Conditions: Leukemia, Lymphocytic, Chronic, B-Cell
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
Intravenous BI 836826 in combination with ibrutinib in relapsed/refractory Chronic Lymphocytic Leukemia (CLL) patients who have been pre-treated with at least one prior line of systemic therapy, and who are eligible for treatment with ibrutinib. Objectives of the trial are to determine the recommended Phase 2 dose of BI 836826, and to document the safety and tolerability of BI 836826 when given in combination with ibrutinib

Detailed description:

Arms:
arm 1: BI 836826 administered in combination with Standard of Care Ibrutinib

Interventions: intervention 1: BI 836826 intervention 2: Ibrutinib
Intervention descriptions: intervention 1: None intervention 2: Standard of Care

Protocol document:
Prot_002.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c03032933-02
BI Trial No.:
1270.15
BI Investigational 
Product(s):
BI 836826
Title:
A Phase Ib, Open label, Single Arm, Multi-center, Dose Escalation 
Trial of Intravenous BI 836826 in Combination with ibrutinib in 
Patients with Relapsed/Refractory Chronic Lymphocytic 
Leukemia
Brief Title:
Intravenous BI 836826 in combination with ibrutinib in 
relapsed/refractory CLL patients who have been pre-treated with at 
least one prior line of systemic therapy, and who are eligible for 
treatment with ibrutinib
Clinical Phase:
Phase Ib
Trial Clinical 
Monitor:
Telephone: 
Fax: 
Coordinating 
Investigator:
Telephone: 
Fax: 
Status:
Final Protocol (Revised Protocol based on Global Amendment 1)
Version and Date:
Version: 2.0
Date: 18 Jul 2018
Page 1 of 115
Proprietary confidential information.
2018 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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 836826
Protocol date:
05 Nov 2015
Trial number:
1270.15
Revision date:
18 Jul 2018
Title of trial:
A Phase Ib, Open label, Single Arm, Multi-center, Dose Escalation 
Trial of Intravenous BI 836826 in Combination with ibrutinib in 
Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia
Coordinating
Investigator
Telephone: 
Fax: 
Trial site(s):
Multicenter Trial conducted in the United States
Clinical phase:
Ib
Objective(s):
The primary objective is to determine the Recommended Phase 2 
Dose (RP2D) of BI 836826 in combination with ibrutinib in 
relapsed/refractory CLL patients.
Methodology:
Open-label, single arm, dose escalation, Bayesian Logistic 
Regression Model (BLRM) with overdose control to confirm safety 
and to evaluate clinical efficacy.
No. of patients: 
Approximately 20 patients
total entered:
Approximately 20 patients


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Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 836826
Protocol date:
05 Nov 2015
Trial number:
1270.15
Revision date:
18 Jul 2018
each treatment:
Dose finding: Approximately 20 patients
Diagnosis :
Patients with relapsed or refractory Chronic Lymphocytic Leukemia, 
who have been pre-treated with at least one prior line of systemic 
treatment and who qualify for treatment with ibrutinib.
Main criteria
for inclusion:
Adult patients ≥ 18 years of age, diagnosed with either relapsed or 
refractory CLL with ECOG 0-2
Test product(s):
BI 836826
dose:
During the dose escalation phase, dose tiers of BI 836826 starting at
100 mg and escalating to the Maximum Tolerated Dose (MTD) in 
combination with ibrutinib will be evaluated.  BI 836826 will be 
administered in 4-week cycles, every two weeks for the first 16 
weeks (Cycles 1-4), and every 4 weeks starting at week 17 (Cycle 5) 
until Cycle 12. Patients experiencing a CR, CRi or a MRD negative 
Partial Response (PR) may continue BI 836826 every 4 weeks with 
12 additional treatment cycles and receive up to a maximum of 24 
treatment cycles. 
mode of 
administration:
BI 836826 i.v. as a rate controlled infusion 
Combination product:
ibrutinib
dose:
420 mg dose daily


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Name of company:
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 836826
Protocol date:
05 Nov 2015
Trial number:
1270.15
Revision date:
18 Jul 2018
mode of 
administration:
Orally, daily
Duration of treatment:
Ibrutinib: Until progression or unacceptable toxicity
BI 836826: All patients may receive 12 Cycles (18 infusions) unless 
progression, unacceptable toxicity, or withdrawal of consent occurs 
earlier. Patients with a CR, CRi or MRD negative PR after 12 Cycles
may prolong therapy to Cycle 24.
Endpoints
Primary endpoints: 
-
RP2D of BI 836826 in combination with ibrutinib and the 
number of patients with dose limiting toxicities in the first 
treatment cycle
Secondary endpoint:
-
Maximum tolerated dose (MTD)
Safety criteria:
Maximum tolerated dose, incidence and severity of adverse events 
graded according to the common terminology criteria for adverse 
events (CTCAE, version 4.0). Incidence of dose limiting toxicity, 
laboratory parameters. In addition, hematological toxicity based on 
laboratory values using the criteria as described in IWCLL 
guidelines.
Statistical methods:
Descriptive statistics and exploratory data analysis
Dose escalation is guided by a BLRM with overdose control that will 
be fitted to binary toxicity outcomes.  The estimate of parameters 
will be updated as data are accumulated using the BLRM. The 
toxicity probability at each dose level will be calculated to determine 
the MTD.


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FLOW CHART – SCREENING THROUGH CYCLE 12
Trial periods1
Screening 
Run -In2
Cycle 1
Cycle 2-121
Response Evaluation at 
the End of Cycle 3, 6, 9 
and 12
EOT3
End of 
Residual Effect 
Period Visit 
(EoR)4
FU for PD and 
Eof FU Visit5
End of Trial 
Status6
Day of Cycle1
(-35 to -15)
(-14 to -1)
1
2
8
15
20 ±320
1
15 
21-28
Informed consent 
x
Informed consent for 
pharmacogenetics and biobanking
x
Demographics and baseline 
conditions
x
Oncology history/Review of in-
/exclusion criteria
x
Review of pre BI 836826 dose 
laboratory values (Section 4.1.4)
x9
BI 836826 Dose Assignment
x10
LABS AND SAFETY ASSESSMENTS
Physical examination (Incl 
Height11)
x
x
x
x
Vital signs12
x
x
x
x
x
x
x
x
ECOG Performance score
x
x
x
x
12 lead-ECG13
x
x
x
Virology screening (HBV, HCV, 
CMV, HIV )
x
HBV DNA monitoring, if 
applicable14
x
x
Safety laboratory tests -
Chemistry and Urine15
x
x
x
x
x
x
x
x
CBC with Differentials15
x
x
x
x
x
x
x
x
x
x
x
CMV monitoring16
x
x
x
x
Pregnancy test if applicable17
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
Concomitant therapies
x
x
x
x
x
x
x
x
x
x
x
x


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Trial periods1
Screening 
Run -In2
Cycle 1
Cycle 2-121
Response Evaluation at 
the End of Cycle 3, 6, 9 
and 12
EOT3
End of 
Residual Effect 
Period Visit 
(EoR)4
FU for PD and 
Eof FU Visit5
End of Trial 
Status6
Day of Cycle1
(-35 to -15)
(-14 to -1)
1
2
8
15
20 ±320
1
15 
21-28
TRIAL MEDICATIONS7
BI 836826 administration
pre-dose         
10 mg
x (50%)7
x (50%) 
x
x
x
BACKBONE MEDICATION19
Ibrutinib administration
Dosing instructions as per the package insert
FULL DISEASE ASSESSMENTS8, 26
Physical Exam
x
x
MRD234(blood)
x
x
x
x


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Trial periods1
Screening 
Run -In2
Cycle 1
Cycle 2-121
Response Evaluation at 
the End of Cycle 3, 6, 9 
and 12
EOT3
End of 
Residual Effect 
Period Visit 
(EoR)4
FU for PD and 
Eof FU Visit5
End of Trial 
Status6
Day of Cycle1
(-35 to -15)
(-14 to -1)
1
2
8
15
20 ±320
1
15 
21-28
Bone marrow examination 
(sample for MRD included in all 
BM obtained during the trial)
x
x
Cross sectional imaging24 (CT
scan) Chest-Abdomen-Pelvis
x
x
x
x
Survival Status (including disease 
progression, response)
x
Next line of therapy for CLL
x
1The planned duration of a treatment cycle is 28 days (4 weeks).  Day 1 of a new cycle should take place on "Day 29" (see Section 6.0).  Visit windows of -2/+14 days for Cycles 2-4 and -2/+14 days for Cycle 5 through Cycle 12 are permitted, unless otherwise 
specified.  Beginning with Cycle 5, BI 836826 Infusions will be administered monthly on Day 1 of each cycle. Day 15 visits are not required. All assessments should be performed prior to the dose administration of BI 836826 on dosing days, unless otherwise 
specified.
2Run-In Phase:  Begins with first dosing of ibrutinib.  Duration of phase is two weeks (+/- 2 days).  Disease assessments (peripheral blood evaluation and clinical evaluation) to be performed close to Day 1 of Cycle 1. Assessments can also be performed on Day 1 
prior to start of 10 mg BI 836826 pre-dose. 
3EOT visit: When the decision is taken to permanently discontinue the study medication. The EOT visit should be performed as soon as possible, but before a new CLL treatment is started. Assessments do not need to be repeated if the EOT is done within 14 days 
after a response assessment visit. For patients who complete Cycle 12 and terminate BI 836826 in the absence of PD, the assessments specified for EoT and EoR can be also combined at the time of EoR
4End of Residual Effect Period (EoR) Visit is to be completed 30 days after the EOT (+ 7 days).  Information collected at this visit should include all new AEs and ConMeds that occurred since the EOT and follow-up of AEs ongoing at the time of the EOT. In case 
the patient completes Cycle 12 and terminates treatment with BI 836826 according to protocol in the absence of PD, the assessments indicated for the EOT and EoR visit in the flowchart may be performed once, at the time specified for the EoR visit
5 Follow-up visits will no longer be required after approval of CTP Amendment 1.Follow-up for patients who terminate for any other reason at any time other than PD: Full response assessment at EOT or EoR; 
6There will be an additional contact with regard to the End of Trial status as soon as the end of the whole trial is reached (see Section 8.6).  Contact can be either a clinic visit or phone call.  Visits will include vital status and anti-cancer treatment for CLL at the 
time of contact.
7Patients are ONLY required to be hospitalized overnight after the first 50% infusion of BI 836826 on Cycle 1 Day 2 if patient is at risk of TLS requiring monitoring and/or prophylactic treatments. 
8Disease Assessment: Should be performed as close to the start date (within 7 days) of Ibrutinib during screening.  Historical CT scans (up to 30 days prior to start of run-in phase) may be used at screening, if no other anti-CLL therapy (ies) have been given.
Minimum of  7 days after BI 836826 administration (preferably between D 21 and D28 of Cycle 2 and 4 ); Subsequent 12 week Disease  Assessments:  >=21 days after BI 836826 administration and prior to start of next cycle (preferably between D21 and D28).   
Assessments to be performed every 12 weeks or 3 cycles from Cycle 1 Day 1 (C3, C6, C9, C12).
9Review of key laboratory  values outlines in Section 4.1.4 prior to first pre-dose administration of BI 836826
10After Informed Consent is obtained and  review of inclusion/exclusion
11In Cycle 1, done at Day 1, before start of BI 836826 infusion; Every 8 weeks during the treatment period, i.e. every other cycle (Cycle 2, 4, etc.) and EOT.  PE to include weight. Height to be recorded at screening only.
12Vital signs (blood pressure, pulse rate and body temperature) will be recorded at every visit during screening, and treatment , before proceeding with any other protocol specific procedure and after at least 5 minutes of rest (See Section 5.3.2 and Section 6.1 for 
assessments)
13Single, resting 12 lead ECG to be performed at Screening, Day 1 of every Cycle and EOT, or whenever deemed necessary by the investigator (See Section 5.3.4).


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14HBV DNA monitoring is only applicable to patients who are HBc antibody positive at screening (see Section 5.3.3.4.1). Patients who are HBc antibody positive at screening will be monitored for potential HBV reactivation by quantitative HBV DNA at visit 1 of 
every even course (Cycle 2, 4, 6, etc.…) and at the EOT.
15Safety lab tests (blood and urine) do not have to be repeated if previous tests are within 48 hours of visit. Safety lab tests will include screening for tumor lysis syndrome. An additional safety lab should be performed on Day 1 of Cycle 1, 1 to 3 hours after the end 
of infusion to check for tumor lysis syndrome.  Additional safety labs may be performed as deemed necessary by the investigator. If neutropenia CTCAE Grade 3 or 4 is observed for more than 7 days, repeat until return to a Grade 2 or lower in order to capture the 
duration of severe neutropenia (see Section 5.3.3). Coagulation tests have only to be performed at screening, at every other cycle and at EOT visit.
16Quantitative CMV DNA PCR or pp65 antigen to be performed every other cycle (see Section 5.3.3.4.2). 
17Urine Pregnancy test is mandatory for all female patients of childbearing potential.  Test must be performed within 7 days prior to first treatment on C1 Day 1, at CxV1of every other cycle (i.e. Cycle 3, 5, etc.) and at EOT. However, in the first cycle, the test will 
be performed on C1D1. To ensure early detection of pregnancy, test might be repeated as necessary during the treatment period. (See Section 5.3.3.1)
18For AE/SAE assessment during FU, refer to  Sections 5.3.7 and 6.2.3
19. Ibrutinib will be administered according to the package insert for CLL indication. Eligible patients must secure sourcing and be on stable ibrutinib dosing for 2 weeks (+/- 2 days)  prior to planned first BI dose (Cycle 1 Day 1). Patients are to be provided a
dosing diary (Run-In and Cycle 1 through Cycle 2 only) and instruct patients not to take ibrutinib dose at home on Day 1 of each Cycle during PK sample collection period and to bring their medicine to clinic for dosing.   Diaries are to be reviewed by site staff to 
confirm compliance.  Daily dosing of ibrutinib can continue as per the label and at the discretion of the investigator or physician.
 
 
 
23MRD in peripheral blood is to be performed at screening, prior to C1D1, at the end of Cycles 3,6, 9, 12, and at EOT. A bone marrow aspirate and biopsy, including MRD evaluation according to IWCLL guidelines is mandatory in patients who meet the criteria 
for CR based on physical examination, complete blood count (two consecutive CBCs matching the criteria for CR), and imaging (see Section 5.2.6).
24At screening, at the end of Cycle 3 (within Day 21 and 28); every 12 weeks if clinically indicated; in case of CR and within 21-28 days after the 12th cycle infusion with BI 836826.   If a patient is in CR, CRi or PR (MRD negative) after a disease assessment, 
he/she may continue with the study treatment for up to a maximum of 24 cycles. 
25 Collection of End of Treatment samples will not be required after approval of CTP Amendment 1.
26Findings on physical examination with potential impact on response assessment should be confirmed by imaging. 
27Sample collection will no longer be required after approval of CTP Amendment 1.


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FLOW CHART – CYCLE 13 THROUGH CYCLE 24
Trial periods1
Day 1 
Cycles 13- 241
Response Evaluation at 
the End of Cycle 16, 20 
and 24
EOT2
End of Residual Effect 
Period Visit (EoR)3
FU for PD and EofFU 
Visit4
End of Trial Status5
Day of Cycle1
1
21-28
Physical examination (Including weight)7
x
x
Vital signs 
x
x
ECOG Performance score
x
x
12 lead-ECG8
x
x
HBV DNA monitoring, if applicable9
x
x
Safety laboratory tests - Chemistry and , Urine10
x
x
CBC with Differentials10
x
x
x
CMV monitoring11
x
x
Pregnancy test if applicable12
x
x
Adverse events
x
x
x
x
Concomitant therapies
x
x
x
x
OTHER ASSESSMENTS
TRIAL MEDICATIONS


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Trial periods1
Day 1 
Cycles 13- 241
Response Evaluation at 
the End of Cycle 16, 20 
and 24
EOT2
End of Residual Effect 
Period Visit (EoR)3
FU for PD and EofFU 
Visit4
End of Trial Status5
Day of Cycle1
1
21-28
BI 836826 administration
x
BACKBONE MEDICATION6
Ibrutinib administration
Dosing instructions as per the package insert
FULL DISEASE ASSESSMENTS,17,21
Physical Exam21
x
MRD18(blood)
x
Cross sectional imaging19 (CT scan) Chest-Abdomen-Pelvis
x
x
x
Survival Status (including disease progression, response)
x
Next line of therapy for CLL
x
1The planned duration of a treatment cycle is 28 days (4 weeks).  Day 1 of a new cycle should take place on "Day 29" (see Section 6).  Visit windows of –2/+14 days for Cycles 
13-24 are permitted, unless otherwise specified.  All assessments should be performed prior to the dose administration of BI 836826 on dosing days, unless otherwise specified.
2EOT visit – When the decision is taken to permanently discontinue the study medication for PD. The EOT visit should be performed as soon as possible, but before a new CLL 
treatment is started. Assessments do not need to be repeated if the EOT is done within 14 days after a response assessment visit. For patients who complete Cycle 24 and 
terminate BI 836826 in the absence of PD, the assessments specified for EoT and EoR can be also combined at the time of EoR.  
3End of Residual Effect Period (EoR) Visit is to be completed 30 days after the EOT (+ 7 days).  Information collected at this visit should include all new AEs and ConMeds that 
occurred since the EOT and follow-up of AEs ongoing at the time of the EOT. In case the patient completes Cycle 24 and terminates treatment with BI 836826 according to 
protocol in the absence of PD, the assessments indicated for the EOT and EoR visit in the flowchart may be performed once, at the time specified for the EoR visit  
5There will be an additional contact with regard to the End of Trial status as soon as the end of the whole trial is reached (see Section 8.6).  Contact can be either a clinic visit or 
phone call.  Visits will include vital status and anti-cancer treatment for CLL at the time of contact.
6Ibrutinib will be administered according to the package insert for CLL indication. Patients must continue to secure sourcing of ibrutinib For patients with CR, CRi or PR (MRD 
negative) at each of the disease assessments, may continue with monthly infusions of BI 836826, until progression, undue toxicity or to the maximum of 24 cycles.  Daily dosing 
of ibrutinib can continue as per the label and at the discretion of the investigator or physician.
7PE to be performed on Day 1 of every Cycle, before start of BI 836826 infusion and at EOT
8Single, resting 12 lead ECG to be performed on Day 1 of every Cycle and EOT, or whenever deemed necessary by the investigator (See Section 5.3.4).
9HBV DNA monitoring is only applicable to patients who are HBc antibody positive at screening (see Section 5.3.3.4.1). Patients who are HBc antibody positive at screening 
will be monitored for potential HBV reactivation by quantitative HBV DNA at visit 1 of every even course  (Cycle  14, 16, 18, etc…) and at the EOT
10Safety lab tests (blood and urine) do not have to be repeated if previous tests are within 48 hours of visit.  Additional safety labs may be performed as deemed necessary by the 
investigator. If neutropenia CTCAE Grade 3 or 4 is observed for more than 7 days, repeat until return to a Grade 2 or lower in order to capture the duration of severe neutropenia 
(see Section 5.3.3). Coagulation tests have only to be performed at every other cycle and at EOT visit.
11Quantitative CMV DNA PCR or pp65 antigen to be performed every other cycle, starting with Cycle 13 (see Section 5.3.3.4.2). 
12Urine Pregnancy test is mandatory for all female patients of childbearing potential.  Test must be performed within 7 days prior to first treatment on C1 Day 1, at CxV1of every 
other cycle starting with Cycle 13 (i.e. Cycle 15, 17, etc..) and at EOT. To ensure early detection of pregnancy, test might be repeated as necessary during the treatment period.
(See Section 5.3.3.1)


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13 Follow-up visits and accompanying assessments will no longer be required after approval of CTP Amendment 1
14 Follow-up visits will no longer be required after approval of CTP Amendment 1
 
17Disease assessment has to be performed prior to starting treatment at Day 1, >=21 days after BI 836826 administration and prior to start of next cycle (preferably between D21 
and D28); Every 4 Cycles.  
18MRD in peripheral blood is to be performed at the end of Cycles 16, 20, 24 and at EOT. A bone marrow aspirate and biopsy, including MRD evaluation according to IWCLL 
guidelines is mandatory in patients who meet the criteria for CR based on physical examination, complete blood count (two consecutive CBCs matching the criteria for CR), and 
imaging (see Section 5.2.6).
19Every 16 weeks if clinically indicated; If a patient is in CR after a disease assessment, he/she may continue with the study treatment for up to the maximum of 24 cycles. A CT 
should be performed whenever a CR is suspected for the first time, if none was performed in the previous last 4 weeks and at EOT if none was performed in the previous last 4 
weeks
20 Sample collection will no longer be required after approval of CTP Amendment 1
21Findings on physical examination with potential impact on response assessment should be confirmed by imaging. 
22 Follow-up visits  and accompanying assessments will no longer be required after approval of CTP Amendment 1


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART – SCREENING THROUGH CYCLE 12 ..................................................5
FLOW CHART – CYCLE 13 THROUGH CYCLE 24.......................................................9
TABLE OF CONTENTS ......................................................................................................12
ABBREVIATIONS................................................................................................................16
1.
INTRODUCTION................................................................................................20
MEDICAL BACKGROUND..............................................................................20
1.1
DRUG PROFILE.................................................................................................21
1.2
1.2.1
BI 836826 ..............................................................................................................21
1.2.2
Ibrutinib (Imbruvica®).......................................................................................24
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT ......26
RATIONALE FOR PERFORMING THE TRIAL..........................................26
2.1
TRIAL OBJECTIVES.........................................................................................27
2.2
BENEFIT - RISK ASSESSMENT .....................................................................27
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION..........................29
OVERALL TRIAL DESIGN AND PLAN ........................................................29
3.1
3.1.1
Administrative structure of the trial..................................................................31
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S).......................................................................................31
SELECTION OF TRIAL POPULATION ........................................................32
3.3
3.3.1
Main diagnosis for trial entry.............................................................................32
3.3.2
Inclusion criteria..................................................................................................32
3.3.3
Exclusion criteria .................................................................................................34
3.3.4
Removal of patients from therapy or assessments............................................36
3.3.4.1
Removal of individual patients..............................................................................36
3.3.4.2
Discontinuation of the trial by the sponsor............................................................37
3.3.4.3
Trial stopping rules in case of unacceptable toxicities ..........................................37
4.
TREATMENTS....................................................................................................38
TREATMENTS TO BE ADMINISTERED......................................................38
4.1
4.1.1
Identity of BI Investigational Product(s), Combination Backbone 
Product(s)..............................................................................................................38
4.1.2
Method of assigning patients to treatment groups ...........................................39
4.1.3
Selection of doses in the trial...............................................................................39
4.1.4
Drug assignment and administration of doses for each patient ......................40
4.1.4.1
BI 836826 infusion rates........................................................................................43
4.1.4.2
Management of infusion related reactions.............................................................44
4.1.4.3
Ibrutinib dosing......................................................................................................46


