Clinical trial NCT01296932
Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
Sponsor: Boehringer Ingelheim
Start date: 2011-02-11; Completion date: 2017-07-10
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Adult patients with chronic lymphocytic leukaemia who experience a relapse after at least two prior treatment regimens may be enrolled in this trial. The trial will examine whether monotherapy with BI 836826 is safe and tolerable at escalating dose levels.

Detailed description:

Arms: arm 1: Patients with relapsed CLL after at least two prior treatment regimens will receive BI 836826.
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_001.pdf: 
Clinical Trial Protocol
Doc. No.: c01568809-08
EudraCT No.:
BI Trial No.:
2010-021488-34
1270.1
BI Investigational
Product(s):
BI 836826
Title:
A Phase I, open, dose escalation trial with BI 836826 in patients with 
advanced chronic lymphocytic leukaemia
Clinical Phase:
Phase I
Trial Clinical 
Monitor:
Phone: 
Fax:
Coordinating
Investigator:
Phone: 
Fax: 
Status, Version, and 
Date of Protocol:
Final Protocol, Version 1, 27 July 2010
Status, Version, and 
Date of Revised 
Protocol
Final Protocol, Version 2, 20 January 2011
Final Protocol, Version 3, 20 September 2011                                             
Final Protocol, Version 4, 2 Aug 2012
Final Protocol, Version 5, 07 Aug 2013
Final Protocol, Version 6, 04 March 2015
Page 1 of 111
Proprietary confidential information. 
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
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:
04 Mar 2015
27 Jul 2010
1270.1
Title of trial:
A Phase I, open, dose escalation trial with BI 836826 in patients with advanced 
chronic lymphocytic leukaemia
Coordinating
Investigator:
Trial site(s) :
Multi-center trial 
Clinical phase:
Phase I
Objective(s):
To investigate the maximum tolerated dose (MTD), safety and tolerability, 
 and efficacy of BI 836826 monotherapy in patients with chronic 
lymphocytic leukaemia (CLL).
Methodology:
Open-label dose escalation
No. of patients: 
About 70
total entered:
About 60
Diagnosis :
Chronic lymphocytic leukaemia (CLL)
Main criteria
for inclusion:
Adult patients with active CLL who have received at least two prior treatment 
regimens
Test product(s) :
BI 836826
dose:
The starting dose for BI 836826 will be 1 mg.
mode of admin. :
BI 836826 administered intravenously as one to three single doses within a 14 day 
course.
Comparator products:
Not applicable.
dose:
mode of admin. :
Duration of treatment: Minimum of one 14-day treatment course. Patients are eligible for repeated courses as 
long as neither patient nor investigator requests treatment discontinuation.


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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:
04 Mar 2015
27 Jul 2010
1270.1
Criteria for efficacy, 
pharmacokinetics,  
pharmacodynamics:
Number of lymphocytes in the peripheral blood, 
, blood counts, best 
overall response, progression free survival, failure free survival,
 
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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FLOW CHARTS
Flow Chart Course 1, Dosing on Day 1 and Day 2
Trial Periods
Screen
Treatment**
EOT/FU
Course *
1 
If no signs of 
progression 
please 
continue to 
Visit 1 Flow 
Chart
Course 2-8
If the patient 
has disease 
progression 
or 
withdraws, 
please  
continue to 
EOT visit on 
Flow Chart  
Course 2-8  
Visit *
Screen
1
2
3
Days 
-14 to -
1
1
2
3 
4
8 
Informed consent
x
Demographics
x
Medical history
x
Review of in-/exclusion criteria
x
x
12 lead-ECG
x
Height
x
Physical examination, 
 
 
ECOG performance status
x
x
Vital signs
x
x
x
x
x
x
Weight
x
x
Dose assignment
x 1
Adverse events
x
x
x
x
x
Concomitant therapy
x
x
x
x
x
x
Administration of BI 836826
x
x
General safety laboratory parameters 3
x
x
x
x
x
x
Screening for Tumour Lysis Syndrome 4
x
x
x
x
Serum pregnancy test 5
x
x
CMV monitoring 6
x
x
x
 
Virology screening 
(HBV, HCV, HIV, CMV)
x
EOT: 
End of treatment, performed 14 days (± 2 days) after the last administration of BI 836826
CMV:
Cytomegalovirus
HBV:
Hepatitis B Virus
HCV:
Hepatitis C Virus
HIV:
Human Immunodeficiency Virus
* 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 …
** the planned duration of a treatment course is 14 days
1
After informed consent, and review of in- and exclusion criteria, and before the first administration of the 
trial drug
 
3
For details refer to Section 5.2.3.1


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4
Screening for tumour lysis syndrome in between safety laboratory assessments (Section 5.2.3.2)
5
For women of childbearing potential only (please refer to Sections 3.3.3 (exclusion criterion 18) and 5.2.3.1)
6
Quantitative CMV DNA PCR or pp65 antigen Section 5.2.3.3.2


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Flow Chart Courses 2 - 8
Trial Periods
Treatment**
EOT
FU
Course *
2 - 8
Visit *
1
2
3
EOT
Days 
1
2
3 (+2)
8 (+2)
12 lead-ECG
x
Physical examination, 
 
 
ECOG performance status
x
x
x
Vital signs
x
x
x
x
x
x
Weight
x
x
x
Adverse events
x
x
x
x
x
x 1
Concomitant therapy
x
x
x
x
x
x 2
Disease / response assessment 
(blood, clinical)
x 8,9
x
x
Administration of BI 836826
x
Eligibility for further course
x 9
General safety laboratory parameters 3, 9
x
x
x
x
x
x
Screening for Tumour Lysis Syndrome 4
x
x
Serum pregnancy test 5
x
x
CMV monitoring 6
x
x
x
x
 
 
End of active trial treatment
x
Outcome (remission, progression,  
death)
x
x
Other therapy for CLL
x
EOT: 
End of treatment, performed 14 days (± 2 days) after the last administration of BI 836826
FU: 
Follow-up, starts after EOT, visits at least every 4 weeks until 6 months after EOT, details see
Section 6.2.3.2
CMV:
Cytomegalovirus
HBV:
Hepatitis B Virus
HCV:
Hepatitis C Virus
HIV:
Human Immunodeficiency Virus
* 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 …
** the planned duration of a treatment course is 14 days
1
For AE assessment during FU refer to Sections 5.2.1 and Section 6.2.3.2
2
Concomitant therapy during FU only in case indicated for treatment of an AE (Section 4.2.1).
3
For details refer to Section 5.2.3.1
4
Screening for tumour lysis syndrome in between safety laboratory assessments (Section 5.2.3.2)
5
For women of childbearing potential only (please refer to Sections 3.3.3 (exclusion criterion 18) and 5.2.3.1)
6
Quantitative CMV DNA PCR or pp65 antigen (Section 5.2.3.3.2)


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8
Disease / response assessment  (peripheral blood, clinical) has to be performed in the first treatment course
prior to starting treatment, and at day 1 of subsequent courses prior to the next administration of BI 
836826,  may be performed 1 day earlier to allow for a timely continuation of the treatment or at day 1 of 
the next course prior to treatment administration.
9
 
 
 
 
 
 
 
If patients continue beyond cycle 8 in agreement with investigator and BI, the same assessments will be
done as applicable for cycle 5-8.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHARTS.................................................................................................4
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 13
1.
INTRODUCTION................................................................................ 16
1.1
MEDICAL BACKGROUND ............................................................................16
1.2
DRUG PROFILE ...............................................................................................17
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT...................................................................................... 20
2.1
RATIONALE FOR PERFORMING THE TRIAL ........................................20
2.2
TRIAL OBJECTIVES.......................................................................................20
2.3
BENEFIT - RISK ASSESSMENT....................................................................20
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.......... 22
3.1
OVERALL TRIAL DESIGN AND PLAN.......................................................22
3.1.1
Administrative structure of the trial ..........................................................23
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP ..........................................................................................23
3.3
SELECTION OF TRIAL POPULATION.......................................................24
3.3.1
Main diagnosis for study entry....................................................................24
3.3.2
Inclusion criteria...........................................................................................24
3.3.3
Exclusion criteria..........................................................................................25
3.3.4
Removal of patients from therapy or assessments ....................................26
3.3.4.1
Removal of individual patients.................................................................26
3.3.4.2 
Discontinuation of the trial by the sponsor ..............................................27
3.3.4.2.1 Trial stopping rules in case of unacceptable toxicities.............................27
4.
TREATMENTS.................................................................................... 28
4.1
TREATMENTS TO BE ADMINISTERED ....................................................28
4.1.1
Identity of BI investigational product and comparator product(s).........29
4.1.2
Method of assigning patients to treatment groups....................................29
4.1.3
Selection of doses in the trial .......................................................................29
4.1.4
Drug assignment and administration of doses for each patient...............30
4.1.5
Blinding and procedures for unblinding....................................................32
4.1.5.1
Blinding....................................................................................................32
4.1.5.2
Procedures for emergency unblinding......................................................32
4.1.6
Packaging, labelling, and re-supply............................................................32
4.1.7
Storage conditions ........................................................................................32
4.1.8
Drug accountability......................................................................................32
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT ....................................................................................................33
4.2.1
Rescue medication, emergency procedures, and additional 
treatments......................................................................................................33
4.2.2
Restrictions....................................................................................................33


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4.2.2.1
Restrictions regarding concomitant treatment..........................................33
4.2.2.2 
Restrictions on diet and life style .............................................................34
4.3
TREATMENT COMPLIANCE .......................................................................34
5.
VARIABLES AND THEIR ASSESSMENT ..................................... 35
5.1
EFFICACY - PHARMACODYNAMICS........................................................35
5.1.1
Endpoints of efficacy....................................................................................35
5.1.2
Assessment of efficacy..................................................................................35
5.1.2.1
Number of lymphocytes in the peripheral blood......................................35
 
5.1.2.3
Blood counts (red blood cells, haemoglobin, platelets, neutrophils) .......36
5.1.2.4
Assessment and definition of overall best response.................................36
5.1.2.4.1 Complete remission (CR).........................................................................36
5.1.2.4.2 Nodular partial remission (nodular PR) ...................................................36
5.1.2.4.3 Partial remission (PR) ..............................................................................37
5.1.2.4.4 Progressive disease (PD)..........................................................................37
5.1.2.4.5 Stable disease (SD)...................................................................................38
5.1.2.5
Progression free survival (PFS)................................................................38
5.1.2.6
Failure free survival (FFS) .......................................................................38
5.2
SAFETY ..............................................................................................................39
5.2.1
Endpoints of safety.......................................................................................39
5.2.1.1
Dose limiting toxicity (DLT) ...................................................................39
5.2.2
Assessment of adverse events ......................................................................40
5.2.2.1
Definitions of adverse events ...................................................................40
5.2.2.2
Adverse event and serious adverse event reporting .................................42
5.2.3
Assessment of safety laboratory parameters .............................................44
5.2.3.1
General safety laboratory parameters.......................................................44
5.2.3.2
Screening for laboratory evidence of tumour lysis syndrome..................45
5.2.3.3
Virology....................................................................................................46
5.2.3.3.1 Screening for hepatitis B, hepatitis C, cytomegalovirus and human 
immunodeficiency virus...........................................................................46
5.2.3.3.2 CMV monitoring......................................................................................46
5.2.4
Electrocardiogram........................................................................................46
5.2.5
Assessment of other safety parameters ......................................................47
5.2.5.1
Vital signs.................................................................................................47
5.2.5.2
Physical examination................................................................................47


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5.4
APPROPRIATENESS OF MEASUREMENTS .............................................49
 
 
6.
INVESTIGATIONAL PLAN.............................................................. 54
6.1
VISIT SCHEDULE............................................................................................54
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS.................54
6.2.1
Screening period...........................................................................................54
6.2.2
Treatment periods ........................................................................................55
6.2.2.1
Visit 1 - day 1 (day 1 of a treatment course)............................................55
6.2.2.2
Visit 1 - day 2 (day 2 of a treatment course)............................................56
6.2.2.3
Visit 2 - day 3 (day 3 in course 1 or day 3 (+2) in course 2-8) ................56
6.2.2.4
Visit 2 - day 4 (day 4 only in course 1)....................................................56
6.2.2.5     Visit 3 - day 8 (day 8 in course 1 and day 8 (+2) in course 2-8) ..............57
6.2.2.6
Visit 3 - day 9 (day 9 only in course 1, if treatment schedule 
according to Section 10.6 is used)............................................................57
6.2.3
End of trial and follow-up period ...............................................................57
6.2.3.1
End of treatment .......................................................................................57
6.2.3.2
Follow-up .................................................................................................58
6.2.3.3
End of the whole trial ...............................................................................59
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE ..................................................................................... 60


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7.1
STATISTICAL DESIGN - MODEL ................................................................60
7.2
NULL AND ALTERNATIVE HYPOTHESES...............................................60
7.3
PLANNED ANALYSES ....................................................................................60
7.3.1
Primary analyses ..........................................................................................60
7.3.2
Secondary analyses.......................................................................................60
7.3.2.1
Number of lymphocytes in the peripheral blood......................................60
7.3.2.4
Blood counts.............................................................................................60
7.3.2.5
Best overall response................................................................................61
7.3.2.6
Progression-free survival, 
, failure-free 
survival, 
7.3.3
Safety analyses..............................................................................................61
7.3.4
Interim analyses............................................................................................62
7.4
HANDLING OF MISSING DATA...................................................................63
7.5
RANDOMISATION...........................................................................................63
7.6
DETERMINATION OF SAMPLE SIZE.........................................................64
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ............................................................................................ 65
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND
INFORMED CONSENT ...................................................................................65
8.2
DATA QUALITY ASSURANCE......................................................................65
8.3
RECORDS ..........................................................................................................66
8.3.1
Source documents.........................................................................................66
8.3.2
Direct access to source data and documents..............................................66
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................67
8.4.1
Listedness ......................................................................................................67
8.4.2
Expedited reporting to health authorities and IECs/IRBs.......................67
8.5
STATEMENT OF CONFIDENTIALITY.......................................................67
8.6
COMPLETION OF TRIAL..............................................................................67
9.
REFERENCES ..................................................................................... 68
9.1
PUBLISHED REFERENCES...........................................................................68
9.2
UNPUBLISHED REFERENCES .....................................................................70
10.
APPENDICES ...................................................................................... 71


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10.4 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE SCORE................................................................................74
10.5
CLINICAL EVALUATION OF LIVER INJURY..........................................74
10.5.1
Introduction ..................................................................................................74
10.5.2
Procedures.....................................................................................................74
 
 
11.
SUMMARY OF CLINICAL TRIAL PROTOCOL 
MODIFICATIONS .............................................................................. 79


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ABBREVIATIONS
ADCC
Antibody dependent cellular cytotoxicity
AE
Adverse Event
ALT
Alanine amino transferase
ANC
Absolute Neutrophil Count
anti-HB
Hepatitis B surface antibody
anti-HBc
Hepatitis B core antibody
anti-HCV
Hepatitis C antibody
AP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time
ASCT
Autologous stem cell transplant
AST
Aspartate amino transferase
 
 
 
 
BLQ
Below the lower limit of quantification
CA
Competent Authority
CD
Cluster of Differentiation
CDC
Complement dependent cytotoxicity
CI
Confidence Interval
CLL
Chronic Lymphocytic Leukaemia
CML
Clinical Monitor Local
CMV
Cytomegalovirus
CR
Complete Remission
CRi
Complete Remission with incomplete marrow recovery
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organisation
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


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DLT
Dose Limiting Toxicity
DSMB
Data Safety Monitoring Board
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EOT
End of active treatment
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration
FFS
Failure free survival
GCP
Good Clinical Practice
G-CSF
Granulocyte colony stimulating factor
GFR
Glomerular filtration rate
HAHA
Human anti-human antibodies
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
IRB
Institutional Review Board
ISF
Investigator Site File
IUD
Intrauterine device
i.v.
intravenous
IWCLL
International Workshop on Chronic Lymphocytic Leukemia
LDH
Lactate dehydrogenase
MTD
Maximum Tolerated Dose
MedDRA
Medical Dictionary for Drug Regulatory Activities
NBE
New biological entity
NC
Not calculated
NHL
Non-Hodgkin-Lymphome
NOA
Not analyzed
OBD
Optimal Biological Dose
OPU
Operative Unit


