Differentiation
CDC
Complement dependent cytotoxicity
CHOP
cyclophosphamide, hydroxydaunorubicin, oncovin , and prednisolone
CI
Confidence Interval


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CLL
Chronic lymphocytic leukaemia
CMV
Cytomegalovirus
CNS
Central nervous system
COPD
Chronic Obstructive Pulmonary Disease
CR
Complete remission
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organisation
CRu
Complete remission unconfirmed
CT
Computer tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug-Induced Liver Injury
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DSMB
Data Safety Monitoring Board
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group


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EOT
End of treatment
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration
FFS
Failure free survival
FL
Follicular lymphoma
FU
Follow-up
GCP
Good Clinical Practice
G-CSF
Granulocyte colony stimulating factor
GFR
Glomerular filtration rate
GvHD
Graft versus host disease
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
INR
International normalised ratio
IPI
International prognostic index
IRB
Institutional Review Board


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ISF
Investigator Site File
IUD
Intrauterine device
i.v.
Intravenous
LDH
Lactate dehydrogenase
MCL
Mantle cell lymphoma
MTD
Maximum tolerated dose
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRT
Mean residence time
NHL
Non-Hodgkin lymphoma
NK cells
Natural killer cells
OBD
Optimal biological dose
OPU
Operative unit
ORR
Overall response rate
PCR
Polymerase chain reaction
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression free survival
PLT
Platelets


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p.o.
per os (oral)
PR
Partial remission
PT
Prothrombin time
RBC
Red blood cell count
RR
Response rate
SAE
Serious adverse event
SD
Stable disease
SDV
Source data verification
SMIP
Small modular immuno pharmaceutical
SOP
Standard operating procedure
SPD
Sum of product of diameter
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal half-life
TDMAP
Trial data management and analysis plan
TLS
Tumour lysis syndrome
 
WBC
White blood cell count
WHO
World Health Organisation


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Non-Hodgkin lymphoma (NHL) encompasses several subgroups of lymphomas with variable 
clinical courses. In the US 65.500 new cases of NHL are estimated for 2010 (website
cancer.org). Approximately 90% of NHL is of B cell origin (B-NHL) (R10-4834) and they 
belong to mature B cell malignancies according to the World Health Organization (WHO) 
classification (R10-6296). The incidence of B-NHL is 15-20 per 100.000 (seer.cancer.gov). 
Historically, the lymphomas are divided into aggressive lymphomas, i.e. rapidly growing 
tumours and indolent lymphomas, i.e. slower growing tumours. The aggressive subtypes 
account for approximately half of the incidence of lymphomas. Among the aggressive 
subgroups, the diffuse large B-cell lymphoma (DLBCL) is the most common one and 
represents 30-40% of all B-NHL in adults (R10-6296). The most frequent indolent subtype is 
follicular lymphoma (FL) accounting for a quarter of the B-NHL (R10-6296). B cell 
lymphoma is occurring in the entire world with an increasing incidence over the last decades. 
The median age at diagnosis is around 65 years. There is a slight male predominance in the 
incidence.
The diagnosis of lymphoma is based on histology of a biopsy, preferably a whole lymph 
node. The classification of lymphomas has developed over the years with the improvement of 
diagnostic tools. Today, WHO classification from 2008 is widely accepted and is based on 
morphology often combined with immunophenotyping and genetics (R10-6296). The 
majority of the B-NHL expresses B-cell markers like CD19, CD20, CD22 and CD79a. A 
homogenous CD37 expression is also observed in the majority of B-NHL, as well as in 
chronic lymphocytic leukaemia (CLL) (R08-2979, R08-2943, R08-2981, R08-2942, R08-
2945). 
The Ann Arbor staging system is used to describe disease involvement in NHL (R10-6400
and appendix 10.4). The disease stage is determined by computerized tomography (CT) 
scanning and bone marrow biopsy/aspirate. Extra-nodal disease as well as B symptoms (i.e.
unexplained fever, night sweats or weight loss) further describes the disease status at 
diagnosis. The addition of 18F-deoxyglucose-positron emission tomography (PET) scanning 
for staging and early response evaluation can identify patients with DLBCL who are likely to 
achieve a durable response (R10-6359). Combination of 18FFlourodeoxyglucose-positron 
emission tomography (PET) with computer tomography (CT) scanning has been reported to 
be superior to PET alone (R10-6358). The role of PET/CT performed during the treatment of 
DLBCL to guide eventual therapy modifications to improve outcome is less clear due to non 
lymphoma specific PET positivity (R10-6313). The role of PET scanning for the indolent 
lymphomas and for refractory setting is more uncertain (R10-1462). 
Risk assessment at diagnosis with the international prognostic index (IPI) has been clinically 
useful for the patients with DLBCL (R10-6349). The index encompasses of 5 parameters: age 
>60 years, stage III or IV, ≥2 extranodal sites, performance status ≥2 and lactate 
dehydrogenase (LDH) above upper limit of normal as prognostic factors. Recently, an 


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analysis of the prognostic relevance of IPI for patients who received rituximab as part of their 
first line therapy confirms the significance of IPI for progression free survival (PFS) and 
overall survival (R10-6639). Similarly, a prognostic index for FL (FLIPI) has been assessed. 
Initially, retrospectively for PFS identifying age >60 years, stage III-IV, haemoglobin <7.5 
mmol/l, serum lactate dehydrogenase (LDH) >upper limit of normal and >4 nodal sites as 
adverse prognostic factors (R10-6350). Recently, a prospectively validated prognostic index 
(FLIPI 2) taking the use of rituximab into account has been established. Age >60 years, 
haemoglobin <7.5 mmol/l, beta2microglobulin >upper limit of normal, largest node longest 
diameter >6 cm and bone marrow involvement were identified as adverse factors (R10-6348). 
The higher the number of risk factors is the poorer the prognosis is. These prognostic markers 
are commonly used in clinical practice.
Over many decades therapy for aggressive B-NHL has been chemotherapy, often as 
combination chemotherapy with the gold standard being cyclophosphamide, doxorubicin, 
vincristine and prednisone (CHOP) (P10-13325). Over the last 15 years, the addition of 
rituximab (anti-CD20 antibody) to chemotherapy (immunochemotherapy) has improved the 
response rates, progression-free survival (PFS) and overall survival significantly for both 
DLBCL and follicular lymphoma (R10-4775, P10-13258, P10-13259, R10-6361). Mantle 
cell lymphoma (MCL) often has an aggressive clinical course remains an essentially 
incurable disease despite improved therapies (P10-13257). Approximately half of the patients 
with aggressive B-NHL will not be cured and will eventually die of their disease (R10-4775, 
R10-4774).
For FL combination chemotherapy, alkylating agents, purine analogs and anthracyclins, 
together with rituximab is the most frequently used first line therapy. Recently, one trial 
showed improved progression free survival (PFS) with bendamustine and rituximab 
compared to R-CHOP in indolent lymphomas (R10-6362). Despite a median overall survival 
of >10 years (R10-6303) the only curable therapy for FL is allogeneic stem cell 
transplantation, which constitutes an experimental therapy option for only a minority of the 
patients (R10-6310). 
For patients with aggressive lymphoma, e.g. DLBCL, who have relapsed after high-dose 
therapy and stem cell support or who are ineligible for transplantation, no proven best 
regimen exists (P10-13007), and treatment options are considered palliative. Primarily 
refractory patients may respond to alternative chemotherapy, but generally they have a poor 
prognosis (R10-6351). Treatment with rituximab given as a single agent was reported to yield 
a response rate of 37% in previously untreated DLBCL elderly patients and patients with 
relapsed/refractory DLBCL who had not previously been treated with rituximab (R10-6352). 
A CD22 monoclonal antibody (mAb) (epratuzumab) tested in a dose-escalation trial led to an 
objective response in 5 out of 33 patients (15%) with relapsed or refractory aggressive NHL 
(R10-6285). In a similar patient population the CD40 mAb (dacetuzumab) led to an overall 
response rate (ORR) of 12% (R10-6360). For relapsed FL response rate (RR) decreases and 
PFS shortens with each additional treatment regimen compared to RR and PFS for first line 
treatment. For patients with relapse, who are not eligible for high-dose therapy with stem cell 
support or who relapse after this therapy, there is no gold standard of care (R10-6310). For 


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patients who have rituximab refractory disease which may also be chemotherapy refractory, 
RR is only 11 to 25% with the novel CD20 antibodies, ofatumumab and afutuzumab (R10-
6363, R10-6316) and with bendamustine the RR was 77% with a median PFS of 8.3 months 
(P10-13065).
1.2
DRUG PROFILE
BI 836826 is a mouse-chimeric antibody of the IgG1 isotype, directed against human CD37.
CD37, a member of the tetraspanin superfamily, is a glycosylated cell surface protein which 
is predominantly expressed on B cells, with highest expression levels on mature peripheral 
blood B cells. The CD37 antigen is expressed on the majority of malignant cells in patients 
with B-NHL and CLL (R08-2979, R08-2943, R08-2981, R08-2945, R08-2942).
The physiological function of CD37 in humans remains unknown (R08-2979, R08-2946). 
Mice deficient for CD37 display no changes in development and cellular composition of 
lymphoid organs but have reduced levels of IgG1 and attenuated T-cell mediated immune 
reactions (R09-5412). Studies with CD37-/- T cells suggest a role for CD37 in T cell 
proliferation and regulation of IgA response (R09-4740, R09-5414).
BI 836826 has been investigated preclinically; This phase 1 trial is the first trial in humans 
with B-NHL malignancies, and few others are in the planning phase. There are also 
additional trials currently ongoing with BI 836826 in patients with chronic lymphocytic 
leukemia (CLL).
In vitro assays demonstrated that BI 836826 specifically recognizes human CD37 and binds 
with high affinity to this antigen. The number of BI 836826 binding sites was 53000 for B 
cells and 1900 for T cells on average, i.e. a 28-fold higher expression is seen on B cells. BI 
836826 was able to deplete endogenous, normal B cells and Ramos Burkitt lymphoma cells
in a human whole blood assay without affecting endogenous T-cells and monocytes. Data 
from the analysis of primary CLL patient derived blood samples indicates that BI 836826 
efficiently depletes malignant CLL cells (R10-6346). BI 836826 is a potent inducer of 
apoptosis and antibody dependent cellular cytotoxicity (ADCC) and does not show CDC 
activity (R10-6345). The pro-apoptotic activity of BI 836826 does not depend on IgG cross-
linking.
 
 
 
 
 
 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT – RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
CD37 is predominantly expressed on B cells, with highest expression levels on mature 
peripheral blood B cells, reduced levels on plasma cells and low levels on monocytes, T cells, 
macrophages, and granulocytes (R08-2979, R09-4740, R09-4739). The physiological 
function of CD37 in humans remains unknown (R08-2979, R08-2946). However, mice 
deficient for CD37 display no changes in development and cellular composition of lymphoid 
organs but have reduced levels of IgG1 and attenuated T cell mediated immune reactions 
(R09-5412). The majority of malignant cells in patients with B-NHL express the CD37 
antigen (R08-2979, R08-2943, R08-2981, R08-2945, R08-2942). Therefore, targeting CD37 
in malignancies of B cell origin may offer a new treatment option.
Clinical data of advanced B-NHL patients who were treated with the fully murine CD37 
antibody MB-1 are published (R10-2734, R10-2735). In these trials, administration of a 
radio-immunoconjugate of MB-1 was safe, led to fast and specific B cell reduction, a low 
degree of T cell reduction and induced tumour shrinkage in advanced B-NHL patients 
already with tracer doses of the attached isotope.
The anti-CD37 small modular immuno-pharmaceutical (SMIP) TRU-016 was well tolerated 
in an ongoing phase I trial at doses up to 20 mg/kg in patients with CLL, with predominantly 
haematological dose limiting toxicities. No formal maximum tolerated dose has been defined
(R10-6640).
The clinical experience with MB-1 and TRU-016 supports the assumption that targeting 
CD37 in the human leads to lymphocyte reduction and consecutive lymph node shrinkage 
with an acceptable side effect profile.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to determine the maximum tolerated dose (MTD) of BI 
836826 in patients with NHL of B cell origin. BI 836826 is a new biological entity and the 
maximum planned single dose was1400 mg. However, the MTD has been reached at 100 mg 
in monotherapy. This dose was declared based on safety demonstrated during the dose 
escalation which was performed in Caucasian patients. During the expansion phase additional 
sites were added in South Korea. A total of 4 patients have been enrolled into expansion 
cohort at 100mg, and all of them were from S. Korea. Three out of 4 Korean patients have 
developed significant toxicities (infections) which lead to the need of exploring a lower dose 
levels (50 and 75mg) in a designated escalation cohort of Korean patients to further 
characterize safety and efficacy of BI 836826 (c02337389-01). Secondary objectives are to 
document the safety and tolerability of BI 836826, to perform 
 
pharmacodynamic analyses and to evaluate relevant biological effects in terms of parameters 
of efficacy.


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2.3
BENEFIT - RISK ASSESSMENT
Progress in understanding the biologic behaviour of the different subtypes of NHL has been 
achieved and effective treatment regimens have been developed. However, most patients with 
indolent NHL and approximately half of the patients with aggressive NHL still die of their 
disease. In particular, patients with resistant disease, patients who are not considered eligible 
for high-dose immunochemotherapy, patients with relapse after high-dose
immunochemotherapy with stem cell support and patients with rituximab refractory disease 
have a need for new therapeutic options. 
Patients with relapse of aggressive B-NHL, either after high-dose immune-chemotherapy 
with stem cell support or patients who are not candidates for high-dose therapy (e.g. due to 
comorbidity) are offered immunotherapy, chemotherapy, radiotherapy and/or prednisone. 
However, these therapies are considered palliative. For patients who are not candidates for 
allogeneic transplantation and have progression of indolent B-NHL after at least two prior 
therapies no standard therapy exists. Available treatment options are not curative and 
response may be limited with short lasting effect. In the clinical setting, the depletion of B 
cells with BI 836826 may potentially result in an anti-tumour activity as a monotherapy. 
Further development in combination with other monoclonal antibodies or cytotoxic drugs 
may be possible in patients with NHL of B cell origin. Targeting CD37 may potentially offer 
a benefit to the patients, because cross-resistance with prior therapies is not expected. 
BI 836826 is a monoclonal antibody which specifically targets CD37. In vitro, BI 836826 
was able to induce apoptosis and antibody dependent cell mediated cytotoxicity of the target 
cells. In vivo studies in mice and cynomolgus monkeys show depletion of B cells from blood 
and lymphatic organs. 
Human experience with BI 836826
Preliminary data from two ongoing Phase 1 monotherapy trials are available, one in relapsed 
CLL and the other in relapsed NHL. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The trial is an open-label, non-randomized phase I dose-escalation trial with modified 3+3 
design to evaluate the tolerability and safety of BI 836826, and to determine the MTD or to 
establish the recommended dose for further development. 
Single patient cohorts will be treated until a drug-related adverse event of CTCAE grade 2 or 
higher occurs during the first two weeks of the first treatment course, i.e. from first infusion 
to 7 days after the second infusion. When this occurs the single patient cohort and all 
subsequent cohorts will be expanded to three patients, following a fixed dose-escalation 
design with dose de-escalation steps (R04-0569), i.e. the single patient cohort will be 
expanded with 2 additional patients to 3 patients in total. When one patient of the cohort of 
three patients experiences a dose limiting toxicity (DLT) (for definition see 5.2.1.1), three 
additional patients will be treated at the same dose level according to a standard 3+3 design. 
If none of the three additional patients experiences a DLT, then the dose-escalation will be 
continued by treating the next cohort of three patients at the next higher dose level. If at least 
two out of up to six patients at a dose level experience a DLT, the MTD has been exceeded 
and the dose will be de-escalated until a dose level is reached in which at most one DLT out 
of six patients is observed (R01-0028). At the MTD, no more than one patient out of six 
patients may experience DLT, i.e. the MTD is defined as the highest dose studied for which 
the incidence of dose-limiting toxicity is no more than 17% during the first 2 weeks of the 
first course.
During the dose-escalation phase, each patient will receive 1 infusion given once weekly 4 
times (days 1, 8, 15 and 22) followed by observation for at least 27 days after the last 
infusion. Unless the first administration will be split (refer section 4.1). Patients, who are
without clinical signs of progression after the first 4 infusions and tolerate the drug well, can 
receive an additional course with 4 infusions (once weekly) at the same dose in agreement 
between investigator and clinical monitor of Boehringer Ingelheim. Course 1 and 2 will have 
duration of 7 weeks each (Figure 3.1: 1). Patients with response or stable disease with clinical 
benefit (e.g. tumour reduction, improvement in disease related symptoms) after the second 
course can receive a third course of 4 infusions (once weekly) if there is good tolerability of 
the drug. The third course can only be started after agreement between investigator and 
clinical monitor of Boehringer Ingelheim. The duration of the third course will be 12 weeks, 
4 infusions once weekly followed by 55 days of observation after last infusion. In general, a
maximum of 12 infusions is allowed per patient. After the end of treatment (EOT) visit the
patients will be followed at least every 6 weeks for up to 6 months after EOT.


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Figure 3.1: 1: Treatment schedule for 1270.2
Enrollment will be sequential during dose-escalation. For early evaluation of adverse events, 
there will be at least 7 days between each patient within a dose cohort and at least 14 days 
between the first infusion of the last patient at a dose level and the first infusion to the first 
patient at the next higher dose level.
Depending on the observed adverse events, dose cohorts on escalating dose levels will be 
enrolled until the MTD has been defined by the occurrence of DLT (see section 5.2.1.1).
Before each dose-escalation, the available data of all previous dose cohorts will be reviewed. 
The data will also be independently assessed by a data safety monitoring board (DSMB) who 
will give recommendation for the dose for the next cohort (see section 4.1.3). Once the MTD 
is defined, a dose for treatment of the expansion cohort will be determined, which will not 
exceed the MTD. In case an MTD will not be reached at the highest predefined dose of 
1400 mg, an OBD may be defined instead. An OBD will be determined by the sponsor of the 
trial using all available data from safety  
 and pharmacodynamic analyses
(e.g. depletion of B cells) and efficacy (e.g. reduction in tumour size). The dose 
recommendation for the expansion cohort (either MTD or OBD) will be independently 
reviewed by the DSMB in the same way as outlined previously for the dose-escalation phase 
of the trial. The competent authority will receive a summary of all safety findings observed 
by that time and the recommended dose for the expansion cohort. 
After the MTD, it was planned to enroll up to 40 patients into an expansion cohort to better 
characterize the safety of BI 836826 and to enable a potential adaptation of the 
recommendation for a phase II dose prior to starting the next trials. Approximately half of the 
patient population in the expansion cohort was planned to have aggressive NHL and 
approximately half would have indolent NHL. Preliminary evaluation of efficacy in the 
expansion cohort was also planned. Due to safety signals in the initial three out of four 
Korean patients enrolled into expansion cohort at the defined MTD of 100mg, this cohort will 
be closed for enrollment. Instead, lower dose escalation cohorts of 50mg and 75 mg will be 
open to test the safety, tolerability 
 in additional Korean patients (3-6 
patients per dose level) following the 3+3 design. An initial safety analysis will be performed
after the first 3 patients have been enrolled at 50mg. If the number of observed DLTs is 0, the 
W2
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dose will be escalated to 75 mg in three additional Korean patients. If there is one DLT 
observed at 50 mg dose, the 50 mg cohort will be expanded to 6 patients. If none of the three 
additional patients experiences a DLT, the dose will be escalated to 75 mg. Patients enrolled 
in the additional cohort of Korean patients will receive the same dosing schedule as described 
above provided that treatment is considered safe based on the emerging data on safety 
 
 from patients treated during the dose-escalation phase. No more 
than one patient can initiate dosing on any given day.
3.1.1
Administrative structure of the trial
Boehringer Ingelheim is the sponsor of this trial. The participating investigators will be 
physicians experienced and specialized in the treatment of NHL and in the conduct of phase I 
trials.
A Data Safety Monitoring Board (DSMB) will perform regular safety assessments, provide 
recommendations for dose-escalation and for continuation, modification or termination the 
trial. Frequency of meetings, functions and responsibilities of the DSMB will be described in 
the DSMB Charter.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The primary objective of this trial is to determine the MTD. The most important secondary 
objective is to assess the safety of BI 836826. This can be achieved by an open-label, single 
arm trial design without a control group.
The investigational drug BI 836826 will be administered as monotherapy. At the lowest dose 
cohorts, single patients are to be enrolled to limit the number of patients who are receiving 
doses of the drug which may not exert a relevant pharmacodynamic effect in humans. 
Stipulated by drug related adverse events CTCAE grade 2 or higher, cohorts of single 
patients will be expanded to cohorts of at least 3 patients as described in section 3.1, and the 
trial design will follow a standard 3+3 design with dose-escalation and de-escalation. 
According to the interim safety analysis of the trial results, the MTD was defined for 
Caucasian patients to be 100 mg. Once the MTD has been defined for Asian patients the 
enrollment will be stopped. Given the recent safety signals at 100 mg, the current expansion 
cohort at MTD of 100 mg will be closed for enrollment after having enrolled 4 patients from 
S Korea, and a new, small cohort will be open to test the 50 mg and 75 mg dose in Korean 
patients.
At screening, blood samples are drawn, a physical examination and a routine CT scan are 
performed, and the patient is evaluated for eligibility in the trial. Bone marrow 
aspirate/biopsy may be performed at the discretion of the investigator. In case a bone marrow 
aspirate/biopsy has been performed after the latest therapy before this trial, it should be 
recorded.