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4.1.4.4
Criteria for administration of BI 836826 at 100% of the assigned dose 
(Cycle 1 Day 15 and Following)............................................................................47
4.1.4.5
Recommendations for dose modification in response to AEs ...............................47
4.1.5
Blinding and procedures for unblinding ...........................................................49
4.1.5.1
Blinding..................................................................................................................49
4.1.5.2
Unblinding and breaking the code.........................................................................50
4.1.6
Packaging, labelling, and re-supply ...................................................................50
4.1.7
Storage conditions................................................................................................50
4.1.8
Drug accountability .............................................................................................50
4.1.8.1
Ibrutinib sourcing and accountability ....................................................................51
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT......................................................................................................51
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) ......51
4.2.1.1 
Rescue medication .................................................................................................51
4.2.1.2 
Concomitant medication........................................................................................51
4.2.1.2.1
Pre-Medication prior to BI 836826 infusion..........................................................52
4.2.1.2.2
Tumor Lysis Syndrome (TLS) prophylaxis and monitoring .................................54
4.2.1.2.3
Antibiotics and antivirals.......................................................................................54
4.2.1.2.4
Growth factors .......................................................................................................55
4.2.2
Restrictions...........................................................................................................55
4.2.2.1
Restrictions regarding concomitant treatment .......................................................55
4.2.2.2
Restrictions on diet and lifestyle............................................................................56
4.2.2.3
Restrictions regarding women of childbearing potential.......................................56
5.
VARIABLES AND THEIR ASSESSMENT .....................................................57
TRIAL ENDPOINTS...........................................................................................57
5.1
5.1.1
Primary endpoint(s).............................................................................................57
5.1.2
Secondary endpoint(s) .........................................................................................57
ASSESSMENT OF EFFICACY.........................................................................58
5.2
5.2.1
Overall response assessment...............................................................................58
5.2.2
CBC and differential............................................................................................59
5.2.3
Bone marrow aspirate and biopsy......................................................................59
5.2.4
Physical examination ...........................................................................................59
5.2.5
Constitutional symptoms.....................................................................................60
5.2.6
Minimal Residual Disease (MRD)......................................................................60
ASSESSMENT OF SAFETY..............................................................................61
5.3
5.3.1
Physical examination ...........................................................................................61
5.3.2
Vital signs..............................................................................................................61
5.3.3
Safety laboratory parameters.............................................................................61
5.3.3.1
General safety laboratory parameters ....................................................................61
5.3.3.2
Serum immunoglobulin levels..............................................................................62
5.3.3.3
Screening for laboratory evidence of Tumor Lysis Syndrome..............................62
5.3.3.4
Virology.................................................................................................................63
5.3.3.4.1
Screening for hepatitis B, hepatitis C and HIV......................................................63
5.3.3.4.2
CMV monitoring....................................................................................................63
5.3.4
Electrocardiogram...............................................................................................63


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5.3.5
Other safety parameters......................................................................................64
5.3.6
Assessment of adverse events..............................................................................64
5.3.6.1
Definitions of AEs .................................................................................................64
5.3.6.2
Dose limiting toxicities..........................................................................................67
5.3.7
Adverse event collection and reporting..............................................................67
OTHER ASSESSMENTS ...................................................................................72
5.6
APPROPRIATENESS OF MEASUREMENTS...............................................73
5.7
6.
INVESTIGATIONAL PLAN .............................................................................74
VISIT SCHEDULE..............................................................................................74
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ..................75
6.2
6.2.1
Screening and run-in period(s)...........................................................................75
6.2.2
Treatment period(s).............................................................................................76
6.2.2.1
End of treatment visit.............................................................................................77
6.2.3
Residual Effect Period (REP) and trial completion..........................................77
6.2.3.1
Residual Effect Period (REP) ................................................................................77
6.2.3.2
Trial completion for an individual patient:............................................................77
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE ......................................................................................................................79
STATISTICAL DESIGN – MODEL .................................................................79
7.1
NULL AND ALTERNATIVE HYPOTHESES ................................................83
7.2
PLANNED ANALYSES......................................................................................83
7.3
7.3.1
Primary endpoint analyses..................................................................................83
7.3.2
Secondary endpoint analyses ..............................................................................84
7.3.4
Safety analyses......................................................................................................84


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INTERIM ANALYSES .......................................................................................85
7.4
HANDLING OF MISSING DATA ....................................................................85
7.5
RANDOMIZATION............................................................................................85
7.6
DETERMINATION OF SAMPLE SIZE..........................................................85
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS.........86
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ............................................................................................................86
DATA QUALITY ASSURANCE.......................................................................87
8.2
RECORDS............................................................................................................87
8.3
8.3.1
Source documents ................................................................................................87
8.3.2
Direct access to source data and documents......................................................87
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
8.4
EVENTS................................................................................................................88
8.4.1
Listedness..............................................................................................................88
8.4.2
Expedited reporting of adverse events...............................................................88
STATEMENT OF CONFIDENTIALITY.........................................................88
8.5
END OF TRIAL...................................................................................................88
8.6
9.
REFERENCES.....................................................................................................89
PUBLISHED REFERENCES ............................................................................89
9.1
UNPUBLISHED REFERENCES.......................................................................93
9.2
10.
APPENDICES......................................................................................................94
RAI CLASSIFICATION.....................................................................................94
10.1
CRITERIA FOR RESPONSE DETERMINATION........................................94
10.2
 
PUBLICATIONS...............................................................................................101
10.5
CALCULATION OF GLOMERULAR FILTRATION RATE....................102
10.6
STATISTICAL APPENDIX INCLUDING MODEL 
10.7
PERFORMANCE AND DATA SCENARIOS................................................103
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)........................................109


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ABBREVIATIONS
ADA
ADCC
Antidrug Antibodies
Antibody-Dependent Cellular Cytotoxicity
AE
Adverse Event
AESI
ALC
ALT
anti-HBs
anti-HBcanti-
HIV
anti-HCV
AP
aPTT
AST
Adverse Event of Special Interest
Absolute Lymphocyte Counts
Alanine Aminotransferase
Hepatitis B Surface Antibody
Hepatitis B Core Antibody
HIV Antibody
Hepatitis C Antibody
Alkaline Phosphatase
Activated Partial Thromboplastin Time
Aspartate Aminotransferase
AUC
Area under the Curve
BCR
BIRDS
BLRM
BLQ
BM
B-NHL
BOR
BORBTK
BUN
B-cell Antigen Receptor
Boehringer Ingelheim Regulatory Documents for Submission
Bayesian Logistic Regression Model
Below the Limit of Qualification
Bone Marrow
B-cell Non-Hodgkin’s Lymphoma
Best Overall Response
Bruton’s Tyrosine Kinase (inhibitor)
Blood Urea Nitrogen
C1D1
CA
CBC
Cycle 1 Day 1
Competent Authority
Complete Blood Count
CICL
CL
CLL
Coordinating Investigator
Clearance
Chronic Lymphocytic Leukaemia
CML
CMV
CR
CRi
Local Clinical Monitor 
Cytomegalovirus
Complete Response
Complete Response with incomplete Marrow Recovery
CRA
Clinical Research Associate
CRF
CRO
Case Report Form
Contract Research Organization
CT
CTCAE
Computerized Tomography
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
DCR
DDI
DEDP
DILI
Clinical Trial Report
Duration of Complete Response
Drug-Drug Interaction
Drug Exposure During Pregnancy
Drug Induced Liver Injury


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DLT
DNA
DOR
ECOG
ECG
Dose Limiting Toxicity
Deoxyribonucleic Acid
Duration of Overall Response
Eastern Cooperative Oncology Group
Electrocardiogram
eCRF
EDTA
Electronic Case Report Form
Ethylenediaminetetraacetic Acid
ELISA
EoFU
EOT
EoR
ERIC
EU
EudraCT
EWOC
Enzyme-Linked Immuno Assay
End of Follow-Up
End of Treatment
End of REP
European Research Initiative on CLL
European Union
European Clinical Trials Database
Escalation With Overdose Control
FCGR
FISH
GCP
G-CSF
GFR
HBsAG
HBV
HCV
HIV
G Fragment C Receptors
Fluorescence In-Situ Hybridisation
Good Clinical Practice
Granulocyte Colony Stimulating Factor
Glomerular Filtration Rate
Hepatitis B Surface Antigen
Hepatitis B Virus
Hepatitis C Virus
Human Immunodeficiency Virus
IB
ICF
ICH
Investigator’s Brochure
Informed Consent Form
International Conference on Harmonisation
IEC
IgA
IgG
IgM
IGHV
Independent Ethics Committee
Immunoglobulin A
Immunoglobulin G
Immunoglobulin M
Immunoglobulin Heavy Chain Variable
INR
IRB
International Normalized Ratio
Institutional Review Board
IRC
IRR
Independent  Review Committee
Infusion-Related Reactions
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
IVRS
IWCLL
Interactive Voice Response System
International Workshop Chronic Lymphocytic Leukemia
IWRS
LCCD
LCMS
LD
LDH
Interactive Web-based Response System
Longest Cranio-caudal Diameter
Liquid Chromatography Tandem Mass Spectrometry Assay
Largest Diameter
Lactate Dehydrogenase


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LDT
LLN
LUC
Lymphocyte Doubling Time
Lower Limit of Normal
Large Unstained Cells
Mab
MedDRA
MRD
MRI
MRT
MS
MTD
NCICTC
NE
NHL
NIMP
NK
NOA
NOR
NOS
Monoclonal Antibody
Medical Dictionary for Drug Regulatory Activities
Minimal Residual Disease
Magnetic Resonance Imaging
Mean Residence Time
Mass Spectrometry
Maximum Tolerated Dose
National Cancer Institute – Common Terminology Criteria
Non Evaluable
Non-Hodgkin’s Lymphoma
Non-investigational Product
Natural Killer
Not Analysed
No Valid Result
No Sample Available
OR
ORR
OS
Overall Response
Overall Response Rate
Overall Survival
PC
PCR
PD
PFS
PGx
PK
PLD
PLT
Patient Completion
Polymerase Chain Reaction
Progressive Disease; Pharmacodynamics
Progression Free Survival
Pharmacogenetics
Pharmacokinetics
Perpendicular Diameter
Platelets
p.o.
per os (oral)
PR
PR-L
PT
RBC
RDC
Partial Response
Partial Response w/ Lymphocytosis
Prothrombin Time
Red Blood Cell Count
Remote Data Capture
REP
RP2D
RNA
Residual Effect Period
Recommended Phase 2 Dose
Ribonucleic Acid
SAE
SCT
Serious Adverse Event
Stem Cell Transplant
SD
Stable Disease
SLL
SLP
SOP
SRC
SUSAR
Small Lymphocytic Lymphoma
Single Lesion Product
Standard Operating Procedures
Safety Review Committee
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor


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TCR
TNF
TTF
TLS
Time to Complete Response
Tumor Necrosis Factor Alpha
Time to Treatment Failure
Tumor Lysis Syndrome
TSAP
ULN
USPI
Vdss/F
WBC
Trial Statistical Analysis Plan
Upper Limit of Normal
United States Product Insert
Distribution at Steady State
White Blood Cell Count


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1.
INTRODUCTION
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in western 
countries and accounts for approximately one third of all leukemias in these regions, 
with an estimated annual age-adjusted incidence of 3–5 per 100 000 people. The 
disease is diagnosed most commonly in the elderly, with the median age at diagnosis of 
72 years [P14-17458], Typically CLL affects more frequently males than females
(ratio: 1.7:1) R14-3818]. The incidence rate rises with age, and almost 70% of patients 
are older than 65 years [P14-17458] at the time of diagnosis. It is expected that with 
aging population the prevalence and mortality of CLL are likely to increase in the years 
to come. 
MEDICAL BACKGROUND
1.1
The absence of curative treatments (with the exception of allogeneic stem cell 
transplantation) has led to “wait and watch” approach for initially diagnosed and 
asymptomatic patients. Once the need for treatment arises the combination of anti 
CD20 antibody with chemotherapy (called chemo-immunotherapy) is considered a 
standard treatment in the first line [R14-3280] [R14-2573].   
However, many patients will relapse within first few years after initial treatment. 
Especially, the relapse is imminent within <2 years in patients who harbor high risk 
disease as defined by deletion on chromosome 17 (del17p), or carrying mutations in 
TP53, NOTCH1, or SF3B1 [R15-0126]. Recently, two kinase inhibitors targeting B-
cell receptor signaling pathways have gained FDA approval in the US for treatment of 
patients with relapsed CLL: Idelalisib (PI3Kδ inhibitor) which is indicated in 
combination with Rituximab for patients for whom rituximab alone would be 
considered appropriate due to other co-morbidities, and ibrutinib (BTK inhibitor) which 
is indicated for CLL patients who have received at least one prior therapy. Both drugs 
are very effective with an Overall Response Rate (ORR) of 39% and 42.6% 
respectively; median Progression Free Survival (PFS) was not reached in both 
registration studies, but at 6 months PFS was 88% for patients on ibrutinib. Moreover, 
the responses are achieved irrespective of the presence of the classic high risk disease 
markers, (e.g. del17p or TP53 mutation). Interestingly, patients treated with ibrutinib or 
idelalisib frequently experience rapid improvement of CLL related symptoms, e.g. 
decrease in lymphadenopathy. This is typically accompanied by an increase in 
peripheral Absolute Lymphocyte Counts (ALC). This transient lymphocytosis is now 
viewed as a class effect of kinase inhibitors targeting the B cell receptor signaling 
pathway [R15-0125], and is not considered a sign of progression of disease. Despite 
durable disease control, most responses on those inhibitors are PR, and it is conceivable 
that the persistence of residual disease will eventually lead to progression or 
transformation. This concern, together with recently described acquired mutations in 
Bruton’s Tyrosine Kinase (BTK) and phospholipase C gamma gene (PLC2γ) [R15-
0127], [R15-0124], in CLL patients progressing on ibrutinib, demonstrate the first 
examples that resistance to ibrutinib has to be expected. Combining ibrutinib with other 
agents (chemotherapy, or monoclonal antibodies (Mab)) might therefore offer 
advantages over monotherapy by increasing the depth of response, and potentially 


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reducing the treatment duration. The first results of such combinations have proven 
safe, but available limited data although encouraging, are still inconclusive in regard to 
added benefit [R15-0151], [R15-0130].  The search for the best partner for such 
combinations still continues. This study will evaluate BI 836826, a novel CD37 
antibody engineered for enhanced antibody-dependent cellular cytotoxicity (ADCC) 
activity in combination with ibrutinib. Besides safety of the combination, this Phase 
Ib/study will evaluate early signals of response, and the depth of response in 
relapsed/refractory CLL patients who have failed at least one prior line of systemic 
therapy.
DRUG PROFILE
1.2
1.2.1
BI 836826
General information:
BI 836826 is a mouse human chimeric Mab against human CD37. BI 836826 has a 
cytotoxic mode of action by directly inducing apoptosis upon binding to the target cell 
independent of Immunoglobulin G (IgG) cross-linking. In addition, BI 836826 harbors 
a mutation in the Fc portion of the molecule which conveys increased ADCC. BI 
836826 is an investigational compound currently in clinical development in mature B-
cell neoplasms, including CLL.
CD37 Antigen:
CD37, a member of the tetraspanin superfamily, is a glycosylated cell surface protein 
with four transmembrane domains and two extracellular loops. CD37 is predominantly 
expressed on B cells with highest expression levels on mature peripheral blood B cells 
and reduced levels on plasma cells (R08-2979, R08-2943). Low level expression of 
CD37 has been reported for monocytes, T cells, macrophages, and granulocytes 
(R08-2979, R09-4740, and R09-4739). The physiological function of CD37 in humans 
remains largely 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 
Immunoglobulin A (IgA) response (R09-4740, R09-5414). The majority of malignant 
cells in patients with B-cell Non-Hodgkin’s Lymphoma (B-NHL) and CLL express the 
CD37 antigen (R08-2979, R08-2943, R08-2981, R08-2945, R08-2942).  Recent data 
provide evidence that CD37 can function as a death receptor on B cells, which can 
mediate dual signal transduction through its N- and C-terminal intracellular domain 
(R12-2850).
Preclinical pharmacology and toxicology:
In vitro assays demonstrated that BI 836826 specifically recognizes human CD37 and 
binds with high affinity to this antigen. BI 836826 is a potent inducer of apoptosis and 
ADCC on Ramos Burkitt lymphoma in vitro, but lacks CDC activity. The pro-apoptotic 
activity of BI 836826 does not depend on IgG cross-linking. Moreover, BI 836826 is 
able to deplete endogenous, normal B cells, spiked Ramos Burkitt lymphoma cells and 
CLL cells from human blood without affecting endogenous T cells and monocytes 
[R10-6346], [R11-4834], [R11-4833]. 


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The combination of BI 836826 with chemotherapeutics (bendamustine, chlorambucil, 
fludarabine) or with the CD20 antibody rituximab results in additive or synergistic 
apoptosis induction on lymphoma cell lines and primary CLL cells [R12-4648].
Due to the lack of cross-reactivity of BI 836826 with CD37 in any preclinical species 
tested, the preclinical safety of BI 836826 was investigated in two toxicologically 
relevant models: 1) Transgenic mouse model, in which the human CD37 protein instead 
of the murine CD37 protein is expressed (HuCD37 transgenic mice) and 2) 
Cynomolgus monkeys, in which an anti-macaque CD37 surrogate antibody (BI 
836847) was used. 
The majority of effects observed in the general toxicity studies with BI 836826 in 
HuCD37 mice and with the surrogate BI 836847 (an anti-macaque CD37 surrogate 
antibody) in cynomolgus monkeys were directly related or secondary to the 
pharmacological activity of BI 836826 and BI 836847. The main target organs 
following repeat intravenous (i.v.) exposure to BI 836826 in HuCD37 mice and to the 
surrogate BI 836847 (an anti-macaque CD37 surrogate antibody) in cynomolgus 
monkeys were the blood and lymphoid system. BI 836826 induced B- but also T-cell 
reduction in HuCD37 mice in peripheral blood and lymphoid organs at all dose levels 
with the histopathological correlate of lymphoid depletion in B-cell areas in spleen and 
lymph nodes. In contrast, the surrogate BI 836847 induced reduction of lymphocytes, 
predominantly B cells and NK cells at low to moderate doses. T cells, granulocytes and 
Platelets (PLT) were reduced at higher doses. Severe and sustained immunosuppression 
in monkeys treated with high doses led to several cases of septicaemia. Furthermore, 
anti-drug antibodies were documented in both animal models. They were of 
neutralizing nature allowing recovery of the pharmacodynamic effects in mice within 
the 5-week study duration and resulted in an immune-complex mediated 
glomerulopathy and uveitis in monkeys. However, anti-drug antibodies in the 
transgenic mouse and the cynomolgus monkey are not considered to be predictive for 
the immunogenic effect in humans. Cytokine release studies demonstrated a transient 
and dose dependent increase in interleukin 6 and interleukin 8 in monkeys and of IL-6 
and TNFα in the in vitro study using the human blood solid phase assay.
Clinical trials in CLL:
Preliminary data from the ongoing Phase 1, first in human, dose escalation trial 1270.1 
in patients with CLL are available. As of June 2015, 36 patients were exposed to BI 
836826, administered intravenously at escalating doses in a 2 week schedule. The 
median age of patients was 68 years (range: 44-80 years). BI 836826 was administered 
at the following dose tiers (n) 1 mg (3), 3 mg (3), 9 mg (6), 25 mg (6), 50 mg (3), 100 
mg (3), 200 mg (6), 400 mg (3) and 800 mg (3). The initial treatment schedule 
employed at dose tiers of 1 mg, 3 mg and 9 mg contained one i.v. infusion of 
BI 836826 at a fixed rate over 3 hours on day 1 of a 14-day treatment course. Due to 
occurrence of infusion related reactions of maximum Grade 2 the infusion schedule was 
amended to increase tolerability. The amendment included a slow increase of the 
infusion rate and division of the first dose into two portions delivered on two 
consecutive treatment days (Day 1 and 2 of course 1) to mitigate the risk for severe 


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Infusion-Related Reactions (IRRs). This schedule was applied to 3 additional patients at 
9 mg, and all patients treated at dose tiers of 25 mg and above. During the dose 
escalation all patients were scheduled to receive 4 treatment courses, and upon clinical 
benefit were allowed to proceed to 8 treatment courses. Those with sustained clinical 
benefit were offered prolonged therapy. Eighteen of 36 patients have initiated 8 or more 
treatment courses.
Infusion-related reaction (IRR) was the most frequent AE, reported in 25 patients 
(69%). With mandatory premedication and an infusion schedule using a split of the first 
dose over two consecutive treatment days and a slowly increasing infusion rate the 
IRRs reported have been manageable at all dose tiers. The majority of IRRs was grade 
1 or 2; only 3 patients experienced a grade 3 reaction.
Decrease in leukocytes, neutrophils, thrombocytes and haemoglobin have frequently 
been reported in patients. Drug related neutropenia was reported in 42% (15/36) of the 
patients, with a worst Common Terminology Criteria for Adverse Events (CTCAE) 
grade 3 or 4 in 14/36 patients (39%). Drug related thrombocytopenia was reported in 
31% (11/36), with a worst CTCAE grade of 3 or 4 in 8 patients (22%). Corresponding 
laboratory data showed that neutrophils and thrombocytes declined immediately after 
the infusion, with recovery by day 8 in the majority of patients. Anemia was considered 
drug related in 28% of the patients and highest grade was CTCAE grade 3. A drug 
related increase of Alanine Aminotransferase (ALT) was reported in 4 patients (11%), 
of Aspartate Aminotransferase (AST) in 5 patients (14%). ALT and AST elevations 
were grade 1 and 2 in all patients except for one patient with a grade 3 ALT elevation. 
The corresponding laboratory data in these patients showed short lasting, reversible 
elevations of AST and/or ALT without concomitant bilirubin elevation. Prior to the 
next administration of BI 836826, ALT and AST had returned spontaneously to normal 
or pre-treatment values.
Efficacy was observed at doses ≥9 mg. The ORR was 40% (12/30 patients), all
responses were PRs. In addition, the decline in ALC was analyzed to assess effect of 
BI 836826 on CLL tumor load in 25 patients treated at doses ≥9 mg, who had an 
elevated ALC at baseline and received at least one full dose of BI 836826 at the 
respective dose tier. A decline in ALC by 50% or more as compared to baseline was 
observed in 80% (20/25 patients) and a reduction to < 4 x 109/L in 56% (14/25 
patients).
The preliminary Pharmacokinetics (PK) data from a Phase I study 1270.1 concludes to 
an increase of Area Under the Curve (AUC) with dose and a Clearance (CL) decrease 
with dose suggesting target mediated drug disposition. No accumulation after repeated 
dosing was observed. Moreover, a quick elimination of BI 836826 from blood was also 
observed.
For a more detailed description of the drug profile, including data on an ongoing trial in 
Non-Hodgkin’s lymphoma, please refer to the current Investigator’s Brochure 
(c01715907-08) which is included in the Investigator Site File (ISF).