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PCR
Polymerase chain reaction
PD
Progressive disease
PFS
Progession free survival
PLT
Platelets
p.o.
per os (oral)
PR
Partial remission
PT
Prothrombin time
RBC
Red blood cell count
SAE
Serious Adverse Event
s.c.
subcutaneous
SD
Stable disease
SDV
Source data verification
SMIP
Small modular immuno pharmaceutical
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SUSAR
Suspected unexpected serious adverse reaction
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
TLS
Tumour lysis syndrome
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan
WBC
White blood cell count
WHO
World Health Organisation


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in Europe and 
North America, accounting for approximately one third of all leukemias in these regions, 
with an estimated annual age-adjusted incidence of 3–5 per 100 000 persons. The disease is 
diagnosed most commonly in the elderly, with the median age at diagnosis of 65 to 70 years. 
CLL is characterized by the accumulation of non-proliferating, mature-appearing, 
monoclonal B-lymphocytes in the blood, bone marrow and lymphatic organs. Commonly 
used staging systems, e.g. the modified Rai- or the Binet-System, classify patients in three 
prognostic groups as low, intermediate or high risk. 
CLL is considered incurable with standard therapy. Despite a high response rate of a first line 
therapy with rituximab, fludarabine and cyclophosphamide, most patients will eventually 
experience disease progression. After subsequent relapses treatment options become 
increasingly limited. This is particularly true in patients refractory to fludarabine, who have 
limited response to salvage therapy and poor survival (R10-4432).
As of today, three monoclonal antibodies have received a marketing authorisation by 
regulatory authorities for the treatment of relapsed or refractory CLL: Rituximab and 
ofatumumab (targeting CD20) and alemtuzumab (targeting CD52).
Rituximab has limited activity as monotherapy in CLL, however is effective in combination 
with cytotoxic chemotherapy. Rituximab is currently introduced into first-line treatment in 
combination with fludarabine containing regimens and it is not clear which patients should be 
re-exposed to rituximab for treatment of relapsed disease.
Ofatumumab is indicated for treatment of fludarabine and alemtuzumab refractory CLL and 
may be a treatment option for patients relapsing after rituximab containing regimens. 
Subgroup analyses in a limited number of patients have shown that treatment with 
Ofatumumab results in similar response rates in patients who had received prior rituximab 
containing regimens compared to those who have not. (R10-4435). 
Treatment with alemtuzumab is effective in patients with unfavourable prognostic markers 
such as 17p deletion, 11p deletion, unmutated VH (R10-4434), however it has limited 
efficacy in patients with bulky nodal disease (R10-4433). Due to the ubiquitous expression of 
CD52 on lymphocytes and monocytes, alemtuzumab causes significant haematological
adverse events and infectious complications. However, infectious complications are 
manageable with adequate antibiotic prophylaxis and treatment, and careful monitoring for 
CMV reactivation and other potential infections (R10-4430). Alemtuzumab has clinical 
activity in relapsed patients with del(17p13), who are resistant to most standard therapies. 
While only 5% of CLL patients have del(17p13) at diagnosis, up to half of patients acquire 
this abnormality as their disease progresses over time (R10-4505).


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To broaden the spectrum of treatment options for subsequent relapses of this chronic disease, 
there is a high need to develop novel treatments targeting CLL-related antigens and 
pathways.
1.2
DRUG PROFILE
BI 836826 is a 
 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 majority of malignant cells in patients with B-NHL and CLL express the 
CD37 antigen (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).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 including CLL 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 10 mg/kg in patients with CLL, with predominantly 
haematological dose limiting toxicities (R10-2733).
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.
This trial will be the first administration of BI 836826 in humans.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to determine the MTD of BI 836826. As BI 836826 is a
new biological entity (NBE) and the MTD may not be reached, an optimal biological dose 
(OBD) may be defined instead, presuming pharmacokinetic or pharmacodynamic markers or 
clinical response parameters will indicate that BI 836826 exerts a relevant biological effect, 
e.g. a relevant reduction of B-cells, at a dose level with a low probability of toxicity. 
Secondary objectives are to document the safety and tolerability of BI 836826, 
 
and to evaluate parameters of efficacy. 
2.3
BENEFIT - RISK ASSESSMENT
Although considerable progress has been achieved in understanding the aetiology and 
biologic behaviour of CLL and the development of more effective treatment regimens, most 
patients with advanced or refractory CLL may eventually not be amenable to established 
forms of treatment. In particular, patients with resistant disease, relapse after fludarabine and 


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alkylating agent containing regimens, a short time to progression after the first treatment, 
and/or leukemia cells with del (17p) should be offered participation in clinical trials testing 
investigative agents according to published recommendations (R10-4429). 
Targeting CD37 in this patient population may potentially offer a benefit to these patients, 
because cross-resistance with prior therapies is not to be expected. 
BI 836826 is a monoclonal antibody which specifically targets CD37. In-vitro, BI 836826 
was able to induce apoptosis of the target cells which resulted in depletion of B-cells from 
blood and lymphatic organs. In the clinical setting, these effects may potentially result in 
antitumour activity as a monotherapy, but also as in combination with other monoclonal 
antibodies or cytotoxic drugs in patients with Non-Hodgkin-Lymphoma (NHL) of B-cell 
origin including CLL.
BI 836826 has not previously been used in humans. CD37 is not expressed outside of the 
haematopoietic and lymphatic system. 
 
 
 
 
 
 
 
 
 
Patients with CLL and active disease requiring treatment after at least two lines of therapy 
with limited or no standard treatment options may benefit from tumour cell reduction, tumour 
stabilization or improvement of tumour-related symptoms resulting from treatment with 
BI 836826. The potential benefit of therapy with BI 836826 is expected to outweigh the 
treatment-related risks.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial will be performed in patients suffering from advanced or refractory chronic 
lymphocytic leukemia (CLL) who have failed two prior lines of therapy. It will be performed 
in an open, non-randomized, modified 3+3 design.
Initially, patients will be treated at escalating dose levels to determine the MTD.
Single patient cohorts will be treated until either a drug-related adverse event of CTCAE 
grade 2 or higher occurs, or until a relevant pharmacodynamic effect (i.e. a reduction of B-
lymphocytes in the blood by more than 50%) is documented in a patient during the first 
treatment course. As soon as one of these criteria applies, cohorts will be expanded to three to 
six patients according to a standard 3+3 design, following a fixed dose escalation design with 
dose de-escalation steps (R04-0569). The dose level will be escalated with each new cohort 
until at least one out of three patients of a cohort experiences a DLT (for definition see 
5.2.1.1). If exactly one out of the three patients of the cohort experiences a DLT, three 
additional patients will be treated at the same dose level. 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 deescalated 
until a dose level is reached in which at most one DLT out of six patients is observed (R01-
0028). The MTD is defined as the dose of BI 836826 that is one dose cohort below the dose 
at which two or more out of six patients experienced DLT. At the maximum tolerated dose, 
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% (i.e., 1/6 patients) during the first course. 
During the dose escalation phase, each patient will receive up to 4 repeated treatment courses.
In patients who show an unequivocal clinical benefit after 4 courses of treatment, the number 
of treatment courses on the same dose level may be increased to 8 in agreement between 
investigator and Clinical Monitor of Boehringer Ingelheim. 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 dose limiting toxicities (DLT).
After definition of the MTD, it is planned to enroll an expansion cohort of 12-30 patients to 
better characterize the safety and possibly adapt the dose recommended for phase II prior to 
starting the next trials. Patients enrolled in the expansion cohort may receive up to 8 repeated 
treatment courses, provided that 4 courses are considered safe based on the available data on 
safety and pharmacokinetic parameters from patients treated during the dose escalation phase.
During the dose escalation phase, enrolment into the same dose cohort will be allowed the 
earliest 7 days after the first administration of the first dose to the previous patient in this 
dose cohort. Enrolment into the next higher dose cohort is allowed after the previous dose 
cohort was found to be safe for the initial application of the last patient in this cohort, i.e. at 


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least 14 days after the first application of drug in this patient. Enrolment in this context refers 
to the day of administration of the first dose to a patient.
Once the MTD is defined, a dose for treatment of the expansion cohort will be determined, 
which will not exceed the MTD. In case the MTD will not be reached, an OBD may be 
defined instead. This dose will be discussed and agreed between Coordinating Investigator 
and the sponsor. The dose recommendation for the expansion cohort 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. During treatment of the 
expansion cohort, new patients may be enrolled at any time.
3.1.1
Administrative structure of the trial
Boehringer Ingelheim is the Sponsor of this trial. The Coordinating Investigator and
participating investigators will be physicians experienced and specialized in the treatment of 
CLL 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 whether to continue, modify or to terminate 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.
Adult patients with CLL who experience a relapse after at least two prior treatment regimens 
are considered eligible for this trial. Treatment options in this population are limited, in 
particular in patients with adverse prognostic markers, such as deletion 17p, who frequently 
do not reach durable responses or a long progression free interval after standard 
chemotherapy based regimens.
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 or the documentation of 
a threshold pharmacodynamic activity as defined in Section 3.1, cohorts of single patients
will be expanded to cohorts of at least 3 patients, and the trial design will follow a standard
3+3 design with dose escalation and de-escalation. Once the MTD has been defined, an 
expansion cohort of 12-30 patients is planned to be enrolled to better characterize the safety 
profile and tolerability of the MTD.
At screening, blood samples and a physical examination including a clinical assessment of 
CLL are done and the patient is evaluated for eligibility in the trial. Evaluation of bone 


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marrow and CT scan may be performed at the discretion of the investigator. Results should 
be reported in case these examinations have been performed within 4 weeks prior to 
screening.
A patient enrolled in a cohort during dose escalation may receive up to 4 courses of 
BI 836826. In patients who unequivocally show clinical benefit from the drug, the 
administration of 4 additional treatment courses may be possible in agreement between the 
investigator and the Clinical Monitor at Boehringer Ingelheim. Provided that the 
administration of 4 courses is considered safe, up to 8 courses may be administered for 
patients enrolled in the expansion cohort.
Each patient will be closely monitored for infusion-related reactions and tumour lysis 
syndrome.
Safety
 will be performed at all visits 
during the treatment phase.
Disease status will be assessed every two weeks until the EOT visit, including physical 
examination, clinical assessment of CLL and blood samples. At the discretion of the 
investigator (i.e., if medically indicated), a CT scan and a bone marrow examination may be 
performed to confirm a CR 8 weeks after a patient for the first time meets the criteria of a 
CR. Results of any CT scan or bone marrow examination performed during the conduct of 
the trial should be reported in the eCRF.
During the follow-up phase, disease status evaluations (physical examination, clinical 
assessment of CLL, and blood samples) should be performed at least every 4 weeks for 6 
months after the EOT visit. 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 
Patients with chronic lymphocytic leukaemia will be eligible for this trial.
3.3.2
Inclusion criteria
1. Diagnosis of relapsed or refractory chronic lymphocytic leukaemia (according to the 
definition of the IWCLL (R10-4429))
2. Previous therapy of CLL with at least two prior treatment regimens
3. At least one of the following criteria for active disease as defined by the IWCLL
(1) Evidence of progressive marrow failure as manifested by the development or 
worsening of anemia and/or thrombocytopenia
(2) Massive (i.e. at least 6 cm below the left costal margin) or progressive or symptomatic 
splenomegaly as assessed by the investigator; 
(3) Massive nodes (i.e. at least 10 cm in longest diameter) or progressive or symptomatic 
lymphadenopathy as assessed by the investigator


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(4) Progressive lymphocytosis with an increase of more than 50% over a 2-month period 
or a lymphocyte doubling time of less than 6 months
(5) Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs:
●
Unintentional weight loss of 10% or more within the previous 6 months
●
Fevers higher than 38.0°C for 2 or more weeks without other evidence of 
infection
●
Night sweats for more than 1 month without evidence of infection
4. Absolute lymphocyte count lower than 200 x 109/l
5. ECOG Performance Status 0, 1 or 2
6. Age ≥18 years.
7. Written informed consent which is consistent with ICH-GCP guidelines and local 
legislation
3.3.3
Exclusion criteria
1. Prior treatment with anti CD 20 therapy within 4 weeks, or alemtuzumab within 8 weeks, 
or any cytotoxic antileukemia therapy within 2 weeks, Ibrutinib or Idelalisib within 1 
week prior to the first administration of the trial drug
2. Prior allogeneic stem cell transplantation
3. Active autoimmune haemolytic anemia
4. Active autoimmune thrombocytopenia
5. Known transformation to an aggressive B-cell malignancy (e.g. large B-cell lymphoma, 
Richter’s syndrome)
6. Concurrent treatment with systemic glucocorticosteroids at doses equivalent to 
prednisolone 20 mg/d or higher.
7. Prior history of malignancy other than CLL (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.
8. AST, and/or ALT > 2.5 x upper limit of normal (CTCAE grade 2 or higher)
9. Total bilirubin > 1.5 x upper limit of normal (CTCAE grade 2 or higher)
10. ANC < 1.0 x 109/L (without growth factor support).
11. Platelets < 25 x 109/L (without growth factor support or transfusions)
12. Estimated GFR <45 mL/min (see Section 10.3)
13. Proteinuria CTCAE grade 2 or higher
14. 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.
15. Any infectious disease requiring treatment at the time of enrolment or within the previous 
2 weeks.
16. Active Hepatitis B or Hepatitis C, or laboratory evidence for a chronic infection.
17. HIV infection
18. CMV viremia
19. 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 


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used consistently and correctly 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 are 
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 post-menopausal for at least two years.
20. Pregnancy or breast feeding.
21. Known or suspected active alcohol or drug abuse.
22. Treatment with another investigational drug within the past four weeks before start of 
therapy or concomitantly with this trial.
23. Prior treatment with BI 836826.
24. Patients unable to comply with the protocol
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient is to be withdrawn from the trial if:

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 which may interfere with the investigational product
(please refer to Section 4.2.2).

The patient is no longer able to participate for other medical 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 no longer able 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 
next scheduled visit and the EOT have to be performed if feasible. Every effort should be 
made to follow-up patients in case an AE is still ongoing at the time of withdrawal.
A patient has to discontinue trial drug administration in case

A DLT occurs which does not recover to a degree that allows treatment continuation.

PD or any other concomitant diagnosis/symptom develops resulting in an indication to 
start any other therapy for CLL, including deterioration of general condition.
Patients who have not completed at least one course will be replaced. Patients who terminate 
trial treatment due to DLT will not be replaced.


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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 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).
3.3.4.2.1 Trial stopping rules in case of unacceptable toxicities
All AEs, including SAEs and deaths will be carefully analyzed by the sponsor. 
Unacceptable toxicity will be defined as: 

Clinically relevant adverse events that are unexpected considering the mode of 
action, and are not manifestations of underlying disease or background events 
typical of the study population 
o
and/or are debilitating, non-reversible, not manageable
o
or lead to a fatal outcome 
where evidence suggests that there was a reasonable possibility that the drug 
caused the adverse event

Higher than expected frequency of specific events (such as known consequences 
of the underlying disease or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than would be expected in the study 
population.
If one or both of the above criteria are met the enrolment to the trial will be stopped to 
allow for in-depth analysis of the safety profile of BI836826. The risk-benefit profile of 
BI 836826 will be re-assessed by the sponsor’s trial team, coordinating investigator and 
DSMB. The outcome of the analysis and the recommendations will be shared with all 
involved regulatory health authorities prior to a possible re-start of enrolment. 
In case the benefit/risk assessment is no longer considered to be positive, the trial will be 
discontinued.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
In course 1, the total dose will be divided into two portions administered on day 1 and 2
(please refer to the Flow Chart: Course 1, Dosing on Day 1 and Day 2). 
The dose on day 1 will be 10% of the total dose, but not exceed 10 mg in case the total dose 
is higher than 100 mg. The dose on day 2 will be the planned total dose minus the dose 
administered on day 1. If adverse events which are related to the infusion schedule, e.g. 
infusion-related reactions or tumour lysis syndrome require administration of a lower dose on
day 2, the total dose in course 1 may be divided into 3 smaller portions on day 1, 2 and 8. In 
this case, the dose on day 1 will remain as defined previously. The difference between day 1 
and the  planned total dose level will be equally divided between day 2 and 8 (reference to 
appendix 10.6). The distribution of the planned total dose in course 1 to two, or if needed to 
three smaller portions will be based on safety data from the previous cohort and will be 
assessed and may be modified by the DSMB. If supported by the DSMB, the same rules may 
be applied to course 2 in case infusion-related adverse events can be controlled by the above 
measures in course 1 but occur in course 2.
In all subsequent treatment courses, BI 836826 will be administered as a rate-controlled 
intravenous infusion on day 1 of each 14-day course.
The first and second infusion will be started at a rate of 10 mL/h. The infusion rate should 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 stepwise increase of 
infusion rate during the third and subsequent infusions may be faster or steps may be omitted, 
but the maximum infusion rate must not exceed 120 mL/h. 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 reasons, 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.
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).