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Clinical disease status will be assessed at screening, at the administration of the first and the 
last of the 4 infusions and 3 weeks after the last infusion of a respective course with physical 
examination, clinical assessment of the B-NHL, and blood samples. CT scans in this trial will 
be performed in accordance with published guidelines for response evaluation in lymphoma 
(R04-1585) and correspond to the use in clinical practice (section 5.1.2.2). A CT scan will be 
done prior to treatment (may be performed up to 8 weeks (preferably 4 weeks) prior to first 
infusion), after 2 courses of treatment, (i.e. at week 13 +/- window), and just before the end of 
treatment (EOT) visit (i.e. week 25 +/- window). If the CT scans are not possible or available,
magnetic resonance imaging can be used instead. However the same imaging methods should 
be used consistently throughout the trial. Bone marrow examination, PET scan and additional 
CT scans will be performed at the discretion of the investigator. Results of CT scan, optional 
PET scan or bone marrow examination performed during the conduct of the trial should be 
reported in the eCRF. After the EOT visit which may occur at the latest at week 26, the 
patient will enter the follow-up phase. During the follow-up phase, disease status evaluations 
(physical examination, clinical assessment of lymphoma, and blood samples) should be 
performed at least every 6 weeks until 6 months after the EOT visit, administration of new 
anti-lymphoma therapy or death, whatever occurs first. More frequent visits may be 
indicated, e.g. for follow-up of laboratory parameters or adverse events which have not been 
resolved at the EOT visit.
3.3
SELECTION OF TRIAL POPULATION
3.3.1
Main diagnosis for study entry 
The eligible patients for the trial are patients with non-Hodgkin lymphoma of B cell origin, 
who have progression of disease either after having received high-dose therapy with stem cell 
support or who are not eligible for high-dose therapy. There is no standard of care for these 
patients and only minorities of the patients obtain durable responses and/or long progression 
free intervals with the current available therapies.
3.3.2
Inclusion criteria
1. Patients with relapsed or refractory non-Hodgkin lymphoma of B cell origin (mature B 
cell lymphoma according to WHO) not considered candidates for intensive anti-
lymphoma therapy
2. Patients must have either aggressive NHL and received at least one prior anti-CD20 
containing immunochemotherapy or indolent NHL and received anti-CD20 therapy and at 
least two prior therapies (see appendix 10.2) 
a. Patients with aggressive NHL who have received at least one prior anti-CD20 
containing immunochemotherapy and have
i. 
relapse/progression and is not considered a candidate for high-dose 
immunochemotherapy with autologous stem cell support or allogeneic 
transplantation
ii.
relapse/progression after high-dose immunochemotherapy with 
autologous stem cell support
iii.
relapse/progression after allogeneic stem cell transplantation if without 


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immunosuppression for at least 8 weeks and no evidence of active 
GvHD (this criterion applies only for the expansion cohort)
b. Patients with indolent NHL who have received anti-CD20 therapy and at least 
two prior therapies and have
i.
relapse/progression and is not considered a candidate for high-dose 
immunochemotherapy with autologous stem cell support or allogeneic 
transplantation
ii.
relapse/progression after high-dose immunochemotherapy with 
autologous stem cell support
iii.
relapse after allogeneic stem cell transplantation if without 
immunosuppression for at least 8 weeks and no evidence of active 
GvHD (this criterion applies only for the expansion cohort)
3. Measurable disease on CT scan with involvement of at least one clearly demarcated 
lesion ≥2 cm or two or more clearly demarcated lesions of >1.5 cm at longest diameter 
(this criterion applies only for the expansion cohort)
4. Relapse or progression of disease with an indication for therapy as per investigator’s
judgement
5. Life expectancy of ≥3 months as per investigator’s judgement
6. ECOG Performance Status 0 or1 (see appendix 10.3)
7. Age ≥18 years
8. Written informed consent which is consistent with ICH-GCP guidelines and local 
legislation
3.3.3
Exclusion criteria
1. Primary central nervous system (CNS) lymphoma or known CNS involvement
2. Prior history of malignancy other than a mature B cell neoplasm according to WHO 
classification (R10-6296) (except basal cell or squamous cell carcinoma of the skin, or 
carcinoma in situ of the uterine cervix or breast treated with curative therapy) unless the 
subject has been free of disease and without treatment for at least 5 years
3. Last chemotherapy < 4weeks prior to visit 1
4. Last anti-CD20 therapy (non-radiolabelled) <4 weeks prior to visit 1
5. Last corticosteroid <2 weeks prior to visit 1 unless the dose is ≤10 mg/day prednisolone
or equivalent
6. High-dose therapy with stem cell support <6 months prior to visit 1
7. Radio-immunotherapy <3 months prior to visit 1
8. Prior allogeneic stem cell transplant (this criterion applies only for the dose-escalation 
cohorts)
9. AST or ALT >2.5 x upper limit of normal (CTCAE grade 2 or higher)
10. Total bilirubin >1.5 x upper limit of normal (CTCAE grade 2 or higher)
11. Absolute neutrophil count <1.0 x 109/L (without growth factor support)
12. Platelets <25 x 109/L (without growth factor support or transfusions)
13. Calculated GFR < 45 mL/min (see appendix 10.5)
14. Proteinuria CTCAE grade 2 or higher


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15. Significant concurrent medical disease or condition which according to the investigator’s 
judgement would either compromise patient safety or interfere with the evaluation of the 
safety of the test drug, e.g. symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia requiring therapy with the exception of extra systoles or minor 
conduction abnormalities
16. Chronic or ongoing infection requiring treatment at the time of enrolment or within the 
previous two weeks
17. Active hepatitis B or hepatitis C, or laboratory evidence for a chronic infection with 
hepatitis B or C (see 5.2.3.3.1)
18. HIV infection
19. CMV viraemia
20. Women of childbearing potential not using a highly effective method of birth control 
during the trial until one year after the last dose. Highly effective methods of birth control 
are defined as those which result in a low failure rate (i.e. less than 1% per year) when 
used consistently and correctly used such as implants, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised 
partner. Barrier methods of contraception are accepted if condom or occlusive cap is used 
together with spermicides (e.g. foam, gel). Female patients will be considered to be of 
childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal 
ligation/salpingectomy, or postmenopausal for at least two years
21. Pregnancy or breast feeding
22. Known or suspected active alcohol or drug abuse as per investigator’s judgment
23. Treatment with another investigational drug within the past four weeks before start of 
therapy or concomitantly with this trial
24. Prior treatment with BI 836826
25. Patients unable to comply with the protocol as per investigator’s judgement
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
A patient has to discontinue trial drug administration in case

A DLT occurs which does not recover to a degree that allows treatment continuation (see 
4.1.4.3)

Progressive disease or any other concomitant diagnosis/symptom develops resulting in an 
indication to start any other therapy for lymphoma, including deterioration of general 
condition
An individual patient is to be withdrawn from trial in case

The patient withdraws consent. Patients are free to discontinue their participation in this 
trial at any time without the need to justify the decision

The patient needs concomitant drugs that may interfere with the investigational product 
(please refer to section 4.2.2)


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
The patient is no longer able to participate for other reasons (e.g. adverse events unrelated 
to therapy or disease progression, concomitant diagnoses, pregnancy, surgery or 
administrative reasons). The investigator may also stop a patient’s participation if the 
patient is unable to attend trial visits
A patient can be withdrawn after discussion between the investigator and the clinical monitor 
at Boehringer Ingelheim if eligibility criteria are violated and/or the patient fails to comply 
with the protocol.
All withdrawals will be documented and the reason for withdrawal recorded and discussed, as 
necessary, in the final report of the trial. As soon as a patient is withdrawn from the trial, the 
EOT has to be performed if feasible (see Flowchart for Course 3). Every effort should be 
made to follow-up patients in case an AE is still ongoing at the time of withdrawal.
Patients who have not completed at least two administrations will be replaced at the same 
dose level. 
Patients who terminate trial treatment due to DLT will not be replaced.
3.3.4.2 
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Violation of GCP, the clinical trial protocol (CTP), or the contract by a trial site or 
investigator, disturbing the appropriate conduct of the trial
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial
3. Failure to meet expected enrolment goals overall or at a particular trial site
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the first reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
BI 836826 will be administered as an intravenous infusion. The first course of treatment has a 
duration of 7 weeks which starts with one infusion weekly 4 times followed by 27 days of
observation after the 4th infusion (Figure 3.1:1), unless the split first dose administration 
described below will be implemented. A second course similar to course 1 can be 
administered, if the drug is well tolerated and the patient has no clinical signs of progression, 
judged by the treating physician. An additional third course of 4 weekly administrations can 
be given to the patients with response (i.e. complete or partial remission) and patients with 
stable disease, who tolerate the drug well and have clinical benefit. Clinical benefit can be 
improvement of clinical symptoms, and/or reduction in tumour size not meeting the criteria 
for a partial remission at the response assessment at the end of the second course.
The first infusion in each course should be started at a rate of 10 mL/h. The infusion rate can 
be increased every 30 (+/-10) minutes by 10 mL/h to a maximum of 80 mL/h as long as 
tolerated by the patient. If considered safe by the investigator, the subsequent infusions may 
be given with shorter interval for increasing the rate, but the maximum rate should not exceed 
120 mL/h.
If adverse events which are considered related to the infusion schedule, e.g. infusion-related 
reaction, are not well controlled by the above schedule an alternative administration will be 
used. The first administration in course 1 will be split into two infusions, a low dose on day 1 
followed by the full dose on the day 2. The first part of the administration will be 10% of the 
full dose, but not exceeding 10 mg given on day 1. The day after the second part of the 
administration will be the full planned dose for the patient (please refer the flowchart in 
section 10.7). The same infusion schedule should be employed as described above, starting 
with a rate of 10 mL/h. Premedication is mandatory before both infusions as they will be 
considered as the first administration (section 4.1.4.1.1.). The potential change of the first 
infusion into two infusions will be assessed and may be modified by the DSMB. In 
subsequent administrations, the full dose of BI 836826 will be administered as a rate-
controlled intravenous infusion on day 1.
If symptoms of an infusion related reaction occur, the infusion should be temporarily 
stopped. Upon recovery, it should be resumed at 50% of the rate at which the reaction 
occurred for at least 30 minutes. Lower rates may be selected if clinically indicated. 
Depending on the time of occurrence and the severity of the reaction, the investigator may 
consider administering additional supportive medication, e.g. corticosteroids. A stepwise re-
increase of the infusion rate to a maximum of 80 mL/h is possible.
For medical reason, the duration of the infusion may be expanded until the use-by date and
use-by time indicated on the label is reached. The actual duration of the infusion needs to be 
documented in the eCRF including actual start and end time, actual time points for 
interruption and restart of the infusion and the actual infusion rates.


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Adverse events during the infusion should be thoroughly documented and characterized to 
allow differentiation between infusion-related reactions and tumour lysis syndrome 
(R10-4428, R10-4517).
4.1.1
Identity of BI investigational product and comparator product
Substance (INN):
BI 836826
Pharmaceutical form: 
Solution for infusion after dilution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/mL (vials with 10 mL)
Daily dose:
See section 4.1.3
Duration of use:
Single dose or split dose (2 doses) only applicable 
for course 1 once weekly for 4 times followed by 
27 days of observation after last administration, i.e
7 weeks = course 1. A similar additional course 2
can be given, if drug is well tolerated and no signs 
of progression. For patients with remission or stable 
disease with clinical benefit additional weekly 
infusion for 4 times followed by 55 days of 
observation can be administered (course 3). 
Maximum 12 infusions = 3 courses.
Further infusions only after agreement between 
sponsor and investigator on a case by case
Route of administration:
Intravenous
Posology:
Rate controlled infusion
See Section 4.1.6
4.1.2
Method of assigning patients to treatment groups
This is a single arm, open-label, dose-escalation trial. Assignment of a patient to a dose has to 
be confirmed by the investigator with the clinical monitor of the sponsor as described below 
in sections 4.1.3 and 4.1.4.
4.1.3
Selection of doses in the trial
BI 836826 will be administered as a rate-controlled, intravenous infusion..
A fixed dose of 1 mg BI 836826 per patient is expected to be the safe first in human starting 
dose for patients with an advanced haematological malignancy. The calculation of the safe 
starting dose of 1 mg in humans was based on data from studies in cynomolgus monkeys and 
from ex vivo experiments with primary B cells obtained from fresh blood samples of CLL 
patients. This dose is anticipated to represent a low pharmacologically active dose which may 
be capable to result in a detectable B cell reduction in the peripheral blood. For details please 
refer to the Investigator’s Brochure, section 5.3.6 (c01715907-08).


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The dose was planned to be escalated in cohorts at predefined dose levels based on a 
multiplication factor of approximately 3 in the low dose range (1-25 mg), a factor of 2 at 
doses of 25-800 mg and from the dose of 800 mg and onwards additional 200 mg per dose. 
The dose levels were initially planned to be: 1 mg, 3 mg, 9 mg, 25 mg, 50 mg, 100 mg, 200 
mg, 400 mg, 800 mg, 1000 mg, 1200 mg and 1400 mg, however the MTD was established at 
100mg based on safety data from Caucasian patients. An additional cohort of Korean patients 
will be tested at 50 and 75mg.Every time a dose-escalation is to be performed, all patients at 
the last cohort must have had 2 infusions of BI 836826 and at least 7 days observation after 
the second infusion. The available data of all previous dose cohorts will be reviewed. The 
data will be provided to the DSMB who will be asked to provide an independent assessment 
including the dose recommendation for the next cohort. As a result, lower dose increments 
than the predefined levels will be possible.
4.1.4
Drug assignment and administration of doses for each patient
Dose allocation will be controlled by the sponsor to ensure safety monitoring and the dose-
escalation schedule is adhered to in the interest of the safety of the patients. In the dose-
escalation phase there will be at least 7 days between first dose for patients in the same dose 
cohort and at least 14 days between first dose for last patient and first dose for first patient in 
different dose cohorts. Each investigational site must notify the sponsor when an eligible 
patient is identified. Prior to inclusion of a new patient during the dose-escalation phase the 
investigator has to confirm the actual dose tier of BI 836826 for the patient with the clinical 
monitor of the sponsor who oversees the dose-escalation steps and the safety data of patients 
from all trial sites. Enrollment will only be possible after the sponsor has notified the site by 
written confirmation of the dose and earliest possible date of first administration.
BI 836826 will be administered as an intravenous infusion under the supervision of the 
investigator or designated personnel.
BI 836826 may be administered at any time during the day. However, to facilitate blood 
sampling for 
 and pharmacodynamic analyses, it is recommended to 
start the infusion during the morning hours.
4.1.4.1
Prophylactic measures
4.1.4.1.1 Premedication
Premedication is mandatory 30-120 minutes prior to the administration of BI 836826 to 
prevent/reduce severity of infusion-related reactions, unless a contraindication for 
premedication exists. The premedication for the first and the second administration of the 
first course should include

Acetaminophen/paracetamol 1000 mg p.o. or a clinically comparable dose, or equivalent

Antihistamine p.o. or i.v., equivalent to diphenhydramine 50 mg i.v.

Glucocorticoid i.v., equivalent to prednisolone 100 mg


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If BI 836826 has been well tolerated without signs of infusion-related reactions during the 
second administration, glucocorticoid premedication may be reduced to 50% of the 
administered dose starting with the third administration, i.e. glucocorticoid i.v., equivalent to 
prednisolone 50 mg at third administration and glucocorticoid i.v., equivalent to prednisolone 
25 mg at fourth administration.
If a second and third course of 4 administrations is initiated, the premedication dose has to be 
repeated with glucocorticoid i.v., equivalent to prednisolone 100 mg at the first and second 
administration of BI 836826. If the infusion is well tolerated, glucocorticoid i.v. can be 
reduced as described above.
4.1.4.1.2 Monitoring for infusion-related reactions
Close monitoring of the patient during and after the infusion of BI 836826 is required for 
evaluation of infusion-related risks. The measures of monitoring include:

Hospitalization of patients with access to intensive care

Frequent measurements and documentation of blood pressure and heart rate (see section 
5.2.5.1)
During the treatment the patients are required to be hospitalized under close surveillance with 
access to intensive care for at least 48 hours during the first infusion of BI 836826 and at least 
24 hours during the second infusion (both in course 1). Hospitalization is also required for at 
least 24 hours during the first infusion in course 2. If there is no relevant infusion-related 
adverse events, the decision to hospitalize the patient is left to the discretion of the 
investigator.
If the split first dose administration is employed patients are required to be hospitalized under 
close surveillance with access to intensive care for at least 72 hours for the 1st visit in course 
1 and at least 24 hours during the second infusion in course 2. Hospitalization is required for 
at least 24 hours during the first infusion in course 2. In case of no relevant infusion-related 
adverse events, the decision to hospitalize the patient is left to the discretion of the 
investigator.
4.1.4.1.3 Tumour lysis syndrome
All patients have to be monitored for clinical or laboratory evidence of tumour lysis 
syndrome (see section 5.2.3.2). To prevent tumour lysis syndrome, all patients should receive 
appropriate hydration and allopurinol according to local standards or available guidelines 
(R10-4517). In addition, close monitoring of laboratory parameters to allow for early 
diagnosis of a possible tumour lysis syndrome is recommended, for details please refer to
section 5.2.3.2.CTCAE classifies TLS in grade 3 (present), grade 4 (life threatening 
consequences; urgent intervention indicated) and grade 5 (death). Presence of TLS is not 
clearly defined by CTCAE (R10-4848). For this trial the Cairo-Bishop classification will be 
used to define presence of TLS, i.e. presence of clinical TLS (R10-4517).


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4.1.4.2
Handling of infusion-related reactions
In case of an infusion-related reaction, appropriate measures depending on the type and 
severity of the reaction should be taken by the investigator according to best medical 
judgement and local guidelines. Supportive therapy including steroids may be used as 
clinically indicated. The time between start and end of infusion may not exceed 24 hours. In 
case management of an infusion-related reaction would require more than 24 hours between 
start and end of the infusion of BI 836826, the infusion has to be stopped at 24 hours and the 
residual solution has to be discarded. The actual dose which has been administered prior to 
reaching this time limit has to be documented.
Changes of the infusion rate and temporary interruptions of the infusion have to be recorded 
in the eCRF.
Infusion-related reactions CTCAE grade 3 and 4 are defined to be significant adverse events 
and have to be reported according to the rules defined for SAE-reporting (see section 5.2.2.1).
The following recommendations for the management of infusion-related reactions may be 
considered by the investigator as guidance:

In the case of an infusion-related reaction CTCAE grade 1, the infusion rate of BI 836826 
should be reduced, e.g. to 50% of the target rate, or the infusion should be temporarily 
interrupted and resumed as soon as considered clinically manageable by the investigator.

In the case of an infusion-related reaction CTCAE grade 2 or 3, the infusion with 
BI 836826 should be stopped immediately. Only in case all symptoms have resolved, 
administration of BI 836826 may be resumed. The investigator may consider to re-start at 
a slower infusion rate, e.g. of 50% of the target rate, and increase the infusion rate as 
tolerated to the target rate.

In the case of an infusion-related reaction CTCAE grade 4, the infusion has to be stopped 
immediately. These patients should not be re-exposed to BI 836826 after the event.
4.1.4.3
Management of infections:
During treatment with BI 836826 patients need to be carefully monitored for infections at 
each clinic visit. Frequent blood counts monitoring will help to identify patients with 
prolonged neutropenia who might be at risk for severe infections. It is highly recommended 
that the treatment of infection starts immediately upon very first clinical symptoms. 
Depending on investigators’ assessment the use of growth factors, antibiotics, antifungals, 
and antivirals should be considered, and implemented with no delay. The next administration
of BI 836826 needs to be delayed until the patient has cleared an infection and has recovered 
from neutropenia as outlined in sec: 4.1.4.4
4.1.4.4
Continuation of Treatment during a Course, or beginning a new course
Adverse events and laboratory values will be evaluated continuously by the sponsor. Prior to 
each administration of BI 836826, adverse events and safety laboratory will be assessed. To 


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continue treatment with a further infusion of BI 836826, all of the following criteria must be 
met:
(1)
No active infection
(2) 
Neutrophils ≥1000 /μL (1.0 x 109/L) and platelets ≥25.000 /μL (25 x 109/L), with or 
without growth factor support or transfusions.
(3) 
no evidence of progressive disease
(4)
Acceptable tolerability (in case of an adverse event at the planned start of a treatment 
course, patients may continue therapy only after recovery to a level which would 
allow further therapy, i.e. CTCAE grade 1 or pre-treatment value.)
In case criterion 1 and/or 4 is not fulfilled, blood counts and/or the adverse event should be 
re-evaluated for up to three weeks. A delay during a course should be communicated to the 
clinical monitor at Boehringer Ingelheim. As soon as all criteria 1-4 are met, the investigator 
in agreement with the clinical monitor at Boehringer Ingelheim may continue the treatment 
(unless other criteria for discontinuation or withdrawal apply, see section 3.3.4.1). If a visit 
with administration of BI 836826 is delayed, all subsequent visits with treatment 
administration will be recalculated based on the actual date of delayed visit. If a visit is 
delayed less than 5 days, the delay may be caught up by shortening the observation period of 
the course after agreement between investigator and clinical monitor of the trial, provided 
that patient fulfills all the requirement for the next treatment (see section 6.1).
In case an adverse event is continuing at a CTCAE grade 2 or higher without recovery to 
grade 1 within 5 weeks after the last BI 836826 infusion and this is above the pre-treatment 
level, the investigator in agreement with the clinical monitor at Boehringer Ingelheim may
continue BI 836826 only in the case that the event is considered not drug-related by 
investigator and sponsor.
Administration of the trial drug has to be stopped temporarily in case of a DLT (see section 
5.2.1.1). Patients may continue therapy only after recovery from the DLT to at least CTCAE 
grade 1 or pre-treatment value. The future dose of BI 836826 must be finally agreed on 
between the sponsor and the investigator. A reduction of the dose will be allowed only once 
for an individual patient during the whole trial. Treatment has to be discontinued in case the
DLT is not reversible.
Intra-patient dose-escalation of BI 836826 will not be allowed in this trial.
During the dose-escalation phase, the first course (4 administrations as weekly infusions) 
should be given to all patients. In absence of clinical progression judged by the investigator, 
treatment with BI 836826 can be continued for the second course, (i.e. another 4 
administrations) in agreement with the investigator and the clinical monitor of the sponsor. 
Patients with a complete or partial remission by CT scan after 8 administrations or stable 
disease with improvement in clinical symptoms may receive additional 4 administrations 
weekly as consolidation therapy after discussion between the investigator and the clinical 


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monitor of the sponsor. Continuation of BI 836826 beyond 12 administrations will only be 
possible on a case by case basis after discussion between the investigator and the clinical 
monitor of the sponsor.
A log of all patients enrolled into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This phase I trial will be performed according to an open-label, single arm design. It will 
recruit patients with relapsed and refractory NHL of B cell origin. This open-label trial will 
be handled in an open fashion by the sponsor throughout, i.e. also for the purpose of data 
cleaning and preparation of the analysis. The eCRF will contain information on the treatment 
and the dose.
4.1.5.2
Procedures for emergency unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
BI 836826 will be supplied in 10 mL vials containing 100 mg BI 836826. For details of 
packaging and the description of the label, refer to the ISF. Medication will be delivered to 
the investigator’s pharmacy where the total dose per patient will be prepared upon request 
from the investigator.
For preparation of the BI 836826 infusion solution, the content of the vial of BI 836826 will 
be diluted in 0.9% sodium chloride. The content of several vials may be needed for 
administration of the requested dose. For further details, please refer to instructions included 
in the ISF.
4.1.7
Storage conditions
BI 836826 has to be stored in a limited access area at the temperature indicated on the trial 
drug label. If the storage conditions are found to be outside the specified range, immediately 
contact the local clinical monitor or the CRA as provided in the list of contacts. For more 
details on BI 836826, please refer to the IB (c01715907-08) and the ISF.
4.1.8
Drug accountability
Drug supplies, which will be provided by the sponsor or a CRO appointed by the sponsor, 
must be kept in a secure, limited access storage area under the storage conditions defined by 
the sponsor. A temperature log must be maintained to make certain that the drug supplies are 
stored at the correct temperature.