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1.2.2
Ibrutinib (Imbruvica®)
Ibrutinib (Imbruvica) is a small molecule inhibitor of BTK inhibitor approved by FDA.  
Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading 
to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell 
Antigen Receptor (BCR) and cytokine receptor pathways. BTK’s role in signaling 
through the B-cell surface receptors results in activation of pathways necessary for B-
cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib 
inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and 
substrate adhesion in vitro. In patients with recurrent B-cell lymphoma > 90% 
occupancy of the BTK active site in peripheral blood mononuclear cells was observed 
up to 24 hours after ibrutinib doses of ≥ 2.5 mg/kg/day (≥ 175 mg/day for average 
weight of 70 kg). Ibrutinib is absorbed after oral administration with a median Tmax of 1 
to 2 hours. Ibrutinib exposure increases with doses up to 840 mg. The steady-state AUC 
(mean ± standard deviation) observed in patients at 560 mg is 953 ± 705 ng⋅h/mL and 
in patients at 420 mg is 680 ± 517 ng⋅h/mL. Administration with food increased 
ibrutinib Cmax and AUC by approximately 2 to 4-and 2-fold, respectively, compared 
with administration of ibrutinib after overnight fasting. Reversible binding of ibrutinib 
to human plasma protein in vitro was 97.3% with no concentration dependence in the 
range of 50 to 1000 ng/mL. The apparent volume of Distribution at Steady State (Vd,
ss/F) is approximately 10000 L. Metabolism is the main route of elimination for 
ibrutinib. It is metabolized to several metabolites primarily by cytochrome P450, 
CYP3A, and to a minor extent by CYP2D6. The active metabolite, PCI-45227, is a
dihydrodiol metabolite with inhibitory activity towards BTK approximately 15 times 
lower than that of ibrutinib. The range of the mean metabolite to parent ratio for PCI-
45227 at steady-state is 1 to 2.8. Apparent clearance (CL/F) is approximately 1000 L/h. 
The half-life of ibrutinib is 4 to 6 hours. 
Ibrutinib, mainly in the form of metabolites, is eliminated primarily via feces. After a 
single oral administration of radiolabeled [14C]-ibrutinib in healthy subjects, 
approximately 90% of radioactivity was excreted within 168 hours, with the majority 
(80%) excreted in the feces and less than 10% accounted for in urine. Unchanged 
ibrutinib accounted for approximately 1% of the radiolabeled excretion product in feces 
and none in urine, with the remainder of the dose being metabolites. Due to potential 
DDI, ibrutinib should not be used with strong CYP3A inhibitors- for detailed 
description (See Section 4.2.2.1
Ibrutinib should not be administered to pregnant women (due to teratogenicity) and to 
nursing mothers. The safety and effectiveness in pediatric populations has not been 
established.
Clinical experience with ibrutinib:
The clinical efficacy of ibrutinib was tested in a randomized, multicenter, open-label 
Phase 3 study. Patients with CLL or Small Lymphocytic Lymphoma (SLL) (n=391) 
were randomly assigned to receive either ibrutinib at 420mg orally daily until disease 
progression, or unacceptable toxicity, or ofatumumab at an initial dose of 300 mg, 
followed one week later by a dose of 2000 mg weekly for 7 doses and then every 4 


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weeks for 4 additional doses. Fifty seven patients randomized to ofatumumab crossed 
over following progression to receive ibrutinib. The median age was 67 years (range, 
30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial 
enrolled 373 patients with CLL and 18 patients with SLL. The median time since 
diagnosis was 91 months and the median number of prior treatments was 2 (range, 1 to 
13 treatments). At baseline, 58% of patients had at least one tumor ≥ 5 cm. Thirty-two 
percent of patients had 17p deletion. Adverse reactions and laboratory abnormalities 
reflect exposure to ibrutinib with a median duration of 8.6 months. The most common 
non hematologic adverse reactions (with a cut off of 20%) in this study occurring in 
195 patients assigned to receive ibrutinib were: diarrhea 48%, nausea 26%, fatigue 28%, 
pyrexia 24%, rash 24%, and musculo-skeletal pain 28%. The following treatment 
emergent laboratory abnormalities per International Workshop Chronic Lymphocytic 
Leukemia (IWCLL) criteria were observed: neutrophils decreased 51% (23% G3-4), 
PLT decreased 52% (5% G3-4), and hemoglobin decreased 36% (no G3-4). 
Approximately five percent of patients receiving ibrutinib discontinued treatment due to 
Adverse Events (AEs). These included infections, subdural hematomas and diarrhea. 
AEs leading to dose reduction occurred in approximately 6% of patients. Additional 
adverse reactions have been observed in patients taking ibrutinib: hemorrhage, 
infections, cytopenias, atrial fibrillation, and second malignancies.
PFS as assessed by Independent Review Committee (IRC) according to IWCLL criteria 
indicated a 78% statistically significant reduction in the risk of death or progression. 
Analysis of Overall Survival (OS) demonstrated a 57% statistically significant 
reduction in the risk of death for patients in the ibrutinib arm. The study included 127 
CLL patients with del 17p. The ORR 63 patients with del17p treated with ibrutinib was 
47.6%, and the median PFS was not reached in this group. Interestingly, upon initiation 
of ibrutinib, an increase in lymphocyte counts (i.e., ≥ 50% increase from baseline and 
above ALC of 5,000/mcL) occurred in 77% of CLL patients. The onset of isolated 
lymphocytosis occurs during the first month of ibrutinib therapy and resolves by a 
median of 23 weeks (range 1 -104+ weeks). This study led to approval of ibrutinib 
(Imbruvica) by FDA for the treatment of patients with CLL who have received at least 
one prior therapy and for the treatment of patients with CLL with 17p deletion 
regardless of prior lines of treatment.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
There has been significant progress in treatment of CLL patients since the recent approval of 
two small molecules that inhibit BCR-associated kinases: ibrutinib, and idelalisib. Both 
agents are highly active in treating B-cell malignancies. Treatment with ibrutinib results in 
ORR of 42.6% in CLL patients, and in longer PFS when compared to ofatumumab, even in 
patients with high risk CLL (ie del17p). However, in most cases patients treated with 
ibrutinib achieve PRs, and only very few patients achieve Complete Response (CR), or 
Minimal Residual Disease (MRD) [R15-0129] negativity on monotherapy. In order to 
maintain responses continuous treatment with inhibitors of BCR-associated kinases seems 
necessary. Besides high cost of such treatment, emerging resistance mechanisms are a 
growing concern that long term exposure to the drug will ultimately result in relapse [R15-
0127], with very few therapeutic options left for the patient. Historical experience with CLL 
indicates that depth of response is important for the outcome of therapy, i.e. prolongation of 
PFS and OS [R15-0128]. A combination approach has been undertaken in several smaller 
studies examining the therapeutic potential of ibrutinib with rituximab, or ibrutinib with 
chemotherapy. So far only limited data are available, and the CR rate reported in those trials 
is low. Therefore, while the combination treatments with ibrutinib remain a very attractive 
option to increase the depth of response in CLL patients- the choice of the best combination 
partner remains a challenge. CD20-targeting monoclonal antibodies: rituximab, ofatumumab, 
obinutuzumab, have proven effective in CLL in combination with cytotoxic agents. Thus, the 
majority of CLL patients will be pre-treated with CD20 antibodies as part of their first line 
treatment. Given the dim CD20 expression on CLL cells, the modest single agent activity of 
rituximab in relapsed CLL, and low CR rate generated by rituximab plus ibrutinib 
combinations, exploration of combination partners outside of rituximab is warranted.
In addition, due to advanced age of typical CLL patients and frequent comorbidities, 
chemotherapy-free combinations are preferred. 
This study will be generating first set of data on the combination of ibrutinib with anti CD37 
antibody.  
BI 836826 is a novel anti-CD37 (chimeric mouse) antibody with intrinsic ADCC activity. 
Strong expression of CD37 (stronger than CD20) has been demonstrated in samples derived 
from CLL patients [R11-4833]. Data available so far from the ongoing first in human phase I
study in patients with relapsed/refractory CLL demonstrate an OR rate of 40% (12/30 
patients treated at doses ≥9 mg). This encouraging monotherapy activity allows generating a 
hypothesis that BI 836826 has a potential to deepen the response when combined with 
ibrutinib in CLL patients. 
This is a single arm, open-label phase Ib study to explore safety and efficacy of combining 
ibrutinib with BI 836826. The study will be conducted in patients with relapsed/refractory 
CLL who have been pre-treated with at least one prior line of systemic therapy, and who 
would otherwise qualify for treatment with ibrutinib. The study will consist of dose escalation 


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where standard dose of ibrutinib will be combined with escalating doses of BI 836826 in 
cohorts of a minimum of 3 patients until an MTD for the combination is established. During 
dose escalation, the Safety Review Committee (SRC) will define a RP2D .
Note: Following a company decision, further development of BI 836826 has been 
discontinued. Recruitment of trial participants will be stopped; however, current subjects on 
treatment will be allowed to complete the trial as per the protocol. Trial procedures and 
endpoint analysis has been amended due to the early termination of the trial.
TRIAL OBJECTIVES
2.2
The primary objective of this trial is to determine the RP2D of BI 836826 in combination 
with ibrutinib in relapsed/refractory CLL patients, which may either be the MTD, or a lower 
dose. In case a formal MTD cannot be determined after dose escalation to the highest 
protocol defined dose, an appropriate clinically active and safe dose will be determined on 
the basis of all relevant study data relating to safety, pharmacodynamics, PK, and signs of 
clinical efficacy. Determination of the MTD is a secondary objective.
 
 
BENEFIT - RISK ASSESSMENT
2.3
BI 836826 is a Mab which specifically targets CD37 positive cells through direct apoptosis 
induction and ADCC [R10-6345].
CD37 is not expressed outside of the haematopoietic and lymphatic system. The anticipated 
side effect profile of BI 836826 based on preclinical studies comprised predominantly 
hematological AEs such as neutropenia and thrombocytopenia. In the ongoing Phase I trial in 
patients, IRRs, neutropenia and thrombocytopenia were among the most frequently observed 
AEs.
Infusion Related Reactions:
Infusion Related Reactions (IRRs) in patients with hematological diseases are considered 
associated with cytokine release and measures for risk mitigation typically include 
premedication, slow infusion rates, patient monitoring and interruption of infusions at the 
occurrence of first symptoms. IRRs have been manageable in the ongoing Phase I CLL trial, 
with 3 out of a total of 36 patients terminating treatment early due to IRRs. 
Neutropenia:
Hematologic AEs, in particular neutropenia, are frequently reported in patients with CLL and 
may be due to the underlying disease infiltrating the bone marrow, previous and current 
treatments or combination of these. A decline in neutrophils has been observed immediately 


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after infusion of BI 836826, lasting up to several days in CLL patients.  Due to the rapid 
onset after infusion, this effect of BI 836826 on neutrophils is considered to be likely an
effect on circulating mature cells, possibly related to re-distribution of cells, rather than a 
cytotoxic effect on bone marrow precursor cells.
Thrombocytopenia:
A decline in PLT, with onset immediately after infusion of BI 836826, and recovery within 
few days has been observed. 
Neutropenia and thrombocytopenia have been observed in patients treated with ibrutinib. 
There is a potential risk that frequency or severity of neutropenia and/or thrombocytopenia 
might be increased compared to each single agent when BI 836826 and ibrutinib are 
combined. In order to mitigate the risks associated with neutropenia and/or 
thrombocytopenia, patients’ blood counts will be frequently monitored, and prophylactic 
measures will be instituted when clinically appropriate. An active surveillance for signs of 
infections will be performed at each clinic visit, and treatment will be instituted immediately 
if patients develop infections. Patients will be provided with supportive care (transfusions, 
growth factors support) if necessary. 
Tumor Lysis Syndrome:
In patients with a high tumor burden who are exposed to a highly effective therapy, there is a 
risk of rapid tumor destruction resulting in Tumor Lysis Syndrome (TLS). Prophylaxis, close 
monitoring and appropriate interventions are the key to preventing and managing TLS. 
Instructions and reference to published guidelines on TLS are included in this protocol as a 
prophylactic measure (see Section 4.2.1.2.2).
Drug-Drug Interaction (DDI) potential of ibrutinib:
Ibrutinib is metabolized to a great extent by 3A enzyme of p450 complex. Strong CYP3A 
inhibitors have been demonstrated to increase Cmax and AUC of ibrutinib by 29-and 24-fold. 
Patients and investigators will be advised to avoid strong and moderate CYP3A inhibitors. 
Drug induced liver toxicity:
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow- up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.3.6.1.
Ongoing safety analysis:
An ongoing safety evaluation will be performed by a SRC composed of members from the 
sponsor together with the Coordinating Investigator (CI) and participating investigators in 
regular intervals after completion of MTD observation period (Cycle 1) for all patients in 
each dose escalation cohort. 
Overall the risk benefit is considered positive for the combination of BI 836826 and ibrutinib. 
Moreover, if proven safe, this combination has the potential to improve the CR rate compared 
to historical data for ibrutinib alone, and to introduce treatment free intervals, which in turn 
might prevent development of drug resistance in CLL patients. Considering the chronic 


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nature of CLL and the need for repeated treatment, this potential benefit of therapy with 
BI 836826 in combination with ibrutinib is expected to outweigh the treatment-related risks.
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a single arm, open label, phase Ib dose escalation study. Approximately 20
relapsed/refractory CLL patients who have been pre-treated with at least one prior line of 
systemic treatment and who qualify for treatment with ibrutinib will be treated with a 
combination of BI 836826 and ibrutinib in this trial.  
Ibrutinib is to be dosed at a fixed, approved dose of 420mg daily in all patients. Stepwise 
dose escalation of BI 836826 will be performed. BI 836826 will be administered on cycle 1 
on following days: D1 (10mg), D2 and D8 (50% of the assigned dose on each day), D15 
(100% dose). In C2-4 BI 836826 will be administered on days: 1 and 15 of each cycle at 
100% of the assigned dose.  
Dose-escalation of BI 836826 will be guided by a BLRM with overdose control (refer to 
Section 7). The BLRM estimates the MTD by updating estimates of the probability of 
observing a DLT in the first cycle for each dose level in the study as patient information 
becomes available. At any time in the trial, it will not be permitted to escalate to a dose which 
does not fulfil the Escalation With Overdose Control (EWOC) criterion (refer to Section 7). 
Dose-increments will be ≤100% of the previous dose level tested in prior cohort. 
For any dose-escalation cohort, at least 3 patients will be required (Section 7). However, in 
the case that only 2 patients are evaluable and neither has experienced a dose- limiting 
toxicity within the first cycle (28 days) of the combination treatment, then dose-escalation can 
occur based on these 2 patients. 
A patient will be considered evaluable for DLT in cycle 1 (D1 to D28 of combination 
treatment) 

if the patient has been observed for at least one cycle and has had sufficient exposure 
to both study drugs, i.e. 4 infusions of BI 836826 (10 mg, 50% of target dose x 2, and 
100% of target dose x1) and ≥ 80 % (22 of 28 doses) of ibrutinib doses.

if the patient has experienced a DLT independent of exposure time in cycle 1.
Patients who do not meet at least one of the above criteria will be considered for the safety 
analysis, but will be replaced by an additional patient for DLT assessment.
After all patients in a cohort have either experienced a DLT or have been observed for at least 
one cycle (28 days) without experiencing a DLT, the Bayesian model will be updated with 
the newly accumulated data. The overdose risk will then be calculated for each dose, and 
escalation will be permitted to all doses which fulfil the EWOC criterion and the additional 
100% escalation rule
If DLTs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrollment to that cohort will be stopped. The BLRM will be re-run to confirm 
that the dose-level still fulfils the EWOC criterion. Based on this information, the SRC will 


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evaluate whether the next patients will be enrolled on the same dose level, or if they will be 
enrolled to a lower dose level.
Based on the model and on additional information, if available (PK, PD, patient profiles), the 
members of the SRC will reach a joint decision on the next dose level to be investigated. The 
SRC may also provide a recommendation for the size for the next dose cohort. However, the 
final decision on the next cohort size will be agreed mutually between the Sponsor and the 
CI.
The SRC may recommend stopping the dose finding phase after the criterion for MTD (see 
Section 7.1) is fulfilled. Further patients may be included to confirm this MTD estimate. 
If a MTD is determined during dose escalation, the RP2D may be either the MTD or a lower 
dose. If no MTD is observed after escalation to the highest possible dose of 1400 mg, 
1400mg or a dose below 1400 mg may be selected as RP2D. The RP2D will be a safe dose at 
which the intended clinical efficacy (e.g. one or more of the following are observed: ALC 
lowering effect, clinical CR, MRD negativity, effect on biomarkers). A minimum of 6 
patients need to be evaluated at the RP2D..
During dose escalation, enrollment into the first dose cohort will be allowed only 
after the first patient in the cohort is evaluable for safety for a minimum of 3 days 
from the first administration (10 mg pre-dose) of BI 836826. Subsequent patients 
within this cohort and subsequent cohorts may be enrolled at any time. 
Enrollment into the next higher dose cohort is allowed after the previous dose cohort is found 
to be safe for all patients in this cohort by the SRC. For the purposes of determining dose 
escalation, DLTs will be assessed based on safety data from cycle 1. However, AEs including 
those qualifying for DLT will be monitored beyond cycle 1 and throughout the trial.
Treatment:
Ibrutinib is going to be dosed at fixed, approved dose of 420mg daily in all patients. Stepwise 
dose escalation of BI 836826 will be performed. BI 836826 will be administered in Cycle 1
on the following days: D1 (10mg), D2 and D8 (50% of the assigned dose on each day), D15 
(100% of the assigned dose). In Cycle 2-4 BI 836826 will be administered at the assigned 
dose on days 1 and 15 of each cycle. In Cycle 5-12 BI 836826 will be administered at the 
assigned dose on day 1 only. Patients will continue the study treatment till disease 
progression, unacceptable toxicity, or withdrawal of consent.  Continued monthly treatments 
beyond cycle 12 are possible for patients with a CR, CRi, or MRD negative PR in the 
response assessment at the end of Cycle 12. In such cases, patients may continue treatment 
with 12 additional cycles of combination treatment up to a maximum and total of 24 
treatment cycles. 
Patients will take two weeks of ibrutinib during the run-in phase, prior to start of BI 836826 
and will continue ibrutinib throughout the whole duration of the study. After completion of
the study the continued treatment with ibrutinib is left to the decision of the investigator or 
patient’s physician, depending on patients’ disease status, and the need for further treatment. 
For selection of doses please refer to Section 4.1.3.


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For dose adaptation in case of AEs please refer to Section 4.1.4.5.
3.1.1
Administrative structure of the trial
Boehringer Ingelheim is the Sponsor of this trial.  The CI for this trial will be 
 
 of the 
.  The CI and participating Investigators will be 
physicians experienced and specialized in the treatment of CLL and in the conduct of Phase 
I/II trials. Relevant documentation on the participating (Principal) Investigators and other 
important participants, including their curricula vitae, will be filed in BIRDS.
Boehringer Ingelheim has appointed a Trial Clinical Monitor (TCM), responsible for 
coordinating all required activities, in order to:

manage the trial in accordance with applicable regulations and internal Standard
Operating Procedures (SOPs),

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

order the materials as needed for the trial,

ensure appropriate training and information of Local Clinical Monitors (CML),
Clinical Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
The SRC will consist of the CI, participating investigators, BI Clinical Program Leader, BI 
TCM and the BI Statistician. Additional experts may be invited as needed. Details will be 
specified in a SRC charter. The information on the overdose risk will be presented by the trial 
statistician to the SRC. Additional information, such as lower grade AEs, PD and PK 
information, individual patient profiles or data listings and other relevant information will 
also be presented. Based on this information, the members of the SRC will reach a joint 
decision on the next dose level to be investigated. This dose level may be above, below or 
identical to the currently investigated dose level. The SRC will also recommend the size for 
the next cohort. However, the final decision on the next cohort size will be made by a mutual 
decision between the Clinical Program Lead and the CI.  Minutes of the SRC meetings and 
recommendations will be documented and archived by the TCM.  
All safety laboratory analyses will be performed locally at each clinic site in the schedule 
outlined in the Flowchart.  
 
 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
There has been significant progress in treatment of CLL patients since the recent approval of 
two small molecule inhibitors: ibrutinib, and idelalisib. Both agents are highly active in 
treating B-cell malignancies. Treatment with ibrutinib may result in long PFS, however, in 
most cases it is achieved through durable PRs, while very few patients achieve a CR, or MRD 
negativity on monotherapy. Data from large randomized phase 3 trials in untreated CLL 
indicates that depth of response is important for the best ultimate outcome which is 


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prolongation of OS. Therefore combining of novel CD37 antibody BI 836826 which has 
demonstrated single agent activity in CLL with ibrutinib provides the opportunity for 
improving the response quality in patients treated with ibrutinib.
This is a single arm, open-label phase Ib study to explore safety and efficacy of combining 
ibrutinib with BI 836826. The study will be conducted in relapsed/refractory CLL patients 
who would otherwise qualify for treatment with ibrutinib as standard of care. The study will 
consist of dose escalation where standard dose of ibrutinib will be combined with escalating 
doses of BI 836826 in cohorts of minimum of three patients. Dose escalation and cohort size 
will be determined based on the recommendation of the SRC, guided by a Bayesian Model 
with overdose control. An EWOC design will increase the chance of treating patients at 
efficacious doses while reducing the risk of overdosing. This design is based on practical
experience and is an efficient algorithmic method due to its ability to identify the dose with a 
desired toxicity rate and its allocation of a greater proportion of patients to doses at, or close 
to, that dose (R13-4802, R13-4804, R13-4805).
SELECTION OF TRIAL POPULATION
3.3
Approximately 20 relapsed/refractory CLL patients will enter combination treatment at an 
estimated number of 4 US sites (approximately 20 patients/ 5 patients per site).
A log of all patients pre-screened and enrolled into the trial (i.e. who have signed informed 
consent) will be maintained in the ISF at the investigational site irrespective of whether they 
have been treated with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Patients must be diagnosed with CLL, have relapsed/refractory disease pre-treated with at 
least one prior line of systemic treatment and qualify for treatment with ibrutinib.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1. Diagnosis of CLL established according to IWCLL criteria (R10-4429) and documented
within medical records.
2. Relapsed or refractory CLL pre-treated with at least one prior line of systemic therapy for
CLL.
3. Indication for treatment consistent with IWCLL criteria, i.e. at least one of the following
criteria should be met
a) Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anaemia and/or thrombocytopenia.


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b) Massive (i.e., lower edge of spleen ≥6 cm below the left costal margin) or 
progressive or symptomatic splenomegaly.
c) Massive nodes (i.e., ≥10 cm in longest diameter) or progressive or symptomatic 
lymphadenopathy.
d) Progressive lymphocytosis in the absence of infection, with an increase in blood ALC 
≥50% over a 2-month period, or a lymphocyte doubling time (LDT) of <6 months (as 
long as initial ALC was ≥30000/µl).
e) Autoimmune anaemia and/or thrombocytopenia that is poorly responsive to 
corticosteroids or other standard therapy.
f)
Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs:
i.
unintentional weight loss of 10% or more within the previous 6 months
ii.
significant fatigue (i.e. ECOG PS 2 or worse; inability to work or perform usual 
activities)
iii.
fevers higher than 100.5°F or 38.0°C for ≥2 weeks without other evidence of 
infection
iv.
night sweats for > 1 month without evidence of infection
4. Clinically quantifiable disease burden defined as at least one of the following: 
a) either ALC >10 000/μL, or
b) measurable lymphadenopathy (at least one node > 1.5 cm in short diameter on CT or
Magnetic Resonance Imaging (MRI) or
c) quantifiable bone marrow infiltration documented in a bone marrow biopsy during 
screening
5. Minimum interval to prior CLL treatment in line with the following requirements:
a) Last dose of a cytotoxic drug, a monoclonal antibody targeting CD20, or an 
investigational drug to treat CLL at least 1 week prior to the first dose of ibrutinib. 
b) Last dose of idelalisib at least 48 hours prior to the first dose of ibrutinib.
c) Last dose of alemtuzumab at least 4 weeks prior to the first dose of ibrutinib.
6. Resolution of all clinically relevant acute non-hematologic toxic effects of any prior  
antitumor therapy resolved to Grade ≤1 with the exception of alopecia or neurotoxicity 
(Grade 1 or 2 neurotoxicity permitted)
7. Must have baseline laboratory data as defined in Table 3.3.2:1


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Table 3.3.2:1
Baseline laboratory parameters
Parameter
Value required for study entry
Hb
>8g/dL
ANC
>1000/µL
PLT
>25000/µL
GFR or Creatinine Clearance (See 
Appendix 10.5)
>30ml/min
AST and ALT
<3 x ULN
Bilirubin (total)
(Exceptions: patients with diagnosed Gilbert’s 
syndrome)
<1.5 x ULN
aPTT
PT or INR
<1.5 x ULN
PT <1.5 x ULN, INR <1.5
8. Male or female patients. Women of childbearing potential* must agree to use highly 
effective methods of birth control per International Conference on Harmonisation (ICH)
M3(R2) that result in a low failure rate of less than 1% per year when used consistently 
and correctly, during the trial and for at least 1 year after the last dose of BI 836826 and 1
month after the last dose of ibrutinib. A list of contraception methods meeting these 
criteria is provided in the patient information. Male patients having a partner of 
childbearing potential must use condoms and ensure their partner is using a highly 
effective method of birth control as described above, during the trial and for at least 1 
year after the last dose of BI 836826 and 3 months after the last dose of ibrutinib.
*Women of childbearing potential are defined as:
Any female who has experienced menarche and does not meet the criteria for "women 
not of childbearing potential" as described below.
Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an alternative 
medical cause) or who are permanently sterilized (e.g., tubal occlusion, hysterectomy, 
bilateral oophorectomy or bilateral salpingectomy).
9. Eastern Cooperative Oncology Group (ECOG),[R01-0787] performance score of 0 to 2
10. Age 18 years and older
11. Eligible and able to secure sourcing for ibrutinib
12. Written Informed Consent consistent with ICH-GCP and local legislation
3.3.3
Exclusion criteria


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1. Known transformation of CLL to an aggressive B-cell malignancy at the time of 
screening (e.g. large B-cell lymphoma, Richter’s syndrome). Patients with Richter's 
Syndrome that has resolved ≥2 years from signing are eligible.
2. Prior allogeneic stem cell transplant within one year or active graft vs. host disease.
3. History of a non-CLL malignancy except for adequately treated in situ, stage 1 or 2 
carcinoma in CR after appropriate treatment, or any other cancer that has been in CR for 
≥2 years after end of cancer treatment.
4. Active, uncontrolled autoimmune cytopenia. Patients with autoimmune cytopenia which 
is controlled with corticosteroids at doses of ≤20 mg prednisolone or equivalent may be 
enrolled.
5. Previous CLL treatment with a CD37-targeting antibody or a CD37-antibody drug 
conjugate.
6. Previous treatment with ibrutinib
7. Previous treatment with another BTK-inhibitor than ibrutinib.
8. Ongoing systemic immunosuppressive therapy other than corticosteroids.
9. Active bacterial, viral, or fungal infection requiring systemic treatment at the time of 
study entry. 
10. Human Immunodeficiency Virus (HIV) infection
11. Active hepatitis B or C as evidenced by detection of virus specific Deoxyribonucleic Acid 
(DNA) or Ribonucleic Acid (RNA).
12. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
13. Chronic persistent atrial flutter or atrial fibrillation. Patients with intermittent atrial 
fibrillation may be enrolled if without episode for ≥ 6 months and without indication for 
anti-coagulation
14. Requirement for chronic anticoagulation with warfarin or with direct oral anticoagulants
at the time of screening.
15. Chronic treatment (i.e. >7 days) with a strong CYP3A inhibitor which cannot be 
terminated prior to the first dose of ibrutinib. Examples include but are not restricted to: 
ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone)
16. Unstable angina pectoris, uncontrolled hypertension, uncontrolled asthma or other 
pulmonary disease


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17. Other concomitant serious illness considered by the investigator to potentially
compromise patient’s safety in this trial or significant co-morbidities that would impede
patients participation in the trial (examples: inability to travel to the site at prescribed
intervals, inability to swallow oral medication)
18. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
19. Known or suspected hypersensitivity to the study medication or excipients
20. Patients unable to comply with protocol
21. Concurrent participation in another therapeutic clinical trial
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient may be withdrawn from BI 836826 trial treatment if:

Disease progression as assessed by investigator

Initiation of any other new anticancer therapy for CLL, in the absence of disease
progression

The patient withdraws consent for study treatment or study participation, without the need
to justify the decision.