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4.1.1
Identity of BI investigational product and comparator product(s)
4.1.1.1 BI 836826
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:
One to three single doses within a 14 day course
Route of administration:
Intravenous
Posology:
Rate controlled infusion
See Section 4.1.6
4.1.2
Method of assigning patients to treatment groups
Not applicable. This is a single arm, open-label, dose escalation trial.
4.1.3
Selection of doses in the trial
BI 836826 will be administered as a rate-controlled, intravenous infusion on day 1, 2 and 
possibly day 8 in course 1 and on day 1 in the subsequent courses.
A fixed dose of 1 mg BI 836826 per patient was determined 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 
of CLL patients. For details please refer to the Investigator's Brochure, Section 5.6.3 (U10-
1892-01).
The dose is planned to be escalated in cohorts at pre-defined dose levels based on a 
multiplication factor of approximately 3 in the low dose range, and a factor of 2 at doses
higher than 25 mg. The dose levels per treatment course are 1 mg, 3 mg, 9 mg, 25 mg, 50 mg, 
100 mg, 200 mg …, up to 1400 mg. At doses higher than 200 mg, the next dose cohort will 
be enrolled at a dose which is at maximum two times of the previous dose.
Every time a dose escalation is to be performed, the data of all previous dose cohorts will be 
reviewed and discussed between the Coordinating Investigator and the sponsor. The same 
data and the recommendation of the Sponsor and Coordinating investigator will be provided 
to the DSMB who will be asked to provide an independent assessment including a dose
recommendation for the next cohort. As a result, lower dose increments than the predefined 
levels will be possible.


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4.1.4
Drug assignment and administration of doses for each patient
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. 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.
 
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/or prophylactic drugs according to local standards or published 
guidelines (R10-4517).
Premedication to prevent infusion-related reactions is obligatory 30 - 120 minutes prior to the 
first and second administration of BI 836826, unless a contraindication for premedication 
exists, and should include

Analgesic/Antipyretic p.o. or i.v., equivalent to Acetaminophen/ or Paracetamol 1000 mg 
p.o.

Antihistamine p.o. or i.v., equivalent to Diphenhydramine 50 mg i.v.

Glucocorticoid i.v., equivalent to prednisolone 100 mg
If BI 836826 has been well tolerated without signs of infusion-related reactions in the first 
and second course, glucocorticoid premedication may be reduced to 50% of the dose in the 
previous course starting with the third course. In case the patient has tolerated the 4th 
treatment course without infusion-related reactions after premedication with doses equivalent 
to prednisolone 25 mg, the investigator may individually decide whether to administer 
premedication in courses 5-8.
During the dose-escalation phase, up to 4 courses may be administered. In case of evidence 
of clinical benefit as judged by the investigator (e.g. PR, CR, disease stabilization, 
amelioration of CLL related symptoms), treatment with BI 836826 can be continued for 
another 4 courses after discussion between the Investigator and the Clinical Monitor of the 
sponsor. During treatment of the expansion cohort, a maximum of 8 courses may be offered 
to all patients. In the dose-escalation phase as well as in the expansion cohort, in patients who 
experience sustained benefit and tolerate treatment well, treatment may be continued beyond 
8 courses on a case by case basis after discussion between the Investigator and the Clinical 
Monitor of the sponsor. If patients continue beyond cycle 8, the same assessments will be 
done as applicable for cycles 5-8. At the end of each treatment course, adverse events and 
safety laboratory will be assessed. To continue treatment with further courses, all of the 
following criteria must be met:
(1)
Neutrophils ≥ 500 /μL (0.5 x 109/L) and platelets ≥ 25.000 /μL (25 x 109/L), with 
or without growth-factor support or transfusions.


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(2)
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 2 is not fulfilled, blood counts and/or the adverse event should be 
re-evaluated for up to three weeks. Any case of a delay in treatment course should be 
communicated to the Clinical Monitor at Boehringer Ingelheim. As soon as criterion 1 is 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). 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 may be considered in agreement between investigator and 
sponsor for selected patients. It is restricted to patients who have received at least 4 treatment 
courses and tolerate the treatment well at the time of dose escalation. Intra-patient dose 
escalation can only be performed at a time when the next higher dose cohort has been 
reviewed and considered safe by the DSMB. The dose escalation step is limited the dose 
which has been administered to the next higher cohort. The treatment courses at the increased 
dose have to follow the instructions as outlined for course 5-8 in the Flow Chart and the 
protocol. In addition, after the first dose at the higher dose level, patients have to be 
monitored for at least 24 hours after the end of the infusion, including safety laboratory for 
tumour lysis syndrome.
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.


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This phase I trial will be performed according to an open, single arm design. It will recruit 
patients with relapsed and refractory CLL and active disease. 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
 
For details of packaging and the description of the label, refer to the Investigator Site File 
(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 (U10-1892-01) 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.
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,


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
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(s). 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(s) received from the sponsor. 
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
Rescue medication to reverse the action of BI 836826 is not available. Potential side effects 
of BI 836826 have to be treated symptomatically. Patients should receive supportive care 
according to local guidelines regarding treatment of infusion-related reactions, blood product 
support, antibiotics, antivirals, 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. The use of growth factors such as granulocyte colony 
stimulating factor (G-CSF) will be allowed, but growth factors should be avoided in the first 
treatment course for better assessment of safety and response parameters.
CMV reactivation during treatment should be treated according to local standards or available 
guidelines (R10-4431).
All concomitant non-antileukaemia therapies to provide adequate care may be given as 
clinically necessary. 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 anaesthesia, it will be sufficient to indicate '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.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Prior antileukemia therapy must have been discontinued in line with the requirement per 
exclusion criterion 1 and the patient must have recovered from all clinically relevant 
reversible toxicities. A time interval of at least 4 weeks must have elapsed from the last 
administration of any other investigational treatment for CLL to the first administration of BI 
836826.
No anti-neoplastic therapy concomitantly is allowed.


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Short term glucocorticoid medications may be used as clinically indicated to treat infusion-
related reactions at any dose. Daily oral steroid treatment may be administered at doses 
equivalent to prednisolone 20 mg per day. All other indications for steroids have to be 
discussed and agreed upon between investigator and sponsor.
Immunoglobulins should be avoided during treatment with BI 836826. However, if medically 
indicated, e.g. for substitution of immunoglobulin deficiency, immunoglobulins may be used. 
Administration within a time window of 2 days before and after the infusion of BI 836826 
should be avoided.
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 - PHARMACODYNAMICS
5.1.1
Endpoints of efficacy
The efficacy endpoints will be assessed at the time points specified in the Flow Chart. 
Efficacy endpoints will be secondary or further endpoints in this trial. 
Secondary endpoints of efficacy are:

Number of lymphocytes in the peripheral blood


Blood counts (red blood cells, haemoglobin, platelets, neutrophils)

Best overall response according to IWCLL criteria (R10-4429)

Progression free survival

Failure free survival
5.1.2
Assessment of efficacy
5.1.2.1
Number of lymphocytes in the peripheral blood
In most patients with relapsed or refractory CLL, malignant B-cells represent the majority of 
lymphocytes in the peripheral blood. Reduction of B-cells can be assessed in the peripheral 
blood by blood cell counts, differential WBC analysis and flow cytometry, which will be 
performed at the time points specified in the Flow Chart.
 
 
 
 
 
 
 


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5.1.2.3
Blood counts (red blood cells, haemoglobin, platelets, neutrophils)

Blood counts including a differential will be done at all visits. In patients with blood 
counts below the limits of normal pre-treatment, improvement in blood counts during 
therapy may indicate a benefit for the patient.
5.1.2.4
Assessment and definition of overall best response
Response will be assessed according to the IWCLL guidelines based on laboratory data from 
the peripheral blood and clinical examination after each course prior to administration of the 
next dose of BI 836826, at the EOT-visit and at all follow-up visits. Bone marrow 
examination will be performed at the discretion of the investigator, e.g. in case clinical and 
laboratory examinations of peripheral blood demonstrate that a CR has been achieved, or for 
assessment of persistent neutropenia, anemia or thrombocytopenia.
5.1.2.4.1 Complete remission (CR)
CR requires all of the following criteria for a period of at least 2 months:
A1
Peripheral blood lymphocytes (evaluated by WBC and differential count) below 
4 x 109/L.
A2
Absence of significant lymphadenopathy, i.e. no lymph nodes > 1.5 cm.
A3
No hepatomegaly.
A4
No splenomegaly.
A5
Bone marrow aspirate and biopsy demonstrate absence of residual disease.
B1
Platelets more than 100 x 109/L (without exogenous growth factors or transfusion).
B2
Hemoglobin more than 110 g/L (without exogenous growth factors or transfusions)
B3
Neutrophils more than 1.5 x 109/L (without exogenous growth factors).
C
Absence of disease-related constitutional symptoms.
4.
Group A criteria define the tumor load, group B criteria define the function of the 
hematopoietic system. In case all criteria A and C are met, but a patient has a persistent 
anemia or thrombocytopenia or neutropenia apparently unrelated to CLL, but related to drug 
toxicity, the patient should be categorized as CR with incomplete marrow recovery (CRi).
5.1.2.4.2 Nodular partial remission (nodular PR)
In case lymphoid nodules are found in the bone marrow, but all other criteria for CR are met, 
the case should be classified as nodular PR


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5.1.2.4.3 Partial remission (PR)
To define a PR, at least 2 criteria of category A and 1 criterion of category B have to be met
for a period of at least 2 months.
A1
Decrease in the number of blood lymphocytes by 50% or more compared to the pre-
treatment value.
A2
Reduction in lymphadenopathy by 50% or more, defined as
a decrease in lymph node size by 50% or more, either in the sum products of up to 6 
lymph nodes or in the largest diameter of the enlarged lymph nodes detected prior to 
therapy, AND
no increase in any lymph node, and no new enlarged lymph node. In small lymph nodes 
(<2cm) an increase of less than 25% is not considered to be significant.
A3
Decrease in hepatomegaly by 50% or more
A4
Decrease in splenomegaly by 50% or more.
A5
Reduction by 50% or more in bone marrow infiltration, or B-lymphoid nodules.
B1
Platelets more than 100 x 109/L or 50% improvement over baseline (without exogenous 
growth factors or transfusion).
B2
Hemoglobin more than 110 g/L or 50% improvement over baseline (without exogenous 
growth factors or transfusions).
B3
Neutrophils more than 1.5 x 109/L or 50% improvement over baseline (without 
exogenous growth factors).
5.1.2.4.4 Progressive disease (PD)
At least one of the following criteria is required:
A1
An increase in the number of blood lymphocytes by 50% or more over baseline with an 
absolute number of B-lymphocytes of at least 5 x 109/L.
A2
Progression of lymphadenopathy, defined as appearance of any new lymph node 
> 1.5 cm or an increase by 50% or more in the greatest determined diameter of any 
previous site, or appearance of a new organ infiltrate other then hepatomegaly or 
splenomegaly.
A3
An increase in the previously noted enlargement of the liver by 50% or more or new 
appearance of hepatomegaly.
A4
An increase in the previously noted enlargement of the spleen by 50% or more or new 
appearance of splenomegaly.
B1
Decrease of platelet counts by more than 50% or to less than 100 x 109/L secondary to 
CLL and unrelated to autoimmune cytopenia
B2
Decrease of hemoglobin levels by more than 20 g/L or to less than 100 g/L secondary to 
CLL and unrelated to autoimmune cytopenia
T
Transformation to a more aggressive histology, e.g. Richter syndrome.
During therapy, cytopenia cannot be used to define disease progression. The progression of 
any cytopenia unrelated to autoimmune cytopenia as defined by criteria B1 and B2 which 


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occurs at least 3 months after treatment, defines disease progression, if the marrow biopsy 
demonstrates an infiltrate of clonal CLL cells.
5.1.2.4.5 Stable disease (SD)
Patients who have not achieved a CR or a PR, and who have not exhibited PD, will be 
considered to have stable disease.
5.1.2.5
Progression free survival (PFS)
PFS is defined as the time from first treatment with BI 836826 until disease progression or 
death.
5.1.2.6
Failure free survival (FFS)
Some patients will receive the next line of therapy, although no formal PD may be diagnosed 
at the time when the next treatment is indicated according to investigator assessment. In 
addition to PFS, the 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 CLL therapy.
 
 
 
 
 
 
 
 
 


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5.2
SAFETY
5.2.1
Endpoints of safety
As this trial is the first in human use of BI 836826, the primary objective is to assess the 
safety of the drug in humans and to determine the MTD of BI 836826. For details on 
determination of MTD, please refer to Sections 3.1, 5.2.1.1 and 7.3.1. 
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 (DLT)
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.
The additional following haematologic adverse events will be considered DLT: 
o
Grade 4 neutropenia lasting more than 7 days.
o
Febrile neutropenia not resolving within 48 hrs with appropriate 
treatment (antibiotics, antivirals, antifungals, growth factor support) 


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o
Grade 4 thrombocytopenia lasting more than 7 days, or grade 3-4 
thrombocytopenia with clinically significant bleeding 
o
Grade 4 anemia
Less severe haematological adverse events are frequently pre-existing in CLL patients, are 
usually manageable with routine supportive measures and are therefore not considered as 
adverse events relevant for DLT definition. Nevertheless, haematological adverse events 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 treatment course.
However, for those patients who receive more than one dose 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.
All DLTs, occurring during the first or repeated treatment course will be reported as 
significant adverse events.
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 event
A 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 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,

Drug-induced liver injury (DILI)
Although rare, 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 


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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 10.5 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 Appendix 10.5 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.
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.


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Worsening of 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.
Changes in vital signs, ECG, 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 and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the observational phase (=6 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, 
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.


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Table 5.2.2.2:1
AE/SAE reporting requirements
Time Period
Reporting requirements
From signature of informed consent 
until 6 weeks (42 days) after last 
administration of study drug
Report all AEs, SAEs regardless of relatedness. 
This includes all deaths.
Post treatment (>42 days after last 
administration of study drug) until 
end of follow-up (6 months after the 
EOT visit)
Report AEs and SAEs which are considered related 
to study drug or study design / procedures.
Please note: Death should always be reported as 
SAE in this trial.
Patients may be hospitalized during selected phases of the study as required per protocol, e.g., 
monitoring of trial drug administration, 
, 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.
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non serious 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event. If the event description is correct, the item 
“serious” needs to be ticked and an SAE has to be reported in expedited fashion following the 
same procedure as above. The list of these adverse events can be found via the RDC-system.
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 


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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 Flow Chart. 
Blood samples should be collected more frequently in case of relevant toxicities; e.g. in 
case of grade 4 neutropenia or thrombocytopenia, to document as accurately as possible 
the duration of the AE. 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 Screening, Visit 1,
Day 1 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 Screening, Visit 
1, Day 1 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) where 
indicated (e.g. treatment with vitamin K antagonists)
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 Flow Chart in patients of childbearing 
potential.


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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
Tumor lysis syndrome (TLS) is characterized by a group of metabolic derangements caused 
by the massive and abrupt release of cellular components into the blood after rapid lysis of 
malignant cells. The release of intracellular metabolites, including nucleic acids, proteins, 
phosphorus, and potassium, 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). 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).
To allow for early treatment in case TLS develops, vigilant monitoring is recommended.
Between the first and the second infusion, during the first 48 hours after the start of the 
second infusion of BI 836826 in course 1 and during the first 24 hours after the start of the 
infusion(s) in course 2, in between timepoints at which a complete safety laboratory has to be 
performed, i.e. every 4-8 hours, the following laboratory parameters need to be determined to 
screen for evidence of a tumour lysis syndrome. In case the schedule as outlined in 
Section 10.6 is used, monitoring for TLS has to be performed for 24 hours also after the 
infusion on day 8. 
Sampling for TLS in course 3 and subsequent courses should be performed as clinically 
indicated.
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) with 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. 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 Flow Chart
according to local standards. Quantitative PCR assays to detect CMV DNA and quantitative 
assays of the pp65 antigen are considered acceptable for the purpose of this trial. The same 
method should be used for all patients treated at the same investigational site. 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
Vital signs (blood pressure, pulse rate and body temperature) will be recorded at every visit 
during screening, treatment and follow-up. Additional time points for blood pressure and 
heart rate at the day of administration of BI 836826 are: prior to the start of premedication 
and infusion, then every 30 (±10) minutes after start of the infusion of BI 836826 and 60 
(±10) minutes after the end of the infusion. At least during the first two courses blood 
pressure, pulse rate and body temperature should be measured every 4-8 hours until at least 
24 hours after the start of the infusion. In case of an infusion-related reaction, the investigator 
should decide whether to intensify or prolong monitoring of vital signs of the patient.
Continuous cardiac monitoring should be performed during the first and second infusion of 
BI 836826, patient surveillance may be modified by the investigator according to tolerability 
of the infusion during subsequent applications.
5.2.5.2
Physical examination
A physical examination including weight and ECOG performance score will be performed at 
screening and at the time points specified in the Flow Chart. During the physical 
examination, the patient should be assessed for possible adverse events.
 