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The investigator and/or pharmacist will receive the investigational drugs delivered by the 
sponsor when the following requirements are fulfilled:

approval of the study protocol by the IRB / ethics committee

availability of a signed and dated clinical trial contract between the sponsor and the Head 
of Trial Centre

approval/notification of the regulatory authority, e.g. competent authority

availability of the curriculum vitae of the principal investigator

availability of a signed and dated clinical trial protocol or immediately imminent signing 
of the clinical trial protocol
The investigator and/or pharmacist must maintain records of the product’s delivery to the trial 
site, the inventory at the site, the use for each patient, and the return to the sponsor or 
alternative disposition of unused product. The investigator / pharmacist will maintain records 
that document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational product received from the sponsor.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment
4.2.1.1 Rescue medication
Rescue medication in term of an antidote to reverse the action of BI 836826 is not available. 
Potential side effects of BI 836826 have to be treated symptomatically. 
4.2.1.2 Supportive care
Patients should receive supportive care according to local guidelines regarding treatment of 
infusion-related reactions (section 4.1.4.2 and section 5.2.5.1), infections, blood product 
support, analgesics, skin and mouth care, etc.
In the case of a tumour lysis syndrome, supportive therapy including rasburicase may be used 
as clinically indicated at the investigator’s discretion (section 5.2.3.2).
4.2.1.2.1 Antibiotics and Antivirals
Prophylactic antibiotics and antivirals are allowed. For patients who are considered to have 
an increased risk for herpes and/or pneumocystis jiroveci infections, the prophylaxis is 
mandatory, unless medically contraindicated (see below). For patients who are considered to 
have an increased risk for other infections, prophylactic therapy is recommended, unless 
medically contraindicated.
Prophylactic antiviral therapy is mandatory for patients with a history of recurrent herpes 
virus infections, herpes infection during previous anti-lymphoma therapy, neutropenia and/or 
low CD4+ cell counts (<200 cells/µl), e.g. acyclovir 400 mg three times a day orally. 


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Prophylactic antiviral therapy (e.g. nucleoside reverse transcriptase inhibitor) and/or 
monitoring of hepatitis B DNA in the blood is recommended for patients with a history of 
hepatitis B infection.
Prophylaxis against pneumocystis jiroveci, e.g. oral trimethoprim/sulfamethoxazole 800 
mg/160 mg every other day is mandatory to patients who are considered at increased risk, e.g.
patients with low CD4+ cell counts (<350 cells/µl). 
Infections should be treated early, i.e. at the first clinical signs, with a broadband antibiotics, 
and other agents (antivirals, antifungals, growth factors), as deemed appropriate by the 
investigator. The investigators are expected to apply treatment according to local 
guidelines/standard.
4.2.1.2.2 Growth factors 
The use of growth factors such as granulocyte colony stimulating factor (G-CSF) will be 
allowed during therapy. However, growth factors are not allowed at inclusion and should be 
avoided, if patient’s condition allows, in the first treatment weeks for better assessment of 
safety parameters.
Prophylactic antibiotics and antiviral drugs are allowed during therapy.
4.2.1.3 Concomitant medication
All concomitant therapies to provide adequate care may be given as clinically necessary, 
unless given as anti-lymphoma therapy. All concomitant treatments should be recorded in the 
eCRF except for vitamins or nutrient supplements. Trade name, indication and dates of 
administration of concomitant therapies will be documented. For parenteral nutrition during 
the trial, the components need not to be specified in detail. It should just be indicated as 
‘parenteral nutrition’. If a patient needs general anaesthesia, it will be sufficient to indicate 
‘general anaesthesia’ without specifying the details.
Concomitant therapy should be recorded in the eCRF during the screening and treatment 
period, starting at the date of signature of informed consent, and ending at the EOT visit. 
After the EOT visit, only concomitant therapy indicated for treatment of an adverse event has 
to be reported or if given as new anti-lymphoma therapy.
CMV reactivation during treatment should be treated according to local standards or available 
guidelines (R10-4431).
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Prior therapies for lymphoma must have been discontinued at least of two weeks before the 
first administration of the trial drug (see exclusion criteria section 3.3.3 for details) and the 
patient must have recovered from all clinically relevant reversible toxicities. A time interval 


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of at least four weeks must have elapsed from the last administration of any other 
investigational treatment for NHL to the first administration of BI 836826.
No anti-neoplastic therapy concomitantly is allowed.
No other investigational therapy concomitantly is allowed.
Additional glucocorticoid medications may be used as clinically indicated to treat infusion-
related reactions at any dose. Short term systemic glucocorticoid for lung disease (asthma or 
COPD) may be used. Daily oral steroid treatment may be administered at doses equivalent to 
prednisolone 10 mg per day. All other indications for steroids have to be discussed and 
agreed upon between investigator and sponsor.
Immunoglobulins may not be used within four weeks prior to the first trial infusion and two 
weeks after the last infusion of BI 836826.
4.2.2.2 Restrictions on diet and life style
No restrictions apply with regard to diet or life style.
4.3
TREATMENT COMPLIANCE
BI 836826 will be administered as a single intravenous infusion under supervision of the 
investigator or dedicated clinic personnel. 
 
 Any discrepancies will be explained in the CRF by the
investigator or his/her deputy.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY
5.1.1
Endpoints of efficacy
The efficacy endpoints will be assessed at the time points specified in the flowcharts. 
Efficacy endpoints will be secondary or further endpoints in this trial.
Secondary endpoints of efficacy are:

Tumour size reduction (lymph nodes, spleen and liver nodules) defined as best % change 
from baseline in SPD (all lymph nodes, only spleen nodules, only liver nodules) from CT 
scan data

Best overall response according to Standardized or Revised Response Criteria for 
Malignant Lymphoma (R04-1585) (see section 5.1.2.2)

Progression free survival

Failure free survival
5.1.2
Assessment of efficacy
5.1.2.1
Tumour size
Tumour size of lymph nodes, spleen and liver, nodules will be measured throughout the trial. 
Nodal, spleen, liver and other locations amenable to clinical examination should be assessed 
at indicated time point as well as by CT scans (see flowcharts). The tumour size of the lymph 
nodes will be measured as sum of products of diameter (SPD) of two perpendicular 
dimensions for up to 6 indicator lesions identified at baseline CT scan. Spleen and liver will 
be described, if considered enlarged at baseline by physical examination or CT scan. If 
nodules are present in spleen and/or liver, the diameter of these will be measured in two 
perpendicular dimensions. The change in SPD, spleen and liver nodules will be compared to 
baseline and will be listed by time point.
CT scan description will rely on the description by the local radiologist at the investigational 
site.


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5.1.2.2
Assessment and definition of overall best response
CT scan will be required for response assessment. CT scan will be performed at screening, at 
week 13 and week 25. A CT scan may be performed at end of treatment if therapy terminates 
earlier, e.g. to document progression. Bone marrow biopsy/aspirate may be performed as 
indicated by the investigator, but it will not be mandatory. The best response at any of CT 
scans done will be overall best response. Response will be assessed according to the 
standardized response criteria from 1999 (R04-1585).
5.1.2.2.1 Complete remission
Complete remission (CR) requires complete disappearance of all evidence of disease.
1. Complete disappearance of all detectable clinical and radiographic evidence of disease 
and disappearance of all disease-related symptoms if present before therapy and 
normalization of those biochemical abnormalities definitely assignable to NHL
2. Absence of significant lymphadenopathy, i.e. lymph nodes ≤1.5 cm at the greatest 
transverse diameter for nodes >1.5 cm before therapy. Nodes between 1.1 and 1.5 cm at 
the long axis and >1 cm at the short axis before therapy must have decreased to ≤1.0 cm 
in their short axis
3. Spleen, if enlarged by CT scan before therapy, must have regressed in size and must not 
be palpable on physical examination 
4. Other organs considered enlarged before therapy due to lymphoma must have regressed 
in size
5. Bone marrow aspirate and biopsy demonstrate absence of residual disease (if performed)
5.1.2.2.2 Complete remission unconfirmed
To have CRu the patients have to fulfil criteria 1 and 3 and 4 under 5.1.2.2.1 and at least one 
of the following features.
1. A residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has 
regressed by more than 75% in their SPD. Individual nodes that were previously 
confluent must have regressed by more than 75% in their SPD compared to the size of 
original mass
2. Indeterminate bone marrow (increased number or size of aggregates without cytologic or 
architectural atypia)
5.1.2.2.3 Partial remission
Partial remission (PR) requires all of the following.
1. Decrease of at least 50% in SPD of up to six of the largest dominant nodes or nodal 
masses
2. No increase in size of other nodes or liver or spleen


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3. Hepatic and splenic nodules must have regressed by ≥50% in SPD or in the greatest 
transverse diameter for single nodules
4. Disease in other organs are considered assessable and not measurable disease
5. No new sites of disease should be observed
5.1.2.2.4 Stable disease
Stable disease (SD) is defined as failure to attain the criteria for a CR, CRu or a PR and does 
not fulfil those for progressive disease.
5.1.2.2.5 Relapsed disease (after CR, CRu)/ Progressive disease (after PR, SD) 
At least one of the following criteria is required:

Any new lesion >1.5 cm in any axis

Increase of ≥50% from nadir in SPD of any previously involved nodes or single nodes or 
the size of hepatic or splenic nodules. A lymph node with a diameter of the short axis of 
<1 cm must increase by ≥50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the 
long axis

≥50% increase in the longest diameter of any single previously identified node >1 cm in 
its short axis
5.1.2.3
Progression free survival
PFS is defined as the time from first treatment with BI 836826 until disease progression or 
death.
5.1.2.4
Failure free survival
Some patients will receive a next line of therapy, although no formal PD may have been
diagnosed at the time when the next treatment is indicated according to investigator 
assessment. In addition to PFS, the failure free survival (FFS) will be calculated to assess this 
group of patients. FFS is defined as the time from first treatment with BI 836826 until 
objective disease progression or death or start of next lymphoma therapy.
 
 


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5.2
SAFETY
5.2.1
Endpoints of safety
The primary objective is to assess the safety of the drug in humans and to determine the MTD 
of BI 836826. If an MTD is not reached, an OBD may be defined. For details on 
determination of MTD/OBD, please refer to sections 3.1, 5.2.1.1 and 7.3.1.


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The safety of BI 836826 will be assessed by a descriptive analysis of incidence and intensity 
of adverse events graded according to CTCAE (version 4.0), the incidence dose limiting 
toxicity (DLT), laboratory data and results of physical examination.
An independent DSMB will review the safety data in regular intervals as well as ad hoc if 
needed.
The safety endpoints will be assessed in a descriptive way without confirmatory analyses.
5.2.1.1 Dose limiting toxicity
Dose limiting toxicity (DLT) is defined as any drug-related non-haematological adverse 
event CTCAE grade 3 or higher, except infusion-related reactions associated with the 
administration of BI 836826.
Complications resulting from haematological adverse events, e.g. bleeding due to
thrombocytopenia or infection due to neutropenia are classified as non-haematological
adverse events and are covered by the above definition of DLT. Nevertheless, haematological
adverse events, e.g. neutropenia, thrombocytopenia and anemia will be considered for 
definition of the dose for further development.
The MTD will be defined on the basis of DLT observed during the first 2 weeks of the first 
treatment course. In case of a delay of the second administration, evaluation of DLT should 
be prolonged to 7 days after the second administration. However, for those patients who 
receive more than two doses of BI 836826, all adverse events corresponding to the above 
definition of DLT will be considered for the purpose of confirming the MTD and for the 
selection of the recommended dose for treatment of the expansion cohort and for further 
development. In regular intervals, all available safety data including adverse events 
qualifying for DLT will be submitted to the DSMB. The DSMB will independently assess 
this information and provide recommendations for trial conduct and dose-escalation.
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Protocol-specified significant adverse events
A protocol-specified significant adverse event is defined as an adverse event which is of
particular concern for safety monitoring within this trial. These adverse events need to be 
handled by the investigator according to the rules defined for SAE reporting. “Significant” in 
this context is a regulatory term that is not related to a clinical assessment. Based on 


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preclinical data and experience with other monoclonal antibodies significant adverse events 
defined for this trial are:

Infusion-related reactions (CTCAE grade 3 or higher)

Tumour lysis syndrome

Any event that qualifies for DLT (refer to 5.2.1.1)

DILI 
Although rare, drug-induced liver injury (DILI) is under constant surveillance by 
sponsors and regulators and is considered a protocol-specified significant adverse event. 
Timely detection, evaluation, and follow-up of laboratory alterations of selected liver 
laboratory parameters to distinguish an effect of the underlying malignancy on liver 
function from other causes such as DILI are important for patient safety. The following 
are considered as Protocol-specified significant events: Hepatic injury defined by the 
following alterations of liver parameters:

For patients with normal liver function (ALT, AST and bilirubin within normal 
limits) at baseline an elevation of AST and/or ALT ≥3 fold ULN combined with 
an elevation of bilirubin ≥2 fold ULN measured in the same blood draw sample. 
Patients showing these lab abnormalities need to be followed up according to 
Appendix 10.6 of this clinical trial protocol and the "DILI checklist" provided in 
the ISF.

For patients with impaired liver function at baseline an elevation of AST and/or 
ALT >5 fold ULN combined with an elevation of total bilirubin >2 fold ULN 
measured in the same blood draw sample. Patients showing these lab 
abnormalities need to be followed up according to Appenddix 10.6 of this clinical 
trial protocol and the “DILI checklist” provided in ISF.
Protocol-specified significant adverse events are to be reported in an expedited manner 
similar to Serious Adverse Events, even if they do not meet any of the seriousness criteria -
for details see section 5.2.2.2. If the investigator determines any protocol-specific significant 
adverse event is related to study drug, the administration of the study drug must be managed 
according to section 4.1.4 of the protocol.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability/incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly/birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.


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Intensity of adverse event
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0, in the eCRF.
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms. 
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
No:
There is no reasonable causal relationship between the investigational product
administered and the AE.
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF.
If progressive disease occurs and is associated with symptoms or meets one of the seriousness 
criteria, the verbatim “Progressive Disease” should not be reported, instead the signs and 
symptoms of progressive disease will be reported as an adverse event or a serious AE (if 
applicable). The only exception to the above is in the event of death when attributed to 
progressive disease but where signs and symptoms are not available. In this situation it is 
acceptable to report the progression as the serious AE with the term Neoplasm Progression.
Changes in vital signs, electrocardiogram, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF, if they are judged clinically relevant by the investigator.
5.2.2.2 Adverse event and serious adverse event reporting
Upon inclusion into a trial, the patient’s condition is assessed (e.g. documentation of medical 
history/concomitant diagnoses and diseases), and relevant changes from baseline are noted 
subsequently.
All adverse events, serious, protocol-specified and non-serious, occurring during the course 
of the clinical trial (i.e., from signing the informed consent onwards through the observational 
phase (up to 8 weeks after last drug administration), table 5.2.2.2:1) will be collected, 
documented and reported to the sponsor by the investigator on the appropriate eCRFs / SAE 
reporting forms. Reporting will be done according to the specific definitions and instructions 
detailed in the ‘Adverse Event Reporting’ section of the Investigator Site File.
For each adverse event, the investigator will provide the onset date, end date, intensity/ 
CTCAE grading (according to CTCAE, version 4.0, (R10-4848) treatment required, outcome, 


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seriousness, and action taken with the investigational drug. The investigator will determine 
the relationship of the investigational drug to all AEs as defined in section 5.2.2.1.
All AEs, including those persisting at the End of Treatment (EOT) visit must be followed 
until recovery or in case of persistence, sufficient characterization has been achieved and the 
clinical monitor and the investigator agree to not pursue them further.
SAEs and any trial drug related AE grade 3 still ongoing after the end of trial have to be 
followed until recovery or assessed to be chronic or stable by the investigator.
Table 5.2.2.2:1
AE/SAE reporting requirements
Time Period
Reporting requirements
From signature of informed consent 
until 8 weeks after last 
administration of study drug
Report all AEs, SAEs regardless of relatedness. 
This includes all deaths.
Post treatment (>8 weeks after last 
administration of study drug) until 
end of follow-up (6 months after the 
end of treatment visit)
Report AEs and SAEs which are considered related 
to study drug or study design / procedures.
Please note: All events leading to death should 
always be reported as SAE in this trial.
After the individual patient’s end of 
the trial
The Investigator does not need to actively monitor 
the patient for AEs but should only report relevant 
SAEs and relevant AESIs of which the Investigator 
may become aware of.
Patients may be hospitalized during selected phases of the study as required per protocol, e.g., 
monitoring of trial drug administration, collection of blood for 
 or 
for administrative reasons. Hospitalizations for administrative reasons and other 
hospitalizations already planned at the screening visit need not be reported as a SAE in case 
they are performed “as planned”.
The investigator must report the following events via telephone/fax using the SAE form 
immediately (within 24 hours or the next business day whichever is shorter) to the sponsor:

SAEs and non-serious AEs occurring at the same time as an SAE and/or which are 
medically related to the SAE(s), and protocol-specified significant events. With receipt of 
any further information to these events, a follow-up SAE report has to be provided.

SAEs and non-serious AEs must include a causal relationship assessment made by the 
investigator.

Protocol defined significant AEs, i.e. infusion-related reactions CTCAE grade 3 or 
higher, tumour lysis syndrome and events qualifying for a DLT (see sections 5.2.1.1 and 
5.2.2.1)


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The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File). This 
immediate report is required irrespective of whether the investigational product has been 
administered or not and irrespective of causal relationship. It also applies if new information 
to existing SAEs or protocol-specified significant events becomes available.
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours or next business day 
whichever is shorter) to the defined unique entry point for SAE forms of the respective BI 
OPU (country-specific contact details will be provided in the Investigator Site File). The 
outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical 
Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
5.2.3.1
General safety laboratory parameters
Blood samples and urine have to be collected at the time points specified in the flowchart. 
Safety laboratory examinations will include haematology, biochemistry, coagulation and 
qualitative urine analysis.
Haematology
Haemoglobin, red blood cell count (RBC), white blood cell 
count (WBC) with differential, platelets (PLT)
Reticulocytes have to be measured only at visit of the first 
and last administration of each treatment course, at the EOT 
visit and during follow-up.
Biochemistry
Glucose, sodium, potassium, calcium, inorganic phosphate, 
creatinine, aspartate amino transferase (AST), alanine amino 
transferase (ALT), alkaline phosphatase (AP), lactate 
dehydrogenase (LDH), total bilirubin (if elevated provide 
direct bilirubin), urea, total protein, albumin, uric acid
Serum immunoglobulin levels (IgG, IgM, IgA), direct 
antiglobulin test have to be measured only at visit of first and 
last administration of each treatment course, at the EOT visit 
and during follow-up.
Coagulation
Activated partial thromboplastin time (aPTT), prothrombin 
time (PT)/international normalised ratio (INR)


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Urine
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be 
analysed by dipstick and reported as semiquantitative 
measurements. In case of pathological findings, further 
evaluation should be performed and results documented.
Pregnancy test
A serum pregnancy test needs to be obtained at the time 
points indicated in the flowchart in patients of childbearing 
potential. 
In case a treatment course is delayed due to an adverse event, the patient should visit the site 
at least once a week for assessment of safety laboratory and adverse events. More frequent 
visits may be appropriate as assessed by the investigator.
5.2.3.2 Screening for laboratory evidence of tumour lysis syndrome
Tumour lysis syndrome (TLS) is characterized by metabolic derangements caused by the 
massive and abrupt release of cellular components into the blood after rapid lysis of 
malignant cells. The release of the intracellular metabolites can overwhelm normal 
homeostatic mechanisms, potentially leading to hyperuricemia, hyperkalemia, 
hyperphosphatemia, hypocalcemia, and uremia. This can result in impaired renal function, 
and in some cases, in acute renal failure and even death (R10-4517). To allow for early 
treatment in case TLS develops, vigilant monitoring is recommended. During the first 48 
hours after the start of the first infusion of BI 836826 in course 1, and during the first 24 
hours after the start of the second infusion in course 1 and of the first infusion in course 2, the 
below listed laboratory parameters need to be determined to screen for evidence of a tumour 
lysis syndrome monitored frequently,i.e. every 4-8 hours between the time points at which a 
complete safety laboratory has to be performed. Monitoring for TLS of the second infusion of 
course 2 and the first and second infusion of course 3 are be performed while the patient is in 
hospital. In case of the split first dose administration the same parameters need to be 
determined during the first 72 hours after the start of the low dose of BI 836826 in course 1, 
and for other infusions the monitoring should be as above described. The actual date and time 
of the blood samples should be recorded in the eCRF.
Haematology
haemoglobin, haematocrit, red blood cell count (RBC), white 
blood cell count (WBC),+ differential, platelets (PLT)
Biochemistry
uric acid, potassium, calcium, inorganic phosphate, lactate 
dehydrogenase (LDH), creatinine, urea


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5.2.3.3
Virology
5.2.3.3.1 Screening for hepatitis B, hepatitis C, cytomegalovirus and human
immunodeficiency virus
Patients with active hepatitis B (HBV), hepatitis C (HCV) or laboratory evidence of a chronic 
infection have to be excluded from the trial, i.e. antigen or antibody positive. The same 
applies to patients with a human immunodeficiency virus (HIV) infection.
The following laboratory parameters have to be determined at the screening visit and reported 
in the eCRF: hepatitis B surface antigen (HbsAg), hepatitis B surface antibody (anti-HBs), 
hepatitis B core antibody (anti-HBc), hepatitis C antibody (anti-HCV), HCV RNA.
Screening for HIV infection should be performed according to local standards. The result of 
the HIV assessment has to be reported in the eCRF.
Cytomegalovirus serology (CMV IgG and IgM) should be included in this assessment to 
allow for differentiation between a primary CMV infection and reactivation of CMV during 
the trial.
5.2.3.3.2 CMV monitoring
Monitoring of CMV has to be performed at the time points indicated in the flowchart
according to local standards. Quantitative PCR assays to detect CMV DNA are considered 
acceptable for the purpose of this trial. The same method should be used for all treated 
patients in the same investigational site. Results have to be reported in the eCRF.
5.2.3.4
Lymphocyte typing
At the time points indicated in the flowchart, lymphocyte sub-populations (B cells, CD4+ T 
cells, CD8+ T cells, NK cells) will be quantitatively analysed by standard flow cytometry 
protocols in a specialized laboratory either at the investigational site or at a centralized 
laboratory. Detailed instructions are included in the laboratory manual in the ISF. Results 
have to be reported in the eCRF.
5.2.4
Electrocardiogram
A 12-lead resting ECG will be performed in all patients at the screening visit and at the EOT 
visit. The ECG will be assessed for pathological results (to be recorded as either concomitant 
disease or AE) by the investigator. Additional examinations should be done whenever the 
investigator deems necessary.