The patient is not able to tolerate a second re-challenge for the same AE (see Section
4.1.4.5)

The patient needs to take concomitant drugs that interfere with BI 836826, ibrutinib, or
the trial results evaluation (see Section 4.2.1 and 4.2.2)

The patient can no longer be treated with trial medication for other medical reasons (such
as another severe intercurrent illness, pregnancy, or breastfeeding)
In the last two cases, consultation with the BI Clinical Monitor is recommended.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart and Section 6.2.3.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the eCRF.
These data will be included in the trial database and reported.
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.
If a patient should become pregnant during the trial, the combination treatment must 
immediately be interrupted. The patient will be followed up until delivery or termination of 
pregnancy (see Section 5.3.7). The data of the patient will be collected and reported in the 
Clinical Trial Report (CTR) until last patient last visit and any events occurring thereafter 
will be reported in BI drug safety database.


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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. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of Good Clinical Practice (GCP), the Clinical Trial Protocol (CTP), or the
contract disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.4.3
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 AEs that are unexpected considering the mode of action and that
are not manifestations of underlying disease or background events typical of the study
population and/or are debilitating, non-reversible, not manageable or lead to a fatal
outcome where evidence suggests that there was a reasonable possibility that the drug
caused the AE.

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, enrollment to the trial will be stopped to allow for 
an in-depth analysis of the safety profile of the combination treatment. The risk-benefit 
profile will be re-assessed by the SRC. The outcome of the analysis and the recommendations 
will be shared with all involved regulatory health authorities prior to a possible re-start of 
enrollment.


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
4.1.1
Identity of BI Investigational Product(s), Combination Backbone Product(s)
Table 4.1.1: 1
Test product: BI 836826
Substance:
BI 836826
Pharmaceutical formulation:
Concentrate for solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/mL (vials with 10 mL)
Posology
Rate controlled intravenous infusion
Cycle 1:
Day 1: administration of a 10 mg pre-dose
Day 2: administration of 50% of the assigned dose
Day 8: administration of 50% of the assigned dose 
Day 15: administration of first full dose (100% of the 
assigned dose) 
Cycles 2-4: administration of a full dose (100% of 
the assigned dose) on Days 1 and 15 of each 28-day 
cycle
Cycles 5 - 12: administration of full dose (100% of 
the assigned dose) on Day 1 of each cycle
Cycles 13-24: (for patients with CR, CRi and MRD-
negative PR only): administration of full dose (100% 
of assigned dose) on Day 1 of each cycle
Route of administration:
Intravenous


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Table 4.1.1: 2
Backbone product:
Ibrutinib Substance:
Ibrutinib
Pharmaceutical formulation:
White opaque capsules
Brand name:
Imbruvica
Source:
Pharmacyclics, Inc.; Janssen Biotech, Inc.
Unit strength:
140 mg capsule
Posology
420 mg once daily*
Route of administration:
Oral**
*As described in the current Package Insert (R15-5127).
**Capsule should be swallowed whole with water. Should not be opened, broken or chewed.
4.1.2
Method of assigning patients to treatment groups
There will be no randomization as this is a single-arm, open-label trial.
BI 836826 medication number will be assigned via the Interactive Response Technology
(IRT) system to allow for tracking of used and available medication vials on site. To facilitate
the use of the IRT, the Investigator will receive all necessary instructions. 
Ibrutinib will not be provided by Boehringer-Ingelheim.  Patients and their insurance will be 
responsible for securing supplies for ibrutinib.  Patients entering the trial will receive daily 
dosing of ibrutinib.
4.1.3
Selection of doses in the trial
The starting dose of BI 836826 for this trial was selected on data from trial 1270.1, the first in 
human, dose escalation trial of BI 836826 in CLL.  A dose of 400 mg was found to be safe in 
1270.1. The first dose tier of BI 836826 to be tested in combination with ibrutinib will be BI 
836826 100 mg. A dose of 100 mg includes a safety margin for the combination, and was 
found to be moderately clinically active.
Based on the Bayesian model in Section 7.1, the dose combination 100mg BI 836826 and 
420mg ibrutinib has a prior probability of overdosing below 25%; it fulfills the overdose 
criterion and is therefore a suitable starting dose combination (see Section 7.1).
The dose is planned to be escalated in dose tiers recommended by the BLRM. A maximum 
escalation step of 100% will be allowed. The provisional dose levels are 100 mg, 200 mg, 
400 mg, 600 mg, 800 mg, and 1400 mg of BI 836826, unless recommended differently by the 
BLRM/SRC. Intermediate or lower dose levels, depending on the number of DLTs observed 


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in the study may be investigated if agreed upon by the SRC. Intra-patient dose-escalation of 
BI 836826 will not be allowed in this trial.
4.1.4
Drug assignment and administration of doses for each patient
All patients enrolled into this study will be treated with a combination of ibrutinib (daily) and 
i.v. infusions of BI 836826.
BI 836826 concentrate for solution for infusion is a clear to slightly opalescent, colorless to
yellowish liquid. BI 836826 is provided as a concentrate for solution for infusion (10 
mg/mL) that is sterile, filtered, and subsequently filled under aseptic conditions into 10 mL 
clear glass vials. Each vial is enclosed with a rubber stopper and sealed with an aluminum
flip-off cap. Each vial contains 100 mg active ingredients (10 mg/mL); dilution is required 
prior to administration.
Detailed instructions for preparation and handling are included in the ISF.
To determine the dose regimen for the next cohort, the available toxicity information 
(including DLTs, AEs that are not DLTs, and AE information post-cycle 1), anti-tumor 
activity information (and –if available- PK/PD data) as well as the recommendations from the 
BLRM will be evaluated by the investigators and BI personnel (including the BI physician 
and statistician responsible for the trial) at the SRC meeting. The parties must reach a 
consensus on whether to declare MTD, escalate the dose any further, or whether to de-
escalate and/or expand recruitment into particular cohorts. Dose escalation will continue until 
identification of the MTD estimate is encountered or until the trial is terminated for other 
reasons.
Prior to inclusion of a new patient during the cohort dose escalation phase, the Investigator
has to confirm the actual dose tier of BI 836826 for the patient with the Sponsor’s Clinical 
Monitor who oversees the cohort dose escalation steps.


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The treatment schedule of BI 836826 and daily dosing of ibrutinib is summarized below:
Treatment details:
Screening: 
Each patient will provide consent and enter the screening period to confirm eligibility.  The 
screening period will be three weeks (Day -35 through Day -15) in duration and prior to the 
start of the run-in phase of ibrutinib administration.  AEs will be collected from the time of
consent; however they will not constitute part of the DLT assessment for combination 
therapy. 
Run-in:
Each patient enrolled, completing the screening period and meeting eligibility will enter the 
run-in phase and start with ibrutinib monotherapy pre-treatment on Day -14 through Day - 1. 
While AEs from this period will be collected, they will not constitute part of the DLT 
evaluation period for combination therapy.  The dose for ibrutinib will be 420mg daily, 
orally.
Cycle 1:
Patients completing the screening period and run-in phase will start the combination 
treatment. For prevention of IRRs and tumor lysis syndrome the first administration of BI 
836826 will be a pre-dose of 10 mg/ml on Day 1. Subsequent two doses will be 50% of the 
target dose on Day 2 and on Day 8, followed by 100% of the target dose on Day 15 of the 
first cycle. Patients will continue to receive ibrutinib on days 1-28 of cycle 1. DLTs from the 
start of the first BI 836826 infusion through the MTD evaluation period (Cycle 1) as well as 
other AEs will be used to assess dose escalation steps and to determine the MTD.


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Cycle 2-4:
Patients will receive 100% of assigned dose of BI 836826 on days 1 and 15 of each cycle. 
Patients will continue to receive ibrutinib on days 1-28 of each cycle (2-4).  At the end of 
Cycle 3 (Imaging and Laboratory) and Cycle 4 (Laboratory) disease assessment will be 
performed. Patients without disease progression of CLL will be allowed to continue with BI 
836826 and ibrutinib.
Cycle 5-12:
Patients will receive 100% of assigned dose of BI 836826 on Day 1 of each cycle. Patients 
will continue to receive ibrutinib on days 1-28 of each cycle. Disease assessment will be 
performed every three cycles or 12 weeks, and will be performed at the end of every third 
cycle, i.e. Day 21 through Day 28 of Cycle 6, 9, and 12. Treatment with BI 836826 will be 
terminated at the end of cycle 12 in all patients who achieve PR (MRD positive), PR-L, 
Stable Disease (SD) or PD in the response assessment at the end of cycle 12. Patients who 
achieve a CR (MRD positive or negative) or a PR (MRD negative), may continue treatment 
with BI 836826 as outlined below for additional 12 cycles. Treatment with ibrutinib 
monotherapy may be continued according to label at the discretion of the investigator or the 
patient’s physician.
Cycle 13-24 (patients with CR and MRD-negative PR only):
Patients will receive 100% of assigned dose of BI836826 on Day 1 of each cycle. Patients 
will continue to receive ibrutinib on days 1-28 of each cycle. Disease assessment will be 
performed at the end of every fourth cycle, i.e. Day 21 through Day 28 of Cycle 16, 20 and 
24. Treatment with BI 836826 will be terminated at the end of cycle 24 in all patients. 
Treatment with ibrutinib monotherapy may be continued according to label at the discretion 
of the investigator or the patient’s physician.


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4.1.4.1
BI 836826 infusion rates
Table 4.1.4.1: 1 provides a summary of planned and modified infusion rates.  Pre-medication 
prior to each administration of BI 836826 is required Section 4.2.1.2.1
Table 4.1.4.1:1  
Planned and modified infusion rates
Day of 
Treatment
Dose of
BI 836826
Initial Rate of Infusion and 
Maximum Escalation Steps*
Maximum 
Allowed 
Infusion 
Duration
Maximum 
Allowed 
Infusion Rate
Cycle 1
Day 1
10 mg
2 mg/hr x 60 min
Escalate by 1 mg/hr every 30 min 
as tolerated to maximum allowed 
rate**
24 hr
5 mg/hr
Cycle 1
Day 2
50% of 
target dose
≤ 50 mg/hr x 60 min
Escalate by ≤ 50 mg/hr every 30 
min as tolerated to maximum 
allowed rate**
24 hr
400 mg/hr
Cycle 1
Day 8
50% of 
target dose
≤ 50 mg/hr x 60 min
Escalate by ≤ 50 mg/hr every 30 
min as tolerated to maximum 
allowed rate**
24 hr
400 mg/hr
Cycle 1
Day 15
100% of 
target dose
≤ 50 mg/hr x 60 min
Escalate by ≤ 50 mg/hr every 30 
min as tolerated to maximum 
allowed rate**
24 hr
400 mg/hr
Cycle 2 
Day 1 and 
subsequent 
Cycles
100% of 
target dose
≤ 50 mg/hr x 30 min, then
≤ 100 mg/hr x 30 min
Escalate by ≤ 100 mg/hr as 
tolerated to maximum allowed 
rate**
24 hr
500 mg/hr
* Infusion rates may be adjusted and given extremely slowly over a longer period of time (not to exceed 24 hours) for 
patients with a White Blood Cell Count (WBC) ≥ 100 x 109/L at the time of infusion, 
** slower start rate or smaller increments allowed at investigator’s discretion
Cycle 1 Day 1: BI 836826 “pre-dose” of 10 mg:
BI 836826 administration will start with a “pre-dose” of 10 mg on Day 1 of the first cycle. 
Pre-medication according to Section 4.2.1.2.1 is mandatory. The initial infusion rate to 
mitigate the risk for severe infusion related reactions is 2 mg/h for the first 60 minutes. In the 
absence of infusion related reactions the rate can be escalated every 30 minutes by increments 
of 1 mg/h to a maximum rate of 5 mg/h. 


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In patients with a high risk for IRRs or TLS (e.g., a WBC ≥ 100 x 109/L at the start of 
infusion), or occurrence of an IRR during the infusion, the infusion may be given extremely 
slowly over a longer period of time, but not exceeding 24 hours.
Cycle 1 Day 2 and Cycle 1 Day 8: BI 836826 at 50% of target dose:
Pre-medication, according to Section 4.2.1.2.1, is mandatory. The recommended initial 
infusion rate to mitigate the risk for severe IRRs should not exceed 50 mg/h for the first 60 
minutes. The rate can be escalated every 30 minutes by increments of 50 mg/h or less to a 
maximum rate of 400 mg/h in the absence of IRRs. A slower start rate or smaller increments 
are possible based on individual risk assessment. Reductions in the infusion rate may be 
applied as indicated to ensure tolerability. In patients with a high risk for IRRs or TLS (e.g., a 
white blood cell count (WBC) ≥ 100 x 109/L at the start of infusion), or occurrence of an IRR 
during the infusion, the infusion may be given extremely slowly over a longer period of time 
but not exceeding 24 hours.
Cycle 1 Day 15: BI 836826 at 100% of target dose:
Pre-medication, according to Section 4.2.1.2.1, is mandatory. The recommended initial 
infusion rate to mitigate the risk for severe IRRs should not exceed 50 mg/h for the first 60 
minutes. The rate can be escalated every 30 minutes by increments of 50 mg/h or less to a
maximum rate of 400 mg/h in the absence of IRRs. A slower start rate or smaller increments 
are possible based on individual risk assessment. Reductions in the infusion rate may be 
applied as indicated to ensure tolerability. In patients with a high risk for IRRs or TLS (e.g., a 
WBC ≥ 100 x 109/L at the start of infusion), or occurrence of an IRR during the infusion, the 
infusion may be given extremely slowly over a longer period of time but not exceeding 24 
hours.
Cycle 2 Day 1 and subsequent cycles: BI 836826 at 100% of target dose:
In the absence of infusion related reactions during the administration of the previous full 
dose, the subsequent administration of BI 836826 is recommended to start at a rate of 50 
mg/h or less for the first 30 minutes, followed by a rate of 100 mg/h or less for 30 minutes. 
Incremental steps thereafter may be larger depending on individual tolerability, but must not 
exceed 100 mg/h. A maximum rate of 500 mg/h is not to be exceeded. A slower start rate and 
smaller increments are possible based on individual risk. Reductions in the infusion rate may 
be applied as indicated to ensure tolerability. Pre-medication should be considered according 
to Section 4.2.1.2.1.
4.1.4.2
Management of infusion related reactions
IRRs are events that are directly related to antibody–antigen interactions and have been also 
characterized as cytokine-release syndromes that result from the interaction of antibody with 
antigen on circulating hematopoietic cells [R14-4170]. Symptoms are often difficult to 
distinguish from anaphylactoid or hypersensitivity reactions. IRRs will be captured as an AE
on the dedicated IRR eCRF page together with the clinically most important symptoms. 
Cytokine-release syndrome should be reported under the term IRR, while a true allergic IgE 
mediated hypersensitivity reaction should be reported on the regular AE page.
Hospitalization and overnight surveillance should be considered by the investigator for 
patients at high risk for TLS in Cycle 1 on Day 2 following the first infusion of BI 836826 at 


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50% of the assigned dose. Surveillance of the patient during and until at least 2 hours after 
the end of each BI 836826 infusion in Cycle 1 is required. Mandatory surveillance can be 
reduced to at least 1 hour in Cycle 2 and subsequent Cycles if no AE which would necessitate 
longer observation as per investigator’s judgement occurs during the infusion or the 1 hour 
surveillance period. Surveillance should be prolonged as clinically indicated to monitor or 
treat AEs.  
During the infusion and surveillance period, appropriate monitoring of vital signs is 
recommended, and access to emergency care should be available. 
In case an IRR is observed, appropriate measures depending on the type and severity of the 
reaction should be taken by the investigator according to best medical judgment and local 
guidelines. Supportive therapy for symptoms of IRRs may be administered at the 
investigator’s discretion as indicated. Additional glucocorticoids should be considered in 
particular in patients with Grade 3 or 4 reactions or potentially life threatening symptoms,
e.g. bronchospasm.
If symptoms of an IRR occur while BI 836826 is administered, the following instructions and 
tabular summary of procedures for rate changes and interruptions of BI 836826 must be 
followed:
Table 4.1.4.2: 1   
BI 836826 management of infusion-related reactions
NCI CTCAE 
Grade of IRR
Action
Continuing BI 836826*
Grade 1
Reduce infusion rate to 
50% of the rate at which 
symptoms occurred; 
infusion may be 
interrupted at 
investigator’s discretion
After resolution of 
symptoms
Increase infusion rate to 
the rate at which the 
reaction occurred
Grade  2
Interrupt infusion
After resolution of 
symptoms
Resume infusion at a 
slower rate than that at 
which the reaction 
occurred
Grade  3
Interrupt infusion
After resolution of 
symptoms
Resume infusion at ≤ 
50% of the rate at which 
the reaction occurred x 
30 minutes
Grade  4
Stop infusion
Do not re-expose

*Once subject is stable after reintroduction of initial infusion rate, proceed per Section 
4.1.4.1, Dosage and Administration of BI 836826

In the case of an infusion-related reaction of CTCAE Grade 1, the infusion rate of 
BI 836826 should be reduced to 50% of the previous rate, but may also be interrupted. 
Upon resolution of symptoms, the infusion may be resumed at an infusion rate not higher 


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than the rate at which the IRR occurred, and escalated at the investigator’s discretion 
within the limits described above.

In the case of an infusion-related reaction of CTCAE Grade 2, the infusion of BI 836826 
should be interrupted. Supportive treatment may be administered as indicated. Upon 
resolution of symptoms, the infusion may be resumed at 50% of the previous infusion rate 
and infusion rate escalated at the investigator’s discretion within the limits described 
above.

In the case of an infusion-related reaction of CTCAE Grade 3, the infusion with 
BI 836826 has to be stopped immediately. Supportive therapy is typically indicated, 
glucocorticoids should be considered for management. Once all symptoms have resolved, 
administration of BI 836826 may be resumed for at least 30 minutes at a rate which 
should not exceed 50% of the rate at which the reaction occurred. Re-increase of the 
infusion rate as tolerated by the subject is possible within the limits described above.

In the case of an IRR reaction of CTCAE Grade 4, the infusion has to be stopped 
immediately. Symptoms should be aggressively treated, glucocorticoids should be 
considered for management. Re-exposure after the event is not permitted.
Changes of the infusion rate and temporary interruptions of the infusion have to be recorded 
in the eCRF.
4.1.4.3
Ibrutinib dosing
Dosing of ibrutinib will be guided by the package insert (R15-5127).  The prescribed dose of 
420 mg of ibrutinib will be administered orally daily.   Capsules should be taken orally with a 
glass of water. The capsules should not be broken, opened or chewed.  Patients should be 
instructed not to drink grapefruit juice, eat grapefruit, or eat Seville oranges while taking 
ibrutinib.
If a dose of ibrutinib is not taken at the scheduled time, it can be taken as soon as possible on 
the same day with a return to the normal schedule the following day. Extra capsules of 
ibrutinib should not be taken to make up for the missed dose. 
On days of BI 836826 dosing, ibrutinib will be administered in the clinic before the start of 
the infusion. Prior to these visits, patients should be reminded to record the time of their dose 
the day prior to their scheduled visit and not to take their morning dose of ibrutinib before 
coming into the clinic. Patients should also be reminded to bring their supply of ibrutinib to 
the clinic for dosing. Ibrutinib administration information, including the exact time of dose, 
administered in the clinic or hospital is to be recorded.
 


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4.1.4.4
Criteria for administration of BI 836826 at 100% of the assigned dose 
(Cycle 1 Day 15 and Following)
Prior to each administration of full dose of BI 836826 (i.e. Cycle 1 Day 15 and subsequent 
administrations), AEs and CBC with differential will be assessed. To continue treatment with 
a further infusion of BI 836826, all of the following criteria must be met:

Neutrophils ≥ 1000 /μL (1.0 × 109/L) 

Platelets ≥ 25.000 /μL (25 × 109/L) 

Acceptable tolerability and recovery from AEs (see Section 4.1.4.5)
In case one of these criteria is not fulfilled, blood counts and/or the AE should be re-
evaluated at in appropriate intervals and additional laboratory data should captured in the 
eCRF. 
Treatment with BI 836826 may be delayed to enable resolution of AEs, concurrent diseases,
recovery from surgical procedures, or other individual reasons. Delays of the next infusion 
for > 4 weeks for other reasons should be discussed and agreed with the Sponsor.
4.1.4.5
Recommendations for dose modification in response to AEs
AEs should be assessed for relatedness as outlined in Section 5.3.6. In case an AE is 
considered related to ibrutinib, recommendations for dose modifications for ibrutinib should 
be considered. In case an AE is considered related to BI 836826, recommendations for dose 
modifications for BI 836826 should be followed. In case an AE is considered related to both 
ibrutinib and BI 836826, it is at the discretion of the investigator whether to modify the dose 
for both drugs at the same time, or only for one drug.
Dose modifications for adverse events related to ibrutinib:
Ibrutinib will be used within the approved label indication as per clinical routine. The 
following recommendations as per label should be considered by the investigator when 
administering ibrutinib: 
‘Interrupt ibrutinib for 

any Grade 3 or greater non-hematological, 

Grade 3 or greater neutropenia with infection or fever, or 

Grade 4 hematological toxicities. 
Once the symptoms of the toxicity have resolved to Grade 1 or baseline (recovery), ibrutinib
may be reinitiated at the starting dose. If the toxicity reoccurs, reduce dose by one capsule 
(140 mg per day). A second reduction of dose by 140 mg may be considered as needed. If 
these toxicities persist or recur following two dose reductions, discontinue ibrutinib.’