 
 
 
 
 
 
 
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
Determination of MTD 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. 


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The criteria to be used for evaluation of response (R10-4429) are well established and 
scientifically accepted.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
During the treatment phase, after administration of BI 836826, patients are required to be 
hospitalized under close surveillance with access to intensive care for at least 48 hours after 
the second dose of BI 836826 in course 1 to allow close monitoring for infusion-related 
reactions, tumour lysis syndrome or other adverse events. After good tolerability of the first 
two doses in course 1 of BI 836826 the investigator may evaluate the risk for an infusion-
related reaction and other adverse events in view of relevant comorbidities or CLL-related 
symptoms, and as a result, shorten the duration of surveillance to 24 hours. 
In case the patient demonstrated benefit after 4 treatment courses, and the investigator in 
agreement with the sponsor decided to administer 4 additional courses, the decision whether 
to hospitalize the patient for application of courses 5-8 is left to the discretion of the 
investigator.
In case a patient misses a visit within one treatment course and the patient belatedly reports to 
the investigator between the missed and the next scheduled visit, 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.
However, in case the day of treatment administration (visit 1 of a course) is delayed, all 
subsequent visits of a course will be recalculated based on the actual date of visit 1 of the 
delayed course.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations as outlined in the Flow Chart will be performed at the respective visits as 
described in detail in the following sections.
6.2.1
Screening period
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.
The following parameters and investigations will be obtained and / or performed:

Informed consent

Demographics (sex, birth date, race)

Medical history (oncological and relevant non-oncological)

Review of inclusion and exclusion criteria (patient eligibility)

12-lead ECG

Informed consent for pharmacogenetics

Physical examination, body height, weight, vital signs and ECOG performance score


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
Disease assessment:
 

Safety laboratory (haematology, biochemistry including serum immunoglobulin levels
and direct antiglobulin test, coagulation, urine; for details please refer to Section 5.2.3.1)

Serum pregnancy test in women of childbearing potential

Virology screening (HBV, HCV, HIV, CMV) and CMV monitoring, for details refer to 
Section 5.2.3.3

 
 

Dose assignment (during dose escalation phase only, before the first administration of the 
trial drug and after informed consent and review of in- and exclusion criteria)

Concomitant therapy
6.2.2
Treatment periods
6.2.2.1
Visit 1 - day 1 (day 1 of a treatment course)
On the treatment days, the following parameters and investigations will be obtained and / or 
performed:

Review of inclusion and exclusion criteria (patient eligibility), in the first cycle only

Blood samples for pharmacogenetic investigations (optional, only after signature of
separate informed consent)

Physical examination, weight
 

Vital signs at time points specified in Section 5.2.5.1

Adverse events (AEs)

Changes in concomitant therapies

Administration of BI 836826 after final confirmation of dose tier

Safety lab parameters before trial drug administration as specified in Section 5.2.3.1

 

Blood samples to screen for evidence of tumour lysis syndrome (see Section 5.2.3.2)

Serum pregnancy test in women of childbearing potential (does not have to be repeated in 
case pregnancy test has been performed within the last 3 days)

CMV monitoring (see Section 5.2.3.3.2)


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
 

Response assessment (blood and clinical assessment) at the end of each treatment course 
prior to next administration of BI 836826, may be performed at day 1 of the next course
prior to treatment administration or up to 1 day earlier to allow for a timely continuation 
of the treatment.

Assessment of eligibility for further courses in all treatment courses except for course 1
6.2.2.2
Visit 1 - day 2 (day 2 of a treatment course)
On the day after the treatment, the following parameters and investigations will be 
obtained/performed

Administration of BI 836826 only in course 1

Vital signs at time points specified in Section 5.2.5.1

Adverse events

Concomitant therapy

Safety lab parameters as specified in Section 5.2.3.1

Blood samples to screen for evidence of tumour lysis syndrome (see Section 5.2.3.2)

 
6.2.2.3
Visit 2 - day 3 (day 3 in course 1 or day 3 (+2) in course 2-8)
On visit 2, the following parameters and investigations will be obtained/performed

Vital signs (see Section 5.2.5.1)

Adverse events

Concomitant therapy

Safety lab parameters as specified in Section 5.2.3.1

6.2.2.4
Visit 2 - day 4 (day 4 only in course 1)

Vital signs (see Section 5.2.5.1)

Adverse events

Concomitant therapy

Safety lab parameters as specified in Section 5.2.3.1

 


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6.2.2.5 Visit 3 - day 8 (day 8 in course 1 and day 8 (+2) in course 2-8)
On visit 3, the following parameters and investigations will be obtained/performed

Administration of BI 836826 only in course 1, if treatment schedule according to 
Section 10.6 is used

Vital signs (see Section 5.2.5.1)

Adverse events

Concomitant therapy

Safety lab parameters as specified in Section 5.2.3.1

Blood samples to screen for evidence of tumour lysis syndrome only in course 1, if 
treatment schedule according to section 10.6 is used

 

CMV monitoring (see Section 5.2.3.3.2)
6.2.2.6
Visit 3 - day 9 (day 9 only in course 1, if treatment schedule according to 
Section 10.6 is used)
On visit 3, the following parameters and investigations will be obtained/performed

Vital signs (see Section 5.2.5.1)

Adverse events

Concomitant therapy

Safety lab parameters as specified in Section 5.2.3.1

Blood samples to screen for evidence of tumour lysis syndrome

6.2.3
End of trial and follow-up period
6.2.3.1
End of treatment
The end of treatment (EOT) visit should be performed 14 days (± 2 days) after the last 
administration of BI 836826. If the patient concludes the trial within a treatment cycle not at 
the end of a treatment cycle, the information required to be collected at the EOT visit should 
be obtained immediately.
The following parameters and investigations will be obtained and / or performed:

Physical examination, weight
 

Vital signs (see Section 5.2.5.1)

12-lead ECG

Adverse events (AEs)


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
Changes in concomitant therapies

Response assessment (blood and clinical assessment)

Safety lab parameters as specified in Section 5.2.3.1

 

Serum pregnancy test in women of childbearing potential (does not have to be repeated in 
case pregnancy test has been performed within the last 3 days)

CMV monitoring (see Section 5.2.3.3.2)

 
 
 

Completion of trial treatment (including reason for conclusion or if applicable premature 
discontinuation of trial, date of last administration of the trial drug)

Outcome: in case the patient had PD the date of first diagnosis of PD has to be recorded
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-neoplastic therapy or in case the investigator and sponsor 
agree not to pursue further follow up visits. Follow-up visits should be performed at 4 weeks 
intervals or earlier 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 for 6 months after the EOT-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:

Physical examination, 
 vital signs and weight

 

Safety laboratory (haematology, biochemistry including serum immunoglobulin levels 
and direct antiglobulin test, coagulation, urine; for details please refer to Section 5.2.3.1)

Response assessment (blood and clinical assessment)

CMV monitoring (see Section 5.2.3.3.2)



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
AEs since last visit in case they occurred during the observational period (6 weeks after 
the last trial drug administration) or are considered drug-related (see Section 5.2.1)

concomitant therapy indicated for treatment of an AE

Follow-up of AEs in case they were not yet recovered at EOT

 
 
 
 
 

Outcome: date death (if applicable), date of progression (in case, the patient experienced 
PD)

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. 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.). After the MTD has been determined, up to 30 patients are additionally 
entered at a dose level supposed to be recommended for Phase II.
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). In order to identify the MTD, 
the number of DLTs at each dose level must be presented. For the analysis of tolerability and 
safety, please refer to Section 7.3.3.
7.3.2
Secondary analyses
7.3.2.1
Number of lymphocytes in the peripheral blood
The number and the change of lymphocytes in the peripheral blood will be analysed 
descriptively by time point. The maximal reduction of lymphocytes with respect to all time 
points after baseline will be analysed.
7.3.2.4
Blood counts
Blood counts will be analysed as part of the laboratory tests (see Section 7.3.3)


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7.3.2.5
Best overall response
Best overall response is the best response (CR, PR, SD or PD in this order) with respect to all 
time points. Remission rate is the rate of patients that either have CR 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.
7.3.2.6
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
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. 
Incidence and intensity of adverse events
The severity, and timing of adverse events will indicate how well the treatment regimen is 
tolerated. Toxicities 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 treatment schedules. Serious adverse events 
will be tabulated. In addition, events leading to dose reduction or treatment discontinuation 
will be 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 started 


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within the period starting with first administration of the trial drug and ending six 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 and the DSMB will perform interim safety evaluations as considered necessary.
No formal interim analyses of efficacy data are foreseen, although efficacy data may be
considered as part of the interim safety evaluations considered above.
If considered necessary, as soon as the MTD is determined an evaluation of the safety aspects 
will be performed. Results of this evaluation will be documented and archived. If applicable 
such an analysis will be 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.


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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.
Together with an assumed number of up to 30 additional patients for the expansion cohort
this leads to an expected sample size of 60 entered patients. Note that in general, the sample 
size is induced by the 3+3 design and is subject to different random factors.


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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, version as of October 1996 (as long as local laws do not require to 
follow other versions), 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 (CA) 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 IEC members, and by inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
The trial will be conducted in compliance with the protocol, the principles laid down in the
Declaration of Helsinki version 1996 (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


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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.
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.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on 
paper or via remote data capture. For drug accountability, refer to Section 4.1.8.
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.
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.


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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 (U10-1892-01). 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
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
R08-2942
Schuurman HJ, Baarlen J van, Huppes W, Lam BW, Verdonck LF, Unnik 
JAM van. Immunophenotyping of non-Hodgking'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 lympoma 
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)


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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)
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
R10-2733
Andritsos L, Furman R, Flinn IW, Foreno-Torres A, Flynn JM, Stromatt 
SC, Byrd JC. A phase I trial of TRU-016, an anti-CD37 small modular 
immunopharmaceutical (SMIP) protein in relapsed and refractory CLL: 
early promising clinical activity. Blood (ASH Annual Meeting Abstracts) 
2009, 114: Abstract 3424
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
R10-4429
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, 
Doehner H, et al. Guidelines for the diagnosis and treatment of chronic 
lymphocytic leukemia: a report form the International Workshop on 
Chronic Lymphocytic Leukemia updating the National Cancer Institute-
Working Group 1996 guidelines. Blood 2008;111(12):5446-5456
R10-4430
Christian BA, Lin TS. Antibody therapy for chronic lymphocytic 
leukemia. Semin Hematol 2008;45(2):95-103
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


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R10-4432
Osterborg A. Ofatumumab, a human anti-CD20 monoclonal antibody. 
Expert Opin Biol Ther 2010;10(3):439-449
R10-4433
Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, et al. 
Alemtuzumab compared with chlorambucil as first-line therapy for 
chronic lymphocytic leukemia. J Clin Oncol 2007;25(35):5616-5623
R10-4434
Stilgenbauer S, Zenz T, Winkler D, Buehler A, Schlenk RF, Groner S, et 
al. Subcutaneous alemtuzumab in fludarabine-refractory chronic 
lymphocytic leukemia: clinical results and prognostic marker analyses 
from the CLL2H study of the German Chronic Lymphocytic Leukemia 
Study Group. J Clin Oncol 2009;27(24):3994-4001
R10-4435
Wierda WG, Kipps TJ, Mayer J, Stilgenbauer S, Williams CD, Hellmann 
A, et al. Ofatumumab as single-agent CD20 immunotherapy in 
fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 
2010;28(10):1749-1755
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.
R10-4848
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
9.2
UNPUBLISHED REFERENCES
U10-1892-01
 Investigator's Brochure: BI 836826 (Version 1). 15 June 
2010.


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10.
APPENDICES
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.4 
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
10.5
CLINICAL EVALUATION OF LIVER INJURY
10.5.1
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: 
10.5.2
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. 
 
 
 
 
 
 
 
 
 


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10.6
FLOW CHART
 FOR COURSE 1, IN CASE THE 
TOTAL DOSE IN THIS COURSE IS DIVIDED INTO THREE PORTIONS 
ADMINISTERED ON DAY 1, DAY 2 AND DAY 8
Flow Chart for Course 1 with administration on Day 1, Day 2 and Day 8
Trial Periods
Screen
Treatment**
EOT
FU
Course *
1 
If no signs 
of 
progression 
please 
continue to 
Visit 1 Flow 
Chart
Course 2-8
If the patient 
has disease 
progression 
or 
withdraws, 
please  
continue to 
EOT visit on 
Flow Chart  
Course 2-8  
Visit *
Screen
1
2
Days 
-14 to -1
1
2
3 
4
8 
9
Informed consent
x
Demographics
x
Medical history
x
Review of in-/exclusion 
criteria
x
x 
12 lead-ECG
x
 
Height
x
Physical examination, 
 
ECOG performance status
x
x
Vital signs
x
x
x
x
x
x
x
Weight
x
x
Dose assignment
x 1
Adverse events
x
x
x
x
x
x
Concomitant therapy
x
x
x
x
x
x
x
Administration of BI 836826
x
x
x
General safety laboratory 
parameters 3
x
x
x
x
x
x
x
Screening for Tumour Lysis 
Syndrome 4
x
x
x
x
x
x
Serum pregnancy test 5
x
x
CMV monitoring 6
x
x
x
 
 
 
 
Virology screening 
(HBV, HCV, HIV, CMV)
x
EOT: 
End of treatment, performed 14 days (± 2 days) after the last administration of BI 836826
FU: 
Follow-up, starts after EOT, visits at least every 4 weeks until 6 months after EOT, details see Section 6.2.3.2
CMV:
Cytomegalovirus


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HBV:
Hepatitis B Virus
HCV:
Hepatitis C Virus
HIV:
Human Immunodeficiency Virus
* 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 …
** the planned duration of a treatment course is 14 days
1
After informed consent, and review of in- and exclusion criteria, and before the first administration of the trial 
drug
3
For details refer to Section 5.2.3.1
4
Screening for tumour lysis syndrome in between safety laboratory assessments (Section 5.2.3.2)
5
For women of childbearing potential only (please refer to Sections 3.3.3 (exclusion criterion 18) and 5.2.3.1)
6
Quantitative CMV DNA PCR or pp65 antigen (Section 5.2.3.3.2)
7
Sampling at the time points specified in (see below) 
 
 
 


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11.
SUMMARY OF CLINICAL TRIAL PROTOCOL 
MODIFICATIONS
Summary of Clinical Trial Protocol Modifications Sheet (SOMS)
Number of CTP modification
1
Date of CTP modification
20 Jan 2011
EudraCT number
2010-021488-34
BI Trial number
1270.1
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase I, open, dose escalation trial with BI 
836826 in patients with advanced chronic 
lymphocytic leukaemia
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: Sections 3.1 and 4.1.3
Change 2: Section 4.1.4
Change 3: Sections 5.2.1, 5.2.2.1, 5.2.2.2, 5.4 and 
9.1
Description of change
Change 1: Description of sequential enrolment 
transferred from Section 4.1.3 to Section 3.1
Change 2: 25,000 corrected to 25.000


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Change 3: CTCAE, version 3.0 changed to 
CTCAE, version 4.0, including update of 
published reference
Rationale for change
Change 1: Clarification of trial design in 
Section 3.1, which now includes a description of 
sequential enrolment which has been previously 
included in Section 4.1.3.
Change 2: Correction of a typing error.
Change 3: Implementation of the current 
version 4.0 of Common Terminology Criteria for 
Adverse Events (CTCAE).