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5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Blood pressure, pulse rate and temperature have to be recorded at each visit. At visits with 
infusion of BI 836826 measures have to be recorded prior to the start of premedication and 
infusion of BI 836826. Additional time points at which blood pressure and pulse rate have to 
be documented are every 30 (±10) minutes after start of the infusion of BI 836826, and 60 
(±10) minutes after the end of the infusion, thereafter every 4-8 hours: For the first infusion 
in course 1 monitoring has to be until at least 48 hours after the start of the infusion. For the 
second infusion in course 1 and the first infusion in course 2 monitoring has to be until at 
least 24 hours after the start of the infusion. In case of the split first dose administration 
monitoring has to be at least 72 hours after the start of the low dose.
Patients have to be monitored by means of an automated monitoring device for continuous 
ECG-monitoring and non-invasive intermittent blood pressure monitoring with alarming 
function during the infusion. Since infusion-related reactions are expected to occur mainly 
during the first and second administration (as documented for other monoclonal antibodies 
used for treatment), intensive surveillance with the automated monitoring device should be 
continued for 24 hours after the start of the first and second infusions in the first course. 
Depending on the tolerability of the infusion, the investigator should decide whether to 
prolong and/or intensify monitoring. Monitoring has to be adequately documented in source 
documents.
For patients who did not experience infusion-related reactions CTCAE grade 2 or higher
during previous infusions, the automated monitoring and vital sign documentation can be 
shorten in duration beyond 60 (±10) minutes after the start of infusion as clinically 
appropriate jugded by the investigator. However, this only applies to the 2nd to 4th infusion 
of the 2nd and 3rd treatment course.
5.2.5.2
Physical examination
A physical examination including weight 
 
 will be performed at screening and at the time points specified in the flowchart. During 
the physical examination, the patient should be assessed for possible adverse events.
5.3
OTHER
5.3.1
Other endpoints
Exploratory evaluation of the parameters outlined in section 5.3.2 will be performed in this 
trial, without being defined as formal endpoints.


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5.3.2
Other assessments
5.3.2.1
Demographics and history
Demographics (sex, birth date, race), and baseline conditions will be collected during the 
screening visit. A detailed cancer history will be obtained. The date of first diagnosis of NHL 
(month and year may be sufficient) will be recorded in the eCRF. The Ann Arbor stage at 
diagnosis and at screening should be recorded (see appendix 10.4). Previously administered 
chemo- and immunotherapy will be documented, including start and end dates (year and 
month may be sufficient), the treatment regimen/protocol with the number of courses 
(chemo-, immunotherapy), the best response obtained (complete remission, partial remission, 
stable disease, progressive disease, unknown) and the date of progression after each prior 
therapy (year and month may be sufficient). If the patient has received chemotherapy with 
autologous or allogeneic stem cell support, procedural details, including the treatment 
regimen prior to stem cell support should be collected. Documentation of previous 
radiotherapy should include the total radiation dose and radiation field(s). Previous surgeries 
within the past five years should be recorded. In addition, any previous surgery, which may 
affect tumour assessment in this trial according to the investigator, e.g. splenectomy or
removal of lymph nodes, should be documented in the eCRF.
5.3.2.2 Concomitant diagnoses
Concomitant diagnoses present at study entry and/or during screening and relevant to the 
patient’s safety during the trial as judged by the investigator will be recorded in the eCRF.
 
 
 
 
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
Determination of MTD (or an OBD/recommended dose for further development) is based on 
toxicities graded according to CTCAE (R10-4848) The CTCAE criteria are commonly used 
in the assessment of adverse events in cancer patients. The criteria to be used for evaluation 
of response are well established (R04-1585).
 
 
 
 
 
 
 
 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
During the treatment phase, patients are required to be hospitalized under close surveillance 
with access to intensive care for at least 48 hours after the first dose of BI 836826 to allow 
close monitoring for infusion-related reactions, tumour lysis syndrome or other adverse 
events. In case of the split first dose administration patients are required to be hospitalized for 
at least 72 hours after the start of the low dose of BI 836826. If the first administration of BI 
836826 was well tolerated by a patient the investigator may evaluate the risk for an infusion-
related reaction and other adverse events in view of relevant comorbidities or disease-related 
symptoms, and as a result, shorten the duration of surveillance up to 24 hours for the second
administration in course 1. If the first 2 infusions of the first treatment course are well 
tolerated, the 3rd and 4th infusion may be administered on an outpatient basis. For the first 
treatment of the second course patients need to be hospitalized with surveillance for 24 hours 
after start of the infusion. If the first infusion of the second treatment course has been well 
tolerated with limited and easily manageable infusion reactions, the second and subsequent
infusions of the second and third treatment course can be administered as an out-patient visit 
at discretion of the investigator.
In case a visit with administration of BI 836826 is delayed please inform the clinical monitor 
or the CRA. All subsequent visits with treatment administration will be recalculated based on 
the actual date of delayed visit. The treatment schedule of weekly infusion should be adhered 
to, but the visit may be delayed 1-2 days for administrative reasons. To allow for recovery 
from adverse events or to fulfil the criteria for treatment continuation, delays of more than 2 
days are possible as outlined in section 4.1.4.3. If a visit is delayed less than 5 days, the delay 
may be caught up by shortening the observation period of the course after agreement between 
investigator and clinical monitor of the trial. Postponement of an infusion for up to 3 weeks 
can be allowed, but further treatment has to be confirmed by the sponsor. This will be a 
maximum length of course 1 and 2 to 10 weeks.
In case a patient misses a visit, where there is no planned treatment, the delayed visit should 
be scheduled as soon as possible and documented with the actual date and the reason for the 
delayed visit. The next visit, should still take place at the time it was originally scheduled in 
this treatment course.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations as outlined in the flowcharts will be performed at the respective visits as 
described in detail in the following sections.
6.2.1
Screening and run-in period(s)
The screening period, i.e. the phase after informed consent and before the first administration 
of the trial drug, may be as long as 14 days. However, a pre trial CT scan, performed as part 
of routine clinical practice, can be used as the baseline CT scan given that the CT scan is


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valid and encompass neck, thorax, abdomen and pelvis, and it should been performed 
preferably within 4 weeks before visit 1. If the patient has not receive any anti lymphoma 
treatments and regarded a clinical stable by the investigator, the pre trial CT scan within 8 
weeks before visit 1 can be employed. Parameters and investigations according to flowchart
for course 1 have to be obtained and / or performed, please refer to flowchart for Course 1.
6.2.2
Treatment periods
The treatment is given in courses with 4 administrations of a weekly infusion followed by 
observation/rest. Patients can receive up to three courses, i.e. 12 administrations. The 
duration of the first two courses is 7 weeks and for the third course 12 weeks, hence a 3-week 
or an 8-week observation/rest after the infusions of BI 836826.
6.2.2.1 Course 1
In the first course there are 4 visits with treatment and 6 visits for safety assessment. The first 
two administrations are given as an in-hospital stay for safety, tumour lysis assessment 
 
Between the visits with infusion of BI 836826 safety visits will be performed. After last 
infusion the safety visits will be weekly. Clinical disease assessment will be performed at the 
first infusion visit (visit 1) and the last infusion visit (visit 7) as well as the last visit in the 
course (visit 10). 
 
 For details see flowchart for Course 1.
In case of the split first dose administration patients are required to be hospitalized under 
close surveillance with access to intensive care for at least 72 hours after the start of the low
dose of BI 836826 to allow close monitoring for infusion-related reactions. Please refer the 
flowchart in section 10.7 for clinical disease, safety 
6.2.2.2 Course 2
In the second course there are 4 visits with treatment and 6 visits for safety and response 
assessment. The first administration is given as an in-hospital stay for safety, tumour lysis 
assessment 
 Between the visits with infusion of BI 836826 safety visits will be 
performed. After last infusion the safety visits will be weekly. Clinical disease assessment 
will be performed at the first infusion visit (visit 1) and the last infusion visit (visit 7). A CT 
scan of neck, thorax, abdomen and pelvis must be performed at visit 9 to be available for the 
disease assessment and response evaluation that are planned to be done at the last visit in the 
course 2 (visit 10). 
 
For details see flowchart for Course 2.
6.2.2.3 Course 3
In the third course there are 4 visits with treatment and 5 visits for safety and response 
assessment. All infusions can be given as out-patient, if recent previous infusions have been 
well tolerated.  Clinical disease assessment will be performed at the first (visit 1) and at the 
last infusion (visit 4). 
 


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 CT scan of neck, thorax, abdomen and pelvis will be performed at visit 9 
(week 25) unless the EOT visit is performed prior to week 26. Disease assessment, response 
evaluation with CT scan 
 (see appendix 10.1) will be done at the 
EOT visit (see below section 6.2.3.1). For details see flowchart for Course 3.
6.2.3
End of treatment and follow-up period
6.2.3.1 End of treatment
The end of treatment (EOT) visit should be performed if patient and investigator refrain from 
further therapy at any time during the treatment period. For patients who receive course 3 (12 
administrations) at the latest 8 weeks after the last administration of BI 836826. If the patient 
concludes the trial within a treatment course, the information required to be collected at the 
EOT visit should be obtained as early as possible, preferably immediately. This includes a CT 
scan, which may be performed if it is considered clinically indicated, e.g. to document 
disease progression. At the EOT visit assessment of all safety and efficacy parameters should 
be performed according to flowchart for course 3. The status of the patient at EOT has to be 
documented, e.g. in case the patient has progressive disease the date of first documentation of 
PD has to be recorded. The reason for the completion of active trial treatment or premature 
discontinuation of trial, if applicable, has to be stated together with date of last administration 
of the trial drug. If the patient receives other therapy for lymphoma, the therapy has to be 
stated by name and date of first treatment. For detail see flowchart for Course 3.
6.2.3.2 Follow-up
Follow-up visits will be performed after the EOT visit in case a patient has completed 
treatment according to protocol or is not eligible for further treatment courses prior to 
administration of the maximum number of courses. Follow-up will end in case the patient is

lost to follow-up

receives new anti-lymphoma therapy

withdraws consent

in case the investigator and sponsor agree not to pursue further follow-up visits

death
Follow-up visits should be performed at 6 weeks intervals or more frequent if appropriate. 
Follow-up visits should be done at the investigational site, but may be performed by 
telephone interview in case the patient is unable to visit the investigator. Follow-up visits 
should be performed up to 6 months after the end of treatment visit. At the last follow-up 
visit, an end of trial assessment will be performed and documented in the eCRF. For follow-
up of patients with adverse events which have not recovered at the last planned follow-up 
visit please refer to section 5.2.2.2.
The following will be obtained and / or performed (see flowchart for Course 3):

Vital signs (see section 5.2.5.1), weight, physical examination 
 


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
Disease assessment: clinical assessment of tumour size (lymph nodes, spleen, liver), 
imaging if applicable

Changes in concomitant therapies

Safety laboratory parameters as specified in section 5.2.3.1

Adverse events

CMV monitoring (see section 5.2.3.3.2)

Lymphocyte typing (see section 5.2.3.4)

Status of the patient: date of progression (in case, the patient experienced PD) date death 
(if applicable)

Treatment with any other anti-lymphoma drug (report start date of treatment and therapy)
6.2.3.3
End of the whole trial
The clinical trial will be analyzed and reported after the last patient has completed his / her 
last visit, i.e. the latest 6 months after the EOT of the last patient. In case the trial is ended by 
the sponsor when patients are still being treated with BI 836826 when the final report of the 
trial is being prepared, the patients will either be included in a follow-up trial or alternatively 
kept on treatment in this trial. Those patients will then be reported in a revised report and it 
will be noted in the original report that such a revised report will be written.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This trial will be performed as an open-label study. The primary objective of the trial is to 
determine the MTD of BI 836826. To determine the MTD, patients are entered sequentially 
into escalating dose tiers, initially in single patient cohorts and later on using the 3+3 design 
(see section 4.1.4.). If MTD is not reached in the trial, an optimal biologic dose (OBD) can be 
selected using all available data from safety
 and pharmacodynamic 
analyses, B cell depletion and reduction of tumour size. After the MTD/OBD has been 
determined, an expansion cohort of up to 20 patients with an aggressive NHL and up to 20 
patient with indolent NHL was planned at a dose level supposed to be recommended for later 
studies. Due to safety signals in the initial three out of four Korean patients enrolled into the 
expansion cohort at the defined MTD of 100 mg the cohort was closed for all patients. Lower 
dose cohorts will be tested in Korean patients to explore safety at lower doses of 50 and 75
mg in Korean patients.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory. No formal statistical tests will be 
performed.
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The primary objective for this study is the tolerability and safety of BI 836826 as reflected by 
the MTD (for a definition of MTD, please refer to section 3.1 and section 5.2.1.1). In order to 
identify the MTD, the number of DLTs during the first two weeks of the first course at each 
dose level must be presented. For the analysis of tolerability and safety, please refer to 
section 7.3.3. If an MTD is not reached, an OBD can be determined from available data on 
safety
 and pharmacodynamic analyses, B cell depletion and reduction in 
tumour size (see sections 2.2 and 3.1).
7.3.2
Secondary analyses
7.3.2.1
Tumour size
The tumour size of the lymph nodes will be measured as sum of products of diameter (SPD)
of two perpendicular dimensions for of up to 6 indicator lesions identified at baseline CT 
scan. Spleen and liver will be described, if considered enlarged at baseline by physical 
examination or CT scan. If nodules are present in spleen and/or liver, the diameter of these 
will be measured in two perpendicular dimensions. The change in SPD, spleen and liver 
nodules will be compared to baseline and will be listed by time point.


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7.3.2.3
Best overall response
Best overall response is the best response (CR, CRu, PR, SD or PD in this order) with respect 
to all time points. Remission rate is the rate of patients that either have CR, CRu or PR as 
best overall response. Best overall response and remission rate will be analysed descriptively. 
Frequency distributions and other descriptive statistical measures will be used to examine 
these variables.
7.3.2.4
Progression free survival, 
 failure free survival, 
 
These time-to-event variables will be analysed descriptively or with the Kaplan-Meier 
method, if applicable. Details of censoring rules will be provided in the statistical analysis 
plan.
 
 
 
7.3.3
Safety analyses
All patients who have received any amount of trial drug will be included in the safety 
analysis. The occurrence of dose limiting toxicity (DLT) as well as the incidence and 
intensity of adverse events, graded according to CTCAE, laboratory parameters and vital 
signs will be evaluated.
The severity and timing of adverse events will indicate the tolerability of the treatment 
regimen. Adverse events will be evaluated using the CTCAE grading scheme. The overall 
incidence and intensity of adverse events, as well as relatedness of adverse events to 
treatment with BI 836826 will be reported for all dose cohorts. Serious adverse events will be 
tabulated. In addition, events leading to dose reduction or treatment discontinuation will be 


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examined, but may not be reported as individual tables, depending upon the extent of overlap 
with the occurrence of DLT.
Descriptive statistics will be used to describe changes in laboratory tests over time. In 
addition, all abnormalities of potential clinical relevance will be reported.
Events that start from first administration of BI 836826 until 8 weeks after the last 
administration of BI 836826 will be considered as having occurred during treatment. In 
general, later events will be attributed to the post study period and will be presented 
separately. However, post study events will be examined to determine whether they need to 
be combined with on treatment events in an additional table.
7.3.4
Interim analyses
The sponsor will continuously monitor the safety. The sponsor and the DSMB will perform 
safety evaluations regularly, and if considered necessary at additional ad hoc meetings. The 
evaluations will be unblinded to dose.
No formal interim analyses of efficacy data are foreseen, although efficacy data when 
available may be considered as part of the safety evaluations.
After the MTD was determined in Caucasian patients an evaluation of the safety aspects was
performed. Results of this evaluation were be documented and archived. The analysis was
defined in more detail in the Statistical Analysis Plan.
 
 
 
 
 
 
 
 


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7.4
HANDLING OF MISSING DATA
No imputation will be performed on missing efficacy data. Missing baseline laboratory 
values will be imputed by the respective values from the screening visit. No other 
imputations will be performed on missing data although every effort will be made to obtain 
complete information on all adverse events, with particular emphasis on potential dose 
limiting toxicities.
7.5
RANDOMISATION
No randomisation will be performed. Patients will be assigned into escalating dose groups by 
order of admission into the trial.
7.6
DETERMINATION OF SAMPLE SIZE
Assuming 3 cohorts of 1 patient only, 3 cohorts of 3 patients (i.e. no patients with DLT at 
given level) and 3 cohorts of 6 patients (i.e. 1 DLT witnessed in first 3 patients so further 3 
patients exposed with no DLTs), 30 patients will be necessary for the dose-escalation part of 
this trial.
The purpose of this amendment is to introduce additional doses to be tested in Korean 
population. The testing will occur accordingly to 3+3 rule, therefore 3-6 patients are needed 
per each dose level (50mg and 75mg) to assess safety. 
With 41 patients enrolled so far, and additional up to 12 patients to be enrolled, the expected 
number of patients on this trial will be approximately 53. 
Note that in general, the final sample size depends on the observations made in the trial.


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8.
INFORMED CONSENT, DATA PROTECTION; TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority according to national and international regulations. The same 
applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.


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8.2
DATA QUALITY ASSURANCE
The trial will be conducted in compliance with the protocol, the principles laid down in the
Declaration of Helsinki (please, refer to section 8), local law and according to the principles 
of GCP and the company standard operating procedures (SOPs). To inform all investigators 
about the trial drugs and the procedures of the trial, either an investigator meeting will be 
performed prior to start of the trial, or each investigator will be visited individually by the 
Clinical Monitor and the Clinical Research Associate (CRA). Each investigator will receive 
an ISF with all information relevant for the performance of the trial. Investigators will be 
visited at regular intervals for on-site monitoring by a Boehringer Ingelheim employee or a 
CRA authorised by BI. At these occasions, source data verification (SDV) will be performed 
and a check will be done whether the eCRFs are kept current. The information in the eCRF 
and information in source documents will be cross-checked as described in section 8.3.1.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via remote 
data capture. For drug accountability, refer to section 4.1.8.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (Clinical monitor local/CRA) or Clinical Quality Assurance auditors appointed by 
Boehringer Ingelheim, by appropriate IEC members, and by inspectors from regulatory 
authorities.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the CTMF. Coding of the 
data obtained will be done by using the medical dictionary for regulatory activities 
(MedDRA) and the WHO dictionary for concomitant medication. Data quality review 
meetings will be performed at regular intervals to evaluate the quality of the data collected. 
Discrepancies in data will be queried.
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.


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8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents 
described in section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is “listed”, i.e. is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For BI 836826 this is the current version of the Investigator’s Brochure (c01715907-08). The 
current versions of these reference documents are provided in the ISF.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IEC and the regulatory authority, i.e. the Paul-Ehrlich-Institute.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient/patient out, unless specified differently in section 6.2.3 of the 
CTP) or early termination of the trial.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P10-13007
Seyfarth B, Josting A, Dreyling M, Schmitz N. Relapse in common 
Iymphoma subtypes: salvage treatment options for follicular Iymphoma, 
diffuse large cell Iymphoma and Hodgkin disease. Br J Haematol 133, 3 –
18 (2006)
P10-13065
Friedberg JW. Bendamustine in patients with rituximab-refractory indolent 
and transformed non-Hodgkin’s lymphoma: results from a phase II 
multicenter, single-agent study. J Clin Oncol 26 (2), 204 (2008)
P10-13257
Geisler CH. Long-term progression-free survival of mantle cell lymphoma 
after intensive front-line immunochemotherapy with in vivo-purged stem 
cell rescue: a nonrandomized phase 2 multicenter study by the Nordic 
Lymphoma Group. Blood 112 (7), 2687 (2008)
P10-13258
Marcus R. CVP chemotherapy plus rituximab compared with CVP as first-
line treatment for advanced follicular lymphoma. Blood 105 (4), 1417 
(2005)
P10-13259
Hiddemann W. Frontline therapy with rituximab added to the combination 
of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) 
significantly improves the outcome for patients with advanced-stage 
follicular lymphoma compared with therapy with CHOP alone: results of a 
prospective randomized study of the German Low-Grade Lymphoma 
Study Group. Blood 106 (12), 3725 (2005)
P10-13325
Fisher RI. Comparison of a standard regimen (CHOP) with three intensive 
chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J 
Med 328 (14), 1002 (1993)
R01-0028
Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. 
Accelerated titration designs for phase I clinical trials in oncology. J Natl 
Cancer Inst 1997; 89 (15): 1138-1147
R01-0787
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, 
Carbone PP. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5, 649 - 655 (1982)
R04-0569
Kang SH, Ahn CW. An investigation of the traditional algorithm-based 
designs for phase 1 cancer clinical trials. Drug Inf J 2002; 36: 865-873


Boehringer Ingelheim
BI Trial No.: 1270.2
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Proprietary confidential information. 
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
001-MCS-40-106_RD-03 (10.0) / Saved on: 20 Oct 2011
R04-1585
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister
TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, 
Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, 
Canellos GP. Report of an international workshop to standardize response criteria 
for non-Hodgkin's lymphomas. J Clin Oncol 17 (4), 1244 - 1253 (1999)
R08-2942
Schuurman HJ, Baarlen J van, Huppes W, Lam BW, Verdonck LF, Unnik 
JAM van. Immunophenotyping of non-Hodgkin’s lymphoma: lack of 
correlation between immunophenotype and cell morphology. Am J Pathol 
129 (1), 140 – 151 (1987)
R08-2943
Barrena S, Almeida J, Yunta M, Lopez A, Fernandez-Mosteirin N, Giralt 
M, Romero M, Perdiguer L, Delgado M, Orfao A, Lazo PA. Aberrant 
expression of tetraspanin molecules in B-cell chronic lymphoproliferative 
disorders and its correlation with normal B-cell maturation. Leukemia 19, 
1376 – 1383 (2005)
R08-2945
Norton AJ, Isaacson PG. Detailed phenotypic analysis of B-cell lymphoma 
using a panel of antibodies reactive in routinely fixed wax-embedded 
tissue. Am J Pathol 128 (2), 225 – 240 (1987)
R08-2946 
Moldenhauer G. CD37. J Biol Regul Homeost Agents 14, 281 – 283 
(2000)
R08-2979
Schwartz-Albiez R, Doerken B, Hofmann W, Moldenhauer G. The B cell-
associated CD37 antigen (gp40-52) structure and subcellular expression of 
an extensively glycosylated glycoprotein. J Immunol 140 (3), 905 – 914 
(1988)
R08-2981
Smith JL, Jones DB, Bell AJ, Wright DH. Correlation between histology 
and immunophenotype in a series of 322 cases of non-Hodgkin’s 
lymphoma. Hematol Oncol (Chichester) 7, 37 – 48 (1989)
R09-4739
Moore K, Cooper SA, Jones DB. Use of the monoclonal antibody WR17, 
identifying the CD37 gp40-45 Kd antigen complex, in the diagnosis of B-
lymphoid malignancy. J Pathol 152, 13 – 21 (1987)
R09-4740
Spriel AB van, Puls KL, Sofi M, Pouniotis D, Hochrein H, Orinska Z, 
Knobeloch KP, Plebanski M, Wright MD. A regulatory role for CD37 in T 
cell proliferation. J Immunol 172, 2953 – 2961 (2004)
R09-5412
Knobeloch KP, Wright MD, Ochsenbein AF, Liesenfeld O, Löhler J, 
Zinkernagel RM, Horak I, Orinska Z. Targeted inactivation of the 
tetraspanin CD37 impairs T-cell-dependent B-cell response under 
suboptimal costimulatory conditions. Mol Cell Biol. 20(15), 5363-9 (2000)