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Dose modifications for adverse events related to BI 836826
Worst NCI CTCAE Grade 
after previous dose
BI 836826
Neutrophil values at nadir after previous dose
< LLN and ≥1 x 109/L
Maintain current dose level and schedule
< 1 x 109/L and ≥0.5 x 109/L
or
<0.5 x 109/L for ≤7 days
Monitor neutrophils until recovery. Delay BI 836826 
until Grade 2. Thereafter resume at full dose.
<0.5 x 109/L for >7 days
Monitor neutrophils until recovery. Delay BI 836826 
until Grade 2. Thereafter may resume at full dose. 
Consider G-CSF support. If neutropenia Grade 4 for > 7 
days recurs despite G-CSF support in subsequent cycle, 
the dose of BI 836826 should be reduced to 50%.
Thrombocytopenia
PLT > 10 000/µL 
Maintain current dose level and schedule
PLT ≤ 10 000/µL at two 
separate measurements (at 
least 24 hours apart)
Monitor thrombocytes until recovery to Grade 3. 
Consider platelet transfusion. Delay BI 836826 until 
Grade 3 (recovery). Upon recovery, BI 836826 may be 
resumed at full dose. 
If a level of PLT ≤ 10 000/µL, at two separate 
measurements at least 24 hours apart, recurs in the 
subsequent cycle, dose of BI 836826 should be reduced 
by 50%.
Hepatic Adverse Events (elevations in ALT, AST)
Grade ≤1
(ALT/AST 3xULN)
Maintain current dose level and schedule
Grade 2
(ALT/AST >3 and 5 x ULN)
Delay BI 836826 until Grade 1. Thereafter resume at 
full dose.
Grade 3 or 4
(ALT/AST >5 and ≤20 x
ULN)
Withhold BI 836826. Monitor ALT/AST at least 1x per 
week until Grade 1. Thereafter, may resume at full dose. 
If ALT/AST elevation Grade ≥3 recurs with BI 836826 at 
full dose, reduce BI 836826 by 50%. Reescalation of BI 
836826 upon resolution of symptoms to 100% possible at 


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Worst NCI CTCAE Grade 
after previous dose
BI 836826
the investigator’s discretion in later infusions.
Hepatic Adverse Events (elevations in bilirubin)
Grade ≤1
(bilirubin 1.5 x ULN)
Maintain current dose level and schedule
Grade 2
(bilirubin >1.5 and 3.0 x 
ULN)
Delay BI 836826 until Grade 1. Thereafter resume at 
full dose.
Grade 3 or 4
(bilirubin >1.5 and 3.0 x 
ULN)
Withhold BI 836826. Monitor bilirubin at least 1x per 
week until Grade 1. Thereafter, may resume at full dose. 
If bilirubin elevation Grade ≥3 recurs with BI 836826 at 
full dose, reduce BI 836826 by 50%. Reescalation of BI 
836826 upon resolution of symptoms to 100% possible at 
the investigator’s discretion in later infusions.
Other Non-haematological Adverse Events
Grade 2
Maintain current dose level and schedule
Grade 3
Withhold study drug until Grade 1. Study drug may be 
resumed at initial or lower dose level or discontinued at 
investigator’s discretion.
A dose reduction of BI 836826 may be performed twice as outlined in the next table. In case 
an AE recurs or persists following two dose reductions, BI 836826 should be discontinued.
Occurrence of a BI 
836826 related AE 
included in previous table
BI 836826 Dose Modification at subsequent Infusion
First
Restart at assigned dose 
Second
Reduce BI 836826 by 50% at next infusion (dose level -1)
Third
Reduce dose level -1 by 50%, i.e. reduce initially assigned 
dose of BI 836826 by 75% at next infusion (dose level-2)
Fourth
Discontinue BI 836826
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Not applicable as this is an open-label single-arm trial.


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4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.  Re-supply of BI 
836826 will be managed by an IRT system.  To facilitate the use of IRT, the investigator will 
receive an IRT manual including all necessary instructions.  
4.1.7
Storage conditions
BI 836826 drug supplies will be kept in their original packaging and in a secure limited 
access storage area according to the recommended storage conditions on the medication 
label. A temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the CML (as provided in 
the list of contacts) and the Interactive Voice Response System/ Interactive Web-based 
Response System (IVRS/IWRS) must be contacted immediately.
For more details on BI 836826, please refer to the IB (c01715907-08) and to the ISF.
Ibrutinib will be stored under the conditions specified in the package insert. Excursions are 
permitted as described in the package insert. 
4.1.8
Drug accountability
The Investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drug BI 836826 delivered by the Sponsor when the following 
requirements are fulfilled:

Approval of the trial protocol by the Institutional Review Board (IRB)/ethics committee,

Availability of a signed and dated clinical trial contract between the Sponsor and the head
of the investigational site,

Approval/notification of the regulatory authority, (e.g. Competent Authority),

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated CTP

Availability of the proof of a medical license for the principal Investigator

Availability of Form 1572
The Investigator and/or pharmacist and/or investigational drug storage manager must 
maintain records of the BI 836826 product’s delivery to the trial site, the inventory at the site, 
the use by each patient, and the return to the Sponsor or alternative disposal of unused 
products.
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / pharmacist / investigational drug storage manager will maintain records that 


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document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor and/or appointed CRO, the Investigator / pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.
4.1.8.1
Ibrutinib sourcing and accountability
Ibrutinib (Imbruvica) will not be supplied by Boehringer-Ingelheim.  Sourcing of ibrutinib 
will be the responsibility of the patient and their insurance.  Ibrutinib is the standard of care 
for patients with relapsed/refractory CLL who have received at least one prior therapy and 
will be prescribed by the investigator or the patient’s physician.  Site staff should request that 
patients bring their backbone medication (i.e., ibrutinib) supply to clinic visits to record 
quantities of capsules and to monitor dosing compliance.  Unused drug should not be 
returned to Boehringer Ingelheim.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
4.2.1.1
Rescue medication
Rescue medication in term of an antidote to reverse the action of BI 836826 is not available. 
Potential side effects of BI 836826 have to be treated symptomatically.
Rescue medication or antidote to reverse the action of ibrutinib is not available or referenced 
in the package insert (R15-5127).  Side effects associated with ibrutinib have to be treated as 
described by the package insert and at the discretion of the Investigator.
4.2.1.2
Concomitant medication
All concomitant therapies to provide adequate care may be given as clinically necessary, 
unless given as anti-leukemia therapy. All concomitant treatments should be recorded in the
eCRF except for vitamins or nutrient supplements. Trade name, indication and dates of
administration of concomitant therapies will be documented. For parenteral nutrition during 
the trial, the components need not to be specified in detail. It should just be indicated as
‘parenteral nutrition’. If a patient needs general anaesthesia, it will be sufficient to indicate
‘general anaesthesia’ without specifying the details. For glucocorticoids and growth factors, 
the dose should be captured in addition in the eCRF.
Concomitant therapy should be recorded in the eCRF during the screening and on-treatment 
period, starting at the date of signature of informed consent, and ending at the end of the 
Residual Effect Period (REP), 30 days after the last infusion of BI 836826 (see Section 
5.3.7).
If a new anti-leukaemia treatment is started, it will be documented in the eCRF on a separate 
page of subsequent therapy, different from the concomitant therapies pages.


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4.2.1.2.1
Pre-Medication prior to BI 836826 infusion
Pre-medication is mandatory 30-120 minutes prior to the administration of BI 836826 to 
mitigate the risk for IRRs. In case a contra-indication for one of the drug exists, the drug may 
be replaced or omitted. If BI 836826 has been well tolerated without signs of IRRs during 
cycle 2, the glucocorticoid dose may be reduced in Cycle 3 while the other drugs are 
maintained. The first step in cycle 3 may be a reduction from 100 mg to 50 mg prednisolone 
or equivalent. If the cycle 3 doses are tolerated without IRR, the glucocorticoid may be 
reduced to 25 mg prednisolone or equivalent prior to a subsequent administration in cycle 4. 
If BI 836826 is tolerated without IRR after pre-medication with prednisolone 25 mg or 
equivalent, acetaminophen and antihistamine in cycle 4, the investigator may individually 
decide whether to administer pre-medication in cycle 5 and subsequent treatment cycles and 
which of the recommended drugs to use.
All pre-medications with doses should be source documented.
If IRRs are still seen at later infusions, pre-medication triplet should continue to be used for 
all administrations.


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Table 4.2.1.2.1:1  
Premedication table
Cycle
Patients 
Requiring 
Premedication
Premedication
Completion
Prior to 
BI 836826
1-2
all patients
Analgesic/Antipyretic p.o. or i.v.1
Antihistamine p.o. or i.v.2
Glucocorticoid i.v., equivalent to 
prednisolone 100 mg
60-120 minutes
3
all patients 
with IRR in the 
previous 
infusion and/or 
with ALC 
≥25000/µl
Analgesic/Antipyretic p.o. or i.v.1
Antihistamine p.o. or i.v.2
Glucocorticoid i.v., equivalent to 
prednisolone 100 mg
60-120 
minutes
3
patients 
without IRR in 
previous 
infusion and 
ALC 
< 25000/µl
Premedication Level -1:
Analgesic/Antipyretic p.o. or i.v.1
Antihistamine p.o. or i.v.2
Glucocorticoid i.v., equivalent to 
prednisolone 50 mg
30-120 
minutes
4 and 
subsequent
Cycles
patients with 
ALC 
< 25000/µl and 
without IRR 
and 
premedication 
at level -1 at 
previous 
infusion
Premedication Level -2:
Analgesic/Antipyretic p.o. or i.v.1
Antihistamine p.o. or i.v.2
Glucocorticoid i.v., equivalent to 
prednisolone 25 mg
30-120 
minutes
5 and 
subsequent
Cycles
patients with 
ALC 
< 25000/µl and 
without IRR 
and 
premedication 
at level -2 at 
previous 
infusion
Premedication at the discretion of 
the investigator
1
equivalent to Acetaminophen/Paracetamol; 21000 mg equivalent to diphenhydramine 50 mg i.v.


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4.2.1.2.2
Tumor Lysis Syndrome (TLS) prophylaxis and monitoring 
Patients at risk for TLS, e.g. with a high tumor burden or preexisting renal dysfunction,
should receive prophylaxis for TLS prior to the initiation of treatment. These subjects must 
be well hydrated. It is desirable to maintain a fluid intake of approximately 2-3 liters per day 
for 1-2 days before the first 50% dose of BI 836826. Treatment with allopurinol (≥300 mg 
p.o./day) or a suitable alternative (e.g., rasburicase) starting ≥ 24 hours prior to the first 
infusion should be considered unless contraindications exist. Repeated prophylaxis with 
allopurinol and adequate hydration should be continued prior to each subsequent infusion, if 
deemed appropriate by the investigator. For all patients, electrolytes, fluid balance and renal 
function should be monitored and corrected. Supportive care should be administered, 
including dialysis, if indicated.
TLS will be classified and recorded according to CTCAE: Grade 3 (present), Grade 4 (life 
threatening consequences; urgent intervention indicated) and Grade 5 (death). 
Clinical tumor lysis syndrome: is considered present if laboratory TLS is diagnosed and one 
or more of the following criteria is met:

increased serum creatinine (≥1.5 times upper limit of normal)

cardiac arrhythmia

seizure
4.2.1.2.3
Antibiotics and antivirals
Prophylactic antibiotics and antivirals are allowed. For patients considered to have an 
increased risk for infections, prophylactic therapy is strongly recommended unless medically 
contraindicated. For restrictions on use of CYP 3A inhibitors, see Section 4.2.2.1
Prophylactic antiviral therapy, e.g. acyclovir 400 mg three times a day orally, should be 
considered for patients at risk for a herpes infection or reactivation, e.g. with a history of 
recurrent herpes virus infections, herpes infection during previous anti-tumour therapy, 
neutropenia and low CD4+ cell counts (< 200 cells/µl). For restrictions on use of CYP 3A 
inhibitors, see Section 4.2.2.1
Prophylaxis against Pneumocystis jiroveci, e.g. oral trimethoprim/sulfamethoxazole 800 
mg/160 mg every other day, should be considered for patients at increased risk, e.g. patients 
with low CD4+ cell counts (< 200 cells/µl). For restrictions on use of CYP 3A inhibitors, see 
Section 4.2.2.1
Cytomegalovirus reactivation during treatment should be treated according to local standards 
or available guidelines [R10-4431]. Treatment with BI 836826 must be interrupted until 
CMV DNA is within limits prior to reactivation.
Infections should be treated according to local guidelines/standard. For restrictions on use of 
CYP 3A inhibitors, see Section 4.2.2.1.


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4.2.1.2.4
Growth factors
The use of growth factors such as granulocyte colony stimulating factor (G-CSF) will be 
permitted during therapy and should be recorded in the eCRF. However, use of G-CSF is not 
allowed within 3 days prior to laboratory at screening to reach the inclusion criterion for the 
neutrophils in patients with pre-existing neutropenia.    
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Prior antineoplastic therapy for CLL must have been discontinued as specified in inclusion 
criterion 5, and the patient must have recovered from all clinically relevant reversible 
toxicities.
No concomitant anti-neoplastic therapy during combination therapy of BI 836826 and 
ibrutinib is allowed.
Steroids:
Short term glucocorticoid medications may be used as clinically indicated to treat IRRs or 
autoimmune phenomena, 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.
CYP3A Inhibitors:
Due to possible DDIs concomitant use of ibrutinib and CYP3A inhibitors or inducers should
be avoided.
Short-term use (i.e. treatment for 7 days or less) of strong CYP3A inhibitors (e.g., antifungals 
and antibiotics) is permitted while ibrutinib therapy is temporarily discontinued. If use of a 
strong CYP3A inhibitor is required for an extended period, i.e. more than 7 days, the patient 
must be discontinued from treatment and trial.
If a moderate CYP3A inhibitor must be used (e.g., fluconazole, darunavir, erythromycin, 
diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, 
and ciprofloxacin), ibrutinib dose has to be temporarily reduced to 140 mg until the CYP3A 
inhibitor is no longer needed. 
Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more 
closely for signs of ibrutinib toxicity.
Anticoagulants and antiplatelet therapy:
Oral anti-coagulants are prohibited throughout the study. If patients require anticoagulation-
the use of unfractionated heparin or low molecular weight heparin is recommended for the 
duration of the treatment with ibrutinib. For patients with a platelet count below 50 x 109/L, 
decisions on treatment and dosage of anticoagulants and/or antiplatelet therapy should be 
made on a case by case basis with the utmost caution (P13-02472). In case the platelet count 


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declines below 50 x 109/L, treatment with acetylsalicylic acid should be paused until the 
platelet count recovers to values > 50 x 109/L.
4.2.2.2
Restrictions on diet and lifestyle
No restrictions apply with regard to diet or lifestyle.
4.2.2.3
Restrictions regarding women of childbearing potential 
Women of childbearing potential must be ready and able to use highly effective methods of 
birth control per ICH M3(R2) that result in a low failure rate of less than 1% per year when 
used consistently and correctly, and this during treatment within the trial and for at least one 
year after last dose of BI 836826 and 1 month after the last dose of ibrutinib (see Section 
3.3.2 and explanation given in the informed consent information form for more information 
on highly effective methods of birth control).
Male patients with partners of childbearing potential need to use condoms and ensure their 
partner is using an additional highly effective method of birth control, during the trial and 
until at least one year after the last dose of BI 836826 and 3 months after the last dose of 
ibrutinib. 


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
Primary endpoints:

Recommended phase 2 dose of BI 836826 in combination with ibrutinib

Number of patients with DLTs during the first treatment cycle
Secondary endpoint:

MTD
5.1.1
Primary endpoint(s)
One primary endpoint is to determine the RP2D of BI 836826 in combination with ibrutinib.
If a MTD can be determined based on the criteria as described in Section 7, the RP2D will be 
either the MTD or a lower dose.  The RP2D will be determined based on safety and efficacy 
criteria. Safety criteria include, but are not limited to the number of DLTs during the first 
treatment cycle, other AE and laboratory abnormalities may be considered in addition. 
Efficacy criteria include, but are not limited to the effect of BI 836826 on ALC, lymph node 
size as assessed by SPD, improvement of decreased blood cell counts related to CLL at 
baseline, overall response. Biomarkers may be considered in addition.
The second primary endpoint is the number of patients with DLT during the first treatment 
cycle. The number of evaluable patients per dose level with DLTs will be used to update the 
Bayesian model and to eventually determine the MTD.
5.1.2
Secondary endpoint(s)
The Secondary endpoint of this trial is the MTD.
The MTD may be considered reached if the probability that the true DLT rate is in the target 
interval [0.16, 0.33) is sufficiently large. For details on determination of MTD, please refer to 
Section 7.1. For the definition of DLT, see Section 5.3.6.2.


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ASSESSMENT OF EFFICACY
5.2
5.2.1
Overall response assessment
Response will be assessed by the investigator according to modified IWCLL guidelines [R10-
4429] (See Appendix 10.2) at all disease assessment timepoints specified in the flowchart.
All relevant clinical and radiographic information required to make each assessment must be 
made available for source verification.
Imaging:
All relevant lymph node areas should be documented with either contrast enhanced 
Computerized Tomography (CT) (preferred) or contrast enhanced MRI at the time points 
indicated in the Flow Chart.
The same method of assessment and the same technique (e.g., scan type, patient position, 
dose of contrast, injection/scan interval) should be used to characterize each identified and 
reported lesion at baseline and during study treatment and follow up. If contraindication for 
contrast agents exists, non-contrast enhanced CT or MRI scans may be performed.
Disease/response status will be assessed with imaging (CT/MRI) at screening prior to the first 
dose of ibrutinib, and at the end of Cycles 3, 6, 9 and 12. In case patients qualify for 
prolonged treatment, CT/MRIs will be performed in addition at the end of cycles 16, 20 and 
24. A CT/MRI scan will be performed at the EOT visit if it was not performed at a scheduled 
visit within 29 days prior to EOT (R10-4429). At the time of clinically suspected disease 
progression, a CT/MRI should be obtained; a confirmatory scan is not required in the case of 
PD.
The disease/response assessment will be based on Complete Blood Count (CBC) and imaging 
(CT or MRI). MRD assessments will coincide with the schedule of imaging studies. Physical 
examination of lymph nodes will be used to exclude PD prior to starting the next treatment 
cycle at visits where no imaging study is scheduled. Bone marrow biopsy results will be used 
to support the evaluation of CR, CRi and PR.


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At all disease/response assessment timepoints, response to treatment (CR/CRi/PR/PR-
L/SD/PD) should be determined based on the modified IWCLL criteria in Appendix 10. 2.  
The BOR is the best response recorded from the start of treatment until disease progression or 
initiation of subsequent therapy. Post-treatment assessments will be considered in the 
determination of best overall response as long as a patient does not initiate a new anti-CLL
therapy.
5.2.2
CBC and differential
A CBC and differential should be obtained at each disease/response assessment timepoint in 
the same laboratory at the investigational site. The sample has to be obtained prior to 
administration of pre-medication and prior to the start of BI 836826, if an infusion is 
administered on the same day. Absolute lymphocyte count, neutrophil count, hemoglobin and 
platelet count have to be captured in the eCRF and will be considered for the 
disease/response assessment, (time points specified in the Flow Chart).
5.2.3
Bone marrow aspirate and biopsy
Bone marrow aspirate and biopsy for response assessment is mandatory according to IWCLL
guidelines [R10-4429] in patients who meet all other IWCLL response criteria for CR. The 
bone marrow should be analysed morphologically and by flow cytometry and/or 
immunohistochemistry to check for CLL infiltration, or to evaluate a possible cause for 
persistent cytopenia.
Each time when a BM assessment is performed, a CBC with differential should be available, 
from the same day as the bone marrow biopsy.
A screening BM assessment is to be performed. Historical data from a BM is acceptable, if 
the BM assessment has been performed within 4 weeks of consent. A BM assessment will 
also be performed at EOT. 
5.2.4
Physical examination 
At day 1 of each treatment cycle, a physical examination will be performed to assess disease 
progression. In case Progressive Disease (PD) is suspected based on physical examination, 
imaging should be performed.


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ECOG Performance Status:
The ECOG performance status is a scale used to assess how a patient’s disease is progressing 
and how the disease affects daily living abilities.  Performance status is graded using the 
following scale from 0 to 5:
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 self-care but unable to carry out any work activities,
Up to about more than 50% of waking hours
3-
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4-
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5-
Dead
5.2.5
Constitutional symptoms
All patients will be evaluated for constitutional symptoms at the same time points when a 
physical examination is indicated in the Flow Chart. Analysis of constitutional symptoms will 
be based on the following parameters which have to be reported in the eCRF:
Unintentional weight loss (10% or more within the previous 6 months)
Significant fatigue (ECOG PS 2 or worse; inability to work or perform usual activities)
Fevers higher than 38.0°C (for 2 or more weeks without other evidence for infection)
Night sweats (for more than 1 month without evidence of infection)
5.2.6
Minimal Residual Disease (MRD)
MRD 
detection will follow a flow 
cytometry protocol in a central laboratory according to established standards as e.g. published 
by the European Research Initiative on CLL (ERIC) [R14-4986]. Modifications according to 
updated guidance are possible.
For MRD assessment, approximately 10 mL of peripheral blood will be required from each 
patient at each of the time points specified in the Flow Chart, i.e. at screening, before Day 1 
of Cycle 1 (C1D1), and at the end of Cycle 3, 6, 9 and 12. For those patients continuing 
beyond Cycle 12, assessments have to be performed at the end of Cycle 16, 20, 24, at the 
EOT visit, and at the first follow-up visit.
MRD negativity is defined as less than 1 leukemic cell per 10000 leukocytes detected in an 
multi-parameter flow cytometry with adequate sensitivity. In case peripheral blood is MRD 
negative, approximately 4 mL of bone marrow aspirate will be taken from the patient in 
addition to peripheral blood at the next time point when a blood MRD assessment is 
scheduled in order to confirm MRD negativity in bone marrow. 
At any time when a BM is performed to confirm a clinical CR or CRi, a blood and bone 
marrow sample should be sent for MRD.


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At all timepoints when MRD sample is obtained, a CBC with differential will be performed 
at the central laboratory. This CBC/differential from the central laboratory should be used for 
disease/response assessment whenever possible.
Detailed instructions for sampling, handling, storage, and shipment of the MRD samples will 
be provided in the laboratory manual included in the ISF. Date of sampling will be recorded 
in the eCRF.
ASSESSMENT OF SAFETY
5.3
Safety will be assessed by:

Overall incidence and severity of AEs, as well as seriousness and relatedness

AE leading to treatment discontinuation

AE leading to death

AE of special interest

Changes in safety laboratory parameters

Changes in vital signs, physical examination, ECG
Changes in laboratory parameters and AEs will be graded according to US NCI CTCAE 
version 4.0 [R10-4848]. In addition, hematological toxicity based on laboratory values will 
be assessed using the criteria as described in IWCLL guidelines (R10-4429).
5.3.1
Physical examination
A physical examination including height (only at screening), weight and ECOG performance 
score (see Section 5.2.4) as well as the tumor size determination (see Section 10.2) 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 AEs.
5.3.2
Vital signs
Vital signs (blood pressure, pulse rate and body temperature) will be recorded at every visit 
during screening, treatment and follow-up, before proceeding with any other protocol specific 
procedure and after at least 5 minutes of rest. More frequent measurements of vital signs must 
happen on the days of study drug administration, at the investigator’s discretion, or to detect 
possible IRRs which have then to be reported as AE. In case of IRR, the investigator should 
decide whether to intensify or prolong the monitoring of vital signs of the patient and to adapt 
patient’s surveillance during subsequent applications.
5.3.3
Safety laboratory parameters
5.3.3.1
General safety laboratory parameters
Blood and urine samples have to be collected at the time points specified in the Flow Chart. 
However, more frequent samplings may be done to perform additional safety laboratory 


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examinations whenever the investigator deems it necessary. Local laboratories of the sites 
will be used for safety laboratory assessments.  Sample and handling will be performed in 
accordance with local site procedures.
Hematology:
Hemoglobin, red blood count (RBC), white blood count (WBC) with 
differential:  neutrophils, basophils, lymphocytes, monocytes, 
eosinophils - expressed preferably in absolute values percentages 
accepted (including Gumprecht shadow (Smudge Cells) and Large 
Unstained Cells (LUC)) and platelets
Biochemistry:
Sodium, potassium, calcium, inorganic phosphate, creatinine, AST, 
ALT, Alkaline Phosphatase (AP), Lactate Dehydrogenase (LDH), 
Blood Urea Nitrogen (BUN), uric acid, total bilirubin. If total bilirubin 
is elevated, direct bilirubin should be provided. 
If direct bilirubin is elevated, the following tests to assess haemolysis 
should be obtained in addition: direct antiglobulin test, reticulocytes, 
haptoglobin.
Coagulation:
Activated Partial Thromboplastin Time (aPTT) in seconds, 
Prothrombin Time (PT) in seconds or International Normalized Ratio 
(INR) have to be measured at screening, at visit 1 of every other cycle 
and at the EOT visit
Urine:
Urine pH, glucose, erythrocytes, leukocytes, protein, nitrite will be 
analysed by dipstick. In case of suspicion of a clinically relevant 
proteinuria, i.e. at least 2 positive results after prior negative tests, 
protein should be quantified in 24 hour urine
Pregnancy test:
A pregnancy test in serum or urine needs to be obtained at the time 
points indicated in the Flow Chart in women of childbearing potential
5.3.3.2
Serum immunoglobulin levels
Serum immunoglobulin levels (IgA, IgG, Immunoglobulin M (IgM)) have to be analysed
quantitatively at screening, at visit 1 of each other cycle (Cycle 2, 4, 6, etc…) and at the EOT 
visit.
5.3.3.3
Screening for laboratory evidence of Tumor Lysis Syndrome
To allow for early treatment in case TLS develops, monitoring is recommended.
After the first 50% dose of BI 836826 in Cycle1 on Day 2, the following laboratory 
parameters should be obtained in appropriate intervals, but at least twice within the first 24 
hours after the end of infusion: 

uric acid

potassium

phosphorus

calcium


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
LDH

creatinine
In case of laboratory values pointing towards laboratory signs of TLS, hospitalization, 
appropriate monitoring and treatment should be initiated (see also Section 4.2.1.2.2).
5.3.3.4
Virology
5.3.3.4.1
Screening for hepatitis B, hepatitis C and HIV
A local laboratory will be used.
Patients with active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or laboratory 
evidence of a chronic infection have to be excluded from the trial. The same applies to 
patients with HIV infection or detection of a HIV infection at screening.
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), HBV DNA and HCV RNA by quantitative 
assays. HIV Antibody (anti-HIV).
Patients can be treated with BI 836826 if:

HBV DNA negative

HCV RNA negative

HIV antibody negative
Patients who are HBc antibody positive at screening will be monitored for potential HBV 
reactivation by quantitative HBV DNA at visit 1 of every even course and at the EOT visit. If 
there is evidence for HBV reactivation, immediately discontinue BI 836826 and start 
appropriate treatment for HBV.
5.3.3.4.2
CMV monitoring 
Monitoring of CMV has to be performed at the time points indicated in the Flow Chart at a 
local laboratory by quantitative Polymerase Chain Reaction (PCR) assays to detect CMV 
DNA. The same method and cutoff should be used for the same patients, and preferably for 
all patients treated at the same investigational site.
Results have to be reported in the eCRF.
5.3.4
Electrocardiogram
A 12-lead resting ECG will be performed in all patients according to the schedule in the Flow
Chart.  The ECG will be assessed locally for pathological results to be recorded as an AE if 
deemed clinically significant by the Investigator, or qualified individual delegated by the PI. 
Additional examinations should be done whenever the Investigator deems necessary.  ECGs
will be stored locally at the clinical sites and not transferred to a central lab.