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Number of CTP modification
2
Date of CTP modification
20 Sep 2011
EudraCT number
2010-021488-34
BI Trial number
1270.1
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase I, open, dose escalation trial with BI 
836826 in patients with advanced chronic 
lymphocytic leukaemia
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: Protocol Synopsis
Change 4: Flow Chart
Change 5: Flow Chart, Section 6.2.2.2, 6.2.2.3, 
6.2.2.4
Change 6: Section 3.1
Change 7: Section 3.1.1
Change 8: Section 3.3.2


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Change 9: Section 3.3.3
Change 10: Section 4.1.4
Change 11: Section 4.1.4
Change 12: Section 4.1.7
Change 13: Section 5.2.2.1
Change 14: Section 5.2.3.2
Change 15: Section 5.2.3.3.2
Change 16: Section 5.2.3.4
Change 17: Section 5.3.3
Change 18: Section 5.5.2
Change 19: Section 5.6.3.1 and Flow Chart
Change 20: Section 5.6.3.2
Change 21: Section 5.6.3.3
Change 22: Section 5.6.3.3
Change 23: Section 10.1
Change 24: Section 9.1 and Section 10.4
Description of change
Change 1: Trial Clinical Monitor changed from 
 to 
Change 2: Deletion of "conducted in one country"
Change 3: CTCAE version 3.0 changed to version 
4.0
Change 4: Addition of footnote 14
Change 5: Timepoints for assessment of weight 
indicated in a separate row in the Flow Chart. 
Measurements which are not needed are deleted 
from visit 1, day 2, visit 2 and visit 3.


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Change 6: Addition of missing words "the first 
dose to"
Change 7: Name of Coordinating Investigator 
deleted from protocol text, addition of "and".
Change 8: Modification of inclusion criterion 4 
from "White blood cell count (WBC) between 20 x 
109/l and 150 x 109/l" to "Absolute lymphocyte 
count between 5 x 109/l and 150 x 109/l"
Change 9: Addition of "and/or" to exclusion 
criterion 8.
Change 10: "and Allopurinol" replaced by 
"and/or prophylactic drugs" and "available" by 
"published"
Change 11: "Acetaminophen/Paracetamole" 
replaced by "Analgetic/Antipyretic, equivalent to 
Acetaminophen or Paracetamole".
Change 12: Clinical Research Associate (CRA) 
added as contact in case of storage conditions 
outside the specified range.
Change 13: "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 or increased, 
•
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."
is replaced by "Worsening of the underlying 
disease or of other pre-existing conditions will be 
recorded as an (S)AE in the (e)CRF."
and


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"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." 
is 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 14: Addition of "Day 1" to specify 
timepoint in Visit 1 at which reticulocytes, serum 
immunoglobulin levels and direct antiglobulin 
test have to be obtained.
Change 15: Addition of " The same method 
should be used for all patients treated at the same 
investigational site."
 
 
 
 
 
 
 
 
Change 18: "For the early time points on the day 
of drug administration" replaced by "During the 
administration of trial drug"
 
 


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Change 23: Revision of Table 10.1:1 to specify 
whether timepoints are relative to start or end of 
infusion.
Change 24: Addition of definitions of Eastern 
Cooperative Group (ECOG) Performance Score 
and corresponding reference
Rationale for change
Change 1: Change of responsibilities
Change 2: The trial may be conducted in more 
than one country in the future
Change 3: Change from CTCAE version 3.0 to 
4.0 has been implemented in previous 
amendment, but without correction of the 
Synopsis which is implemented in this version.
 
 
 
Change 5: Clarification that body weight has to 
be obtained only at day 1 of each treatment 
course.
Change 6: Correction of typo by addition of 
missing words "the first dose to" in paragraph 6.
Change 7: Administrative change. The name of 
the Coordinating Investigator is deleted from 
theprotocol text because it is mentioned on the 
Title and the Signature page, thus a repetition in 
this protocol section is not needed. In addition, a 


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clarification on the qualification of all 
investigators is included by addition of "and".
Change 8: Lymphocytes represent the majority of 
white blood cells in active CLL, and the number 
of circulating lymphocytes rather than the total 
number of white blood cells will be used to 
characterize the population. Patients with a 
lymphocyte count of 5 x 109/l will be evaluable for 
all endpoints and are expected to be comparable 
to patients with a white blood count of 20 x 109/l 
regarding the risk for adverse reactions.
Change 9: Clarification of Exclusion Criterion 8.
Change 10: Standards for phrophylaxis of tumour 
lysis syndrome vary, and allopurinol may not be 
considered standard in all countries. To allow 
prophylaxis according to local standards and 
published guidelines accross countries, the 
wording was modified.
Change 11: Acetaminophen or Paracetamol may 
not be available in all countries for 
premedication. In this case, an equivalent other 
analgesic and antipyretic drugs should be 
administered.
Change 12: Addition of the CRA as a second 
contact person in case of storage conditions 
outside the specified range.
Change 13: Clarification of (S)AE reporting.
Change 14: Clarification at which day during 
Visit 1 reticulocytes, immunoglobulin levels and 
direct antiglobulin test have to be measured.
Change 15: Clarification that the same method of 
quantitative CMV testing should be applied to all 
patients treated at each investigational site.
 
 


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Change 23: In case of adverse events, the 


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administration of BI 836826 may be extendend to 
8 hours. 
 
 
 
 
 
Change 24: Clarification of definitions of ECOG 
Performance Score.


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Number of CTP modification
3
Date of CTP modification
2 August 2012
EudraCT number
2010-021488-34
BI Trial number
1270.1
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase I, open, dose escalation trial with BI 
836826 in patients with advanced chronic 
lymphocytic leukaemia
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: Flow Chart
Change 3: Table of Contents
Change 4: Abbreviations


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Change 5: Section 3.1
Change 6: Section 3.2
Change 7: Section 3.3.2
Change 8: Section 4.1
Change 9: Section 4.1.1
Change 10: Section 4.1.3
Change 11: Section 4.1.4
Change 12: Section 5.2.2.1
Change 13: Section 5.2.2.2
Change 14: Section 5.2.3.1
Change 15: Section 5.2.3.2
Change 16: Section 5.2.3.2
Change 17: Section 5.3.2.1
Change 18: Section 5.5.1
Change 19:Section 5.5.2
Change 20: Section 5.6.3.4
Change 21: Section 6.1
Change 22: Section 6.2.2.
Change 23: Section 7.6 
Change 24: Section 10.1
Change 25: Section 10.5
Change 26:Section 10.6
Description of change
Change 1: "over 3 hours as single agent 
treatment on day 1 of each 14-day course" was
replaced by "as one to three single doses within a 
14 day course"


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Change 2: Flow Chart and Footnote was deleted
Flow Chart Course 1, Dosing on Day 1 and Day 
2 and Footnote was added
Flow Chart Courses 2 - 8 and Footnote was 
added  
Change 3: Table of Contents was updated
Change 4: Abbreviations were updated
Change 5: "Enrolment in this context refers to the 
day of administration of the first dose to a 
patient" was added
Change 6: "Intra-patient dose escalation will not 
be allowed." was deleted."
Change 8: "BI 836826 will be administered as an 
intravenous infusion over a period of 3 hours on 
day 1 of each 14-day course. In case a patient 
experiences an adverse event during the infusion" 
was replaced by " In course 1, the total dose will 
be divided into two portions administered on day 
1 and 2 (please refer to the Flow Chart: Course 
1, Dosing on Day 1 and Day 2). The dose on day 
1 will be 10% of the total dose, but not exceed 10 
mg in case the total dose is higher than 100 mg. 
The dose on day 2 will be the planned total dose 
minus the dose administered on day 1. If adverse 
events which are related to the infusion schedule, 
e.g. infusion-related reactions or tumour lysis 
syndrome require administration of a lower dose
on day 2, the total dose in course 1 may be 
divided into 3 smaller portions on day 1, 2 and 8. 
In this case, the dose on day 1 will remain as 
defined previously. The difference between day 1 
and the  planned total dose level will be equally 
divided between day 2 and 8 (reference to section 
10.6). The distribution of the planned total dose in 
course 1 to two, or if needed to three smaller 
portions will be based on safety data from the 
previous cohort and will be assessed and may be 
modified by the DSMB. If supported by the 


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DSMB, the same rules may be applied to course 2 
in case infusion-related adverse events can be 
controlled by the above measures in course 1 but 
occur in course 2.
In all subsequent treatment courses, BI 836826 
will be administered as a rate-controlled  
intravenous infusion on day 1 of each 14-day 
course.
The first and second infusion will be started at a 
rate of 10 mL/h. The infusion rate should 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 
stepwise increase of infusion rate during the third 
and subsequent infusions may be faster or steps 
may be omitted, but the maximum infusion rate 
must not exceed 120 mL/h. 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.
"In case a patient experiences an adverse event 
during the infusion" was replaced by "For 
medical reasons" 
Change 9:"Single dose on day 1 of in a 14 day 
course" was replaced by " One to three single 
doses within a 14 day course"
"Infusion over 4 hours" and "Rate: 83,4 mL/h" 
was deleted and replaced by "Rate controlled 
infusion"
Change 10:"over 3 hours on day 1 of each 
course" was replaced by " on day 1, 2 and 
possibly day 8 in course 1 and on day 1 in the 


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subsequent courses"
"per treatment course" was added
Change 11: "Intra-patient dose escalation of BI 
836826 will not be allowed in this trial " was 
replaced by "Intra-patient dose escalation may be 
considered in agreement between investigator 
and sponsor for selected patients. It is restricted 
to patients who have received at least 4 treatment 
courses and tolerate the treatment well at the time 
of dose escalation. Intra-patient dose escalation 
can only be performed at a time when the next 
higher dose cohort has been reviewed and 
considered safe by the DSMB. The dose 
escalation step is limited the dose which has been 
administered to the next higher cohort. The 
treatment courses at the increased dose have to 
follow the instructions as outlined for course 5-8 
in the Flow Chart and the protocol. In addition, 
after the first dose at the higher dose level, 
patients have to be monitored for at least 24 
hours after the end of the infusion, including 
safety laboratory for tumour lysis syndrome."
Change 12: "Protocol-specified" and "Drug 
induced liver injury (DILI) Although rare, 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 


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need to be followed up according to Appendix
10.5 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 Appendix 10.5 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." were added.
Change 13: "BI has set up a list of AEs which are 
defined to be always serious. In order to support 
the investigator with the identification of these 
“always serious adverse events”, if a non serious 
AE is identified to be serious per BI definition, a 
query will be raised. The investigator must verify 
the description and seriousness of the event. If the 
event description is correct, the item “serious” 
needs to be ticked and an SAE has to be reported 
in expedited fashion following the same 
procedure as above. The list of these adverse 
events can be found via the RDC-system." Was 
added
Change 14: "Screening"," total" and "( if elevated 
direct bilirubin)" were added 
Change 15: "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 


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(R10-4517)." 
"Between the first and the second infusion", "the 
second", "i.e. every 4-8 hours" and "In case the 
schedule as outlined in Section 10.6 is used, 
monitoring for TLS has to be performed for 24 
hours also after the infusion on day 8. Sampling 
for TLS in course 3 and subsequent courses 
should be performed as clinically indicated." 
were added
Change 16: "with differential" was added
Change 17: "ethnicity, if it is not prohibited by 
the local laws" was added
Change 18: "from 0 to the last quantifiable 
plasma concentration" and "t" were added
Change 19:"and in Appendix 10.6" was added
 
 
 
 
 
 
Change 21:"the first and second" and " in course 
1" were added
"administration" was replaced "by two courses"
"Administration of BI 836826 only in course1" 
was added
"The actual date and time of blood sampling must 
be recorded in the eCRF." was deleted
"of a treatment course" was replaced by "day 3 
day 3 in course 1"and " in course 2-8"
"The actual date and time of blood sampling must 
be recorded in the eCRF." was deleted


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"6.2.2.4 Visit 2 - day 4 (day 4 only in course 1)

Vital signs (see Section 5.2.5.1) Adverse events 

Concomitant therapy

Safety lab parameters as specified in 
Section 5.2.3.1

 
 
"of a treatment course" was replaced by "day 8 
day 8 in course 1 or" and " in course 2-8"
"Administration of BI 836826 only in course 1, if 
treatment schedule according to section 10.6 is 
used" and "Blood samples to screen for evidence 
of tumour lysis syndrome only in course 1, if 
treatment schedule according to section 10.6 is 
used" were added
"The actual date and time of blood sampling must 
be recorded in the eCRF." was deleted
"6.2.2.6 Visit 3 - day 9 (day 9 only in course 1, if 
treatment schedule according to section 10.6 is 
used) 
On visit 3, the following parameters and 
investigations will be obtained/performed 

Vital signs (see Section 5.2.5.1) 

Adverse events 

Concomitant therapy 

Safety lab parameters as specified in 
Section 5.2.3.1 

Blood samples to screen for evidence of 
tumour lysis syndrome 

 
Change 23: "n" was added


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Change 24: Flow Chart was replaced by Course 
1, Dosing on Day 1 and Day 2 and Course 2-8 
"If no signs of progression please continue to 
Visit 1 Flow Chart Course 2-8. If the patient has 
disease progression or withdraws, please 
continue to EOT." was added
"The time for infusion may vary, depending on 
infusion rate and occurrence of infusion-related 
reactions. The exact start and end time of the 
infusion should be recorded. The assumed 
planned time of 5 hours is based on a stepwise 
increase of the rate every 30 (+/-10) minutes by 
10 mL/h to a maximum of 80 mL/h without any 
interruptions." was added
"If the time for infusion prolongs is longer than 3 
hours, e.g. in case of infusion related reactions, the 
exact start and end time should be recorded. If the 
infusion is interrupted, the stop time and the time 
when it is re-started need to be documented " was 
deleted
 
Change 25:The  whole section 10.5 was added
Change 26:The  whole section 10.6 was added
Rationale for change
Changes 1, 2, 8, 9, 10, 24, 26: To prevent infusion
related reactions or tumour lysis syndrome after 
the first infusion, the infusion schedule for course 
1 will be modified. Modification will include two 
elements: a small dose on day 1 to lower the risk 
for reactions related to the first infusion and to 
improve tolerability of a larger dose on day 2, 
and a slower infusion rate.
The total dose in course 1 will be divided into 2 
smaller portions. The dose on day 1 will be 
reduced to 10% of the planned dose and will not 
exceed 10 mg at planned doses of 100 mg and 


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above. The planned dose minus the dose 
administered on day 1 will be given on day 2. In 
case infusion related adverse events on day 2 
would require also a modification of the infusion 
on day 2, the dose in course 1 may be distributed 
to days 1, 2 and 8 in agreement with the DSMB. 
Due to the change in the infusion scheme the 
Flow Chart was split in course 1 and course 2-8 
(change 2), and a separate Flow Chart for the 
distribution of the total dose to 3 portions was 
provided (change 25). The infusion will remain 
rate controlled, but the infusion rate will be 
increased in small steps as tolerated by the 
patient not only in course 1 but in all treatment 
courses. Therefore the time for infusion will be 
longer than 3 hours and time for infusion will 
vary. 
Change 3: Clarification and update of Table of 
Contents
Change 4: Explanation of abbreviation
Change 5: Clarification of definition of sequential 
enrolment
Changes 6 and 11: Intra-patient dose escalation 
will be allowed for selected patients in case the 
next higher dose cohort is free of DLT and 
considered safe. This is not considered a safety 
risk because it will be restricted to patients who 
have tolerated four courses of BI 836826 at the 
time of dose escalation and may offer a potential 
benefit to patients enrolled at a lower dose.
Change 7: 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 increased risk for the patient.
Change 12: Clarification that the significant AEs 
are the defined protocol specific AEs and Liver 
injury (DILI) was added. (S)AE reporting change 
required by regulatory authority.  
Change 13: Clarification of serious adverse event 


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reporting.
Change 14: Clarification of the timepoints for 
safety laboratory values. Clarification that total 
bilirubin value is to be obtained. In case bilirubin 
is elevated, direct bilirubin will be needed for 
clinical interpretation.
Change 15: Definition of classification of tumor 
lysis syndrome which will be used. Clarification 
of blood sampling for monitoring of tumour lysis 
syndrome.
 