Boehringer Ingelheim
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Page 76 of 112
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
001-MCS-40-106_RD-03 (10.0) / Saved on: 20 Oct 2011
R09-5414
Spriel AB van, Sofi M, Gartlan KH, Schaaf A van der, Verschueren I, 
Torensma R, et al. The tetraspanin protein CD37 regulates IgA responses 
and anti-fungal immunity. Plos Pathogens 2009; 5 (3): e1000338
R10-1462
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, 
Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, 
Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, 
Federico M, Diehl V. Revised response criteria for malignant lymphoma.
J Clin Oncol 25 (5), 579 – 586 (2007)
R10-2734
Press OW, Eary JF, Badger CC, Martin PJ, Appelbaum FR, Levy R, 
Miller R, Brown S, Nelp WB, Krohn KA, et al. Treatment of refractory 
non-Hodgkin’s lymphoma with radiolabeled MB-1 (anti-CD37) antibody.  
J Clin Oncol. 7(8): 1027-38 (1989)
R10-2735
Kaminski MS, Fig LM, Zasadny KR, Koral KF, DelRosario RB, Francis 
IR, Hanson CA, Normolle DP, Mudgett E, Liu CP, et al. Imaging, 
dosimetry, and radioimmunotherapy with iodine 131-labeled anti-CD37 
antibody in B-cell lymphoma. J Clin Oncol.10(11):1696-711 (1992)
R10-4428
Chung CH. Managing premedications and the risk for reactions to 
infusional monoclonal antibody therapy. Oncologist 2008;13:725-732
R10-4431
O’Brien SM, Keating MJ, Mocarski ES. Updated guidelines on the 
management of cytomegalovirus reactivation in patients with chronic 
lymphocytic leukemia treated with alemtuzumab. Clin Lymphoma 
Myeloma 2006; 7 (2): 125-130
R10-4505
Zenz T, Mertens D, Kueppers R, Doehner H, Stilgenbauer S. From 
pathogenesis to treatment of chronic lymphocytic leukaemia. Nat Rev 
Cancer 2010; 10: 37-50.
R10-4517
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the 
management of pediatric and adult tumor lysis syndrome: an evidence-
based review. J Clin Oncol 2008; 26 (16): 2767-2778.
R10-4774
Pfreundschuh M, et al, MabThera International Trial (MinT) Group
CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy 
alone in young patients with good-prognosis diffuse large-B-cell 
lymphoma: a randomised controlled trial by the MabThera International 
Trial (MinT) Group. Lancet Oncol 7, 379 – 391 (2006)
R10-4775
Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, 
Morel P, Neste E van den, Salles G, Gaulard P, Reyes F, Gisselbrecht C
CHOP chemotherapy plus rituximab compared with CHOP alone in 
elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 


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001-MCS-40-106_RD-03 (10.0) / Saved on: 20 Oct 2011
(4), 235 – 242 (2002)
R10-4776
Weng WK, Levy R. Two immunoglobulin G fragment C receptor 
polymorphisms independently predict response to rituximab in patients 
with follicular lymphoma. J Clin Oncol 21 (21), 3940 – 3947 (2003)
R10-4777
Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, 
Watier H. Therapeutic activity of humanized anti-CD20 monoclonal 
antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. 
Blood 99 (3), 754 - 758 (2002)
R10-4834
Non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of 
the International Lymphoma Study Group classification of non-Hodgkin’s 
lymphoma. Blood 89 (11), 3909 – 3918 (1997)
R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010). 
weblink//evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pd f (2010)
R10-6285
Leonard JP, Coleman M, Ketas JC, Chadburn A, Furman R, Schuster MW, 
Feldman EJ, Ashe M, Schuster SJ, Wegener WA, Hansen HJ, Ziccardi H, 
Eschenberg M, Gayko U, Fields SZ, Cesano A, Goldenberg DM. 
Epratuzumab, a humanized anti-CD22 antibody, in aggressive non-
Hodgkin’s lymphoma: phase I/II clinical trial results. Clin Cancer Res 10, 
5327 – 5334 (2004)
R10-6296
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, et al, editors
WHO classification of tumours of the haematopoietic and lymphoid 
tissues. 4th ed. Lyon: International Agency for Research on Cancer (IARC) 
(2008)
R10-6303
Fisher RI, LeBlanc M, Press OW, Maloney DG, Unger JM, Miller TP
New treatment options have changed the survival of patients with 
follicular lymphoma. J Clin Oncol 23 (33), 8447 – 8452 (2005)
R10-6310
Gribben JG. How I treat indolent lymphoma. Blood 109 (11), 4617 – 4626 
(2007)
R10-6311
Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa 
R, Savage KJ, Shenkier T, Sutherland J, Gascoyne RD, Connors JM
The revised International Prognostic Index (R-IPI) is a better predictor of 
outcome than the standard IPI for patients with diffuse large B-cell 
lymphoma treated with R-CHOP. Blood 109 (5), 1857 – 1861 (2007)


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001-MCS-40-106_RD-03 (10.0) / Saved on: 20 Oct 2011
R10-6313
Moskowitz CH, Schoder H, Teruya-Feldstein J, Sima C, Iasonos A, 
Portlock CS, Sraus D, Noy A, Palomba ML, O’Connor OA, Horwitz S, 
Weaver SA, Meikle JL, Filippa DA, Caravelli JF, Hamlin PA, Zelenetz 
AD. Risk-adapted dose-dense immunochemotherapy determined by 
interim FDG-PET in advanced-stage diffuse large B-cell lymphoma. J Clin 
Oncol 28 (11), 1896 – 1903 (2010)
R10-6316
Salles A, Morschhauser F, Thieblemont C, Solal-Celigny P, Lamy T, Tilly 
H, Feugier P, Gouill S le, Gyan E, Bouabdallah R, Wenger M, Birkett J, 
Cartron G. Promising efficacy with the new anti-CD20 antibody GA101 in 
heavily pre-treated patients – first results from a phase II study in patients 
with relapsed/refractory indolent NHL (INHL). 15th Cong of the European 
Hematology Association (EHA), Barcelona, 10 – 13 Jun 2010
Haematologica 95 (Suppl 2), 229 – 230, Abstr 0558 (2010)
R10-6345
Heider KH, Ostermann E, Lamche H, Kuepcue Z, Jacobi A, Konopitzky 
R, Hirt U, Reichardt V, Borges E. Novel Fc-engineered antibodies to 
CD37 with pro-apoptotic and enhanced ADCC activity. 52nd Ann Mtg of 
the American Society of Hematology (ASH), Orlando, 4 – 7 Dec 2010. 
Blood 116 (21), 31, Abstr 3916 (2010)
R10-6346
Zenz T, Volden M, Mast T, Nordhausen K, Winkler D, Schnaiter A, 
Buehler A, Heider KH, Reichardt V, Doehner H, Stilgenbauer S. 
Exceptional in vitro activity of CD37 antibodies in CLL. 52nd Ann Mtg of
the American Society of Hematology (ASH), Orlando, 4 – 7 Dec 2010. 
Blood 116 (21), 31, Abstr 2460 (2010)
R10-6348
Federico M, Bellei M, Marcheselli L, Luminari S, Lopez-Guillermo A, 
Vitolo U, Pro B, Pileri S, Pulsoni A, Soubeyran P, Cortelazzo S, Martinelli 
G, Martelli M, Rigacci L, Arcaini L, Raimondo F di, Merli F, Sabattini E, 
McLaughlin P, Solal-Celigny P. Follicular Lymphoma International 
Prognostic Index 2: a new prognostic index for follicular lymphoma 
developed by the International Follicular Lymphoma Prognostic Factor 
Project. J Clin Oncol 27 (27), 4555 – 4562 (2009)
R10-6349
Shipp MA, et al. A predictive model for aggressive non-Hodgkin’s 
lymphoma: the International Non-Hodgkin’s Lymphoma Prognostic 
Factors Project. N Engl J Med 329 (14), 987 – 994 (1993)
R10-6350
Solal-Celigny P, et al. Follicular Lymphoma International Prognostic 
Index. Blood 104 (5), 1258 – 1265 (2004)
R10-6351
Armitage JO. How I treat patients with diffuse large B-cell lymphoma. 
Blood 110 (1), 29 – 36 (2007)


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001-MCS-40-106_RD-03 (10.0) / Saved on: 20 Oct 2011
R10-6352
Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, 
Lister A, Feuring-Buske M, Radford JA, Capdeville R, Diehl V, Reyes F
Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients 
with relapsing or refractory aggressive lymphoma: a multicenter phase II 
study. Blood 92 (6), 1927 – 1932 (1998)
R10-6358
Allen-Auerbach M, Quon A, Weber WA, Obrzut S, Crawford T, 
Silverman DHS, Ratib O, Phelps ME, Czernin J. Comparison between 2-
deoxy-2-[18F]fluoro-D-glucose positron emission tomography and 
positron emission tomography /computed tomography hardware fusion for 
staging of patients with lymphoma. Mol Imaging Biol 6 (6), 411 – 416 
(2004)
R10-6360
Advani R, Forero-Torres A, Furman RR, Rosenblatt JD, Younes A, Ren 
H, Harrop K, Whiting N, Drachman JG. Phase I study of the humanized 
anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent 
non-Hodgkin’s lymphoma. J Clin Oncol 27 (26), 4371 – 4377 (2009)
R10-6361
Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A, Doelken G, 
Naumann R, Knauf W, Freund M, Rohrberg R, Hoeffken K, Franke A, 
Ittel T, Kettner E, Haak U, Mey U, Klinkenstein C, Assmann M, 
Gruenhagen U von Rituximab added to first-line mitoxantrone, 
chlorambucil, and prednisolone chemotherapy followed by interferon 
maintenance prolongs survival in patients with advanced follicular 
lymphoma: an East German Study Group Hematology and Oncology 
study. J Clin Oncol 25 (15), 1986 – 1992 (2007)
R10-6362
Rummel MJ, Niederle N, Maschmeyer G, Banat A, Gruenhagen U von, 
Losem C, Heil G, Welslau M, Balser C, Kaiser U, Ballo H, Weidmann E, 
Duerk HA, Kofahl-Krause D, Roller F, Barth J, Hoelzer D, Hinke A, 
Brugger W Bendamustine plus rituximab is superior in respect of 
progression free survival and CR rate when compared to CHOP plus 
rituximab as first-line treatment of patients with advanced follicular, 
indolent, and mantle cell lymphomas: final results of a randomized phase 
III study of the StiL (Study Group Indolent Lymphomas, Germany). 51st
Ann Mtg of the American Society of Hematology (ASH), New Orleans, 5 
– 8 Dec 2009. Blood 114 (22), Abstr 405 (2009)
R10-6359
Spaepen K, Stroobants S, Dupont P, Steenweghen S van, Thomas J, 
Vandenberghe P, Vanuytsel L, Bormans G, Balzarini J, Wolf-Peeters C de, 
Mortelmans L, Verhoef G. Prognostic value of positron emission 
tomography (PET) with fluorine-18 fluorodeoxyglucose ([18F]FDG) after 
first-line chemotherapy in non-Hodgkin’s lymphoma: is [18F]FDG-PET a 
valid alternative to conventional diagnostic methods. J Clin Oncol 19 (2), 
414 – 419 (2001)


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001-MCS-40-106_RD-03 (10.0) / Saved on: 20 Oct 2011
R10-6360
Advani R, Forero-Torres A, Furman RR, Rosenblatt JD, Younes A, Ren 
H, Harrop K, Whiting N, Drachman JG. Phase I study of the humanized 
anti-CD40 monoclonal antibody dacetuzumab in refractory or recurrent 
non-Hodgkin’s lymphoma. J Clin Oncol 27 (26), 4371 – 4377 (2009)
R10-6363
Hagenbeek A, Fayad L, Delwail V, Rossi JF, Jacobsen E, Kuliczkowski K, 
Link BK, Pinter-Brown L, Radford J, Hellmann A, Gallop-Evans E, Gupta 
I, Arning M, Beetrup K, Schultz M, Bang B, Russell CA, Czuczman MS
Evaluation of ofatumumab, a novel human CD20 monoclonal antibody, as 
single agent therapy in rituximab-refractory follicular lymphoma.
51st Ann Mtg of the American Society of Hematology (ASH), New 
Orleans, 5 – 8 Dec 2009. Blood 114 (22), Abstr 935 (2009)
R10-6400
Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M
Report of the Committee on Hodgkin’s Disease Staging Classification.
Cancer Res 31, 1860 – 1861 (1971)
R10-6639
Ziepert M, Hasenclever D, Kuhnt E, Glass B, Schmitz N, Pfreundschuh M, 
Loeffler M. Standard International Prognostic Index remains a valid 
predictor of outcome for patients with aggressive CD20+ B-cell lymphoma 
in the rituximab era. J Clin Oncol 28 (14), 2373 - 2380 (2010)
R10-6640
Furman RR, Andritsos L, Flinn IW, Forero-Torres A, Foon KA, Pagel JM, 
Singhal A, Stromatt SC, Byrd JC. Phase 1 dose escalation study of TRU-
016, an anti-CD37 SMIP protein in relapsed and refractory CLL. 52nd 
Ann Mtg of the American Society of Hematology (ASH), Orlando, 4 - 7 
Dec 2010. Blood 116 (21), 31, Abstr 56 (2010)
9.2
UNPUBLISHED REFERENCES
c01715907-08
 Investigator's Brochure: BI 836826 (Version 5). 
08 April 2015.
c02337389-01
. Clinical Safety Report –
Phase I Safety Analysis Report. 13 February 2015


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10.
APPENDICES
 
 
 
 
 
 


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10.2
AGGRESSIVE AND INDOLENT LYMPHOMA
Protocol defined aggressive lymphoma (de novo or transformation):

Diffuse large B-cell lymphoma

Mantle cell lymphoma

Mediastinal large B-cell lymphoma

Intravascular large B-cell lymphoma
ALK positive large B-cell lymphoma

Plasmablastic lymphoma

Primary effusion lymphoma

Burkitt lymphoma
Protocol defined indolent lymphoma:

Follicular lymphoma

Lymphoplasmacytic lymphoma

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue 
(MALT)

Splenic marginal zone lymphoma

Nodal marginal zone lymphoma

Primary cutaneous follicular center lymphoma
10.3
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE SCORE
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature; e.g. light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
Reference R01-0787


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10.4
ANN ARBOR STAGING
Stage
Definition
I
Involvement of one region and/or local involvement of one extra nodal site 
(IE)
II
Involvement of >one region on the same site of diaphragma without or with 
one extra nodal site (IIE)
III
Involvement of regions on both sites of diaphragma, involvement of spleen 
without or with one extra nodal site (IIIE)
IV
Diffuse or disseminated disease in extra nodal organs
A – without disease symptoms
B – with symptoms like night sweats, weight loss >10% over 6 months, fever without 
infection
E – extranodal disease
Reference R10-6400
10.5
CALCULATION OF GLOMERULAR FILTRATION RATE
Glomerular filtration rate (GFR) may be estimated based on commonly used and accepted 
formulae, i.e
Cockroft Gault formula
(140 - age)  x  weight  x  FS
GFR = 
─────────────────────
Serum Creatinine  x  72
Units: GFR [ml/min], age [years], weight [kg], serum creatinine [mg/dl], FS is a correction 
Factor for Sex: in males FS = 1, in females FS = 0.85
Modification of Diet in Renal Disease (MDRD) formula
GFR = 170 x Serum Creatinine-0.999 x Age-0,176 x BUN -0.170 x Albumin +0.318 x FS
Units: GFR [ml/min], age [years], serum creatinine [mg/dl], FS is a correction Factor for 
Sex: in males FS = 1, in females FS = 0.762


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Variations of the MDRD formula
GFR = 186 x Serum Creatinine-1.154 x Age-0,203 x FS
Units: GFR [ml/min], age [years], serum creatinine [mg/dl], FS is a correction Factor for 
Sex: in males FS = 1, in females FS = 0.742
Alternative methods of calculation of GFR may be agreed between Investigator and the Trial 
Clinical Monitor at Boehringer Ingelheim.
10.6
CLINICAL EVALUATION OF LIVER INJURY
10.6.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (Protocol-Specified
Significant Adverse Events), are to be further evaluated using the following procedures:
10.6.2
Procedures
Repeat the following lab tests: ALT, AST, and bilirubin (total and direct) - within 48 to 
72hours. If ALT and/or AST ≥3 fold ULN combined with an elevation of total bilirubin ≥2 
fold ULN are confirmed (if normal values at baseline/screening), or ALT and/or AST >5 fold 
ULN combined with an elevation of total bilirubin >2 fold ULN are confirmed (if elevated 
values at baseline/screening) results of the laboratory parameters described below must be 
made available to the investigator and to BI as soon as possible.
In addition,

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF

obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
according to the “DILI checklist” provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider homeand work 
place exposure) according to the “DILI checklist” provided in the ISF;
and report these via the CRF.
Provide abdominal ultrasound or other appropriate imaging to rule out biliary tract, 
pancreatic or intrahepatic pathology, e.g. bile duct stones or neoplasm.
Clinical chemistry
alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferrin, amylase, lipase, fasting glucose, cholesterol, triglycerides


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Serology
Hepatitis A (RNA), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-HCV, RNA), 
Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-
HEV IgM positive), Cytomegalovirus (repeat CMV DNA), Anti-Smooth Muscle antibody 
(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody
Hormone
Thyroid stimulating hormone
Haematology
White blood count + differential, haemoglobin, thrombocytes
In case AST/ALT remain elevated and the previous testing does not provide a likely cause for 
the elevation, the following tests should be performed: Epstein Barr Virus (VCA IgG, VCA 
IgM), herpes simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), 
toxoplasmosis (IgG, IgM)
Initiate close observation of subjects by repeat testing of ALT, AST, and total bilirubin (with
fractionation by total and direct) at least weekly until the laboratory ALT and / or AST 
abnormalities stabilize or return to normal, then according to the protocol. Depending on 
further laboratory changes or additional parameters identified, follow-up should be based on 
medical judgement and Good Clinical Practice (GCP).


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10.7 
FLOWCHART 
 FOR THE SPLIT FIRST DOSE
ADMINISTRATION (LOW DOSE AND FULL DOSE)
10.7.1 
Flowchart for Course 1
Trial Periods
Screen
Treatment and observation/rest
EOT
FU
Course *
1
If no signs of 
progression 
and 
agreement on 
further 
treatment for 
the patient, 
please 
continue to 
Visit 1 on 
Flowchart 
for Course 2
If the patient 
has disease 
progression 
or 
withdraws, 
please 
continue to 
EOT visit on 
Flowchart 
for Course 3
Week
1
2
3
4
5
6
7
Visit **
Screen
1
2
3
4
5
6
7
8
9
10
Days
-14 to
-1
1
2
3
4
+
2
8
9
10
+2
15
17
+2
22
29
±2
36
±
2
43
±2
Informed consent
x
Demographics
x
Medical history
x
Review of in-/exclusion 
criteria
x
x
1
Eligibility for trial
x
12-lead ECG
x
 
x
 
x
Height
x
Weight
x
x
x
x
x
x
x
x
Physical examination, 
incl. tumour size (lymph 
nodes, spleen, liver), 
x
x
x
x
Vital signs 2
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Dose assignment
x3
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x
x
x
x
General safety laboratory 
parameters 4
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Administration of BI 
836826
x
x
x
x
x
Screening for Tumour 
Lysis Syndrome 5
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
Disease/response assessm. 
(clinical/imaging)
x
x
6
x6
x6
Serum pregnancy test 7
x
x
x
CMV monitoring 8
x
x
x
x
x
x
x
Lymphocyte typing 
(B/T/NK cells)
x
x
x
x
x
x
x
x
x
x
 
Anti-drug antibodies 9
x
x
Virology screening 10
(HBV, HCV, HIV, CMV)
x
x
CT scan of neck, thorax, 
abdomen and pelvis
x11


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EOT: 
End of treatment visit, to be performed at withdrawal from further treatment (<12 administrations) or at the latest 8 
weeks after the last administration of BI 836826 (12 administrations)
FU: 
Follow-up visits (starts after EOT) at least every 6 weeks until 6 months after EOT visit, details see section 6.2.3.2
CMV:
Cytomegalovirus
HBV:
Hepatitis B virus
HCV:
Hepatitis C virus
HIV:
Human immunodeficiency virus
* the planned duration of course 1 is 7 weeks (49 days)
** the visit number follows the course number, i.e. visit 2 course 1 will read C1_V2 and visit 2 course 2 will read C2_V2 …
1
Review of eligibility
2
For details during and after infusion of BI 836826, refer to section 5.2.5.1
3
After informed consent, and review of in- and exclusion criteria, and before the first administration of the trial 
drug
4
For details refer to section 5.2.3.1
5
Screening for tumour lysis syndrome in between safety laboratory assessments (section 5.2.3.2)
6
Disease / response assessment will be based on clinical judgement when recent CT is not available
7
For women of childbearing potential only (please refer to sections 3.3.3 (exclusion criterion 20) and 5.2.3.1)
8
Quantitative CMV DNA PCR (section 5.2.3.3.2)
9
Sampling at the time points specified in table 10.1.1 (Appendix 10.1)
10
Please refer to section 5.2.3.3.1
11
CT scan may be performed up to 4 weeks prior to first infusion according to the standard of care in this patient 
population


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Summary of Clinical Trial Protocol Modifications Sheet (SOMS)
Number of global amendment
1
Date of CTP revision
21 May 2012
EudraCT number
2010-024456-29
BI Trial number
1270.2
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase I, Open-Label, Dose-Escalation Trial 
with BI 836826 in Patients with Relapsed or 
Refractory non-Hodgkin Lymphoma of B cell 
Origin
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Change 1: Trial Clinical Monitor
Change 2: Protocol Synopsis
Change 3: Flow Chart
Change 4: TABLE OF CONTENTS
Change 5: ABBREVIATIONS
Change 6: Section 3.1


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Number of global amendment
1
Change 7: Section 3.2
Change 8: Section 3.2
Change 9: Section 3.3.2
Change 10: Section 3.3.3
Change 11: Section 3.3.3
Change 12: Section 4.1.4.1.3
Change 13:Section 4.1.7
Change 14: Section 5.2.2.1
Change 15: Section 5.2.2.2
Change 16: Section 5.2.3.1
Change 17: Section 5.2.3.2
Change 18: Section 5.2.3.2
Change 19: Section 5.2.3.3.2
Change 20: Section 5.2.3.4
Change 21: Section 5.2.5.1
Change 25: Section 6.1
Change 26: Section 6.2.1
Change 28: Section 10.2


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Number of global amendment
1
Change 29: Section 10.6
Description of change
Change 1:Tria Clinical Monitor change
Change 2: Deletion of "conducted in one 
country".
 