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5.3.5
Other safety parameters
Not Applicable.
5.3.6
Assessment of adverse events
5.3.6.1
Definitions of AEs 
Adverse Event:
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious Adverse Event (SAE):
A SAE is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

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 judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
AEs considered “Always Serious”:
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the Remote Data Capture (RDC) A 
copy of the latest list of “Always Serious AEs” will be provided to you upon request. These 
events should always be reported as SAEs.
Every new occurrence of cancer of new histology must be classified as serious event 
regardless of the time since the discontinuation of the trial medication and must be reported 
as described in 5.3.7, subsections “AE collection” and “AE reporting to sponsor and timelines


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Adverse events of special interest:
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
The following events are considered as AESIs:
1. Hepatic injury
2. Late onset infections
3. Any AE qualifying for a DLT
Hepatic injury:
Although rare, drug-induced liver injury is under constant surveillance by sponsors and 
regulators and is considered an AESI.  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 are important for patient safety.
In patients with normal transaminases and bilirubin at baseline, a hepatic injury is defined by 
any of the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT ≥3 fold Upper Limit of Normal (ULN) combined 
with an elevation of total bilirubin ≥2 fold ULN measured in the same blood sample, 
and/or

marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
In patients with elevated transaminases and/or bilirubin at baseline in line with in- and 
exclusion criteria of this protocol, a hepatic injury is defined by the following alterations of 
hepatic laboratory parameters: 

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 sample, and/or

marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “Drug Induced Liver Injury (DILI)
checklist” provided via the RDC-system and within the ISF.
Work-up as outlined in the “DILI-checklist” will serve to confirm the initial abnormality, 
obtain a comprehensive history and medical assessment, assess the severity of liver injury, 
evaluate data for potential alternative causes and decide on management of trial drug. Follow 
up of the potential DILI case should be initiated within 48 hours of the initial laboratory alert, 
or as soon as possible if timelines cannot be met. When performing all of the required 
examinations, the investigator may use clinical judgement, based on the patient’s disease, 
comorbidities, clinical situation, past viral infections and risk for reactivation, exposure, prior 
therapy for malignant disease, co-medications and other factors as applicable. The sequence 
of tests in the DILI checklist may be used as guidance. The findings from the hepatic imaging 
(including comparison to prior imaging if available) must be made available as soon as 


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possible as part of the AE reporting process and/or on the respective CRF pages. In the event 
the etiology of the abnormal liver test results is not identified based on the imaging (e.g. 
biliary tract, pancreatic or intrahepatic pathology), the “DILI checklist” must be completed. 
Virus reactivation should be assessed by viral load and PCR testing where possible. 
Diagnostics for auto-immune hepatitis, Wilson’s disease and hemochromatosis can be 
completed at the end of all assessments, as these examinations will not change within a short 
time period but can be considered proof of a long persisting chronic condition. In case a 
laboratory parameter of the DILI checklist cannot be performed, the investigator should 
provide a comment including a brief assessment of the relevance of this parameter for the 
overall evaluation of DILI.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
If the investigator determines any AESI is related to study drug, the administration of the 
study drug must be managed according to Section 4.1.4 of the protocol.
Late onset infections with onset date during the extended follow-up period and considered 
clinically relevant and/or BI 836826 related by the investigator are also AESIs. 
Any AE qualifying for a DLT:
No other AESIs have been defined for this trial.
Severity of AEs:
The severity of AEs should be classified and recorded in the (e)CRF according to the CTCAE 
v 4.0. 
Causal relationship of AEs:
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.
Yes:
There is a reasonable causal relationship between the trial medication
administered and the AE.
No:
There is no reasonable causal relationship between the trial medication
administered and the AE.
The causal relationship must be provided by the Investigator for the trial medication BI 
836826 investigational drug and for the backbone therapy, ibrutinib.
The reason for the decision on causal relationship needs to be provided on the SAE form (if 
applicable).


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5.3.6.2
Dose limiting toxicities 
All drug related AEs, including SAEs and deaths, will be carefully evaluated by investigators 
for DLT. Dose escalation decisions will be based on DLTs observed in Cycle 1.  Dose 
Limiting Toxicity is defined as follows:

Any non-hematologic AE of Grade ≥ 3 related to BI 836826 and/or ibrutinib will be 
considered DLT, except:
-
Infusion-related reaction, any Grade
-
Grade 3 AST- and/or ALT elevation without concomitant bilirubin 
elevation or any other asymptomatic Grade 3 laboratory abnormality with 
spontaneous recovery within 1 week

The following hematologic AEs related to BI 836826 and/or ibrutinib will be 
considered DLT:
-
Grade 4 neutropenia with concomitant infection
-
Grade 4 febrile neutropenia, and Grade 3 febrile neutropenia not resolving 
within 72 hours with appropriate treatment (antibiotics, antivirals, antifungals, 
growth factor support)
-
Grade 4 thrombocytopenia with clinically significant bleeding
-
Grade 4 anemia
-
Any Grade 5 hematologic AE 
Patients will be evaluable for MTD in Cycle 1 if:

a DLT occurs at any time, or

a minimum exposure to BI 836826 and ibrutinib has been achieved. The minimum 
exposure is defined as ≥80% of the planned ibrutinib doses (since Day 1 of Cycle 1) 
and all planned administrations of BI 836826 in Cycle 1. If the administration in 
Cycle 1 on Day 15 is delayed, the DLT evaluation will be prolonged to cover 14 days 
after the D15 administration.
All patients who have started trial treatment, but do not meet at least one of the above criteria 
at the end of Cycle 1 will be evaluated for safety, but replaced for MTD evaluation.
5.3.7
Adverse event collection and reporting
AE Collection:
The following must be collected and documented on the appropriate eCRF by the 
Investigator:
-
From signing the informed consent onwards through REP, until individual patient’s 
end of trial:
all AEs (non-serious and serious), and all AESIs.
-
After the individual patient’s end of trial:  the investigator does not need to actively 
monitor the patient for new AEs but should only report relevant SAEs and relevant 
AESIs of which the investigator may become aware of.  


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The REP is defined as 30 days after the last application of BI 836826. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment please see Section 7.3.4. 
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). In 
specific occasions the Investigator could inform the Sponsor upfront via telephone. This does 
not replace the requirement to complete and fax the BI SAE form.
Information required:
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form (if applicable)
The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if 
applicable):

Worsening of pre-existing conditions other than the underlying disease
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after trial completion must be followed up until they 
have resolved, have been sufficiently characterized, or no further information can be obtained.
Pregnancy:
In the rare case that a female patient participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
Drug Exposure During Pregnancy (DEDP) to the Sponsor’s unique entry point (country-
specific contact details will be provided in the ISF). The Investigator must also report 
pregnancies that occurred in a female partner of a male subject. The Pregnancy Monitoring 
Form for Clinical Trials (Part A) should be used. 
The outcome of the pregnancy associated with the DEDP must be followed up and reported 
to the Sponsor’s unique entry point on the Pregnancy Monitoring Form for Clinical Trials 
(Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
Exemptions to SAE Reporting:


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Progressive Disease (PD) in oncology trials is a trial endpoint for analysis of efficacy. PD is 
exempted from reporting as a (S)AE.  Progression of the subject's underlying malignancy will 
be recorded in the appropriate pages of the (e)CRF as part of efficacy data collection.  Death 
due to PD is to be recorded on the appropriate CRF page and not on a SAE form.
Examples of exempted events of PD are:
•
Progression of underlying malignancy PD: if PD is clearly consistent with the suspected 
progression of the underlying malignancy as defined by the respective response criteria. 
•
Hospitalization/Procedures due solely to the progression of underlying malignancy PD
•
Clinical symptoms and/or signs of progression (with or without confirmation by objective 
criteria e.g. imaging, clinical measurement): if the symptom can exclusively be 
determined to be due to the progression of the underlying malignancy and does meet the 
expected pattern of progression for the disease under study.
However, when there is evidence suggesting a causal relationship between the study drug and 
the progression of the underlying malignancy, the event must be reported as an (S)AE on the 
SAE form and on the (e)CRF.
 
 
 
 
 
  
 


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OTHER ASSESSMENTS
5.6
Not applicable.


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APPROPRIATENESS OF MEASUREMENTS
5.7
The endpoints chosen for this study are generally recognized methods of assessing efficacy
and safety in CLL studies and are in line with the recommendation from International 
Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group 
published in 2008 (R10-4429).
Adverse events will be graded according to the NCI CTC AE criteria version 4.0 (R10-4848), 
which is commonly used in the assessment of AEs in cancer patients.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
The screening period is a maximum of 21 days prior to the start of the Run-In Phase.  Patients
who meet all trial eligibility criteria will continue into the Run-in phase and begin two weeks 
(+/- 2 days) of ibrutinib monotherapy dosing prior to the first infusion of BI 836826.
Treatment with BI 836826 will be administered in cycles of 28 days duration. The dose of BI 
836826 will be tapered up to the target dose during Cycle 1 to mitigate the risk for IRRs and 
TLS. Treatment with BI 836826 starts with the first administration of 10 mg (‘pre-dose’) on 
Cycle 1 Day 1 (see Section 3.1), followed by 50% of the target dose of BI 836826 on Cycle 1 
Day 2 and Cycle 1 Day 8. The first full dose of BI 836826 (100% of the target dose) will be 
administered on Cycle 1 Day 15.  
In Cycles 2 to 4, patients will receive 100% of the target dose of BI 836826 on Day 1 and 
Day 15 of each cycle. In Cycles 5 to 12, BI 836826 will be administered at 100% of the target 
dose on Day 1 only. A response evaluation, including imaging (if clinically indicated), will 
be performed at the end of Cycle 3, 6, 9 (Day 21-28) and 12 (Day 21-30). Only those patients 
with CR, CRi, or MRD negative PR in the response assessment at the end of Cycle 12 will be 
allowed to continue with additional 12 Cycles of combination treatment or until relapse, 
undue toxicity, withdrawal of consent or until the end of the maximum treatment duration of 
BI 836826 at the end of 24 Cycles, whichever comes first. In patients who continue treatment 
beyond 12 cycles and proceed to Cycles 13-24, a response evaluation including imaging (if 
clinically indicated) will be performed at the end of Cycles 16, 20, and 24.  
Once a patient stops the BI 836826 treatment, he/she will undergo an End of Treatment 
(EOT) visit. 
In case the patient completes Cycle 12 or Cycle 24 and terminates treatment with BI 836826 
according to protocol in the absence of PD, the assessments indicated for the EOT and End of 
REP (EoR) visit in the flowchart may be performed once at the time specified for the EoR 
visit.
In case a patient experiences PD, an EOT visit including imaging should be performed as 
soon as possible after discontinuation of BI 836826 and prior to initiation of subsequent 
therapy. An EoR visit should be performed 30 days (+ 7 days) after EOT.
In case BI 836826 is discontinued permanently for reasons other than PD, at any other 
timepoint than end of cycle 12 or end of cycle 24, e.g. due to AEs, the patient should 
complete an EOT visit as soon as possible after discontinuation of BI 836826 or when the 
decision to discontinue BI 836826 is taken. 
If the EOT is performed less than 30 days after the last dose of BI 836826, an additional EoR 
visit has to be scheduled after 30(+ 7 days), if the EOT visit is ≥30 days after the last dose of 
BI 836826, the EOT and EoR may be performed on the same date.
The “last-patient-last-visit-primary-endpoint” is defined in Section 8.6.  


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All patients should adhere to the visit schedule as specified in the Flow Chart. However, in
case a patient misses a visit and the patient reports to the investigator between the missed and 
the next scheduled visit, the procedures that were planned at the missed visit should be done 
and the actual date and the reason for the delay should be documented in the eCRF.  In the 
case a Day 1 treatment of BI 836826 is delayed, all subsequent visits of a cycle will be 
recalculated based on the actual date of Visit 1 of the delayed cycle.
Some flexibility is allowed in scheduling the visits according to the time window specified in 
the Flow Chart.
If pathological laboratory values or other issues require an additional unscheduled visit, new 
eCRF pages will be completed for the unscheduled visit. At the unscheduled visit, it is 
sufficient to record only the clinical relevant labs/examinations performed. 
In case ibrutinib is to be discontinued permanently for other reasons than PD, patients may be 
kept on BI 836826 and follow the treatment visit schedule as outlined in the Flow chart.
Treatment may be delayed to enable resolution of AEs, concurrent diseases or recovery from 
surgical procedures, or other individual reasons. Day 15 in Cycles 1-4 may be delayed by 1 
week, in case a longer delay would be required, this dose should be omitted. Day 1 in Cycles 
2-24 may be delayed by up to 4 weeks. In case longer delays would be required, this should 
be discussed and agreed between the investigator and the sponsor’s Clinical Monitor.  
Ibrutinib dose modifications will be at the discretion of the Investigator.  Changes in ibrutinib 
dosing will be recorded in the eCRF.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
The investigations as outlined in the Flow Chart will be performed at the respective visits.
All assessments should be performed prior to BI 836826 administration on dosing days, 
unless otherwise specified.
6.2.1
Screening and run-in period(s)
Screening Period:
The examinations required for the screening visit may be conducted within a time interval of 
21 days prior to the start of ibrutinib and up to 35 days from the first drug administration of 
BI 836826 on Cycle 1 Day 1.  Pre-ibrutinib disease assessments should be performed close to 
the start of ibrutinib (within 7 days).  Patients who have consented should secure sourcing 
and be on a stable and continuous dosing of ibrutinib prior to Cycle 1 Day 1.  
The site should call IRT after informed consent is obtained to register the patient as enrolled. 
The patient will be officially entered via IRT after all the eligibility criteria are met.
If for administrative or medical reasons, the patient does not start with study medication after 
the defined screening period, it is allowed to re-screen a patient within 7 days. In case a 
patient is re-screened, he/she will keep the same patient number and an unscheduled 
additional screening visit will be created with the examinations that were re-performed for 
screening. 


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Biomarkers tests, imaging and virology testing may not need to be repeated if performed 
within the permitted window, relative to Cycle 1 Day 1.  Other tests (i.e. safety labs) must be 
performed if older than 48 hours. 
Baseline Conditions:
Concomitant diagnoses present at study entry and/or during screening and relevant to the 
patient’s safety during the trial as judged by the investigator will be recorded in the eCRF.
Demographics and Oncological History:
Demographics (sex, birth date, race and ethnicity) will be collected during the screening visit. 
A detailed cancer history will be obtained. The date of first diagnosis of CLL (month and 
year may be sufficient) will be recorded in the eCRF. The current stage according to the Rai
classification (See Section 10.1) should be recorded [R10-4429]. Previously administered 
chemo-and immunotherapy will be documented, including start and end dates (year and 
month may be sufficient), the treatment regimen/protocol with the number of courses 
(chemo-, immunotherapy), the best response obtained (CR, Cri, PR, PR-L, SD, PD, 
unknown). If the patient has received an autologous Stem Cell Transplant (SCT) or an 
allogeneic stem cell transplant, procedural details, including the treatment regimen prior to 
transplantation should be collected. Documentation of previous radiotherapy should include 
the total radiation dose and radiation field(s). Previous surgeries within the past 5 years 
should be recorded. In addition, any previous surgery, which may, according to the 
investigator affect tumor assessment in this trial, e.g. splenectomy or removal of lymph nodes, 
should be documented in the eCRF.
Re-screening:
Sites will be allowed to re-screen patients.  If more than 3 weeks have elapsed prior to re-
screening, all screening procedures must be repeated.  In case a patient is re-screened, the 
patient will keep the same assigned patient number.
Below are the specific requirements during the screening period.  For a global overview of 
tests to be performed, please refer to the Flow Chart.
Run-In Phase:
Patients who complete the screening phase and are still eligible will enter the run-in phase.  
The run-in phase will begin with the first dose of ibrutinib and continue for two weeks of 
dosing (+/- 2 days) until Cycle 1 Day 1. Patients who are unable to receive ≥ 80% of ibrutinib 
doses (12 doses) during the run-in phase will be ineligible to continue on trial and would be 
considered “screen failures”.  These patients do not need to continue on trial nor complete an 
EOT Visit or follow-up. They will need to be replaced.  To confirm compliance with daily 
dosing of ibrutinib during the run-in phase and Cycle 1, patients entered in the trial will be 
required to maintain and complete a dosing diary.  At the end of the run-in phase and prior to 
the first infusion of BI 836826 on day 1, patients must meet the laboratory requirements listed 
in Section 4.1.4 .
6.2.2
Treatment period(s)


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The first BI 836826 dose should within 35 days after the first screening procedure has been 
performed and within 14 days after the start of ibrutinib, on Day 1 of the first cycle, as a pre-
dose infusion of 10 mg, starting with the first half dose the next day, on Day 2 of first cycle
and the second half dose on Day 8. A treatment cycle is defined as 28 days. 
Patients may continue with BI 836826 treatment beyond 12 cycles if they achieve a CR
(MRD negative or positive) or a PR (MRD negative) at the Cycle 12 disease assessment time 
point.  Treatment beyond Cycle 12 may continue until relapse, undue toxicity, withdrawal of 
consent or until a maximum of 24 treatment cycles with BI 836826. 
Site staff to contact IRT at each dosing visit to obtain medication number(s) of vial(s) to be 
used.
All peripheral blood and bone marrow samples will be handled according to the laboratory 
manual instructions in ISF and lab manual.
For a global overview of tests to be performed, please refer to the Flow Chart.
6.2.2.1
End of treatment visit
The EOT visit will be performed after permanent discontinuation of BI 836826 (for any 
reason) and as soon as possible, but no later than 7 days after the last administration of BI 
836826.  Site staff to contact IRT to register the patient as discontinued. Ibrutinib dosing 
may continue throughout the EOT period and beyond based on the discretion of the 
Investigator or patient’s physician.  
If the decision is to discontinue a patient from combination treatment on a scheduled protocol 
visit and the last dose of BI 836826 has been less than 7 days, the visit can be used as the 
EOT and tests do not need to be repeated.  
6.2.3
Residual Effect Period (REP) and trial completion
6.2.3.1
Residual Effect Period (REP)
The REP is defined in Section 5.3.7. The EoR visit should not be performed earlier than 30 
days after permanent discontinuation of the trial medication. The EoR visit should be 
performed at the end of the REP (+ 7 days).  Patients who discontinue the trial due to PD will 
be considered off trial at the completion of the EoR visit. There will be an additional contact 
with regard to the End of Trial status as soon as the end of the whole trial is reached (see 
Section 8.6).
The information collected at this visit should include all new AEs and associated concomitant 
medications and anti-cancer treatments that occurred after EOT and a follow-up of AEs
ongoing at EOT.
6.2.3.2
Trial completion for an individual patient:
A patient is considered to have completed the trial in case any of the following applies:


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
Completion of planned treatment period 

Withdrawal of Consent

Death
At the earliest of the above criteria, the Patient Completion (PC) information should be 
entered in the CRF. There will be an additional contact with regard to the End of Trial status 
as soon as the end of the whole trial is reached (see Section 8.6).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN – MODEL
7.1
This trial will be performed as an open-label single-arm study. The primary objective of the 
trial is to determine the RP2D of BI 836826 in combination with ibrutinib. The RP2D will be 
either the MTD or a lower dose. To determine the MTD, patients are entered sequentially into 
escalating dose cohorts. The dose-finding will be guided by a Bayesian 5-parameter logistic 
regression model with overdose control (R13-4806), (R13-4803). This design is based on
practical experience and is a preferable algorithmic method due to its superior ability to 
identify the dose with a desired toxicity rate and its allocation of a greater proportion of 
patients to doses at, or close to, that dose (R13-4802, R13-4804, R13-4805).
In the following, DLT denotes a dose-limiting toxicity occurring during the first cycle. The 5-
parameter logistic regression model is defined as follows. Let π1,d1 be the probability of 
having a DLT when giving dose d1 of BI 836826, and π2,d2 the probability of having a DLT
when giving dose d2 of ibrutinib, respectively. A logistic regression is used to model the dose-
toxicity relationship for each of these drugs individually:
BI 836826:
logit(π1,d1) =log(α1) + β1log(d1/d1*)
Ibrutinib:
logit(π2,d2) =log(α2) + β2log(d2/d2*)
Here, the doses d1* = 200mg and d2* = 420mg BBB represent the reference doses for BI 
836826 and ibrutinib, respectively. 
Under independence, the probability of a DLT when giving the combination dose d1, d2 is 
obtained as 
π0
12,d1,d2 = π1,d1 + π2,d2 - π1,d1π2,d2
with corresponding odds 
odds(π0
12,d1,d2)= π0
12,d1,d2 /(1- π0
12,d1,d2)
In order to account for a potential positive (higher toxicity than expected under 
independence) or negative (lower toxicity than expected under independence) interaction 
between BI 836826  and ibrutinib, a dose-dependent interaction term -∞<η<∞ is introduced 
in the model:
odds(π12,d1,d2) = odds(π0
12,d1,d2) exp(η d1/d1* d2/d2*)
and π12,d1,d2 is used in the likelihood
rd1,d2 ~ Binomial(nd1,d2,π12,d1,d2)
where rd1,d2 denotes the number of DLTs observed in nd1,d2 patients at dose combination d1, d2.
Since a Bayesian approach is applied, prior distributions f for each of the parameter vectors 
θ1=(log(α1),log(β1)), θ2=(log(α2),log(β2)) and for the interaction term η need to be specified. 