Change 17: Adaptation to local laws
Change 18: Clarification
Change 19: Clarification of Sample Collection
 
 
Changes 21 and 22: Adaptation of hospital 
surveillance and visit schedule to the modified 
infusion schedule.
Change 23: Correction of typo
Change 25:Procedure of Clinical Evaluation in 
case of Liver Injury


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Number of CTP modification
4
Date of CTP modification
7 Aug 2013
EudraCT number
2010-021488-34
BI Trial number
1270.1
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase I, open, dose escalation trial with BI 
836826 in patients with advanced chronic 
lymphocytic leukaemia
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: Title page
Change 2: Synopsis
Change 3: Synopsis and section 4.1.4
Change 4: Flow Chart course 1


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Change 5: Flow Chart course 1
Change 6: Flow Chart courses 1
Change 7: Flow Chart course 1
Change 8 : Flow Chart course 1
Change 9 : Flow Chart, courses 2-8
Change 10 : Flow Chart, courses 2-8
Change 11 : Flow Chart, courses 2-8
Change 12 : Flow Chart, courses 2-8
Change 13 : Abbreviations
Change 14: Section 3.1
Change 15: Section 3.2
Change 16: Section 3.2
Change 17: Sections 3.3.2, 5.1.1 and 5.1.2
Change 18: Section 3.3.2
Change 19: Section 3.3.3
Change 20: Section 3.3.3
Change 21: Section 4.1.1
Change 22 : Section 4.1.4
Change 23: Section 4.2.2.1
Change 24 : Section 5.1.2.4
Change 25 : Section 5.2.5.1
Change 26: Section 5.3.4.2 and 5.5.1
Change 27 : Sections 5.6.3.2 and 5.6.3.3
Change 28 : Section 6.1
Change 29: Section 6.2.1


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Change 30 : Section 6.2.2.1
Change 31 Section 6.2.2.5
Change 32:Section 6.2.3.2
Change 33: Section 7.1
Change 34 : Section 7.6
Change 35: Section 10.1, Table 10.1 :1
Change 36: Section 10.1, Table 10.1 :1
Change 37: Section 10.6
Change 38 : Section 10.6
Change 39: Section 10.6
Change 40: Section 10.6
Change 41: Section 10.6
Description of change
Change 1: 
 was replaced by 
 and 
by 
.
Change 2: “60” was replaced by “70” and “50”
by “60”.
Change 3: synopsis:“up to 8” was 
deleted.Section 4.1.4:"coordinating" was deleted, 
“In the dose-escalation phase as well as in the 
expansion cohort” and “If patients continue 
beyond cycle 8, the same assessments will be 
done as applicable for cycle 5-8” were added.
Change 4: +2 was added to day 8.
Change 5: Screening for TLS: cross on day 4 was 
added (48 h monitoring).
Change 6, 40: Some assessments were deleted.
Change 7, 41: Some footnotes were deleted and 
the numbering was changed
 


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Change 9: +2 was added to day 8.
Change 10: Footnote 8: “may be performed up to 
3 days earlier” was replaced by “may be 
performed 1 day earlier”.
 
 
 
 
 
 
 
 
Change 12: “If patients continue beyond cycle 8 
in agreement with investigator and BI, the same 
assessments will be done as applicable for cycle 
5-8” was added.
Change 13: NCI was replaced by IWCLL, 
NCIWG deleted and IWCLL added to 
abbreviations.
Change 14: 12-20 was replaced by 12-30.
Change 15: 12-20 was replaced by 12-30.
Change 16: “doses” was replaced by “courses”.
Change 17: NCI was replaced by IWCLL.
Change 18: “between 5 x 109/l and 150” was 
replaced by “lower than 200”.
Change 19: “Treatment with anti CD 20 therapy 
within 28 days or alemtuzumab within 8 weeks 
prior to enrolment” was modified to  “Prior 
treatment with anti CD 20 therapy within 4 weeks 
or alemtuzumab within 8 weeks, or any other 
antileukemia therapy within 2 weeks prior to the 
first administration of the trial drug”.


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Change 20: GFR<60mL/min was replaced by
GFR<45 mL/min.
Change 21:” Volume: 250 mL” was replaced by 
“See section 4.1.6”
Change 22: "or pre-treatment value" and 
“future” were added.”and only with a reduced 
dose of BI 836826”, “new”, “The reduced dose 
will be valid for all following treatment courses in 
the individual patient”,  “In case, a patient 
experiences a second episode of DLT with the 
reduced BI 836826 dose, the treatment has to be 
permanently discontinued.” and “Likewise” were 
deleted.
Change 23: “may not be used within 4 weeks 
prior to the first trial infusion and 2 weeks after 
the last infusion of BI 836826” was replaced by 
“should be avoided during treatment with BI 
836826. However, if medically indicated, e.g. for 
substitution of immunoglobulin deficiency, 
immunoglobulins may be used. Administration 
within a time window of 2 days before and after 
the infusion of BI 836826 should be avoided.”
Change 24: “or 50% improvement over baseline” 
was added.
 
 
 
 
 
 
 


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Change 28: “after administration of BI 836826” 
was added, “first and” was deleted and 
“courses” was replaced by “doses in course 1”.
 
 
 
Change 31: +2 was added to day 8, “and” was 
added. “day 8”, “or day 8(+1)” were deleted.
Change 32: "receives new anti-neoplastic 
therapy" was added.
Change 33: “20” was replaced by “30”.
Change 34: “12-20” was replaced by “up to 30” 
and “42-50” was replaced by “60”.
Change 35: Horizontal line was added.
 
 
Change 37: Screening for TLS: cross on days 3 
and 4 was added (48 h monitoring).


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Change 38: Crosses struck out from the EOT and 
FU visit assessments.
Rationale for change
Change 1: Contact details of new TCM were 
added.
Changes 2, 14, 15, 33, 34: The option to recruit 
more patients in the expansion cohort (from 12-
20 to 12-30) was added. This is to obtain more 
safety information on the monotherapy MTD as 
subsequent development of BI 836826 will be
based on combination treatment.
Change 3: To add a clarification that individual
prolongation of treatment beyond 8 courses is 
possible and how this prolongation is agreed.
Changes 4, 9, 31: To allow some flexibility in the 
courses, a visit window +2 days was added on 
day 8.
Change 5, 37: Correction: Screening for TLS: 
Crosses were added to be in line with 48 hours 
close monitoring.
Changes 6, 40: Correction: The deleted
assessments were not necessary since the Flow 
Chart is for course 1. 
Changes 7, 41: Correction: The deleted footnotes 
were not necessary since the Flow Chart is for
course 1. The numbering of the remaining 
footnotes had to be changed accordingly.
 
 


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Change 12: Clarification of the assessments 
beyond cycle 8.
Changes 13, 17: In-text reference to citation R10-
4429 was corrected.
Change 16: Correction of wording due to 
schedule change in amendment 3.
Change 18: Inclusion criterion 4 modified to 
include patients with a lymphocyte count up to 
200 x 109/L. Lymphocyte counts between 150 and 
200 x 109/L are common in relapsed/refractory 
CLL. This modification is considered to allow 
more patients to be enrolled without additional 
safety risk.
Change 19: Concomitant therapy restriction 
already existing in the Restriction section 4.2.2.1 
was added into the exclusion criteria as a 
clarification.
Change 20: GFR decreases with age. In view of 
the average age of CLL patients, exclusion 
criterion 12 was modified to exclude only patients 
with a GFR<45 mL/min.
Change 21: Clarification: Volume of 250 mL was 
replaced by reference to section 4.1.6.
Change 22: Clarification of handling of DLT to 
allow for risk benefit assessment for the patient 
receiving BI 836826.
Change 23: Immunoglobulins deficiency in 
relapsed CLL is commonly treated by 
immunoglobulin substitution to decrease the risk 
of infections. Use of immunoglobulins as a 
concomitant medication was modified to allow 
medically indicated use of immunoglobulins in 
patients which otherwise would have to be 
removed from the protocol and to provide 


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guidance when to administer in relation to trial 
drug.
Change 24: Correction of PR criterion B3.
Change 25: Correction due to new infusion 
scheme after last amendment and clarification to 
allow more flexibility concerning vital signs 
measurement.
 
Change 28: Correction for clarification.
Change 32: Clarification of the end of follow-up 
period. Follow-up will end once new anti-
neoplastic therapy starts.
Change 35: Correction of table formatting
Change 38: Correction of mistake: EOT/FU 
assessments are defined in the Flow Chart for 
courses 2-8.


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Number of CTP modification
5
Date of CTP modification
04 March 2015
EudraCT number
2010-021488-34
BI Trial number
1270.1
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase I, open, dose escalation trial with BI 
836826 in patients with advanced chronic 
lymphocytic leukaemia
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: Flowchart for Course 1 and Section 
6.2.2.5 Visit 3, Day 8
Change 2: 3.3.3 Exclusion criterion 1 and 4.2.2 
Restrictions
Change 3: Section 3.3.4.2.1: Trial stopping rules
Change 4: Section 5.2.1.1: Dose limiting toxicity 


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(DLT)
Change 5: Section 5.2.3.1: General safety 
laboratory parameters
 
Description of change
Change 1: Deletion of visit window: Course 1, 
Day 8
Change 2: Exclusion criterion 1 was changed 
from “…or any other antileukemia therapy within 
2 weeks, ...” to “…or any cytotoxic antileukemia 
therapy within 2 weeks, Ibrutinib or Idelalisib 
within 1 week….” The restrictions section was 
changed from: “Prior antileukemia therapy must 
have been discontinued at least two weeks before 
the first administration of the trial drug…” to 
“Prior antileukemia therapy must have been 
discontinued in line with the requirements per 
exclusion criterion 1…”
Change 3: Sub-section 3.3.4.2.1 was added 
describing Trial stopping rules
Change 4: The following was added: “The 
additional following haematologic adverse events 
will be considered DLT: 

Grade 4 neutropenia lasting more than 7 
days.

Febrile neutropenia not resolving within 48 
hrs with appropriate treatment (antibiotics, 
antivirals, antifungals, growth factor support) 

Grade 4 thrombocytopenia lasting more than 
7 days, or grade 3-4 thrombocytopenia with 
clinically significant bleeding 

Grade 4 anemia”
The following was deleted: “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.”


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Change 5: “Blood samples should be collected 
more frequently in case of relevant toxicities; e.g. 
in case of grade 4 neutropenia or 
thrombocytopenia, to document as accurately as 
possible the duration of the AE.” was added.
Rationale for change
Change 1: To ensure that all patients can be
assessed for duration of neutropenia and 
thrombocytopenia on the same day during the 
MTD evaluation period
Change 2: Ibrutinib and Idelalisib were recently 
approved in the countries in which the trial is 
recruiting patients. Both drugs have a short half 
live and should be eliminated after 7 days after 
the last dose, therefore not posing additional risks 
for interaction with trial medication. Patients 
should not receive the first dose of BI 836826 
earlier than 1 week after the last dose of Ibrutinib 
or Idelalisib to ensure elimination prior to 
starting BI 836826, while also allowing 
expeditious access to the investigational 
treatment for patients in need of treatment 
options.
Change 3: Trial stopping rules were described in 
more details according to FDA recommendations
Change 4: The DLT definition was refined to 
include specific haematologic adverse events
according to FDA recommendations
Change 5: More frequent measurements in case 
of relevant findings, e.g. to quantify the duration 
of Grade 4 neutropenia and/or thrombocytopenia 
 
 
 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number:  
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01568809
8.0
clinical-trial-protocol-revision-6
A Phase I, open, dose escalation trial with BI 836826 in patients with advanced
chronic lymphocytic leukaemia
Author-Trial Statistician
04 Mar 2015 12:49 CET
Author-Clinical Pharmacokineticist
04 Mar 2015 12:51 CET
Approval-Therapeutic Area 
04 Mar 2015 13:45 CET
Approval-Team Member Medicine
04 Mar 2015 21:00 CET
Author-Trial Clinical Monitor
05 Mar 2015 08:57 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01568809
8.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c02100724-03
BI Trial No.:
1270.1
Title:
A Phase I, open, dose escalation trial with BI 836826 in patients 
with advanced chronic lymphocytic leukaemia (including Protocol 
Amendments 1 to 5 [c01568809])
Investigational
Product(s):
BI 836826
Responsible trial 
statistician(s):
Phone: 
Fax:     
Date of statistical 
analysis plan:
13-OCT-2016 REVISED
Version:
Revised
Page 1 of 50
Proprietary confidential information
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATION..................................................................6
3.
INTRODUCTION..................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......9
4.1 CLARIFICATIONS......................................................................................................9
5.
ENDPOINTS ........................................................................................11
5.1
PRIMARY ENDPOINTS..................................................................................11
5.2
SECONDARY ENDPOINTS............................................................................11
5.2.1
Key secondary endpoints..............................................................................11
5.2.2
Other Secondary endpoints..........................................................................11
5.4.4
Adverse events ...............................................................................................20
5.4.5
Laboratory parameters.................................................................................21
5.4.5.1 General safety laboratory parameters ............................................................21
5.4.5.2
Laboratory values of special interest..........................................................23
6.
GENERAL ANALYSIS DEFINITIONS...........................................25
6.1
TREATMENTS..................................................................................................25
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................26
6.3
PATIENT SETS ANALYSED..........................................................................27
.....................................................................................................28
6.5
POOLING OF CENTRES ................................................................................28
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................28
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................28
7.
PLANNED ANALYSIS.......................................................................30
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........30
7.1.1
Disposition of patients...................................................................................30
7.1.2
Important protocol violations ......................................................................30
7.1.3
Demographic and other baseline characteristics........................................31
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................31
7.3
TREATMENT COMPLIANCE .......................................................................31
7.4
PRIMARY ENDPOINT(S) ...............................................................................31
7.5
SECONDARY ENDPOINTS............................................................................32
7.5.1
Key secondary endpoints..............................................................................32
7.5.2
Secondary endpoints .....................................................................................32
..................................................................................33


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7.7
EXTENT OF EXPOSURE................................................................................35
7.8
SAFETY ANALYSIS.........................................................................................35
7.8.1
Adverse events ...............................................................................................35
7.8.1.1
Maximum tolerated dose and dose limiting toxicity ..................................35
7.8.1.2
Adverse events............................................................................................40
7.8.1.3 Protocol-specified significant adverse events................................................41
7.8.1.4 Adverse events by user-defined categories....................................................42
7.8.1.5 Other significant AEs ....................................................................................42
7.8.2
Laboratory data.............................................................................................43
7.8.3
Vital signs.......................................................................................................44
7.8.4
ECG ................................................................................................................44
7.8.6
Others .............................................................................................................44
8.
REFERENCES.....................................................................................45
.46
..46
..46
..47
..48
10.
HISTORY TABLE...............................................................................49


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LIST OF TABLES
Table 5.2.2: 1 Derivation rules for progression-free survival..................................................13
Table 5.2.2: 2 Derivation rules for failure-free survival..........................................................14
................................................15
................................................16
................................................16
Table 5.4.5.1: 1 List of primary laboratory parameters ...........................................................21
Table 5.4.5.1: 2 List of secondary laboratory parameters........................................................22
Table 5.4.5.2: 1 Definition of abnormal laboratory values according to Cairo Bishop...........24
Table 6.1: 1 Definition of analysing treatment period(s).........................................................25
Table 6.2: 1 Important protocol violations ..............................................................................27
........................46
........................47
........................48
Table 10:1 History table...........................................................................................................49


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LIST OF FIGURES


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2.
LIST OF ABBREVIATION
AE
Adverse Event
ADA
Anti-Drug-Antibodies
ATC
Anatomical Therapeutic Chemical classification system
AUC
Area Under the Curve
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
BMI
Body Mass Index
BRPM
Blind Report Planning Meeting
BSA
Body Surface Area
CR
Complete Remission
CTP
Clinical Trial Protocol
CRi
Complete Remission with incomplete marrow recovery
CLL
Chronic Lymphocytic Leukaemia
CL
Clearance
CTCAE
Common Terminology Criteria of Adverse Event
CTh
Concomitant therapies
DBL
Database Lock
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
eCRF
electronic Case Report Form
EOT
End Of Treatment
FFS
Failure Free Survival
G-CSF
Granulocyte-Colony Stimulating Factor
ICH
International Conference of Harmonization
IRR
Infusion Related Reaction
IPV
Important Protocol Violation
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum Tolerated Dose
MRT
Mean Residence Time


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NE
Not Evaluable
OBD
Optimal Biological Dose
O*C
Oracle Clinical
PR
Partial Remission
PD
Progressive Disease
PFS
Progression Free Survival
PK
Pharmacokinetic
PKS
Pharmacokinetic Set
PV
Protocol Violation
PK/PD
Pharmacokinetic/Pharmacodynamic
PT
Preferred Term
REP
Residual Effect Period
SAE
Serious Adverse Event
SCR
Screened Set
SD
Stable Disease
SPD
Sum of Product Diameter
SOC
System Organ Class
SOP
Standard Operating Procedure
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TLS
Tumour Lysis Syndrome
UDAEC
User-Defined Adverse Event Category
ULN
Upper Limit of Normal
WBC
White Blood Cell 
WHO DD
World Health Organisation Drug Dictionary


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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. This TSAP follows the Boehringer 
Ingelheim (BI) internal guideline for developing a TSAP (1).
The primary objective of this trial is to determine the Maximum Tolerated Dose (MTD) or 
Optimal Biological Dose (OBD) of BI 836826 in patients with advanced chronic lymphocytic 
leukaemia. Secondary objectives are the collection of overall safety and anti-tumour efficacy 
data and the determination of the pharmacokinetic profile of BI 836826.
In the following, study medication always refers to BI 836826.
SAS® Version 9.4 (or higher) will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
4.1 CLARIFICATIONS
As this trial is the first in human use of BI 836826, the primary objective as defined by the 
Clinical Trial Protocol (CTP) is to determine the maximum tolerated dose (MTD) of BI 
836826. The MTD is determined via the number of dose limiting toxicities (DLTs). The CTP 
does not contain any definition of primary endpoint. But to follow the definition of the 
primary objective of the trial as defined by the CTP, the MTD and the number of patients 
with DLTs during the MTD evaluation period are defined as primary endpoints (see Section 
5.1).
During the course of the trial it was decided to change the definition of some of the secondary 
and further endpoints:
1. Number of lymphocytes in the peripheral blood
The definition of this endpoint was changed from “Number of lymphocytes in the peripheral 
blood” to “Best % change from baseline in number of lymphocytes in the peripheral blood”. 
2. Blood counts (haemoglobin, platelets, neutrophils, red blood cells)
The definition of this endpoint was changed from “Blood counts (haemoglobin, platelets, 
neutrophils, red blood cells)” to “number of patients with improved haemoglobin count for at 
least two subsequent response assessments”, “number of patients with improved platelet 
count for at least two subsequent response assessments” and “number of patients with 
improved neutrophil count for at least two subsequent response assessments”. It was decided 
to abandon the definition of a separate secondary endpoint for red blood cells, since red blood 
cells are highly correlated with haemoglobin count and are thus reflected in this endpoint.
 