Change 4: 10.6 was added in table of content 
Change 5: DILI was added in the abbreviations
Change 6: Full stop was added
Change 7: The part "(may be performed up to 8 
weeks (preferably 4 weeks) prior to first 
infusion)" was added.
Change 8: The sentence "If the CT scans are not 
possible or available, magnetic resonance imaging 
can be used instead. However the same imaging 
methods should be used consistently throughout 
the trial" was added.
Change 9: "1" was added."1" was replaced by "2".
Change 10: "NHL" was replaced by "a mature B 
cell neoplasm according to WHO classification 
(R10-6296)".
Change 11:"prednisolone or equivalent" was 
added.
Change 12: "CTCAE classifies TLS in grade 3 
(present), grade 4 (life threatening consequences; 
urgent intervention indicated) and grade 5 (death). 
Presence of TLS is not clearly defined by CTCAE 
(R10-4848). For this trial the Cairo-Bishop 
classification will be used to define presence of 
TLS, i.e. presence of clinical TLS (R10-4517)." 
was added.


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Change 13: "CRA" was added.
Change 14: "protocol-specified" and "DILI 
Although rare, drug-induced liver injury (DILI) is 
under constant surveillance bysponsors and 
regulators and is considered a protocol-specified 
significant adverse event. Timely detection, 
evaluation, and follow-up of laboratory alterations 
of selected liver laboratory parameters to 
distinguish an effect of the underlying malignancy 
on liver function from other causes such as DILI 
are important for patient safety. The following are 
considered as Protocol-specified significant 
events: Hepatic injury defined by the following 
alterations of liver parameters:

For patients with normal liver function 
(ALT, AST and bilirubin within 
normal limits) at baseline an elevation 
of AST and/or ALT ≥3 fold ULN 
combined with an elevation of 
bilirubin ≥2 fold ULN measured in the 
same blood draw sample. Patients 
showing these lab abnormalities need 
to be followed up according to 
Appendix 10.6 of this clinical trial 
protocol and the "DILI checklist" 
provided in the ISF.

For patients with impaired liver 
function at baseline an elevation of 
AST and/or ALT >5 fold ULN 
combined with an elevation of total 
bilirubin >2 fold ULN measured in the 
same blood draw sample. Patients 
showing these lab abnormalities need 
to be followed up according to 
Appenddix 10.6 of this clinical trial 
protocol and the “DILI checklist” 
provided in ISF" 
.
Protocol-specified significant adverse events are 
to be reported in an expedited manner similar to 
Serious Adverse Events, even if they do not meet 


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Number of global amendment
1
any of the seriousness criteria - for details see 
section 5.2.2.2. If the investigator determines any 
protocol-specific significant adverse event is 
related to study drug, the administration of the 
study drug must be managed according to section 
4.1.4 of the protocol." were added 
"the" was add.
"Expected fluctuations or expected deterioration 
of the underlying disease and other pre-existing 
conditions should not be recorded as an AE unless 
at least one of the following criteria is met:

the worsening of the disease constitutes an 
SAE

the investigational drug is discontinued or the 
dose is reduced

additional treatment is required, i.e.
concomitant medication is added or changed

an unexpected deterioration from baseline has 
occurred in the opinion of the investigator" 
was replaced by "Worsening of the underlying 
disease or of other pre-existing conditions will be 
recorded as an (S)AE in the (e)CRF."
"with the term Neoplasm Progression" was added.
"Changes in vital signs including blood pressure, 
pulse rate, electrocardiogram (ECG), physical 
examination, and laboratory tests will be only 
then recorded as AEs if they are not associated 
with an already reported AE, symptom or 
diagnosis, and the investigational drug is either 
discontinued, reduced or increased, or additional 
treatment is required, i.e. concomitant medication 
is added or changed" was replaced by "Changes 
in vital signs, ECG, physical examination and 
laboratory test results will be recorded as an 
(S)AE in the (e)CRF , if they are judged clinically 
relevant by the investigator."
Change 15: "protocol-specified" was added.
Change 16:"total" and "(if elevated provide direct 
bilirubin)"was added.


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Number of global amendment
1
Change 17: "of the second infusion in course 1" 
and "Monitoring for TLS of the second infusion 
of course 2 and the first and second infusion of 
course 3 are be performed while the patient is in 
hospital" were added.
Change 18: "+differential" was added.
Change 19: "The same method should always be 
used for all treated patients in the same 
investigational site" was added.
Change 20: "in the laboratory at the 
investigational" was replaced by "in a specialized 
laboratory either at the investigational site or at a 
centralized laboratory. Detailed instructions are 
included in the laboratory manual in the ISF."
Change 21:"appropiate" was replaced by 
"appropriate".
 
 
 
 
 
 
 
 
 
Change 25: "please inform the clinical monitor or 
the CRA" was added.
Change 26:"has" was replaced by "should".


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Number of global amendment
1
"preferably" was added.
"If the patient has not receive any anti lymphoma 
treatments and regarded a clinical stable by the 
investigator, the pre trial CT scan within 8 weeks 
before visit 1 can be employed." was added.
Change 28: "(de novo or transformation):"was 
added.
Change 29: The whole section 10.6 was added.
Rationale for change
Change 1: Change of personnel.
Change 2: The trial may be conducted in other 
countries as well.
 
 
Change 4: Explanation of abbreviation.
Change 5: Clarification of Liver Injury.
Change 6:Typo.
Change 7: Clarification of CT scan time frame 
prior to treatment.
Change 8: Other imaging than CT scan is allowed 
to enable patients to enroll where additional
radiation exposure else would be limiting for 
enrolment.
Change 9: ECOG status 2 was added to allow 
patients with lower performance status to be 
included as the performance status may be related 
to underlying disease and not per se considered an 
increase risk for the patient.


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1
Change 10: To precisely define which previous B 
cell neoplasms are allowed. 
Change 11: To clarify on the dose and to allow 
other steroid than prednisolone.
Change 12: Definition of which TLS 
classification will be used.
Change 13: Addition of CRA as a second contact 
person.
Change 14: Clarification that significant AEs are 
the defined protocol specific AEs and Liver injury 
(DILI) was added. (S)AE reporting change 
required by regulatory authority.
Change 15: Clarification of (S)AE reporting.
Change 16: Clarification that total bilirubin value 
is to be obtained. In case bilirubin is elevated, 
direct bilirubin will be needed for clinical 
interpretation.
Change 17: Clarification of the screening 
schedule of tumour lysis syndrome to be 
consistent with the sampling indicated in the 
flowcharts.
Change 18: Additional pharmacodynamic and 
safety evaluation without changing blood 
sampling.
Change 19: Emphasizing the need that a standard 
method should be applied through out the study.
Change 20: To ensure comparability of 
lymphocyte testing, only a limited number of 
diagnostic instruments and protocols should be 
used. Therefore, method and qualification of 
laboratories at the sites will be assessed and 
decision taken by the sponsor whether 
measurement can be performed at the site or 
should be delegated to a central laboratory. 


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1
Change 21:Typo.
 
 
 
 
Change 25: Clarification of the operation process.
Change 26: Expansion of the time window for pre 
trial CT scan to minimize the use of CT scan 
where these are not considered indicated for 
documentation of disease status.
 
 
Change 28: Clarification that subtypes of 
aggressive lymphoma can be as a de novo 
lymphoma or as transformation of another mature 
B cell malignancy.
Change 29: Procedure of Clinical Evaluation on 
case of Liver Injury.


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Number of global amendment
2
Date of CTP revision
14 Feb 2013
EudraCT number
2010-024456-29
BI Trial number
1270.2
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase I, Open-Label, Dose-Escalation Trial 
with BI 836826 in Patients with Relapsed or 
Refractory non-Hodgkin Lymphoma of B cell 
Origin
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Change 1: Synopsis
Change 2: Section 3.1
Change 3: Section 3.2
Change 4: Section 3.3.1  
Change 5: Section 3.3.3
Change 6: Section 4.1
Change 7: Section 4.1.1
Change 8: Section 4.1.4.1.2


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Number of global amendment
2
Change 9: Section 4.1.4.2
Change 10: Section 5.2.3.2 
Change 11: Section 5.2.5.1 
Change 12: Section 6.1
Change 13: Section 6.2.2.1
Change 14: Section 7.1
Change 15: Section 7.6
 
Description of change
Change 1: Total patient number adapted 
Change 2: 

836286 was replaced by 836826

"Over 3 hours" was deleted

"Unless the first administration will be 
split ( refer section 4.1). " was added

"Coordinating Investigator" and "The 
data will be discussed and aligned with 
the coordinating investigator" were 
deleted.

Patient number changed

Patient population of expansion cohort 
defined
Change 3: Patient population of expansion cohort 
was defined. "an expansion cohort of up to 20 
patients is planned to be enrolled to better 
characterize the safety profile and tolerability of 
the MTD." was deleted. 
Change 4: "a minority" was replaced by 
"minorities"


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Number of global amendment
2
Change 5: Addition of exclusion criterion
Change 6:

"over 3 hours" was deleted and "unless the 
split first dose administration described 
below will be implemented" was added. 

"The first infusion in each course should 
be started at a rate of 10 mL/h. The 
infusion rate can be increased every 30 
(+/-10) minutes by 10 mL/h to a 
maximum of 80 mL/h as long as tolerated 
by the patient. If considered safe by the 
investigator, the subsequent infusions may 
be given with shorter interval for 
increasing the rate, but the maximum rate 
should not exceed 120 mL/h. If adverse 
events which are considered related to the 
infusion schedule, e.g. infusion-related 
reaction, are not well controlled by the 
above schedule an alternative 
administration will be used. The first 
administration in course 1 will be split 
into two infusions, a low dose on day 1 
followed by the full dose on the day 2. 
The first part of the administration will be 
10% of the full dose, but not exceeding 10 
mg given on day 1. The day after the 
second part of the administration will be 
the full planned dose for the patient 
(please refer the flowchart in section 
10.7). The same infusion schedule should 
be employed as described above, starting 
with a rate of 10 mL/h. Premedication is 
mandatory before both infusions as they 
will be considered as the first 
administration (section 4.1.4.1.1.). The 
potential change of the first infusion into 
two infusions will be assessed and may be 
modified by the DSMB. In subsequent 
administrations, the full dose of BI 
836826 will be administered as a rate-
controlled intravenous infusion on day 1. 
If symptoms of an infusion related 


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Number of global amendment
2
reaction occur, the infusion should be 
temporarily stopped. Upon recovery, it 
should be resumed at 50% of the rate at 
which the reaction occurred for at least 30 
minutes. Lower rates may be selected if 
clinically indicated. Depending on the 
time of occurrence and the severity of the 
reaction, the investigator may consider 
administering additional supportive 
medication, e.g. corticosteroids. A 
stepwise re-increase of the infusion rate to 
a maximum of 80 mL/h is possible. For 
medical reason" was added. 

"In case a patient experiences an adverse 
event during the infusion" was deleted.
Change 7: 

"or split dose (2 doses) only applicable for 
course 1"was added.

"Infusion over 3 hours" was replaced by 
"Rate controlled infusion".

"coordination  investigator" and "Rate: 
83.4 mL/h" was deleted.
Change 8: "If the split first dose administration is 
employed patients are required to be hospitalized 
under close surveillance with access to intensive 
care for at least 72 hours for the 1st visit in course 1 
and at least 24 hours during the second infusion in 
course 2. Hospitalization is required for at least 24 
hours during the first infusion in course 2. In case of 
no relevant infusion-related adverse events, the 
decision to hospitalize the patient is left to the 
discretion of the investigator." was added.
Change 9: "8" was replaced by "24".
Change 10: "In case of the split first dose 
administration the same parameters need to be 
determined during the first 72 hours after the start 
of the low dose of BI 836826 in course 1, and for 
other infusions the monitoring should be as above 
described" was added.


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2
Change 11: "In case of prolongation of the 
infusion time additional measures have to be 
documented every 30 minutes. In case of the split 
first dose administration monitoring has to be at 
least 72 hours after the start of the low dose."was 
added.
Change 12: "In case of the split first dose 
administration patients are required to be 
hospitalized for at least 72 hours after the start of 
the low dose of BI 836826" was added.
Change 13: "In case of the split first dose 
administration patients are required to be 
hospitalized under close surveillance with access 
to intensive care for at least 72 hours after the 
start of the low dose of BI 836826 to allow close 
monitoring for infusion-related reactions. Please 
refer the flowchart in section 10.7 for clinical 
disease, safety 
 was added.
Change 14: "up to 20 patients are additionally 
entered at a dose level supposed to be 
recommended for later studies." was replaced by 
"an expansion cohort of up to 20 patients with an 
aggressive NHL and up to 20 patient with 
indolent NHL are additionally entered at a dose 
level supposed to be recommended for later 
studies."
Change 15: " with an aggressive NHL and up to 
20 patients with indolent NHL" was added.
"50" was replaced by "70". "enrolled" was 
deleted.
 
 
 
Rationale for change
Change 1: Please refer Section 10
Change 2:


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Number of global amendment
2

Typo

Clarification of Infusion schedule

Clarification of Infusion schedule

Clarification of Responsibility

Please refer Change 14 concerning the 
number

To ensure enrolment of both indolent and 
aggressive lymphomas
Change 3: Please refer to Change 14
Change 4:Typo
Change 5: The prohibited use of immunoglobulin 
already described in section 4.2.2.1 is added as an 
exclusion criterion for clarity.
Change 6: Clarification of Infusion time and split  
of administration to reduce the risk and grade of 
infusion related reaction.
Change 7: Clarification of infusion scheme and 
agreement of further treatment.
Change 8: Clarification of Hospitalization.
Change 9: Change to maximal allowed Infusion 
time.
Change 10: Clarification of Safety Monitoring
Period.
Change 11: Clarification of Vital Signs 
Monitoring Period.
Change 12: Clarification of Hospitalization.
Change 13: Clarification of Course 1 in case of 
split dosing.
Change 14: An expansion cohort of up to 20 
patients with an aggressive NHL and up to 20 
patient with indolent NHL are planned to be 
enrolled to better characterize the safety profile 


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Number of global amendment
2
and tolerability of BI 836826 in the respective 
lymphoma types.
Change 15: Please refer Change 14.
 
 


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Number of global amendment
3
Date of CTP revision
07 Aug 2013
EudraCT number
2010-024456-29
BI Trial number
1270.2
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase I, Open-Label, Dose-Escalation Trial 
with BI 836826 in Patients with Relapsed or 
Refractory non-Hodgkin Lymphoma of B cell 
Origin
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Change 1: Section 3.3.3
Change 2: Section 4.1.1
Change 3: Section 4.1.4.3
Change 4: Section 4.2.1.2.1 
Change 5: Section 5.2.5.1
Description of change
Change 1: "GFR<60mL/min" was replaced by
"GFR<45 mL/min".
Change 2: ”Volume: 250 mL” was replaced by 
“See section 4.1.6”


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Number of global amendment
3
Change 3: "and only with a reduced dose of BI 
836826" was replaced by "or pre-treatment value 
"; "new" was replaced by "future"; "The reduced 
dose will be valid for all following treatment 
courses in the individual patient" was deleted; "In 
case, a patient experiences a second episode of 
DLT with the reduced BI 836826 dose, the 
treatment has to be permanently discontinued. 
Likewise, treatment" was replaced by 
"Treatment".
Change 4: "Prophylactic antiviral therapy (e.g. 
nucleoside reverse transcriptase inhibitor) and/or 
monitoring of hepatitis B DNA in the blood is 
recommended for patients with a history of 
hepatitis B infection." was added.
Change 5: "60 (±10), 90 (±10), 120 (±10), 150 
(±10) and 180 (±10)" was replaced by "every"; "In 
case of prolongation of the infusion time additional 
measures have to be documented every 30 minutes" 
was deleted.
 
 
 
 
 
 
 
 
 
 
Rationale for change
Change 1: GFR decreases with age. In view of the 
average age of NHL patients, exclusion criterion 
13 was modified to exclude only patients with a 
GFR<45 mL/min.
Change 2: Volume of 250 mL was replaced by 
reference to section 4.1.6 for clarification
Change 3: Clarification of handling of DLT to 


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Number of global amendment
3
allow for risk/benefit assessment for the patient 
receiving BI 836826.
Change 4: Recommendation for 
prophylaxis/monitoring for patients with prior 
hepatitis B infection.
Change 5: Vital Signs Clarification.
 


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4
Date of CTP revision
01 Oct 2015
EudraCT number
2010-024456-29
BI Trial number
1270.2
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase I, Open-Label, Dose-Escalation Trial 
with BI 836826 in Patients with Relapsed or 
Refractory non-Hodgkin Lymphoma of B cell 
Origin
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Change 1: Trial Responsibility for Trial Clinical 
Monitor changed from
to 
Change 2: Synopsis – No of patients changed 
from approx. 80 to approx. 66, no of entered 
patients changed from approx. 70 to approx. 53, 
treatment was modified in order to display the 
required number of Korean patients for both 
treatment dosages (50 and 75mg)
Change 3: Section 1.2 DRUG PROFILE –
currently performed trials in B-NHL malignancies 
and chronic lymphocytic leukemia were added.


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Number of global amendment
4
Change 4: Section 2.2 TRIAL OBJECTIVES –
addition of results, which were generated in this 
trial and analysed after an interim database lock, 
to display changed recruitment expectation based 
on the safety analyses. 
Change 5: 2-3 BENEFIT-RISK ASSESSMENT –
further in vitro, in vivo and first in human 
experiences with treatment of BI 836826 were 
added. Furthermore the risk of increased 
neutropenia was added and the information, that 
infections should be treated in an early stage.
Change 6: Section 3.2 DISCUSSION OF TRIAL 
DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP – modified trial design 
concerning inclusion of Asian patients.
Change 7: Section 3.3.3 EXCLUSION 
CRITERIA – criterion 26 was deleted as already 
reflected by criterion #4.
Change 8: Section 4.1.1 IDENTITY OF BI 
INVESTIGATIONAL PRODUCT AND 
COMPARATOR PRODUCT – Exact volume of 
infusion was deleted and instead a reference to 
section 4.1.6 with detailed explanation included.
Change 9: Section 4.1.3 SELECTION OF 
DOSES IN THE TRIAL – MTD doses as 
examined in Caucasian patients was added and 
the new possible doses for Asian patients added.
Change 10: Section 4.1.4.3 New section added 
‘MANAGEMENT OF INFECTIONS’ to 
establish a standardized process in case of 
infections due to additional safety precaution.
Change 11: Section 4.1.4.4 CONTINUATION 
OF TREATMENT DURING A COURSE -
Criteria for re-start of trial medication were 
expanded by two criteria (‘no active infection’ 
and ‘no evidence of progressive disease’) .


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001-MCS-40-106_RD-03 (10.0) / Saved on: 20 Oct 2011
Number of global amendment
4
Change 12: Section 4.2.1.2 SUPPORTIVE CARE 
– infections were added in order to take 
supportive care infections.
Change 13: Section 4.2.1.2.1 ANTIBIOTICS 
AND ANTIVIRALS – more detailed procedure 
for how to treat infections was added.
Change 14: Section 4.2.2.1 RESTRICTIONS 
REGARDING CONCOMITANT TREATMENT 
– typo was corrected.
Change 15: Section 5.2.2.2 ADVERSE EVENT 
AND SERIOUS ADVERSE EVENT 
REPORTING – According to internal guidelines, 
clarification of SAE follow-up was included.
Change 16: Section 5.5.3 ANALYTICAL 
DETERMINATION – description of the 
analysation method was corrected.
 
 
Change 18: Section 7.3.2.1 TUMOUR SIZE size 
was deleted
Change 19: Section 7.3.2.3 BLOOD COUNTS –
complete section was deleted as it will not be 
followed anymore.
Change 20: Section 7.3.2.4 BEST OVERALL 
RESPONSE - Analysation of CRu was added
Change 21: Section 7.3.4. INTERIM 
ANALYSES – adaptation to reflect the result of 
the interim analyse with regard to MTD.
 
 


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Number of global amendment
4
Change 23: Section 7.6 DETERMINATION OF 
SAMPLE SIZE – explanation was added, what is 
statistical rationale for determination of the 
chosen sample size.