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The prior distributions for θk will be specified as a mixture of two bivariate normal 
distributions, 
f (θk) = a1,k f1 (θk) + a2,k f2 (θk)
with
a1,k, a2,k the prior mixture weights (a1,k + a2,k = 1), k=1,2 and
fi(θk) = MVN(µik, ∑ik) a bivariate normal distribution with mean vector µik and covariance 
matrix ∑ik where
Σ = 	


,

 ,
 ,

 ,
 ,


,

Mixture prior distributions have the advantage that they allow for specification of different
logistic dose-toxicity curves, therefore making the prior more robust. A weakly-informative 
normal prior distribution will be used for η.
The estimated probability of DLT at each dose level from the model will be summarized 
using the following intervals:
Under dosing: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over dosing: [0.33, 1.00]
The BLRM-recommended dose for the next cohort is the level at which the probability for 
the target toxicity interval is maximal out of the dose candidates satisfying the escalation 
overdose control criterion EWOC. Per EWOC it should be unlikely (<25% posterior 
probability) that the DLT rate at the dose combination will exceed 0.33. The overdose control 
criterion requires the probability of overdosing to be below 0.25.However, the maximum 
allowable dose increment for the subsequent cohort will be no more than 100% for each drug
The MTD may be considered reached if the following criteria are fulfilled:
1.
The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of 
the MTD is above 0.50, OR
2. At least 15 patients have been treated in the study, of which at least 6 at the MTD.
Prior derivation:
To determine the prior distributions for (log(α1), log(β1)) and (log(α2), log(β2)), a meta-
analytic predictive (MAP) approach will be used. Toxicity information on BI 836826 from 
the 1270.1 Phase I study and from two published studies of ibrutinib will be incorporated.
Exact details on the derivation of the prior distributions and on the evaluation of the model 
using hypothetical data scenarios and operating characteristics are provided in the statistical 
appendix; a brief description is given here.
The historical data for BI 836826 can be found in Table 7.1:1. For ibrutinib, the historical 
data can be found in Table 7.1:2.


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Table 7.1:1  
Historical data for BI 836826
Study
Dose(mg)
N of DLTs during first cycle
/ N of patients
1270.1
1
0/3
3
0/3
9
0/6
25
0/6
50
0/3
100
0/3
200
1/6
400
0/3
800
1/2


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Table 7.1:2  
Historical data for ibrutinib
Study
Dose(mg)
N of DLTs / N of patients
Byrd et al*
420
2 / 51
840
4 / 34
Advani et al**
87.5
0 / 7
175
1 / 9
350
0 / 6
560
0 / 9
581
1 / 18
875
0 / 7
* No DLTs were reported for this study. The number of DLTs was therefore approximated by the number of AEs leading to 
discontinuation.
** Dosing based on mg/kg was used. The corresponding fixed dose was calculated as the dose corresponding to a weight of 
70kg. 
The following steps were used to derive the prior distributions for all parameters:
1. log(α1), log(β1): 
a.
The meta-analytic-predictive prior was derived using the information in Table 
7.1:1, allowing for moderate to substantial between-trial heterogeneity. This 
mixture component was assigned 90% mixture weight.
b. A second, weakly-informative component was added with 10% mixture 
weight.
2. log(α2), log(β2): 
a.
The meta-analytic-predictive prior was derived using the information in Table 
7.1:2, allowing for large to very-large between-trial heterogeneity. This 
mixture component was assigned 90% mixture weight.
b. A second, weakly-informative component was added with 10% mixture 
weight.
3. η: based on the a priori assumption of no interaction between the two compounds, a 
normal distribution with mean 0 and standard deviation 0.56 was chosen. A the 
starting dose combination, the corresponding 95% prior interval covers an up to 1.4
fold increase (or decrease) in the odds of DLT over no interaction.
The prior distributions are given in Table 7.1:3. The corresponding prior probabilities of a 
DLT at different doses and the corresponding probability of under-dosing, targeted dosing 
and overdosing are shown in Table 7.1:4. As can be seen from Table 7.1:4, the dose 
combination 100mg BI 836826 and 420mg ibrutinib has prior probability of overdosing 
below 25%; it fulfills the overdose criterion and is therefore a suitable starting dose 
combination.


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Table 7.1:3  
Prior distributions
Parameter
means, standard deviations, correlation
mixture weight
log(α1), log(β1): component 1
(-2.282, 0.062, 1.065, 0.699, -0.105)
0.9
log(α1), log(β1): component 2
(-2.282, 0.062, 2, 1, 0)
0.1
log(α2), log(β2): component 1
(-2.819, -0.522, 1.303, 0.926, -0.047)
0.9
log(α2), log(β2): component 2
(-2.819, -0.522, 2, 1, 0)
0.1
η
0, 0.56
N/A
Table 7.1:4  
Prior probabilities of DLT 
Dose BI 
836826
Dose 
ibrutinib
Probability of true DLT rate in 
Quantiles
[0,0.16]
[0.16,0.33]
[0.33,1]
Mea
n
StD
2.5%
50%
97.5%
50mg
420mg
0.695
0.209
0.096
0.144
0.140
0.011
0.099
0.545
100mg
420mg
0.607
0.262
0.131
0.171
0.150
0.016
0.125
0.592
200mg
420mg
0.448
0.312
0.241
0.233
0.181
0.025
0.181
0.707
300mg
420mg
0.347
0.279
0.373
0.302
0.226
0.025
0.243
0.843
400mg
420mg
0.305
0.232
0.463
0.361
0.268
0.021
0.298
0.931
NULL AND ALTERNATIVE HYPOTHESES
7.2
The analyses in this trial are descriptive and exploratory. No formal statistical tests will be 
performed.
PLANNED ANALYSES
7.3
For the analysis of all primary, secondary and further endpoints, all treated patients (i.e. 
treated with at least one dose of trial medication) will be included in the analysis.
For the determination of MTD only MTD evaluable patients will be considered.
Cohorts of patients treated with BI 836826 in combination with ibrutinib will be evaluated 
continuously based on the totality of the safety data available in order to determine the RP2D 
and MTD.
The primary analysis of all primary, secondary and further endpoints will be conducted when 
“last-patient-last-visit-primary-endpoint” has been reached (see Section 8.6).
7.3.1
Primary endpoint analyses


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RP2D and number of patients with DLTs in first cycle, measured from first administration of 
BI 836826 until the end of the first cycle.  The number of patients with DLTs at each dose 
level will be presented (all cycles and cycle 1 separately).
7.3.2
Secondary endpoint analyses
The secondary endpoint MTD will be analysed via the number of patients with DLTs during 
the first treatment cycle.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
AEs with an onset between start of treatment with BI 836826 and end of the REP, a period of 
30 days after the last dose of BI 836826, will be assigned to the treatment period for 
evaluation. All treated patients will be included in the safety analysis. In general, safety 
analyses will be descriptive in nature and will be based on BI standards. No hypothesis 
testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between start of treatment with BI 836826 and end of the REP will be 
considered ‘treatment-emergent’.  The REP is defined as last administration of BI 836826 
plus 30 days.  Adverse events that start before first intake of BI 836826 and deteriorate under 
treatment will also be considered as ‘treatment-emergent’. Adverse events occurring during 
screening and/or run-in period with ibrutinib as well as during post-treatment will be listed 
separately.
Analyses of AEs of all treatment cycles will be carried out under the initial treatment.
Adverse events will be graded according to CTCAE Version 4 and reported according to BI 
standards.
Serious Adverse Events, drug-related AEs and AESI will be tabulated. In addition, events 
leading to treatment discontinuation will be examined.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of the MedDRA.
Descriptive statistics will be used to describe changes in laboratory tests over time. In 
addition, all abnormalities of potential clinical significance will be reported. In general, 
potential clinical significance is defined as at least CTC Grade 2 and an increase in CTC 


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classification from baseline. Hematologic toxicity based on laboratory values will be not only 
described using CTCAE grading but also using the criteria described in the ‘Guidelines for 
the diagnosis and Treatment of CLL (R10-4429).
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
 
INTERIM ANALYSES
7.4
No formal interim analysis is planned for this trial.  Interim safety evaluations will be 
performed as considered necessary.  Safety evaluations will be performed after each dose 
cohort by the SRC (for SRC details refer to Section 3.1).   SRC meeting minutes and outputs 
provided for these SRC meetings will be documented and archived in the clinical trial master 
file.  
HANDLING OF MISSING DATA
7.5
In general, missing data will not be imputed. Every effort will be undertaken to obtain the 
date of progression or response for patients known to have progressed or experienced a 
response and to obtain complete information on all AEs. Consequently no missing data will 
be imputed unless otherwise specified.
For partial or missing AE onset and/or end dates, BI internal rules will be applied for 
imputation.
RANDOMIZATION
7.6
No randomisation will be performed. Patients will be assigned into escalating dose cohorts by 
order of admission into the trial.
DETERMINATION OF SAMPLE SIZE
7.7
Approximately 20 patients  will be expected for this trial. The exact number of patients 
within a cohort of the trial will be based on the recommendation of the SRC and the criteria 
specified (see Section 7.1). Based on the simulation study to evaluate operating 
characteristics of the BLRM (see Section 10.7), 20 patients should be a good estimate for 
patients to be treated in the dose escalation part for the model to have reasonable operating
characteristics relating to its MTD recommendation.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for GCP and relevant BI SOPs*.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, and also of any serious breaches of the 
protocol or of ICH GCP*.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. 
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF.
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective 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 Investigator must give a full explanation to trial patients including the items listed below 
in association with the use of the patient information form, which is prepared avoiding the 
use of technical terms and expressions. The patient is given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the patient’s own free 
will with the Informed Consent Form (ICF) after confirming that the patient understands the 
contents. The Investigator must sign (or place a seal on) and date the ICF. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.


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DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB/IEC 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.
RECORDS
8.3
Case Report Forms/ (e)CRF for individual patients will be provided by the Sponsor. 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 reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For the CRF, the following data need to be derived from source documents:

Patient identification (gender, date of birth)

Patient participation in the trial (substance, trial number, patient number, date patient was
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical/Oncology history (including trial indication and concomitant diseases, if
applicable)

medication history

AE and outcome events (onset date (mandatory), and end date (if available))

SAEs (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results (in validated electronic format, if available)

Completion of Patient’s Participation in the trial”

Prior to allocation of a patient to a treatment into a clinical trial, there must be
documented evidence in the source data (e.g. medical records) that the trial participant
meets all inclusion criteria and does not meet any exclusion criteria. The absence of
records (either medical records or testing conducted specific for a protocol) to support
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
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. 
CRF/eCRF 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 (CRA) /on site monitor 


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and auditor may review all CRF/eCRF, and written informed consents. The accuracy of the 
data will be verified by reviewing the documents described in Section 8.3.1.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular AE 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 (IB).
For ibrutinib this is the US-PI, or another regulatory label document; 
The current versions of these reference documents are provided in the ISF. 
8.4.2
Expedited reporting of adverse events
BI is responsible to fulfill their legal and regulatory reporting obligation in accordance with 
regulatory requirements. Exemptions from expedited reporting are described in Section 5.3.7, if
applicable..
STATEMENT OF CONFIDENTIALITY
8.5
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 IRB/IEC and the regulatory authorities.
END OF TRIAL
8.6
The end of the trial is defined as:

The trial is completed once the RP2D for the combination of BI 836826 with ibrutinib 
has been defined by the SRC (see Section 3.1)
Last patient last visit (primary endpoint)
The “last-patient-last-visit-primary-endpoint” will be reached once: 

all patients have completed the REP
At this time, the CTR will be written. In case, the end of the whole trial is not reached at the 
time the report of the trial is being performed revised main results will be reported in a 
revision to the report after the end of the whole trial. There will be an additional patient 
contact with regard to the End of Trial status as soon as the end of the whole trial is reached.


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9.
REFERENCES
PUBLISHED REFERENCES
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Schuurman HJ, Baarlen J van, Huppes W, Lam BW, Verdonck LF, Unnik 
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et al. Aberrant expression of tetraspanin molecules in b-cell chronic 
lymphoproliferative disorders and its correlation with normal b-cell 
maturation. Leukemia 19. 2005.1376-1383
R08-2945
Norton AJ, Isaacson PG. Detailed phenotypic analysis of b-cell lymphoma
using a panel of antibodies reactive in routinely fixed wax-embedded tissue. 
Am J Pathol 128 (2). 1987. 225-240
R08-2946
Moldenhauer G. CD37. J Biol Regul Homeost Agents 14. 2000. 281-283
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). 1988. 905-914
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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. 1989. 37-48
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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-
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Spriel AB van, Puls KL, Sofi M, Pouniotis D, Hochrein H, Orinska Z, et al. A 
regulatory role for cd37 in t cell proliferation. J Immunol 172. 2004. 2953-
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R09-5412
Knobeloch KP, Wright MD, Ochsenbein AF, Liesenfeld O, Loehler J, 
Zinkernagel RM, et al. Targeted inactivation of the tetraspanin cd37 impairs t-
cell-dependent b-cell response under suboptimal costimulatory conditions. 
Mol Cell Biol 20 (15). 2000. 5363-5369
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 5 (3). 2009. e1000338
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 from the International Workshop on Chronic Lymphocytic 
Leukemia updating the National Cancer Institute-Working Group 1996 
guidelines. Blood. 2008. 111(12): 5446-5456 
R10-4431
O'Brien SM, Keating MJ, Mocarski ES. Updated guidelines on the 
management of cytomegalovirus reactivation in patients with chronic 
lymphocytic leukemia treated with alemtuzumab. Clin Lymphoma Myeloma. 
2006. 7(2): 125 - 130 
R10-4517
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).
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pd f (2010)
R10-6345
Heider KH, Ostermann E, Lamche H, Kuepcue Z, Jacobi A, Konopitzky R et 
al.  Novel Fc-engineered antibodies to CD37 with pro-apoptotic and enhanced 
ADCC activity. 52nd Ann Mtg of the American Society of Hematology 
(ASH), Orlando, 4 - 7 Dec 2010
R10-6346
Zenz T, Volden M, Mast T, Nordhausen K, Winkler D, Schnaiter A et al.   
Exceptional in vitro activity of CD37 antibodies in CLL. 52nd Ann Mtg of the 
American Society of Hematology (ASH), Orlando, 4 - 7 Dec 2010
R11-4833
Krause G, Patz M, Isaeva P, Wigger M, Baki I, Vondey V et al. Action of 
novel CD37 antibodies on chronic lymphocytic leukemia cells. Leukemia. 
2012. 26(3): 546-9
R11-4834
Heider KH, Kiefer K, Zenz T, Volden M, Stilgenbauer S, Ostermann E et al.  
A novel Fc-engineered monoclonal antibody to CD37 with enhanced ADCC 
and high proapoptotic activity for treatment of B-cell malignancies. Blood. 
2011. 118 (15): 4159-4168 


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R12-2850
Lapalombella R, et al. Tetraspanin cd37 directly mediates transduction of 
survival and apoptotic signals. Cancer Cell 21. 2012. 694-708
R12-4648
Heider KH, Baum A, Schweiger I, Rodi N, Ruzicka R, Adolf G, et al.
Improved efficacy of MAb 37.1, a novel FC-engineered CD37 antibody, in 
combination with chemotherapy and rituximab in models of B-cell lymphoma.
17th Cong of the European Hematology Association (EHA), Amsterdam, 14 -
17 Jun 2012. 2012. Haematologica 97(Suppl 1): 437, Abstract 1073
R13-4802
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a 
comparison of trial designs. Cancer Chemother Pharmacol 71. 2013. 1107-
1114
R13-4803
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian 
approach to phase I cancer trials. Stat Med. 2008. 27, 2420-2439 
R13-4804
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. 
Translation of innovative designs into phase I trials. J Clin Oncol 25 (31). 
2007. 4982-4986
R13-4805
Tourneau C le, Gan HK, Razak ARA, Paoletti X. Efficiency of new dose 
escalation designs in dose-finding phase I trials of molecularly targeted agents. 
Plos One 7 (12). 2012. e51039
R13-4806
Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose 
escalation with overdose control. Stat Med. 1998. 17, 1103-1120 
R14-2573
Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM et al.  
Obinutuzumab plus chlorambucil in patients with CLL and coexisting 
conditions. N Engl J Med. 2014. 370(12): 1101-1110 
R14-3280 
Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al., 
German Chronic Lymphocytic Leukaemia Study Group.  Addition of 
rituximab to fludarabine and cyclophosphamide in patients with chronic 
lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010. 
376: 1164-1174 
R14-3818
Hallek M. Chronic lymphocytic leukemia: 2013 update on diagnosis, risk 
stratification and treatment. Am J Hematol. 2013. 88 (9), 804-816 
R14-4170
Dillman RO, Hendrix CS. Unique aspects of supportive care using monoclonal 
antibodies in cancer treatment. Support Cancer Ther. 2003. 1(1): 38-48 
R14-4986
Rawstron AC, Villamor N, Ritgen M, Bottcher S, Ghia P, Zehnder JL et al. 
International standardized approach for flow cytometric residual disease 
monitoring in chronic lymphocytic leukaemia. Leukemia. 2007. 21(5), 956 -
964 


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R14-5042
Majid A, Lin TT, Best G, Fishlock K, Hewamana S, Pratt G et al. CD49d is an 
independent prognostic marker that is associated with CXCR4 expression in 
CLL. Leuk Res. 2011. 35(6): 750-756 
R15-0100
Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N.
CD38 and chronic lymphocytic leukemia: a decade later. Blood. 2011. 
118(13): 3470-3478 
R15-0124
Furman RR, Cheng S, Lu P, Setty M, Perez AR, Guo A et al. Ibrutinib 
resistance in chronic lymphocytic leukemia. N Engl J Med. 2014. 370(24):
2352-4. Erratum in: N Engl J Med. 2014. 370(26): 2547. 
R15-0125
Wiestner A.  Emerging role of kinase-targeted strategies in chronic 
lymphocytic leukemia. Blood. 2012.120(24): 4684-91. Erratum in: Blood. 
2013. 122(17): 3090. 
R15-0126
Stilgenbauer S, Schnaiter A, Paschka P, Zenz T, Rossi M, Döhner K et al. 
Gene mutations and treatment outcome in chronic lymphocytic leukemia: 
results from the CLL8 trial. Blood. 2014.  123(21) :3247-54
R15-0127
Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS et al. 
Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib.  N 
Engl J Med. 2014. 370(24): 2286-94. 
R15-0128
Böttcher S, Ritgen M, Fischer K, Stilgenbauer S, Busch RM, Fingerle-Rowson 
G et al. Minimal residual disease quantification is an independent predictor of 
progression-free and overall survival in chronic lymphocytic leukemia: a 
multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol.
2012. 30(9): 980-8. 
R15-0129
Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA et al.
Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N 
Engl J Med. 2013. 369(1): 32-42 
R15-0130
Brown J, Barrientos J, Flinn I, Barr P, Burge Jr. J, Navarro T et al. The 
Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib combined with 
bendamustine and rituximab is active and tolerable in patients with 
relapsed/refractory CLL, interim results of a PHASE IB/II study. 
Haematologica. 2012. 97(S1):218. (Abstract 0543)
R15-0151
Burger JA, Keating MJ, Wierda WG, Hoellenriegel J, Jeyajumar G, Ferrajoli 
A, et al.  Ibrutinib in combination with rituximab (ir) is well tolerated and 
induces a high rate of durable remissions in patients with high-risk chronic 
lymphocytic leukemia (CLL): new, updated results of a Phase II trial in 40 
patients.  Blood. 2013. 122(21): 675


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R15-0873
Erturk SM, Mortele KJ, Tuncali K, Saltzman JR, Lao R, Silverman SG. Fine-
needle aspiration biopsy of solid pancreatic masses: comparison of ct and 
endoscopic sonography guidance. Am J Roentgenol 187 (6). 2006. 1531-1535
R15-0874
Bezerra AS, D'Ippolito G, Faintuch S, Szejnfeld J, Ahmed M. Determination 
of splenomegaly by ct: is there a place for a single measurement? Am J 
Roentgenol 184 (5). 2005. 1510-1513
R15-4921
Cheson BD, Byrd JC, Rai KR, Kay NE, O'Brien SM, Flinn IW, et al. Novel 
targeted agents and the need to refine clinical end points in chronic 
lymphocytic leukemia.  J Clin Oncol 30 (23), 2820 - 2822 (2012)
R15-4922
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Doehner 
H, et al. Clarification of iwCLL criteria for a partial response to therapy (13 
November 2013, e-letter). Blood, (2013)
R15-4923
Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F,  Dighiero G, Doehner 
H, et al. Response assessment in chronic lymphocytic leukemia treated with 
novel agents causing an increase of peripheral blood lymphocytes (4 June 
2012, e-letter).  Blood, (2012)
R15-5127
Imbruvica (ibrutinib) capsules, for oral use (Pharmacyclics) (U.S. prescribing 
information, revised: 01/2015)
UNPUBLISHED REFERENCES
9.2
c01715907-08  
.  Investigator's brochure. BI 836826.  Indications: 
Chronic lymphocytic leukemia; B-cell non-Hodgkin's lymphoma.  1270.P1, 
1270.P2.  April 2015. Version 5.


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10.
APPENDICES
RAI CLASSIFICATION
10.1
Rai staging system as reported in the IWCLL guideline (R10-4429):
This system divides CLL into 5 stages: 

Rai stage 0 (Low Risk): Lymphocytosis in blood or bone marrow 

Rai stage I (Intermediate Risk): Lymphocytosis and enlarged lymph nodes. 

Rai stage II (Intermediate Risk): Lymphocytosis and enlarged liver or spleen with 
or without lymphadenopathy 

Rai stage III (High Risk): Lymphocytosis and anemia (Hgb <11 g/dl) with or 
without enlarged liver, spleen or lymph nodes

Rai Stage IV (High Risk): Lymphocytosis and thrombocytopenia (platelet count 
<100,000/µl) with or without anemia or enlarged liver, spleen or lymph nodes
CRITERIA FOR RESPONSE DETERMINATION
10.2
The determination of CLL response and progression will be based on IWCLL criteria (R10-
4429), including recently published clarifications and modifications (R15-4922, R15-4923,
R15-4921) and clarifications as outlined below. In case a CR or a PD is suspected for the first 
time based on clinical examinations, imaging should be performed for complete response 
assessment. 
At all protocol defined response evaluation time points, i.e. at the end of Cycle 3, Cycle 6, 
Cycle 9 and Cycle12, as well as EOT, a response assessment will be performed based on 
CBC with differential and imaging assessment of CLL manifestations. In case a CR or a PD
are suspected based on physical examination and laboratory data at any other timepoint, 
imaging should be obtained to confirm CR or PD. An exception is possible if unequivocal 
diagnosis of PD is based on criteria other than lymph node, liver or spleen size. 
The ALC, neutrophil count the platelet count and hemoglobin will be used for the response 
assessment and all efforts should be made to obtain all parameters for response assessment on 
the same day. If the CBC/Differential is missing on the date of imaging, the values from a 
previous date as close to the imaging as possible may be used, provided that this date is 8 
days or more after the last administration of BI 836826. In case ANC, PLT or hemoglobin is 
considered influenced by supportive therapy, e.g. growth factors, transfusions, a CR, CRi, 
PR, PR-L should not be based on these laboratory values. Reevaluation of blood counts 
should be performed as close as possible to the imaging to evaluate response. Findings on 
physical examination with potential impact on response assessment should be confirmed by 
imaging. A CBC with Differential will be performed at a central laboratory at all timepoints 
where MRD is assessed, and absolute lymphocyte count, absolute neutrophil count, platelet 
count and hemoglobin from the central laboratory should be used for disease/response 
assessment when available.