 
 
 
 
 
 
 
 
 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary objective of this study is the tolerability and safety of BI836826 as reflected by 
the MTD. Thus, primary endpoints of this trial are the MTD and the number of patients with
DLTs during the MTD evaluation period. Instead of the MTD, an optimal biological dose 
(OBD) might be defined instead.
Maximum tolerated dose (MTD):
The MTD is defined as the highest dose studied for which the incidence of DLT is no more 
than 17% (i.e., 1/6 patients) during the MTD evaluation period.
The MTD evaluation period is defined as the duration of the first treatment course (i.e. 14 
days after first administration of BI 836826).
For the definition of DLT please refer to the CTP Section 5.2.1.1. Please note that the 
definition of DLT was changed during the trial by amendments of the CTP. With CTP 
version 6 (04 March 2015), the following additional haematologic AEs were considered 
DLT:

Grade 4 neutropenia lasting more than 7 days

Febrile neutropenia not resolving within 48 hrs with appropriate treatment 
(antibiotics, antivirals, antifungals, growth factor support)

Grade 4 thrombocytopenia lasting more than 7 days, or grade 3-4 thrombocytopenia 
with clinically significant bleeding

Grade 4 anemia
The respective definition of DLT included in the CTP effective at the start time of the 
Adverse Event (AE) qualifying for a DLT was used.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints 
Not applicable.
5.2.2
Other Secondary endpoints
Note: For the response/efficacy analyses with respect to overall response assessment by 
investigator used: If patients would have their examinations contributing to the disease 
assessment over a number of days, the earliest date of the multiple examinations should be 
considered.


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For the response/efficacy analyses with respect to lymphocytes and blood counts only 
laboratory data assessed >= 8 days after the last infusion and with reported laboratory 
response assessment on-treatment and before start of new Chronic Lymphocytic Leukaemia
(CLL) therapy is used. The reason for this approach is that otherwise the respective values of 
lymphocytes and blood counts would be biased due to the infusion after which an immediate 
change in values of the respective blood parameters is observed. This change though does not 
reflect an efficacy effect.
Number of lymphocytes in the peripheral blood
The secondary endpoint with respect to number of lymphocytes in the peripheral blood is 
defined as “Best % change from baseline in number of lymphocytes in the peripheral blood”. 
Blood counts (haemoglobin, platelets, neutrophils)
The secondary endpoints with respect to blood counts are defined as 
-
“Number of patients with improved haemoglobin count for at least two subsequent 
response assessments”
-
“Number of patients with improved platelet count for at least  two subsequent 
response assessments”
-
“Number of patients with improved neutrophil count for at least two subsequent 
response assessments” 
An improvement is indicated by the fulfilment of the criteria for “Complete Remission” or 
“Partial Remission”, i.e.
-
Haemoglobin count: Greater than 11g/dL or increase of 50% or more compared to 
baseline if haemoglobin is less than or equal to 11g/dL
-
Platelet count: Greater than 100 000/µL or increase of 50% or more compared to 
baseline if platelets are less than or equal to 100 000/µL
-
Neutrophil count: Greater than 1500/ µL or increase of more than 50% compared to 
baseline if neutrophil count is less than or equal to 1500/µL
Best overall response:
Response will be assessed according to the NCIWG guidelines (R10-4429) based on 
laboratory data from the peripheral blood and clinical examination by the investigator. Each 
patient will be assigned to one of the following categories:

complete remission (CR)

complete remission with incomplete marrow recovery (CRi)

partial remission (PR)

stable disease (SD)


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
progressive disease (PD)

not evaluable (NE)
Best overall response (CR, CRi, PR, SD, PD or NE in this order) is defined as the best overall 
response obtained since the start of study treatment until PD or start of next CLL therapy.
Post-treatment assessments will be considered for the evaluation of best overall response as 
long as no further CLL therapy has started.
Progression free survival (PFS):
PFS is defined as the time from first treatment with BI 836826 until disease progression or 
death, whichever occurs first. A patient has an evaluable response assessment if either CR, 
CRi, PR, SD or PD has been assigned by the investigator. 
Derivation of PFS is defined as PFS [days] = date of outcome – date of first administration of 
BI 836826 + 1.
The censoring rules and the applicable dates of outcome for PFS are given following table.
Table 5.2.2: 1 Derivation rules for progression-free survival
Situation
Outcome (event 
or censored)
Date of outcome
Disease progression or death
Event
Date of first disease 
progression or death
No disease progression or death without 
additional CLL therapy
Censored
Date of last response 
assessment
No disease progression or death with 
additional CLL therapy
Censored
Date of last response 
assessment before start of 
new CLL therapy
No baseline or post-baseline disease 
assessment and without death
Censored
Date of first administration 
of BI 836826
No baseline or post-baseline disease 
assessment and death on or before second 
planned disease assessment (i.e. 28 days 
after first administration of BI 836826)
Event
Date of death
No baseline or post-baseline disease 
assessment and death after second planned
disease assessment (i.e. 28 days after first 
administration of BI 836826)
Censored
Date of first administration 
of BI 836826


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Failure free survival (FFS):
FFS is defined as the time from first administration of BI 836826 until disease progression or 
death or start of next CLL therapy.
Derivation of FFS is defined as FFS [days] = date of outcome – date of first administration of 
BI 836826 + 1.
The censoring rules and the applicable dates of outcome for FFS are given in following table.
Table 5.2.2: 2 Derivation rules for failure-free survival
Situation
Outcome (event 
or censored)
Date of outcome
Disease progression or death or start of 
next CLL therapy
Event
Date of first disease 
progression or death or start 
of next CLL therapy
No disease progression, death or new 
CLL therapy
Censored
Date of last response 
assessment
No baseline or post-baseline disease 
assessment and without death or new 
CLL therapy
Censored
Date of first administration 
of BI 836826
No baseline or post-baseline disease 
assessment and death on or before 
second planned disease assessment (i.e. 
28 days after first administration of BI 
836826)
Event
Date of death
No baseline or post-baseline disease 
assessment and death after second 
planned disease assessment (i.e. 28 days 
after first administration of BI 836826)
Censored
Date of first administration 
of BI 836826


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5.4.4
Adverse events
Severity of adverse events is rated according to Common Terminology Criteria of Adverse
Event (CTCAE version 4.0; R10-4848)
In the CTP, protocol-specified significant adverse events were defined as AEs which were of 
particular concern for safety monitoring within the trial. These AEs needed to be handled by 
the investigator according to the rules defined for SAE reporting (see CTP Section 5.2.2.2). 
The following protocol-specified significant adverse events were defined:

Infusion-related reactions (IRR) (CTCAE grade 3 or higher)

Tumour lysis syndrome (TLS)

any event that qualifies for DLT

Drug-induced liver injury (DILI)
For the definition of hepatic injury inducing alterations of liver parameters refer to the CTP 
Section 5.2.2.1.
Definitions of AEs by user-defined categories in terms of MedDRA codes and sub-searches 
can be found in Section 9.4 of this TSAP.


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Other significant AEs are all serious or non-serious AEs leading to treatment discontinuation 
or dose reduction.
5.4.5
Laboratory parameters
5.4.5.1 General safety laboratory parameters
Original values will be converted into standard units and the CTCAE grades will be assigned 
to parameters which have a CTCAE definition (CTCAE version 4.0) (R10-4848)
Primary List: Tables and figures for these laboratory values and urine measurement will be 
displayed in Section 15 of the CTRs, if applicable. 
Table 5.4.5.1: 1 List of primary laboratory parameters
Worsening direction
Laboratory
Parameter
low value
Haematology
haemoglobin (HGB)
white blood cell count (WBC, total leukocyte 
count)
platelets (thrombocytes, PLTCT)
Differentials
neutrophils (NEUT)
Biochemistry
inorganic phosphate (P)
high value
Enzymes
aspartate amino transferase (AST)
alanine amino transferase (ALT)
Substrates
creatinine (CRE)
total bilirubin (TBILI)
Biochemistry
lactate dehydrogenase (LDH)
uric acid (URIC)
high and low value
Electrolytes
potassium (K)
calcium (CA)
Differentials
lymphocytes (lymphopenia) (LYMPH)
Secondary List: Tables for these laboratory values and urine measurement will be displayed 
in Appendix 16.1.9.2 of CTRs, if applicable. All laboratory values other than those in the 
primary list will be considered as secondary, including but not limited to the parameters listed 
in the following table. Urine measurement (based on dipsticks with 0, +, ++, and +++; the 


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more + the worse) will be displayed if needed. For urine measurement based on dipsticks
conversion rules can be found in Section 9.3.
Table 5.4.5.1: 2 List of secondary laboratory parameters
Worsening direction
Laboratory
Parameter
low value
Haematology
red blood cell count (RBC)
Differentials
CD3+ T cell count (CD3V)
CD4+ T cell count (CD4V)
CD8+ T cell count (CD8V)
CD56+ natural killer cell count (CD56V)
Biochemistry
total protein (TPRO)
albumin (ALB)
immunoglobulin M (IGM)
immunoglobulin G (IGG)
Urine
urine PH (UPH)
high value
Enzymes
alkaline phosphatase (ALKP)
Coagulation
international normalised ratio of 
prothromin time (INR)
activated partial 
thromboplastin time (aPTTs)
prothrombin time (PRTsec)
Biochemistry
urea (UREA)
direct bilirubin (BILID)
Urine
urine glucose (UGLU)
urine nitrite (UNIT)
urine protein (UPROZ)
urine erythrocytes (URBCZ)
urine leukocytes (UWBCZ)
high and low value
Haematology
reticulocytes (RET)
haematocrit (HCT)
Differentials
CD19+ B cell count (CD19V)


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Table 5.4.5.1: 2 List of secondary laboratory parameters (cont.)
Worsening direction
Laboratory
Parameter
Differentials
monocytes (MONO)
basophils (BAS)
eosinophils (EOS)
Electrolytes
sodium (NA)
Substrates
glucose (GLUA, GLUB)
Biochemistry
immunoglobulin A (IGA)
5.4.5.2
Laboratory values of special interest
Neutropenia, thrombocytopenia and leukopenia
Episodes of low neutrophil, platelets and WBC counts are of special interest. Episodes with 
CTCAE grade 3 and 4 and CTCAE grade 4 lasting 7 or more days will be analyzed.
An episode of e.g. low neutrophils starts with the first occurrence of a CTCAE grade ≥ 3 and 
lasts until the first time the CTCAE grade falls back to ≤ 2.
In case the episode starts during EOT or Follow-up, the duration of this episode is defined to 
be missing. The reason for this approach is that after EOT laboratory data is only captured 
infrequently and therefore the duration of an episode would be overestimated due to lack of 
data. 
If the episode starts before EOT and the CTCAE grade of the respective parameter does not 
fall back to grade ≤ 2 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.
Hepatic enzyme elevations (potential Hy’s law cases)
Special attention will be paid to patients fulfilling the criteria for potential Hy’s law cases.
These are defined as those cases where a combination of all of the following events occurred: 
any on-treatment value of ALT and/or AST > 3 times upper limit of normal (3 x ULN) with 
total bilirubin ≥2 x ULN and ALKP < 2 x ULN. The events can occur in any order, but must 
occur within 14 days of the previous event, i.e. the second event must occur within 14 days of 
the first event, and the third event must occur within 14 days of the second event.
Possible clinically significant abnormal lab values
Possible clinical significance based on CTCAE grading is defined as CTCAE grade 2 or 
higher with an increase of at least one CTCAE grade from baseline, please refer to Section 
9.2. for further details. If the baseline value is missing, all post-baseline values with CTCAE 


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grade 2 or higher will be classified as possibly clinically significant. For the laboratory 
parameters recorded that do not have a CTCAE grading defined, the BI default rules for 
clinical significance should be applied (5).
Tumour lysis syndrome (TLS)
The presence of laboratory TLS will be considered according to Cairo-Bishop classification.
Under this system, laboratory TLS is investigated based on the serum values of uric acid, 
potassium, inorganic phosphate, and calcium. TLS is considered to be present if within the 
time window of 3 days before until 7 days after administration of BI 836826, two or more of 
these laboratory parameters are abnormal, or change from baseline by ≥25%.
Table 5.4.5.2: 1 Definition of abnormal laboratory values according to Cairo Bishop
Laboratory parameter
abnormal Value
Change from baseline
Uric acid
≥476 µmol/L or 8 mg/dL
≥25% increase
Potassium
≥ 6.0 mmol/L or 6 mg/L
≥25% increase
Inorganic phosphate
≥1.45 mmol/L
≥25% increase
Calcium
≤1.75 mmol/L
≥25% decrease


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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 are being administered. The data will be presented for all dose 
cohorts separately and in total over all dose cohorts. To justify the MTD determination, DLTs 
occurring during the MTD evaluation period (during the first treatment course) will be 
presented separately from those occurring during the complete on-treatment period.
“Analysing treatment” will be used for reporting of treatment emergent adverse events (AE) 
and to differentiate between screening, on-treatment, post-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. Table 6.1:1 defines the “analysing 
treatment period” which will be used for reporting of treatment emergent AEs and safety 
laboratory parameters. Safety data recorded during the Residual Effect Period (REP) will be
considered as on-treatment. 
If not specified otherwise, all safety tables will be based on the on-treatment period. 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. 
Table 6.1: 1 Definition of analysing treatment period(s)
Analysing treatment 
period
Start date (including)
Stop date (excluding)
Screening
Date of informed consent
Date of first administration 
of study medication
On-treatment
Date of first administration 
of study medication
Start date of ‘Follow-up’
Follow-up
Date of end of REP +1
Start date of ‘Post-study’
Post-study
Last date patient status 
obtained / last date patient 
known to be alive + 1 (if 
patient is lost to follow-up) / 
date of refusal + 1 day / the 
date patient died + 1
During the trial: open / 
empty; after database lock 
(DBL): DBL + 1 day
The initial study medication assigned at the beginning of the first treatment course will be 
used as the label of the analysing treatment.


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The actual dose of study 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.
PVs are summarised into categories and are coded in O*C. The following table defines the 
different categories of important PVs. 