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001-MCS-40-106_RD-03 (10.0) / Saved on: 20 Oct 2011
Number of global amendment
5
Date of CTP revision
13 Apr 2016
EudraCT number
2010-024456-29
BI Trial number
1270.2
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase I, Open-Label, Dose-Escalation Trial 
with BI 836826 in Patients with Relapsed or 
Refractory non-Hodgkin Lymphoma of B cell 
Origin
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Change 1: Section 2.2 Trial Objectives – ‘Three 
out of 4 Korean patients have developed 
significant toxicities (infections) which lead to the 
need of exploring a lower dose levels (50 and 
75mg) in a designated escalation cohort of 
Korean patients to further characterize safety and 
efficacy of BI 836826 (c02337389-01).’  This was 
added to clarify that a new patient in Korea is not 
part of the expansion cohort.
Change 2: Section 2.3 Benefit - Risk Assessment 
– Percentage of patients with mantle cell 
lymphoma corrected to 6 (14.6%)
Change 3: Section 2.3 Benefit Risk Assessment –
‘As a result the enrollment into the trial 1270.2 


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Number of global amendment
5
has been halted, and this current amendment is 
submitted to allow for testing lower dose of 50 
and 75mg in Korean patients in an escalation 
cohort for Asian patients.’ This was added to 
clarify that a new patient in Korea is not part of 
the expansion cohort.
Change 4: Section 3.1 Overall trial design and 
plan – ‘Instead, lower dose escalation cohorts of 
50mg and 75 mg will be open to test the 
safety,…’. This was clarified to stress the 
escalation status of Korean patients on 50 and 
75mg. 
Change 5: Section 3.3.2 – Clarification of 
inclusion criteria 3 and 6.
Change 6: Section 4.1.4.1.1 Premedication
‘Acetaminophen/paracetamol 1000 mg p.o. or a 
clinically comparable dose, or equivalent’ was 
modified to reflect slight flexibility concerning 
the dose of paracetamol.    
Change 7: Section 4.1.4.4 – Correction of 
neutrophil count in brackets and correction of 
administrative mistake in former protocol.
Change 8: 4.2.2.1 - Correction of administrative 
mistake in former protocol
Change 9: 5.1.2.10 – Correction of mistake in 
former protocol.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02158149
9.0
clinical-trial-protocol-version-06
A Phase I, Open-Label, Dose-Escalation Trial with BI 836826 in Patients with
Relapsed or Refractory non-Hodgkin Lymphoma of B cell Origin
Author-Statistician
13 Apr 2016 14:53 CEST
Author-Trial Clinical Monitor
13 Apr 2016 16:38 CEST
Approval-Therapeutic Area 
13 Apr 2016 23:25 CEST
Approval-Team Member Medicine
20 Apr 2016 12:57 CEST
25 Apr 2016 17:16 CEST
Verification-Paper Signature
Completion
27 Apr 2016 07:32 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02158149
9.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c02204387-02
BI Trial No.:
1270.2
Title:
A Phase I, Open-Label, Dose-Escalation Trial with BI 836826 in
Patients with Relapsed or Refractory non-Hodgkin Lymphoma of B 
cell Origin (including protocol amendments 1 to 5 [c02158149-09])
Investigational
Product(s):
BI 836826
Responsible trial 
statistician(s):
Phone:
Fax:    
Date of statistical 
analysis plan:
28 AUG 2017 REVISED
Version:
Revised
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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATION..................................................................5
3.
INTRODUCTION..................................................................................8
5.
ENDPOINTS ........................................................................................10
5.1
PRIMARY ENDPOINTS..................................................................................10
5.2
SECONDARY ENDPOINTS............................................................................10
5.2.1
Key secondary endpoints..............................................................................10
5.2.2
Other Secondary endpoints..........................................................................10
5.4.4 
Adverse events ...............................................................................................22
5.4.5
Laboratory parameters.................................................................................22
5.4.5.1
General safety laboratory parameters.........................................................22
5.4.5.2
Tumour lysis syndrome (TLS)/Laboratory signs of cell destruction .........23
6.
GENERAL ANALYSIS DEFINITIONS...........................................25
6.1
TREATMENTS..................................................................................................25
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................25
6.3
PATIENT SETS ANALYSED..........................................................................26
.....................................................................................................27
6.5
POOLING OF CENTRES ................................................................................27
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................27
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................27
7.
PLANNED ANALYSIS.......................................................................29
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........29
7.1.1
Disposition of patients...................................................................................29
7.1.2
Important protocol violations ......................................................................29
7.1.3
Demographic and other baseline .................................................................29
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................30
7.3
TREATMENT COMPLIANCE .......................................................................30
7.4
PRIMARY ENDPOINTS..................................................................................30
7.5
SECONDARY ENDPOINTS............................................................................31
7.5.1
Key secondary endpoint................................................................................31
7.5.2
Secondary endpoints .....................................................................................31
................................................................................31
7.7
EXTENT OF EXPOSURE................................................................................33
7.8
SAFETY ANALYSIS.........................................................................................33
7.8.1
Adverse events ...............................................................................................33


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7.8.1.1
Maximum tolerated dose and dose limiting toxicity ..................................33
7.8.1.2
Adverse events............................................................................................34
7.8.1.3
Protocol-specified significant AEs  and AEs by user-defined category 
(UDAEC)....................................................................................................35
7.8.1.4
Other significant AEs .................................................................................35
7.8.1.5
Infusion-related reactions (IRR).................................................................35
7.8.1.6
Tumour lysis syndrome ..............................................................................36
7.8.2
Laboratory data.............................................................................................36
7.8.3
Vital signs.......................................................................................................38
7.8.4
ECG ................................................................................................................38
7.8.5
Others .............................................................................................................38
8.
REFERENCES.....................................................................................39
9.
ADDITIONAL SECTIONS ................................................................40
9.1
INTERIM SAFETY ANALYSIS......................................................................40
9.1.1
Time point and general content ...................................................................40
9.1.2
Tables and eCRF pages to be cleaned .........................................................40
 
2
10.
HISTORY TABLE...............................................................................44


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LIST OF TABLES
Table 5.2.2:1
Derivation rules for progression-free survival............................................12
Table 5.2.2:2
Derivation rules for failure-free survival....................................................13
Table 5.4.5.2:1
Definition of abnormal lab values for laboratory signs of cell destruction 24
Table 6.2:1
Important protocol violations..........................................................................26
...........................41
...........................41
...........................42
Table 10:1
History table ....................................................................................................44


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2.
LIST OF ABBREVIATION
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
ALB
Albumin
ALKP
Alkaline phosphatase
ALT
Alanine amino transferase
aPTT
Activated artial thromboplastin time
AST
Aspartate amino transferase
ATC 
classification
Anatomical, Therapeutic, Chemical classification
BAS
Basophils
BMI
Body Mass Index
BRPM
Blinded Report Planning Metting
BSA
Body Surface Area
CA
Calcium
COOMB
Direct antiglobulin test
CR
Complete remission
CRu
Complete remission unconfirmed
CRE
Creatinine
CT
Computer tomography
CTh
Concomitant therapy
CTC
Common Terminology Criteria  
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical trial protocol
CTR
Clinical trial report
DBL
Database lock
DILI
Drug-induced liver injury
DLT
Dose limiting toxicity
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
ECOG
Eastern Cooperative Oncology group
eCRF
Electronic case report form
EMEA
European Agency for the Evaluation of Medicinal Products


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Term
Definition / description
EOS
Eosinophils
EoT
End-of-text
FFS
Failure free survival
GLU
Glucose
HCT
Haematocrit
HGB
Haemoglobin
ICH
International Conference on Harmonisation
IGA
Immunoglobulin A
IGG
Immunoglobulin G
IGM
Immunoglobulin M
INR
International normalised ratio of prothromin time (INR)
IRR
Infusion related reaction
K
Potassium
LDH
Lactate dehydrogenase
LYMPH
Lymphocytes
MedDRA
Medical Dictionary for Regulatory Activities
MONO
Monocytes
MRT
Mean residence time
MTD
Maximum tolerated dose
NA
Sodium
NE
Not evaluable
NEUT
Neutrophils
NHL
Non-Hodgkin Lymphoma
NK cells
Natural Killer cells
OBD
Optimal biological dose
O*C
Oracle Clinical
P
Inorganic phosphate
PD
Progressive disease
PFS
Progression free survival


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Term
Definition / description
PLT
Platelets
PR
Partial remission
PRT
Prothrombin time
PT
Preferred term
PV
Protocol violation
RBD
Red blood cell count
RD
Relapsed disease
RET
Reticulocytes
SAE
Serious adverse event
SCR
Screened set
SD
Stable disease
StD
Standard deviation
SOC
System Organ Class
SOP
Standard Operating Procedure
SPD
Sum of products of diameter
TBILI
Total bilirubin
TCM
Trial Clinical Monitor
TLS
Tumour lysis syndrome
ToC
Table of contents
TPRO
Total protein
TS
Treated set
TSAP
Trial statistical analysis plan
WBC
White blood cells


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3.
INTRODUCTION
As per International Conference of Harmonisation, statistical principles for clinical trials, E9
(ICH E9), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analyses described in the clinical trial protocol 
(CTP), and to include detailed procedures for executing the statistical analysis of the primary 
and secondary variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the protocol, including 
protocol amendments. In particular, the TSAP is based on the planned analysis specifications 
as written in CTP Section 7, “Statistical Methods and Determination of Sample Size”. 
Therefore, TSAP readers may consult the CTP for more background information on the 
study, e.g., on study objectives, study design and population, treatments, definition of 
measurements and variables, planning of sample size, randomisation. This TSAP follows the 
Boehringer Ingelheim (BI) internal reference (1).
The primary objective of this trial is to determine the maximum tolerated dose (MTD) of 
BI 836826 in patients with non-Hodgkin lymphoma (NHL) of B-cell origin. BI 836826 is a 
new biological entity and the maximum planned single dose is 1400 mg. If the MTD is not 
reached with this dose, an optimal biological dose (OBD) may be defined instead.
The MTD of BI 836826 was defined as 100 mg in this trial for Caucasian patients. This dose 
was declared based on safety demonstrated during the dose escalation which was performed 
in 37 Caucasian patients. The results have been reported in the “CTR – Phase I Safety 
Analysis Report” (8).
The planned additional expansion phase enrolled 4 patients (all 4 in Korea). After 3 of these 4 
Korean patients developed significant toxicities (ie. infections associated with Grade 4 
neutropenia), the protocol was amended for the need of exploring lower dose levels (50 mg 
and 75 mg) in a designated escalation cohort of Korean patients, with the aim of defining a 
MTD in Korean patients. Thus, the expansion phase on 100 mg had been stopped. Secondary 
objectives are the collection of overall safety and anti-tumour efficacy data and the 
determination of the 
 profile of BI 836826.
In the following, study medication always refers to BI 836826.
SAS® Version 9.2 (or higher) will be used for all analyses.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary endpoints of this trial are the MTD and the number of dose limiting toxicities 
(DLTs) during the MTD evaluation period. Instead of the MTD, an OBD might be defined 
instead.
Maximum tolerated dose (MTD):
MTD is defined as the highest dose studied for which the incidence of DLTs is no more than 
17% (i.e., 1/6 patients) during the MTD evaluation period.
The MTD evaluation period is defined as the time from the first administration of study 
medication to 7 days after the second administration.
Note that in case of administration of split dose during course 1, both infusions on 
consecutive Days 1 and 2 of Course 1 are considered as the first administration.
Additionally, all information, including adverse events (AEs) qualifying for a DLT from later
times, will be considered in the final determination of the dose recommended for Phase II.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints 
Not applicable.
5.2.2
Other Secondary endpoints
Tumour size reduction (indicator lesions, spleen and liver nodules)
Tumour size reduction of indicator lesions, spleen nodules and liver nodules will be analysed 
separately as secondary endpoints as follows:
Tumour size reduction of indicator lesions will be analysed as secondary endpoint “Best % 
change from baseline in SPD” from imaging data.
Tumour size reduction of liver nodules will be analysed as secondary endpoint “Best % 
change from baseline in SPD” from imaging data.
Tumour size reduction of spleen nodules will be analysed as secondary endpoint “Best % 
change from baseline in SPD” from imaging data. Best overall response (according to 
investigator assessment):
Response will be assessed according to the Standardized or Revised Response Criteria for 
Malignant Lymphoma from 1999 ([R04-1585]). Each patient will be assigned to one of the 


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following categories:

complete remission (CR)

complete remission unconfirmed (CRu)

partial remission (PR)

stable disease (SD)
progressive disease (PD)
Best overall response (CR, CRu, PR, SD, PD in this order) is defined as the best overall 
response obtained since the start of study treatment. Best overall response will be evaluated 
in two different ways: first, all responses as documented by the investigator (independent of 
the assessment procedure) will be evaluated. In a further analysis, only disease evaluations 
for which imaging data are available in the eCRF will be evaluated. In case PD is captured by 
the investigator, the response PD will be always considered as PD, independent whether 
imaging data is available at this timepoint or not. For both evaluations only response 
assessments prior to any further NHL therapy and until PD will be taken into account.
For the calculation of the date of response: if patients would have their examinations 
contributing to the disease assessment over a number of days, the earliest date of the multiple 
examinations will be considered.
Progression free survival (PFS):
PFS is defined as the time from first administration of study medication until disease 
progression or death, whatever occurs first.
Patients administered a new additional therapy for NHL recorded in the electronic case report 
form (eCRF) but not presenting with disease progression before the start of this new NHL
therapy will be censored at the date of last response assessment during which the patient was 
evaluable and did not have the event before the new NHL therapy has started.
Patients not administered another NHL therapy and not presenting with disease progression
or death during the trial will be censored at the date of the last response assessment during 
which the patient was evaluable and did not have the event.
A patient is said to have an evaluable response assessment if a response of CR, CRu, PR, SD 
or PD has been assigned.
The censoring rules and the applicable dates of outcome for PFS are given in the following 
table.


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Table 5.2.2:1
Derivation rules for progression-free survival
Situation
Outcome (event 
or censored)
Date of outcome
Baseline and post-baseline disease 
assessment: disease progression or death
without prior additional NHL therapy
Event
Date of first disease 
progression or death
Baseline and post-baseline disease 
assessment: disease progression or death 
and prior additional NHL therapy
Censored
Date of last response 
assessment before start of 
new NHL therapy
Baseline and post-baseline disease 
assessment: No disease progression or 
death without additional NHL therapy
Censored
Date of last response 
assessment
Baseline and post-baseline disease 
assessment: No disease progression or 
death with additional NHL therapy
Censored
Date of last response 
assessment before start of 
new NHL therapy
No baseline or post-baseline disease 
assessment: without death
Censored
Date of first administration 
of BI 836826
No baseline or post-baseline disease 
assessment: death on or before the first 
planned disease assessment (i.e. at week 4
assessment)
Event
Date of death
No baseline or post-baseline disease 
assessment: death after first planned 
disease assessment (i.e. at week 4
assessment)
Censored
Date of first administration 
of BI 836826
Remark: determination of the response status via disease assessment refers to any disease 
assessment via imaging or via physical assessment
Progression free survival (PFS) [in days] is therefore the time from first administration of 
study medication to the earlier date of disease progression or death (minimum date of disease 
progression or death – date of first administration of study medication + 1).
Progression free survival (PFS) censored [in days] is therefore the time from first 
administration of study medication to the date of last response assessment (date of last 
response assessment – date of first administration of study medication + 1).


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Failure free survival (FFS):
FFS is defined as the time from first administration of study medication until disease 
progression or death or start of next NHL therapy.
Patients not administered another NHL therapy and not presenting with disease progression
or death during the trial will be censored at the date of the last response assessment during 
which the patient was evaluable and did not have the event.
The censoring rules and the applicable dates of outcome for FFS are given in the following 
table.
Table 5.2.2:2
Derivation rules for failure-free survival
Situation
Outcome (event 
or censored)
Date of outcome
Baseline and post-baseline disease 
assessment: disease progression or death 
or start of next NHL therapy
Event
Date of first disease 
progression or death or start 
of next NHL therapy
Baseline and post-baseline disease 
assessment: No disease progression, 
death or new NHL therapy
Censored
Date of last response 
assessment
No baseline or post-baseline disease 
assessment: no death or new NHL 
therapy
Censored
Date of first administration 
of BI 836826
No baseline or post-baseline disease 
assessment: death/next NHL therapy on 
or before the first planned disease 
assessment (i.e. week 4 assessment)
Event
Date of death/next NHL 
therapy
No baseline or post-baseline disease 
assessment: death/next NHL therapy
after the first planned disease assessment 
(i.e. week 4 assessment)
Censored
Date of first administration 
of BI 836826
Remark: determination of the response status via disease assessment refers to any disease 
assessment via imaging or via physical assessment
Failure free survival (FFS) [in days] is therefore the time from first administration of study
medication to the earlier of disease progression or death or start date of next NHL therapy. 
(minimum date of disease progression, death or start of next NHL therapy – date of first 
administration of study medication + 1).


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Failure free survival (FFS) censored [in days] is therefore the time from first administration 
of study medication to the date of last response assessment (date of last response assessment 
– date of first administration of study medication + 1).


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5.4.4
Adverse events
Severity of AEs is scaled according to Common Terminology Criteria of Adverse
Event (CTCAE version 4.0, [R10-4848]).
Besides analysis with regard to primary system organ class and preferred term, AEs by user-
defined AE categories (UDAEC) will be analysed. Definitions of user-defined categores in 
terms of MEdDRA codes and subsearches can be found in Section 9.4 of this TSAP.
5.4.5
Laboratory parameters
5.4.5.1
General safety laboratory parameters
In this trial the original laboratory values will be converted into standard units and the 
CTCAE grades will be assigned to all parameters which have a CTCAE definition. For this 
study, the laboratory parameters and their functional groups, together with the direction of 
concern are:
Haematology: Haemoglobin (HGB) (-), haematocrit (HCT) (-), red blood cell count (RBC) 
(-), white blood cells (WBC) (-), platelets (PLT) (-) and reticulocytes (RET) (-), 
Differential:
Neutrophils (NEUT) (-), lymphocytes (LYMPH) (+ and -), monocytes 
(MONO) (-), basophils (BAS) (+) and eosinophils (EOS) (+), CD3+ T cell 
count (CD3V) (-), CD4+ T cell count (CD4V) (-), CD8 T cell count (CD8V) (-
), CD56+ natural killer cell count (CD56V) (-), CD 19+ B cell count (+ and-)
Electrolytes: Sodium (NA) (+ and -) and potassium (K) (+ and -)
Enzymes:
Aspartate amino transferase (AST) (+), alanine amino transferase (ALT) (+), 
alkaline phosphatase (ALKP) (+)
Substrates: 
Total bilirubin (TBILI) (+), glucose (GLU) (+ and -) and creatinine (CRE) (+)
Coagulation: International normalised ratio of prothromin time (INR) (+), activated artial 
thromboplastin time (aPTT) (+) and prothrombin time (PRT) (+)
Urine (measured by dipstick): pH, glucose, erythrocytes, leukocytes, protein, nitrite
Biochemistry: Calcium (CA) (+ and -), corrected calcium (+ and -), inorganic phosphate (P) 
(-), lactate dehydrogenase (LDH) (+), urea (UREA) (+), total protein (TPRO) 
(-),
albumin (ALB) (-), uric acid (URIC) (+), Immunoglobulin A (IGA) 
(+ and - ),Immunoglobulin M (IGM) (-), Immunoglobulin G (IGG) (-), 
direct antiglobulin test  (COOMB), CMV DNA (qual.)  
The signs + (-) means the above (below) the reference ranges. For the parameters TPRO,
ALB, URIC, IGA, IGM, IGG, and direct antiglobulin test, no CTCAE grade definition is 


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available. The direction of concern will be investigated with regard to their respective 
reference ranges. 
Urine measurement (based on dipsticks with 0, +, ++, and +++; the more + the worse) will be 
displayed if available. For urine measurement based on dipsticks conversion rules can be 
found in Section 9.3.
The grading of hypocalcemia is based on corrected calcium as calcium can be falsely low if 
hypoalbuminemia is present. The following corrective calculation will be performed:
Corrected calcium (mg/dL) = Total Calcium (mg/dL) – 0.8[Albumin (g/dL)-4)
No correction of the reference range has to be done. The reported reference range of total 
calcium should be used for analyses.
Corrected calcium can be only derived at a certain time point in case both laboratory values, 
total calcium and albumin, have been reported for the patient in the same laboratory sample. 
The following laboratory parameters are considered as prioritized laboratory values as 
defined on project level: Haemoglobin, WBC, neutrophils, lymphocytes, platelets, ALT, 
AST, total bilirubin, LDH, creatinine, uric acid, potassium, inorganic phosphate, calcium, 
corrected calcium, albumin,CD4+ T cell count. Prioritized laboratory values will be 
presented in Section 15 of the CTR, while all other laboratory parameters of concern will be 
displayed in Appendix 16.1.9.2.
5.4.5.2
Tumour lysis syndrome (TLS)/Laboratory signs of cell destruction
The presence of TLS will be mainly investigated via adverse event reporting (see Section 
7.8). In addition, laboratory signs of cell destruction will be investigated based on the 
laboratory values uric acid, potassium, inorganic phosphate and creatinine. Laboratory signs 
of cell destruction may be considered present if within the time window of the day of BI 
836826 infusion and the following 6 days two or more of these laboratory parameters are 
considered abnormal simultaneously. Simultaneously means that abnormality of these ≥2 lab 
parameters occurs within 24 hours within the 7 day window after BI 836826 infusion. The 
definition of abnormal laboratory values is given in Table 5.4.5.2: 1 below. .In case 
laboratory signs of cell destruction are observed, it will be checked whether an AE episode 
that may indicate clinical TLS is reported within the 7 day time window after BI 836826 
infusion. For the respective UDAEC see Section 7.8.


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Table 5.4.5.2:1
Definition of abnormal lab values for laboratory signs of cell 
destruction
Laboratory parameter
abnormal value
Uric acid
≥476 µmol/L AND increase 
from relative baseline by 
≥25%
Potassium
Only if relative baseline is < 
6.0 mmol/L: value  ≥ 6.0 
mmol/L 
Inorganic phosphate
≥1.45 mmol/L AND increase 
from relative baseline by by 
≥25%
Creatinine
Absolute increase from 
relative baseline by 26.5 
µmol/L AND increase from 
relative baseline by ≥50%
Definition of relative baseline: relative baseline is the last laboratory value prior to BI 836826 
infusion, ie. it will be derived for the four laboratory values separately for each infusion.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
In this Phase I trial, treatments are not randomised (open-label, dose escalation). Different 
dose levels of BI 836826 can arise. The data will be presented for all dose cohorts separately,
where Korean patients will be presented as a separate dose cohort from Caucasian patients. 
 
 In addition, the results for all patients in total, 
all Caucasian patients in total, and all Korean patients in total will be presented.
To justify the MTD determination, DLTs occurring during the MTD evaluation period (very 
first infusion of BI 836826 until the day of second infusion in Course 1 + seven days) will be 
presented separately from those occurring during the complete on-treatment period.
“Analysing treatment” will be used for reporting of treatment emergent AEs and to 
differentiate between screening, on-treatment and post-study safety data. The inequalities 
start date ≤ onset date of AE < end date will determine whether the AE will be assigned to the 
“analysing treatment” or not.
For the on-treatment period and the MTD evaluation period, the initial trial medication 
assigned at the beginning of the first treatment course will be used as the label of the 
analysing treatment.
AEs that have an onset date during the screening or post-study periods will be displayed in 
separate listings from those occurred during the on-treatment period. 
The actual planned dose of trial medication administered on the day each AE started will also 
be derived. This will be presented in patient listings, but will not be used for defining 
treatments for analysis.
Labels of each analysing treatment period, analysis numbers, the labels used for display in the 
tables and listings in the CTR, as well as codes, decodes, sort order and labels for each trial 
medication used in this trial are provided in the TSAP technical document “ADS Plan”.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Due to the fact that this is a phase I study, no per protocol population is needed, however 
important protocol violations (PV) should be identified for patients in the treated set (see 
Section 6.3). Any PV which may affect safety, efficacy or the patient’s rights will be 
determined.
The following table defines the different categories of important PVs. If the data show other 
important PVs, this table will be supplemented accordingly latest at the blinded report 
planning meeting (BRPM).


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Table 6.2:1
Important protocol violations
Category
/Code
Description
Example/Comment
Excluded 
from
A
Entrance criteria not met
A1
Patient has condition that may 
cause additional risk from 
study medication
Ex 16 - 21,23,24
None
A2
Patient has laboratory 
assessments that may cause 
additional risk.
Ex 9 – 14, 
None
A3 
Patient is unable to comply 
with the protocol
Ex 22, 25
None
A4
Patient does not have trial 
diagnosis or is not part of the 
target population
In 1 - 2, 4, 6-7, Ex 1 – 7, Ex 8 
None
B
Informed consent
B1
Informed consent not given or 
too late
In 8
None
C
Trial medication and 
randomisation
C1
Drug not administered 
according to the protocol
Administration according to 
protocol="No" and medical review 
of associated comments
None
C2
Drug not administered 
according to protocol
Individual pre-medication 
taken="No" and medical review 
whether premedication would have 
been required according to 
protocol
None
6.3
PATIENT SETS ANALYSED
The Screened Set (SCR) includes all patients who signed informed consent form and will be 
used to summarize patient disposition.
The Treated Set (TS) consists of all patients who received at least one application of the BI 
drug BI 836826. The TS will be used for all planned safety analyses.
 