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Table 6.2: 1 Important protocol violations
Category
/Code
Description
Example/Comment
Exclude
d from
A
Entrance criteria not met
A11
Patient has condition that may 
cause additional risk from 
study medication
In 5, Ex 3 - 4, 15 - 20 
None
A21
Patient has laboratory 
assessments that may cause 
additional risk.
Ex 8 - 13
None
A3 1
Patient is unable to comply 
with the protocol
Ex 21, 24
None
A41
Patient does not have trial 
diagnosis or is not part of the 
target population
In 1 -  4, Ex 1 - 2, 5 - 7
None
A51
HIV test not done at screening
See Ex 17
None
B
Informed consent
B11
Informed consent not given or 
too late
In 7
All
C
Trial medication and 
randomisation
C12
Drug not administered 
according to the protocol
Administration according to 
protocol="No" and medical review of 
associated comments
None
C22
Drug not administered 
according to the protocol
Individual pre-medication taken="No" 
and medical review whether 
premedication would have been 
required according to protocol
None
[1] IPV will be derived automatically
[2] IPV will be identified via individual review at MQRM/BRPM/DBL
6.3
PATIENT SETS ANALYSED
The Screened Set (SCR) includes all patients who signed the informed consent form and will 
be used to summarize patient disposition.


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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 and efficacy analyses.
The MTD evaluation set: This patient set includes all patients who were documented to have 
received at least one dose of study medication and were not replaced for the MTD evaluation. 
The MTD evaluation set will be used for the primary analyses of DLTs and MTD 
determination.
Rules for replacement of patients are defined in Section 3.3.4.1 of the CTP. The list of 
replaced patients will be provided by the Trial Clinical Monitor no later than the last BRPM 
and should be attached to the BRPM minutes.
 
No per protocol population will be used for analyses.
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 “Handling of 
missing and incomplete AE dates” (2))
If the day of birth date is missing then the imputed day will be the 15th. If start of new CLL 
therapy date is incomplete (only month given), then the start date will be imputed with the 1st
of months 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.


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Unless otherwise specified, baseline is defined as the time-point closest to but prior to first 
administration of study medication. If no time is specified and the date is the same as the first 
administration date, then it will still be considered baseline if not specified otherwise.
Laboratory values: Baseline is defined as the latest time-point before start of the very first 
administration of study medication. For laboratories where not only the examination date but 
also time are 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 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.


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7.
PLANNED ANALYSIS
For End-Of-Text tables, the set of summary statistics is: N / Mean / standard deviation [StD] / 
Min / Median / Max. Efficacy data are presented by dose cohort. Displays of safety data will 
be presented by dose cohort and in total.
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 months 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. An overview table 
with respect to analysis sets (as defined in Section 6.3) together with the primary reason for 
exclusion will be provided.
7.1.2
Important protocol violations
A listing with protocol violations by patient will be created in Section 15 of the CTR.


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7.1.3
Demographic and other baseline characteristics
Standard descriptive analysis and summary tables for all patients treated by initial treatment 
will be created for demography, alcohol status, ECOG performance score, previous therapies, 
baseline values of haemoglobin, neutrophil, platelet, lymphocyte count, tumour size, virology 
and oncology history.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant therapies (CTh) will be coded according to World Health Organisation Drug 
Dictionary (WHO DD). They 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.
Summaries will be presented for previous and concomitant medications started at baseline 
and for concomitant therapies started after first administration of the trial medication. 
Separate summaries will be presented for concomitant medications with missing or 
incomplete start dates.
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. A separate listing will be provided for patients receiving Granulocyte-Colony 
Stimulating Factor (G-CSF) and transfusions (ATC Codes L03AA, B05AA, B05AX). 
7.3
TREATMENT COMPLIANCE
Compliance will be evaluated by whether or not the medication was always administered 
according to protocol for BI 836826.
A listing will show all administrations of trial drug including the comment if administration 
was not according to protocol and also the administration of premedication 
acetaminophen/paracetamol, antihistamine and glucocorticoid will be included.
7.4
PRIMARY ENDPOINT(S)
The primary endpoints of this trial are the MTD and the number of patients with DLTs during 
the MTD evaluation period. The MTD is determined from the occurrences of DLTs during 
the MTD evaluation period, i.e. the number of patients with DLTs during the first course. An 
overall summary of the DLTs (see CTP Section 5.2.1.1 for definitions of DLT) which 
occurred during the MTD evaluation period will be provided for each dose cohort of the 
MTD evaluation set. Patients, if any, who did not complete the first treatment course with BI 
836826 for reasons other than DLT will be excluded from the analysis of the primary 


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endpoint, since they are by definition not part of the MTD evaluation set. These patients were
replaced at the same dose level. A summary of the number of patients with DLTs overall in 
any course will be also given by initial treatment and displayed in a similar format to the 
summary of DLTs occurring in the MTD evaluation period.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
Not applicable.
7.5.2
Secondary endpoints
Number of lymphocytes in the peripheral blood
The number of lymphocytes in the peripheral blood will be analyzed in terms of the best 
percentage change from baseline until start of subsequent CLL therapy or PD. Best percent 
change is thereby derived by taking the difference between the baseline value and the 
minimum of all observed values over time. For the primary analysis of this endpoint, 
summary statistics will be presented for all patients of the TS by dose cohort and in total. In 
addition, summary statistics will be presented separately for patients of the TS with an 
abnormal and normal lymphocyte count at baseline. An abnormal baseline count is defined as 
a lymphocyte count > 4*10^9/L. In addition, the following will be analysed:
Summary statistics will additionally be presented for minimum values of certain lymphocyte 
types (CD19+ B-cells, CD3+ T-cells, CD4+ T-cells, CD8+ T-cells and CD56+ NK-cells).
For CD4+ T-cells and CD19+ B-cells, the lowest count since start of treatment (nadir) and 
the time point of occurrence of (nadir) will be derived and described by summary statistics 
for all dose cohort together and separated by dose cohort. The association of values at 
baseline and values at nadir will be displayed graphically.
A waterfall plot will also be generated to summarise reduction of lymphocytes graphically 
and lymphocyte values will be graphically displayed over time for patients of the Treated Set.
Furthermore, the number of lymphocytes and the change in lymphocyte count from baseline 
will be listed by time point.
Blood counts (haemoglobin, platelets, neutrophils)
A frequency table will be given for the endpoints “Number of patients with improved 
haemoglobin / platelet / neutrophil count for at least 2 subsequent response assessments” for 
all patients of the Treated Set. Additionally, graphical presentations of mean values of 
haemoglobin, platelet and neutrophil counts over time will be provided by dose cohorts. For 
neutrophils, the nadir and the time point of occurrence of nadir will be derived and described 
by summary statistics for all dose groups together and separated by dose group. The 
association of values at baseline and at time to nadir will be displayed graphically.


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Best overall response
Best overall response will be analysed descriptively. Frequency distributions will be used to 
examine this endpoint. The number of patients that have either CR, CRi or PR as best overall 
response will be tabulated separately (to determine the remission rate).
Progression-free and Failure-free survival
PFS and FFS will be analysed exploratory using Kaplan-Meier methods for all patients of the 
Treated Set.


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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 and descriptive table by dose 
group. The purpose of these tables is to summarize and document the data that led to the 
selection of MTD.
7.8.1
Adverse events
7.8.1.1
Maximum tolerated dose and dose limiting toxicity
A table displaying DLTs by primary system organ class and preferred term will be provided 
by initial treatment  for the MTD evaluation period for the MTD evaluation set as well as for 
the treated set. The same table will additionally be displayed for all treatment courses of the 
on-treatment period for the treated set.
A summary of the number of patients with DLT within the MTD evaluation period (treatment 
course 1) and for all treatment courses of the on-treatment period will be given by initial 
treatment for the treated set.


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In order to explore the behaviour of DLTs with respect to the actual dose of BI 836826, the 
dose response relationship will be examined descriptively, using DLTs in the MTD 
evaluation period and DLTs up to the end of the on treatment phase, in separate analyses. 
 
 
 
 
 
 
 
 
 
 
 
 


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7.8.1.2
Adverse events
Unless otherwise specified, adverse events analysis will be performed for on-treatment 
periods. Selected analyses (e.g. summary of AEs) will be repeated for the MTD evaluation 
period.
The analyses of AEs will be descriptive in nature and will follow the standard procedure laid 
down in the DM & SM (including all required tables and listings; guideline 'Handling and 
Summarization of AE Data for CTR and Integrated Summaries' (4). 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 system organ classes will be sorted alphabetically. In tables displaying AEs by dose 
cohort preferred terms 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 adverse events occurring between first administration of BI 836826 until 6 weeks 
after last administration of BI 836826 will be assigned to the on-treatment period. All adverse 
events occurring before first administration of BI 836826 will be assigned to “Screening” and 
all adverse events occurring after last administration of BI 836826 + 6 weeks will be assigned 
to “post-study (for listings only). 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. For details on the treatment definition please refer to Section 6.1.
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 
system organ class (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.
An overall summary of adverse events will be presented.
Reporting of CTCAE grades
CTCAE grading within AE tables is displayed as “all grades”, “Grade 1/2”, “Grade 3/4” 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 categories “Grade 1/2", “Grade 
3/4" and “Grade 5” might not sum up to the category “all grades”. A separate table will show 


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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 Grade”, “Grade 1”, “Grade 2”, “Grade 
3”, “Grade 4” and “Grade 5” are used, but the “missing grade” column should only be 
displayed in case AEs with a missing CTCAE grade occured.
AE attributes “CTCAE Grade 1/2", "CTCAE Grade 3/4” and “CTCAE Grade 5” combined 
with drug relationship 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” and “Drug 
relationship combined with seriousness of the AE and CTCAE grade” is needed similarly to 
the AE attribute “CTCAE Grade 1/2", "CTCAE Grade 3/4" and “CTCAE Grade 5” combined 
with drug relationship respectively, as described above.
Frequencies of patients with AEs will be summarised by treatment, highest CTCAE grade, 
primary SOC and PT. Tables will be provided for patients with AEs of incidence > 10%, with 
drug-related AEs, with serious AEs (SAEs), with drug-related SAEs, with AEs leading to 
treatment discontinuation, with AEs leading to dose reduction, with protocol-specified 
significant AEs, with AEs leading to death, and with infusion-related reactions (IRRs).
7.8.1.3 Protocol-specified significant adverse events
Protocol-specified significant AEs are defined in the CTP, Section 5.2.2.1.
Infusion-related reactions (IRR) 
Frequency of IRRs with CTCAE grade 3 or higher 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 9 mg dose cohort), the term IRR only or 
the symptoms of an IRR reported as AEs but not captured explicitly as symptoms of an IRR. 
For these patients, potential symptoms of an IRR can be only identified over pre-defined AE 
preferred terms (refer to Table 9.4:1). 
For patients from following dose cohorts (including some patients of the 9 mg cohort), not 
only IRRs are reported with the AE term “Infusion-related reaction” but also their symptoms 
which are additionally marked as symptoms of an IRR. 
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 (up to the 9mg dose 
cohort only).


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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 will be displayed graphically 
by administration visit together with its CTCAE grade for all patients. 
Tumour lysis syndrome
A frequency table displaying patients with clinical TLS (TLS reported as protocol-specified 
significant AE) will be provided. Additionally to cases of clinical TLS, laboratory TLS will 
be analysed (please refer to Section 7.8.2).
Any event that qualifies for DLT
Please refer to Section 5.2.1.1 of the CTP.
Drug-induced liver injury (DILI)
Please refer to Section 5.4.4. The frequencies of these protocol-specified significant AEs will 
be displayed in the CTR.
7.8.1.4 Adverse events by user-defined categories
A frequency table of AEs by user-defined categories,worst CTCAE grade, and preferred term 
as well as a frequency table of AEs by user-defined categories and worst CTCAE grade for 
the on-treatment period will be displayed.
7.8.1.5 Other significant AEs
Frequency tables of patients with AEs leading to dose reduction and AEs leading to treatment 
discontinuation will be provided by dose cohort and total, worst CTCAE grade, primary 
system organ class and preferred term for the on-treatment period.


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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 SOP “Display and Analysis of Laboratory Data” (5).  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. Patients 
with missing CTCAE grade at baseline or no baseline value but with post-baseline laboratory 
values will be displayed in the category “Missing CTCAE grade at baseline”
Single time courses by initial treatment will be used to display converted laboratory values 
over time by dose cohort. The graphs may be truncated if sufficient data is not available. 
These graphs will be displayed in Chapter 16.1.9.2 for the following parameters.
Haematology: haemoglobin, WBC count and platelets
Differentials: neutrophils (absolute count), absolute lymphocyte count, and natural killer 
(NK) cells
Enzymes: LDH
Clinically relevant abnormalities (as defined in Section 5.4.5.1) will also be summarised.
Descriptive statistics, including change from baseline, frequency of patients with transitions 
relative to the references range, will be provided. No post-study laboratory values will be 
considered. CTCAE grade for applicable laboratory parameters will be calculated according 
to CTCAE v4.0. The following outputs will be presented:

Baseline, last value and difference from baseline

Worst CTCAE grade experienced during the on-treatment period

Transitions of the CTCAE grade from baseline to the worst lab values, from baseline to 
the last lab values, and from the worst to last values during the on-treatment period

Possible clinically significant laboratory values
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 initially. 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.


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Patients with hepatic enzyme elevation will be tabulated. With respect to neutropenia, 
thrombocytopenia and leukopenia episodes the number of episodes and mean and median 
duration will be displayed. Additionally, laboratory values of special interest as described in 
Section 5.4.5 will be analyzed. 
Additionally, a frequency table displaying number of patients with episodes of grade 4 
neutropenia and concomitant AEs in the user-defined AE category (UDAEC)
 
of any grade and grade 3/4 will be provided. In this context, 
concomitant AE is defined as AE with onset date within the neutropenia episode. The same 
table will be done for grade 3/4 episodes of neutropenia and concomitant AEs in the UDAEC 
of any grade and grade 3/4 will be done.
The same applies for the display of patients with thrombocytopenia and bleeding events. For 
the definitions of neutropenia, thrombocytopenia and leukopenia episodes please refer to 
Section 5.2.5.2. 
The prioritized laboratory values (see Section 5.4.5) will be displayed in Section 15 of the 
final CTR while all other laboratory parameters will be displayed in the Appendix of the 
CTR.
7.8.3
Vital signs
A summary table and a listing of vital signs at each planned time will be provided for the 
treated set.
7.8.4
ECG
No analyses are planned. 
 
7.8.6
Others
Not applicable.


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8.
REFERENCES
1
001-MCG-160: "Guideline for Developing a Trial Statistical Analysis Plan", 
current version; IDEA for CON.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
4
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", version 5.0; IDEA for CON.
5
001-MCG-157: "Display and Analysis of Laboratory Data", current version, 
IDEA for CON.
R10-4429
Hallek M., Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Doehner 
H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ. Guidelines for the 
diagnosis and treatment of chronic lymphocytic leukemia: a report from the 
International Workshop on Chronic Lymphocytic Leukemia updating the 
National Cancer Institute-Working Group 1996 guidelines. Blood 111 (12), 5446 
- 5456 (2008)
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).
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).


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10.
HISTORY TABLE
Table 10:1 History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
19-JUL-2016
None
This is the final TSAP without any 
modification
Revised
13-OCT-2016
All 
Sections
Correction of typos.
 
 
 
 
 
 
 
 
 
5.2.2
Clarification that if patients would have 
their examinations contributing to the 
overall response assessment over a 
number of days, the earliest date of the 
multiple examinations should be 
considered.
5.4.4
Deleting sentence about further in-
depth analyses for AEs by user-defined 
categories as text was misleading.
5.4.5
Correction of laboratory parameters to 
be displayed in section 15.3 and 
16.1.9.2 of the report.
 
 
 
 
7.3 
No summary table for treatment 
compliance will be done as as often 
investigator said administration was not 
according to protocol because of an 
AE, but actually it is according to 


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Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
protocol to interrupt because of AEs. 
Instead only a listing of administration 
of study drug including the comment 
about administrations not according to 
protocol will be done.
7.7
Clarification that a listing of each dose 
taken at each treatment course will be 
provided for all patients and not just 
patients treated with different doses.
7.8.1.1
 
 
7.8.1.5
Clarification which analyses will be 
done for other significant AEs.
7.8.2
Converted values will be used for all 
laboratory plots instead of normalised 
values for some plots.
Deletion of rule for GFR as this 
parameter is not assessed in the study.
No possible clinically significant 
abnormal laboratory values and tumour 
lysis syndrome frequency tables will be 
provided for patients with hepatic 
enzyme elevations. If needed the 
information can be extracted from 
patient listings.
Clarification what analyses will be 
done for neutropenia and 
thrombocytopenia and how terms are 
defined.


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Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change