 


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Replacement of patients is defined in Section 3.3.4.1 in the CTP. The final list of replaced 
patients is supplied by the Trial Clinical Monitor (TCM) no later than at the last BRPM 
before the DBL.
No per protocol population will be used for analyses.
Study medication is defined as BI 836826.
First administration of study medication is defined as date of first administration of BI 
836826.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
If not stated otherwise, missing data will not be imputed and remain missing. Potential 
outliers will be reported and analysed as observed.
Missing or incomplete AE dates are imputed according to BI standards (see (5)).
Missing data and outliers 
 are handled according to 001-MCS-36-472 (2).
If the day of birth is missing, then the imputed days will be the 15th. If start of new NHL
therapy date is incomplete (only month given), then the start date will be imputed with the 1st
of month unless the first day leads to a date before the stop date of study medication, then the 
study medication stop date +1 will be imputed. If more than only the day is missing, dates 
will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study days and visits will be labelled according to the flow chart of the CTP.
Unless otherwise specified, baseline is defined as the time-point closest to but prior to first 
administration of trial medication in the first treatment phase, where the first administration 


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of trial medication is defined in Section 6.3 above. If this criterion is not fulfilled, then no 
baseline will be derived.
For laboratories where not only the examination date but also time is recorded, examination 
time has to be taken into account when defining baseline. That is, a laboratory value on the 
same date as the first study drug administration is considered as baseline value if and only if 
the time of laboratory value is before or the same as the date and time of the start of first 
study drug administration.
If any of these times are missing (either no time of start of first study drug administration or
no lab sample stating that it was taken prior to start of first study drug administration) and so
it cannot be concluded whether the blood sampling was done before or at the same time of
the start of first study drug administration, the last available laboratory assessment before first
study drug administration will be taken (Screening laboratory) .
For graphical presentations of laboratory data, baseline will be coded as Day = 1.
The definition of relative baseline for the investigation of  laboratory signs of cell destruction 
is given in Section 5.4.5.2.


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7.
PLANNED ANALYSIS
For end-of-text (EoT) tables, the set of summary statistics is: N / Mean / standard deviation 
[StD] / Minimum [min] / Median / Maximum [max]. 
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, StD, min and max.
For time-to-event analysis tables, the set of statistics is: number of patients [N(%)], Number 
of patients with event [N(%)], <Time to event> [months] followed by P25 (25th percentile), 
median, P75 (75th percentile), Number of patients censored [N(%)]. If not specified 
otherwise, the duration as well as the time to event will be displayed in days and a final 
decision will be made at the last BRPM.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values. The 
denominator of the main categories is defined by the number of patients in the used patient 
set. The main categories define the denominators of the subcategories. Subcategories should 
be intended and “[N(%)]” will be displayed only for the main category. If a table includes 
only categorical data, “[N(%)]” is to be displayed in the column header.
If applicable, conversion from days to weeks, months and years will be as follows:

Weeks = Days/7

Months = (Days ×12)/365.25

Years = Days/365.25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
7.1.1
Disposition of patients
For patient disposition the standard descriptive table will be populated. Additionally, patients 
with discontinuations by initial treatment and the reasons will be listed.
7.1.2
Important protocol violations
A listing with the number of patients with protocol violations by initial treatment will be 
created in Section 15 of the CTR.
7.1.3
Demographic and other baseline
Standard descriptive analysis and summary tables for all patients treated by initial treatment 
will be created for demography, smoking/alcohol status, previous therapies, physical 


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examination, disease evaluation at baseline, virology screening, ECOG and oncological
history.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant therapies will be coded according to World Health Organisation Drug 
Dictionary (WHO DD). Concomitant therapies (CTh) will be classified according to the 
Anatomical, Therapeutic, Chemical (ATC) classification system. The third ATC level will be 
used to categorise CThs by therapy type. In situations where a medical product may be used 
for more than one equally important indication, there are often several classification 
alternatives. As appropriate, patients receiving CThs with more than one possible ATC level-
three category will be counted more than once; footnotes will clarify this possible double 
counting in tables.
A summary of the most frequently used concomitant medications (drug classes and generic 
name) during the treatment and before starting of treatment will be reported. Separate 
listings/tables will be provided for therapy starting before therapy and those therapies starting 
after first administration of the trial drug as well as for therapies with missing or incomplete 
start dates. A summary of concomitant therapy will be given.
Listings of the data will present the concomitant therapy PT and verbatim text as well as the 
verbatim text of the indication. In addition the listings will include study day for start and 
stop dates and duration of therapy. Patients with no concomitant therapy will not be included 
in the listing. 
7.3
TREATMENT COMPLIANCE
Compliance will be evaluated by whether or not the medication was always administered 
according to protocol for BI 836826.
The numbers of patients complying with the administration of trial medication according to 
protocol (yes/no) will be listed.
For patients with administration "not according to the protocol" a listing with comments will 
be presented.
Furthermore, a listing will show all administrations of trial drug including also the 
administration of premedication acetaminophen/paracetamol, antihistamine and 
glucocorticoid.
7.4
PRIMARY ENDPOINTS
The primary endpoints of this trial are the MTD and the number of DLTs during the MTD 
evaluation period. The MTD is determined from the occurrences of DLTs during the MTD 
evaluation period, which is from treatment start until the second infusion of BI 836826 plus 7 
days. An overall summary of the DLTs (see CTP Section 5.2.1.1 for definitions of DLT) 


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which occurred during the MTD evaluation period will be provided for each dose cohort. 
Patients, if any, who did not complete at least two administrations of BI 836826 for reasons 
other than DLT will be excluded from the analysis of the primary endpoint. These patients 
will be replaced at the same dose level. 
At the end of the dose escalation phase, a brief interim safety analysis was performed and 
reported to further describe the dose escalation steps actually occurred and to justify the 
determination of MTD, see also Section 9.1 and “CTR – Phase I Safety Analysis Report” (8).
 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
Tumour size of target lesions, spleen nodules and liver nodules (from imaging data) will be 
analysed in terms of their SPD best percentage change from baseline. Summary statistics will 
be presented for all cohorts. A waterfall plot will also be generated to summarise tumour size 
reduction graphically for the SPD of the indicator lesions identified at baseline imaging. 
Furthermore, the tumour size of indicator lesions, liver nodules and spleen nodules and the 
change with respect to baseline will be listed by time point (for imaging data as well as for
data from physical assessment).
Best overall response will be analysed descriptively. Frequency distributions and other 
descriptive statistical measures will be used to examine this endpoint. The number of patients 
that have either CR, CRu or PR as best overall response will be tabulated separately (to 
determine the remission rate, the rate of patients that have either CR, CRu or PR as best 
overall response).
PFS and FFS will be analysed exploratory using Kaplan-Meier methods.


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7.7
EXTENT OF EXPOSURE
Standard descriptive analyses over all treatment courses will be performed. This will include 
a summary of the variables already described in Section 5.4.2. This descriptive analysis will 
comprise a mixture of frequency and percentages, as well as summary statistics.
For the sequence of doses, there will be a listing of each dose taken at each treatment course 
for all patients.
7.8
SAFETY ANALYSIS
The primary analysis is for determination of MTD. No statistical model is foreseen allowing 
assessment of MTD; descriptive analysis is confined to a listing by dose group. The purpose 
of these tables is to summarize and document the data that led to the selection of the MTD.
 
With regard to the final CTR, 
no selected MTD analyses for Caucasian patients will be displayed since the determination of 
the MTD for Caucasian patients has been already described in the “CTR – Phase I Safety 
Analysis Report” see (8)). 
 
7.8.1
Adverse events
7.8.1.1
Maximum tolerated dose and dose limiting toxicity
A summary of the number of patients with DLT within the MTD evaluation period will be 
given by initial treatment.
In order to explore the behaviour of DLTs with respect to the actual dose of BI 836826, we 
will examine descriptively the dose response relationship, using DLTs in the MTD evaluation 
period and DLTs up to the end of the on treatment phase, in separate analyses. Still, the 
determination of the MTD of Caucasian patients had been already described in the “CTR –
Phase I Safety Analysis Report” (8) and will thus not be described again in the final CTR. 


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7.8.1.2
Adverse events
AE analysis will be performed for all treatment periods and selected analyses for the MTD 
evaluation period.
The analyses of AEs will be descriptive in nature and will follow the standard procedure laid 
down in the Data Management and Statistics Manual (DM & SM) (including all required 
tables and listings) (current guideline 'Handling and Summarization of AE Data for CTR and 
Integrated Summaries' (6)). AEs will be coded with the most recent version of Medical 
Dictionary for Regulatory Activities (MedDRA). The version number will be displayed as a 
footnote in the respective tables and listings. The SOC will be sorted alphabetically, and PTs
will be sorted by descending frequency of adverse events in the “Total” BI 836826 group
Each patient can be observed during the trial under several doses. Analysing the AE of all 
treatment courses will be carried out under the initial treatment. No formal statistical analysis 
is planned for the safety comparison. 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs occurring between the first administration of BI 836826 until 8 weeks after last 
administration of BI 836826 will be assigned to the on-treatment period. AEs will be 
distinguished for the treatment course in which the subjects are on-treatment as well as for 
screening, and post-study. The actual planned dosage of BI 836826 administered on the day 
each AE starts will also be derived and will be included in the listing. Listings of screening 
events will not be sorted by initial treatment. Post-study listings will be sorted by initial 
treatment.
According to the BI standards, multiple recordings of AEs will be collapsed to episodes on 
the lowest level term and multiple episodes will be condensed to records on the PT and SOC 
level. CTCAE grade will be an additional criterion for collapsing and condensing AEs. The 
maximum CTCAE grade will be assigned to episodes and records. CTCAE grade and DLT 
information will be displayed in AE listings. MedDRA levels for condensing will be SOC 
and PT.
CTCAE grading within AE tables is displayed as “all Grades”, “Grade 1”, “Grade 2”, “Grade 
3”, “Grade 4” and “Grade 5”. AEs with missing CTCAE or CTCAE grades not equal to 1 to 
5 will be displayed under the category “all grades”, but no category “missing grade” is 
displayed. A footnote is explaining that AEs with missing CTCAE or CTCAE grades not 
equal to 1 to 5 will be displayed under the category “all grades” and therefore the separate 
categories might not sum up to the category “all grades”. A separate table will show AEs 
leading to death. In this table no CTCAE grades will be shown. In the appendix (Section 
16.1.9.2), the categorization“all grades”, “missing grades”, “Grade 1/2”, “Grade 3/4” and 
“Grade 5” is used, but the “missing grade” column should only be displayed in case AEs with 
a missing CTCAE grade occured.


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AE attributes
AE attributes "CTCAE Grade 3/4 combined with drug relation" and “CTCAE Grade 5 
combined with drug relation” will be derived to avoid incorrect condensing.  Consider, for 
instance, a patient with coincident drug-related abdominal pain with CTCAE Grade 1, and 
non-related vomiting with CTCAE Grade 3.  Without the new attribute these AEs would be 
reported as drug-related Grade 3/4 under the SOC Gastrointestinal Disorder. With the new 
AE attribute these AEs would be excluded.
Additional AE attributes “Drug relationship combined with seriousness of the AE” is needed 
similarly to the AE attribute "CTCAE Grade 3/4 combined with drug relation" and “CTCAE 
Grade 5 combined with drug relation”, respectively, as described above.
Frequency of patients with AEs will be summarised by treatment, highest CTCAE grade, 
primary SOC and PT. Tables will be provided for patients with related AEs, with serious 
adverse events (SAEs), with non-serious AEs, with DLTs, with protocol-specified significant 
AEs, with other significant AEs, with Adverse events of special interest (AESIs), AEs by 
user-defined AE category, with Infusion-related reactions (IRRs), with AEs leading to 
permanent discontinuation of study medication, with AEs leading to dose reduction, and with 
AEs leading to death.
7.8.1.3
Protocol-specified significant AEs and AEs by user-defined category (UDAEC)
Protocol-specified significant AEs as defined in the CTP, Section 5.2.2.1, will be 
summarized..
AEs by UDAEC will be displayed in a frequency table of AEs by user-defined category, 
preferred term and worst CTCAE grade as well as in a frequency table by user-defined 
category and worst CTCAE grade. UDAEC categories are described in Section 9.4.
7.8.1.4
Other significant AEs
Other significant AEs are serious and non-serious AEs leading to treatment discontinuation
and/or serious and non-serious AEs leading to dose reduction. Respective frequency tables by 
worst CTCAE grade, primary system organ class and preferred term will be provided.
7.8.1.5
Infusion-related reactions (IRR)
Frequency of IRRs will be displayed in separate listings and tables where it will be 
differentiated between the reported AE term “Infusion-related reaction” and the symptoms of 
an IRR that are reported as AEs.
For patients at the beginning of this trial (up to the 50 mg dose cohort (enrolment before 
April 2013)), the symptoms of an IRR are reported as AEs but not captured explicitly as 
symptoms of an IRR. For these patients, potential symptoms of an IRR can be only identified 
by pre-defined AE preferred terms as given by the user-defined category . For patients from 
following dose cohorts (including some patients of the 50mg cohort), not only IRRs are 
reported with the AE term “Infusion-related reaction” but also its symptoms which are 


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additionally marked as symptoms of an IRR. IRR tables capturing IRR symptoms can be only 
displayed for these patients. A listing will show all patients with IRR episodes as well as 
reported symptoms of these IRRs. Furthermore symptoms of IRRs will also be displayed 
where it will be distinguished between symptoms marked as such and potential symptoms of 
an IRR.
The number of episodes of IRRs as well as the frequency of its symptoms and CTCAE grades 
will be displayed graphically for those patients where the symptoms of an IRR are reported as 
such. 
The frequency of the AE “Infusion-related reaction” episodes based on the preferred 
MedDRA term will be displayed by administration visit together with its CTCAE grade for 
all patients. 
7.8.1.6
Tumour lysis syndrome
Potential clinical tumour lysis syndrome will be analysed via the UDAECs for TLS as 
defined in Section 9.4.
In addition, screening for laboratory signs of cell destruction based on the laboratory values 
of uric acid, potassium, phosphorus and creatinine will be done as described in Section 
5.4.5.2.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will follow the standard 
procedure laid down in the DM & SM (Guideline 'Display and Analysis of Laboratory Data'
(7)).
Patients will be counted under the initial treatment. The analysis of laboratory data will use 
the same ‘analysing treatments’ as described for the AEs, except for that the baseline 
laboratory value (as defined in Section 6.7) will be included in the ‘on-treatment’ period.
Patients having at least one post-baseline laboratory value will be displayed in the descriptive 
analyses. 
Single time courses by initial treatment will be used to display laboratory values over time. 
The graphs may be truncated if sufficient data is not available. These graphs will be displayed 
in Chapter 16.1.9.2 of the CTR for the following parameters, using the BI standardized values 
for haematology and differentials.
Haematology: haemoglobin, WBC count and platelets
Differentials: neutrophils (absolute count), absolute lymphocyte count, absolute Monocyte 
count and Natural Killer (NK) cells, CD 4 T-cell count
Biochemistry: LDH.
Clinically relevant abnormalities (as defined in Section 9.2) will also be summarised.


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The change of the laboratory value will be calculated for all laboratory parameters from 
baseline to the end of the treatment for the whole treatment duration. No post-study 
laboratory values will be considered.
Worst laboratory value and its CTCAE grade (highest CTCAE grade) over all courses will be 
calculated for each laboratory parameter. 
The change of the CTCAE grade of the lab value will be calculated

from baseline to the last laboratory value on treatment

from baseline to the worst value on treatment

from worst value on treatment to last value on treatment
Note: For calculating the change in CTCAE grade from baseline, patients with a CTCAE 
grade of -9 (no CTCAE grade defined) will be treated as a CTCAE grade 0 for all analyses. 
In laboratory listings, the CTCAE grade is displayed as -9.
For Uric Acid and Hypokalemia, the CTCAE grade cannot always be assigned by the 
laboratory parameter itself as two different CTCAE grades have the same laboratory 
constellation, but are distinguished by additional clinical parameter. In this case a CTCAE 
grade of -1 will be assigned inititally. Patients with a CTCAE grade of -1 will be treated as

Grade 1 for Uric Acid

Grade 1 for Hypokalemia
for all analyses. In laboratory listings, the CTCAE grade will be displayed as -1.
Patients with hepatic enzyme elevation will be tabulated.
Patients with possibly clinically significant laboratory values will be tabulated (see Section 
9.2).
The prioritized laboratory values (see Section 5.4.5.1) will be displayed in Section 15 of the 
final CTR while all other laboratory parameters will be displayed in the Appendix of the 
CTR.
Neutropenia, thrombocytopenia and leukopenia 
Episodes of low neutrophil, platelet and WBC counts are of special interest. Episodes with 
CTCAE grade 3/4 as well as episodes with CTCAE grade 4 lasting 7 or more days will be 
analysed separately. 
An episode of low blood counts of grade 4 starts with the first occurrence of a CTCAE grade 
4 and lasts until the first time the CTCAE grade falls back to <=3 (analogously for an episode 
of CTCAE grade 3/4) .
In case the episode starts during the EOT or Follow-up, the duration of this episode is defined 
to be missing. The reason for this approach is that after the EOT laboratory data is only 


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captured infrequently and therefore the duration of an episode would be overestimated due to 
lack of data.
If an episode starts before EOT and the CTCAE grade of the respective parameter does not 
fall back to the respective grade that ends the episode and the patient dies, the end of the 
episode is defined by the date of death. If the episode starts before EOT and lasts during 
Follow-up, the episode is censored with the date of DBL.
Number of patients with respective episodes, number of episodes, episodes per patient, 
duration of individual episode, number of episodes divided by number of infusion per patient, 
mean and median duration of episode per patient will be displayed.
Additionally, a frequency table displaying number of patients with episode of neutropenia 
Grade 4 and concomitant AEs in the UDAEC Infections (incl. respiratory infections and 
sepsis) of any grade as well as only for Grade 3 or 4 infections will be provided. In this 
context, concomitant AE is defined as AE with onset date within the neutropenia episode. 
This will be also done for CD4+ T-cell count Grade 4 and concomitant CD4 related specific 
infections from the UDAEC CD4 related specific infections.
The same way, a frequency table displaying number of patients with episode of 
thrombocytopenia Grade 4 and concomitant AEs in the UDAEC bleeding of any grade as 
well as only for Grade 3 or 4 bleeding will be provided. 
7.8.3
Vital signs
Descriptive statistics of absolute values  for vital signs (including body weight) will be 
provided by initial treatment and planned time or visit over all treatment courses.
7.8.4
ECG
No analyses are planned. 
7.8.5
Others
Not applicable.


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8.
REFERENCES
1
001-MCG-160_RD-01: "TSAP annotations", current version; IDEA for
CON.
2
001-MCS-36-472 "Standards and processes for analyses performed 
within clinical 
Pharmacodynamics”, current version; 
IDEA for CON.
3
001-MCS-36-472_RD-01 “Noncompartmental 
Pharmacodynamic Analyses of Clinical Studies”, 
current version; IDEA for CON.
4
001-MCS-36-472_RD-03 “Description of Analytical Transfer Files and 
PD Data Files”, current version; IDEA for CON.
5
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON.
6
001-MCG-156: "Handling and summarisation of adverse event data for 
clinical trial reports and integrated summaries", current version; IDEA 
for CON.
7
001-MCG-157: "Display and Analysis of Laboratory Data", current 
version, IDEA for CON.
8
c02337389-01 “Clinical Trial Report – Phase I Safety Analysis Report”
[R04-1585]
Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, 
Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, 
Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, 
Carter W, Hoppe R, Canellos GP. Report of an international workshop 
to standardize response criteria for non-Hodgkin’s lymphomas. J Clin 
Oncol 17 (4), 1244-1253, 1999.
[R01-0787]
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, 
Carbone PP. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol (5), 649 – 655, 1982.
[R10-4848]
Common terminology criteria for adverse events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010).
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf 2010
[R10-4517]
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the 
management of pediatric and adult tumor lysis syndrome: an evidence-
based review. J Clin Oncol 26 (16), 2767-2778, 2008.


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9.
ADDITIONAL SECTIONS
9.1
INTERIM SAFETY ANALYSIS
After the MTD (or, if applicable, the OBD) has been defined, an interim safety analysis was
performed and the results were consolidated in in the “CTR – Phase I Safety Analysis
Report” (8). 
9.1.1
Time point and general content
After all patients treated in the dose finding phase of this trial have either completed the MTD 
evaluation period or dropped out of the study, safety analyses were performed to justify the 
dose to be used in the expansion phase of this trial. For this purpose, a database snapshot was
performed. This snapshot has not been done following the process of an interim DBL. The 
safety analyses summarized results regarding safety of patients and did contain the 
determination of the MTD of BI 836826 as well as a recommendation for the dose of BI 
836826 to be used in the expansion phase of this study. No efficacy and PK analyses were
performed for the safety analyses.
A version of the TSAP was signed and archived before the snapshot of the safety analyses 
has been performed.
9.1.2
Tables and eCRF pages to be cleaned
Selected tables and listings from trial patients with regard to the safety evaluation were
provided for the safety analyses.
The tables and listings that are contained in the report for the safety analyses were specified 
more precisely in the table of contents (ToC). The Oracle Clinical (O*C) database was as 
clean as possible before the snapshot was taken. Nevertheless, it was considered that the data 
might be unclean at that time point. eCRF pages that were particularly focused on in the 
cleaning process were the following:

pages related to AEs

pages related to laboratory data (note: only the prioritized laboratory values, see 
Section 5.4.5.1, will be displayed in the safety update report)

administration of study medication pages

pages related to patient disposition


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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP.
Table 10:1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
28-Apr-14
None
This is the final TSAP without any 
modification
Revised
28-Aug-17
All
Correction of spelling and grammar 
mistakes
3
Explanation that the expansion phase of 
the trial was cancelled
 
4
Clarifications deleted since these points 
have been already clarified in the CTP 
amendment
 
 
 
5.2.2
Wording changes to clarify that SPD 
will be calculated based on indicator 
lesions 
Deletion of liver and spleen endpoints 
(have been deleted in CTP amendment)
Clarification that response endpoints 
will be evaluated separately: based on 
imaging data only and based on all 
response assessments by the 
investigator
Clarification of derivation of date of 
response assessment
Censoring rules for PFS added
Censoring rules for FFS added


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Table 10:1
History table (cont.)
 
 
5.4.5
Further safetly lab parameters added
Derivation of corrected calcium added
Corrected calcium, albumin and CD4+ 
T-cell count added as prioritized lab 
values
Analysis of TLS/laboratory signs of 
cell destruction revised after PVWG 
decision 
6.1
Clarification that Korean patients will 
be presented separately
6.2
IPV table revised
6.3
6.7
Clarification of laboratory baseline 
values


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Table 10:1
History table (cont.)
7.8.1
 
Specific DLT analyses deleted (lack of 
data for analysis)
Display of CTCAE poolings clarified
Analysis of TLS/laboratory signs of 
cell destruction  revised
7.8.2
Handling of -1 and -9 lab values 
revised
Analyses with regard to neutropenia, 
thrombocytopenia, leukopenia nd low 
CD4+ T-cell count added