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On imaging studies, the CLL manifestations will be classified as target lesions and non-target 
lesions.
Target lesions:
At baseline, up to 6 pathologically enlarged lymph nodes or lymph node masses should be 
selected as target lesions which will be used at each subsequent imaging for quantitative 
lymph node assessments during the study. Ideally, the target lesions should represent nodal 
disease burden due to CLL, if possible be located in disparate regions of the body, and should 
be reproducibly measurable in 2 perpendicular dimensions on repeated measurements.
Whenever possible, mediastinal and retroperitoneal areas of disease should be considered as 
target lesion.
Target lesions will be measured and recorded at baseline and at all subsequent imaging time 
points. Bi-dimensional measurements of the Largest Diameter (LD) and the corresponding 
Perpendicular Diameter (PLD) will be recorded for each target lesion. The product of the LD 
and PLD will be calculated for each target Single Lesion Product (SLP) and the sum of the 
product of diameters (SPD) for all target lesions will be calculated and recorded. The baseline 
SPD will be used as reference for assessment of best response during treatment. The nadir LD 
of individual target lesions and the nadir SPD of all target lesions will be used as reference 
for PD.
To be considered pathologically enlarged and measurable at baseline, a lymph node must be 
at least 1,5 cm in short axis and measurable in two perpendicular dimensions. Smaller lymph 
nodes should be classified as non-target lesions if considered pathological.
At post baseline imaging time points, the LD for individual lesions and the SPD of all target
lesions will be considered. Once selected, all target lesions should be measured as accurate as 
possible. Once a lymph node shrinks to a LD <1.5 cm, the node is considered of normal size.
Any new node considered a manifestation of CLL that measures ≥1.5 cm in short axis will be
considered PD.
A lymph node mass may be selected as a target lesion if it is measurable at baseline. In case a
lymph node mass splits into separate nodes, all separate nodes should be assessed according 
to the rules for single lesions and will be used in calculating the SPD. Progression of the
lesion will be based on the SPD of split lesions.
Liver and spleen size:
Liver and spleen size will be measured as the Longest Cranio-Caudal Diameter (LCCD) on 
CT/MRI scan. The baseline and nadir values for the LCCD of liver and spleen will be used as
a reference to assess tumor response. The LCCD may be directly measured on appropriate 
coronal or sagittal planes, or will be calculated as the product of the number of axial sections
on which the organ is visualized (between the most superior and the most inferior margin)
and the thickness of the sections.
The spleen will be considered enlarged if the LCCD is >12 cm (R15-0874). A LCCD 
decrease ≥50% (minimum 2 cm) compared to baseline, if the spleen was enlarged at baseline, 
or a decrease to ≤ 12 cm is required for a spleen response. An increase in spleen LCCD by 


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≥50% from nadir (minimum increase of 2 cm and minimum total size of 14 cm) is required 
for diagnosis of splenic progression.
The liver if will be considered enlarged if it is >18 cm in LCCD (R15-0873). A LCCD 
decrease ≥50% (minimum 2 cm) compared to baseline, if the liver was enlarged at baseline, 
or a decrease to ≤18 cm is required for a liver response. Conversely, an increase in liver 
enlargement by ≥50% from nadir (minimum increase of 2 cm, and minimum total size of 20 
cm) is required for diagnosis of liver progression.
Non-target lesions:
Any other measurable and pathological nodal lesions not selected as target lesion may be 
considered a non-target lesion. In addition, non-measurable evidence of CLL may be 
considered non-target lesion, e.g. nodal lesions too small to qualify as target lesion, 
extranodal lesions, bone lesions, ascites, pleural or pericardial effusions, non-measurable 
nodal masses.
Even if measurable, non-target lesions will not be quantitatively assessed. The persistence, 
unequivocal progression or complete disappearance/absence of non-target lesions should be 
recorded at baseline and at the subsequent imaging time points. If present at baseline, up to 6 
non-target lesions should be recorded. The non-target lesions selected at baseline will be used
as a general reference to further characterize regression or progression of CLL during
response assessments.
Responses will be based on imaging and laboratory data, bone marrow examination needs to 
be added to complete response assessment for CR, and PR in some cases. Responses will be 
categorized as CR, CRi, PR, PR-L, SD or PD by the investigator. All data used for the
assessment should be reflected in the eCRF.
Definitions of response and progression:
Complete Response (CR)
CR requires all of the following criteria to be met:

Absolute lymphocyte count below 4 x 109/L.

Regression of all target nodes/masses, i.e. all target lesions have a LD < 1.5 cm

Disappearance/absence of all non-nodal non-target lesions, regression of all nodal 
nontarget lesions to normal sized lymph nodes

Normal liver size (≤18 cm), based on CT imaging or non-palpable by Physical Exam

Normal spleen size (≤12 cm), based on CT imaging or non-palpable by Physical 
Exam

No evidence of new disease.

Morphologically negative bone marrow, defined as normocellular marrow in relation 
to patient age, less than 30% of nucleated cells being lymphoid cells and no lymphoid 
nodules.

Platelet count more than 100 x 109/L (without exogenous growth factors or 
transfusion).

Hemoglobin more than 110 g/L (without exogenous growth factors or transfusions)


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
Absolute Neutrophil Count more than 1.5 x 109/L (without exogenous growth
factors).
Patients who fulfil all criteria for a CR (including a bone marrow examinations ) but who 
have a persistent anaemia, thrombocytopenia, neutropenia or a hypocellular bone marrow 
related to prior or ongoing CLL therapy, but unrelated to CLL should be classified as CRi.
Partial Response (PR)
To define a PR, all of the following criteria must be met:

No evidence of new disease

At least one of the following laboratory criteria is present:
i.
Platelet count higher than 100 x 109/L, or ≥50% improvement over baseline
(without exogenous growth factors or transfusion)
ii.
Hemoglobin higher than 110 g/L, or ≥50% improvement over baseline (without
exogenous growth factors or transfusions)
iii.
Absolute Neutrophil Count higher than 1.5 x 109/L, or ≥50% improvement over
baseline (without exogenous growth factors)

Reduction in tumor load documented by at least two of the following criteria, with
exceptions in the following situations where only 1 criterion needs to be met: (a)
lymphadenopathy is the only disease manifestation (b) only lymphocytosis without
lymphadenopathy is present at baseline, (c) a bone marrow assessment at screening
shows quantifiable bone marrow infiltration as the only site of disease. In situation (a)
only criterion (ii) will be applicable, in situation (b) only criterion (i), and in situation
(c) only criterion (v).
i.
In patients with lymphocytosis at baseline (ALC ≥4 x 109/L), decrease in the
ALC by ≥50% or more compared to baseline, or a decrease to <4 x 109/L.
ii.
In patients with nodal disease at baseline, decrease of SPD of target lesions by
≥50% compared to baseline.
iii.
If spleen enlarged at baseline (LCCD >12 cm), decrease of LCCD by ≥50%,
or to normal size (LCCD ≤12 cm).
iv.
If liver enlarged at baseline, (LCCD >18 cm), decrease of LCCD by ≥50%, or
to normal size (LCCD ≤18 cm).
v.
Bone marrow infiltration of CLL decreases by ≥50% compared to baseline,
either in diffuse infiltration, or in B-lymphoid nodules.

No target lesion and no non-target lesion (if present at baseline) are unequivocally
progressing. No increase in liver and/or spleen LCCD by ≥50%
Partial Response with Lymphocytosis (PR-L)
To define a PR-L, the following criteria must be met:

No evidence of new disease

At least one of the following laboratory criteria is present:
i.
Platelet count higher than 100 x 109/L, or ≥50% improvement over baseline
(without exogenous growth factors or transfusion)


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ii.
Hemoglobin higher than 110 g/L, or ≥50% improvement over baseline 
(without exogenous growth factors or transfusions)
iii.
Absolute Neutrophil Count higher than 1.5 x 109/L, or ≥50% improvement 
over baseline (without exogenous growth factors)

Reduction in tumor load documented by at least two of the following criteria. In 
patients with only one localization at baseline, improvement of this single criterion is 
sufficient:
i.
In patients with nodal disease at baseline, decrease of SPD of target lesions by 
≥50% compared to baseline.
ii.
If spleen enlarged at baseline (LCCD >12 cm), decrease of LCCD by ≥50%, 
or to normal size (LCCD ≤12 cm).
iii.
If liver enlarged at baseline, (LCCD >18 cm), decrease of LCCD by ≥50%, or 
to normal size (LCCD ≤18 cm).
iv.
Bone marrow infiltration of CLL decreases by ≥50% compared to baseline, 
either in diffuse infiltration, or in B-lymphoid nodules.

No PD criterion met, i.e. no target lesion and no non-target lesion (if present at 
baseline) are unequivocally progressing, and no increase in liver and/or spleen LCCD 
by ≥50%. 

Lymphocytosis during therapy with ibrutinib if occurring in isolation without other 
objective evidence of progressive disease will not be considered evidence of PD and 
will not preclude a patient from the PR-L category. 
Progressive Disease (PD)
Any of the following criteria constitutes the diagnosis of PD:

Evidence of new disease:
o
any new pathologically enlarged lymph node (>1.5 cm in short axis) 
considered a manifestation of CLL
o
new or recurrent increase of the liver LCCD by ≥50%, with a minimum 
absolute liver LCCD of 20 cm
o
new or recurrent increase of the spleen LCCD by ≥50%, with a minimum 
absolute spleen LCCD of 14 cm
o
any new unequivocal extranodal non-target lesion (if the non-target lesion is 
an effusion without additional indication for progression of CLL, there should 
be histological or cytological evidence that this effusion is due to CLL)
o
unequivocal reappearance of an extranodal non-target lesion that had 
disappeared completely on treatment

Evidence of worsening of disease
o
SPD increase of target lesions from baseline/nadir by G50%
o
Increase of LD in any individual nodal target lesion from baseline/nadir by 
G50%
o
Liver progression, i.e. enlargement of the liver LCCD by G50% from 
baseline/nadir (with a minimum increase of 2 cm and minimum total LCCD of 
20 cm)
o
Spleen progression, i.e. enlargement of the spleen LCCD by G50% from 
baseline/nadir (with a minimum increase of 2 cm and minimum total LCCD of 
14 cm)


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o
unequivocal progression of non-target lesions overall (should not be based 
solely on worsening of a pleural effusion or ascites as the only location for 
disease progression)
o
transformation into a more aggressive histology (e.g. Richter’s syndrome), 
diagnosed by cytology or histology

Worsening in laboratory values attributable to CLL
o
Platelet count is less than 100 x 109/L and has decreased by G50% compared to 
the highest platelet count on study (values obtained within one day after a 
transfusion should be excluded)
o
Hemoglobin is <110 g/L and has decreased by > 20 g/L from the highest 
hemoglobin value on study (values obtained within one day after a transfusion 
should be excluded)

Lymphocytosis during therapy with ibrutinib will only be considered evidence of 
worsening of disease if it is not occurring in isolation, but associated with other 
objective evidence of progressive disease as outlined above.
Worsening of constitutional symptoms in the absence of other objective evidence of 
worsening of CLL will not be considered disease progression, and other causes for 
constitutional symptoms, e.g. infections should be considered.
Ibrutinib can mobilize CLL cells from tissues into the peripheral blood. This characteristic
pharmacologic action can be prominent early in therapy, but it can also persist over time, and 
should not be confused with PD unless the treated patient develops other CLL-related signs 
or symptoms of PD. In the absence of other objective evidence of PD, lymphocytosis alone
should not be considered an indicator of PD. Patients with lymphocytosis and no other 
evidence of PD should continue therapy until they develop other definitive signs of or the 
occurrence of another reason to discontinue therapy.
During therapy, anemia and/or thrombocytopenia may be difficult to differentiate from drug 
related effects on PLT or hemoglobin. If there is uncertainty whether there is true 
progression, the patient should continue study treatment and remain under close observation, 
e.g. with additional unscheduled assessments, which should be captured in the eCRF. If 
subsequent evaluations indicate CLL progression, the date of progression should be the date
at which progression was first documented.
Stable Disease (SD)
For SD, the following criteria must be met:

No evidence of new disease

There is neither sufficient evidence of tumor shrinkage to qualify for CR/CRi/PR/PR-
L nor sufficient evidence of tumor growth to qualify for definitive PD
Non Evaluable (NE)
In a patient who does not have clinical evidence for PD based on CBC/Diff, the response 
assessment may be NE in the following situations:

No imaging study performed.


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
Inadequate imaging quality, or missing sections which do not allow assessment of all 
areas in which target lesions were selected. (PD may be assigned at any timepoint 
regardless of the extent of missing target lesions)

Images of liver and/or spleen missing (exception: splenectomized patient).


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PUBLICATIONS
10.5
The sponsor will have unrestricted publication rights on data resulting from the study and 
may give the data to third parties for publication.
In a multi-center study, the primary publication shall be a full publication of the study results 
from all appropriate study sites. If such a full publication is not submitted within twelve (12) 
months after conclusion of the study at all sites, or after the sponsor confirms there will be no 
primary full publication, investigator(s) may publish individually in accordance with this 
Section.
Any written, oral or audio-visual publication resulting from the study, either in part or in total 
(abstracts in journals or newspapers, oral presentations, posters etc.) by investigators and/or 
their representatives, including publications of experimental substudies, will require pre-
submission review by the sponsor. The sponsor is entitled to delay any publication in order to 
protect patentable inventions and/or to avoid disclosure of proprietary matters which require 
protection, including but not limited to, trade secrets and know-how (for details, see contract). 
Moreover, the sponsor has the right to edit or remove confidential information, prior to 
submission for publication. In general, the sponsor will not veto any publication.
The International CI will have the unrestricted right to publish on data resulting from the 
study and will be given the choice to be the first author, or the last author. The selection and 
order of the subsequent authors (i.e. author(s) 2.-x.) will be based on (a) the numbers of 
recruitment, i.e. the number of subjects treated with BI 836826 in the study, (b) data quality 
and (c) significant scientific input to the study, unless otherwise agreed.
A representative of the sponsor substantially involved in the implementation of the study will 
serve as co-author in the primary full publication of the study, unless otherwise agreed. 
Moreover, the sponsor will retain the right to include in the authorship list up three (3) 
Boehringer Ingelheim authors.


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For any interim publication(s,) the order of the authors will be determined in accordance with 
(a) the numbers of recruitment and (b) data quality, after consultation with the International 
CI.
For publication(s) of experimental substudies only, co-authorship will be offered to all 
authors according to their individual contributions, unless otherwise agreed. The sponsor 
shall have the right to publish results of the study in whole or in part for regulatory purposes, 
unless otherwise agreed.
All publications of the results of the study shall be compiled in adherence to the rules of 
Good Scientific Practice and the guidelines for publications of clinical Study data as outlined 
e. g. by editors of the major medical journals.
CALCULATION OF GLOMERULAR FILTRATION RATE
10.6
Glomerular Filtration Rate (GFR) may be estimated based on commonly used and accepted
formula, i.e.
Cockroft Gault formula:
Modification of Diet in Renal Disease (MDRD) formula:
Variations of the MDRD formula:
Alternative methods of calculation of GFR may be agreed between Investigator and the Trial
Clinical Monitor at Boehringer Ingelheim.


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STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
10.7
AND DATA SCENARIOS
The model was assessed by two different metrics: hypothetical on-study scenarios and long-
run operational characteristics.
Hypothetical Data Scenarios
Hypothetical data scenarios are shown in Table 10.7:1. These scenarios reflect the potential 
on-study data constellations and related escalation as allowed by the model and the 100% 
escalation limit. For each scenario, the probability of overdose for the current dose, as well as 
the next potential dose and related probabilities of under-dosing, target toxicity and over-
dosing are shown.
For example, scenario 1 represents the case that no DLT is observed in three patients at the 
starting dose of 420mg on Ibrutinib and 100mg of BI 836826. In this case, the next dose 
permitted by the model and by the 100% escalation rule is 420mg of Ibrutinib and 200mg of 
BI 836826. Similarly, scenario 6 represents the case that no DLT is observed in the first 
cohort of 3 patients at 420mg of Ibrutinib and 100mg of BI 836826, and 1 DLT is observed in 
the cohort of 3 patients at 420mg Ibrutinib and 200 mg of BI 836826. In this case, the model 
suggests re-enrolling patients at the current dose level of 200mg BI 836826. 
In scenario 17, 1 DLT is observed with 6 patients at a BI 836826 dose of 200mg. Here, the 
model suggests to only increase the dose up to 300mg BI 836826 and to not use the 100% 
dose escalation. In scenario 22, it is assumed that at a dose of 1400mg BI 836826, 2 DLTs 
occur in 3 patients. Despite the fact that no DLTs have been observed in the previous 4 
cohorts, the model reacts immediately to the data observed and requires de-escalation to 
600mg. This case illustrates the adaptive behavior of the model in more extreme situations.


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Table 10.7:1 
Hypothetical data scenarios
Scen
ario
Dose 
Ibrutinib, 
Bi 836826 
[mg]
# DLT
# Pat
Curren
t dose: 
Next 
dose 
Ibrutinib
, BI 
836826 
[mg]
Next dose
P(over 
dosing)
P(under 
dosing)
P(target 
toxicity)
P(over 
dosing)
1
420,100
0
3
0.036
420, 200
0.577
0.304
0.119
2
420,100
1
3
0.201
420, 100
0.431
0.394
0.174
3
420,100
2
3
0.491
NA
NA
NA
NA
4
420,100
0
2
0.055
420,200
0.541
0.316
0.144
5
420, 100
420, 200
0
0
3
3
0.033
420, 400
0.498
0.254
0.248
6
420, 100
420, 200
0
1
3
3
0.208
420, 200
0.418
0.418
0.163
7
420, 100
420, 200
0
2
3
3
0.426
420, 100
0.429
0.43
0.141
8
420, 100
420, 100
1
1
3
3
0.227
420, 100
0.304
0.47
0.227
9
420, 100
420, 100
1
0
3
3
0.063
420, 200
0.399
0.401
0.2
10
420, 100
420, 100
1
2
3
3
0.487
NA
NA
NA
NA
11
420, 100
420, 100
2
0
3
3
0.227
420, 100
0.304
0.47
0.227
12
420, 100
420, 100
2
1
3
3
0.497
NA
NA
NA
NA
13
420, 100
420, 200
420, 400
0
0
0
3
3
3
0.056
420, 800
0.622
0.168
0.209


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Table 10.7:1 (cont.) 
Hypothetical data scenarios
Scen
ario
Dose 
Ibrutinib, 
Bi 836826 
[mg]
# DLT
# Pat
Current 
dose: 
Next 
dose 
Ibrutinib
, BI 
836826 
[mg]
Next dose
14
420, 100
420, 200
420, 400
0
0
1
3
3
3
0.284
420, 300
0.455
0.419
0.125
15
420, 100
420, 200
420, 300
0
0
0
3
3
3
0.039
420, 600
0.589
0.193
0.218
16
420, 100
420, 200
420, 300
0
0
1
3
3
3
0.194
420, 300
0.409
0.397
0.194
17
420, 100
420, 200
420, 200
0
1
0
3
3
3
0.061
420, 300
0.401
0.377
0.223
18
420, 100
420, 200
420, 200
0
1
1
3
3
3
0.206
420, 200
0.291
0.503
0.206
19
420, 100
420, 200
420, 200
0
1
2
3
3
3
0.44
420, 100
0.401
0.473
0.126
20
420, 100
420, 200
420, 400
420, 800
0
0
0
2
3
3
3
3
0.721
420, 400
0.258
0.541
0.201


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Table 10.7:1 (cont.) 
Hypothetical data scenarios
Scen
ario
Dose 
Ibrutinib, 
Bi 836826 
[mg]
# DLT
# Pat
Current 
dose: 
Next 
dose 
Ibrutinib
, BI 
836826 
[mg]
Next dose
P(over 
dosing)
P(under 
dosing)
P(target 
toxicity)
P(over 
dosing)
21
420, 100
420, 200
420, 400
420, 800
0
0
0
0
3
3
3
3
0.035
420, 
1400
0.833
0.083
0.084
22
420, 100
420, 200
420, 400
420, 800
420, 1400
0
0
0
0
2
3
3
3
3
3
0.651
420,600
0.321
0.552
0.127
Operational Characteristics
Operating characteristics are a way to assess the long-run behavior of a model. Under an 
assumed true dose-toxicity curve, metrics such as the probability of recommending a dose 
with true DLT rate in the target interval can be approximated via simulations. Table 10.7.2.
describes 4 assumed true dose-toxicity scenarios which were used to assess the operating 
characteristics of the model. These scenarios reflect a wide range of possible cases as 
follows:

Scenario 1: aligned with prior means

Scenario 2: high-toxicity scenario

Scenario 3: low-toxicity scenario

Scenario 4: low-toxicity followed by high-toxicity


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Table 10.7: 2  
Dose-toxicity scenarios
Scenario
BI 836826 dose (mg)
P(DLT)
100
200
400
600
800
1400
1 (Prior)
0.13
0.18
0.30
0.40
0.47
0.63
2 (High 
Tox)
0.24
0.30
0.40
0.50
0.63
0.75
3 (Low Tox)
0.08
0.13
0.20
0.22
0.25
0.30
4 (Low-
High)
0.08
0.13
0.20
0.40
0.50
0.63
For each of these scenarios, 1000 trials were simulated. It was then assessed how often a dose 
was declared as MTD with true DLT rate in the under-, targeted or over-dose range.
Furthermore, the average, minimum and maximum number of patients per trial and the 
average number of DLTs per trial are reported. Results are shown in Table 10.7:3.
Table 10.7:3
Min/Max number of patients per trial and average number of DLTs
Scenario
% of trials declaring the MTD with true DLT rate 
in
# Patients
# DLTs
underdose
Target 
toxicity
overdose
Stopped
(too toxic
Mean
(Min-
Max)
Mean
(Min-
Max)
1 (Prior)
12.1
75.8
3.6
8.5
16.10
(3-42)
3.12
(2-11)
2 
(HighTox)
0
67.1
2.5
30.4
11.58 
(3-36)
3.25
(2-10)
3 (Low 
Tox)
56.9
41.0
0
2.1
19.47
(3-45)
2.30
(1-9)
4 (Low-
High)
61.5
27.6
8.8
2.1
18.66
(3-42)
3.22 
(1-10)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
75.8% of the simulated trials declared a dose as MTD with the true DLT rate in the targeted 
dose range. Considering that 100mg has a DLT probability of 0.13 which is relatively close 
to the lower bound of the target toxicity interval (0.16), one could consider this as an MTD as 
well, and the target rate would thus be even higher.
In scenario 2 (high toxicity), the starting dose already has a >20% probability of a DLT in the 
first cohort. This contributes to the high percentage (30.4%) of all simulated trials for which 


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the trial is stopped since none of the doses is considered tolerable anymore. This is an 
expected situation for a high-toxicity scenario.
In scenario 3 (low toxicity scenario), nearly 60% of trials declare a dose in the under-dose 
interval as the MTD. Since the 200mg cohort has a DLT probability of 0.13 which is 
relatively close to the lower bound of the target toxicity interval (0.16), one could consider 
this as an MTD as well, and the target rate would thus be much higher than the formal 41% 
target rate. 
In scenario 4, even though formally only 27.6% of simulated trials declared a dose as MTD 
with the true DLT rate in the target interval, as in Scenario 1 and 3, considering the dose with 
a true DLT rate of 0.13 also as target interval, the target rate would be much higher.
The mean patient numbers range from 11.58 (high-toxicity scenario) to 19.47 patients (low-
toxicity scenario) and the maximum number of patients was 45. Therefore, the patient 
numbers are as expected and increase when moving away from the high-toxicity scenario. In 
summary, the considered data scenarios show a reasonable behavior of the model and the 
operating characteristics demonstrate a good precision of MTD determination.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
18 Jul 2018
EudraCT number
Not Applicable
BI Trial number
1270.15
BI Investigational Product(s)
BI 836826
Title of protocol
A Phase Ib, Open label, Single Arm, Multi-center, 
Dose Escalation Trial of Intravenous BI 836826 in 
Combination with ibrutinib in Patients with 
Relapsed/Refractory Chronic Lymphocytic
Leukemia
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
2.1 Rationale for Performing the Trial
Description of change
Added: “Note: Due to the rapid evolution of the 
treatment landscape of CLL, further development 
of BI 836826 has been discontinued. Recruitment 
of trial participants will be stopped, however, 
current subjects on treatment will be allowed to 
complete the trial as per the protocol. Trial 
procedures and endpoint analysis has been 
amended due to the early termination of the trial.”
Rationale for change
Early termination of trial, discontinue recruitment
of new trial subjects, and completion of treatment 
for current subjects as per protocol.


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Section to be changed
Throughout the document
Description of change
Any reference to Phase II of the study including 
(but not limited to) sections on study rationale, 
Objectives, Number of patients, data collection and 
analysis, primary and secondary end points for 
phase II has been deleted. Phase Ib also removed in 
most sections as the removal of Phase II eliminates 
the need to differentiate between phases.
Rationale for change
Phase II of the study will not be conducted.
Section to be changed
Throughout the document
Description of change
Number of patients included in the study changed 
from 60 patients to 20 patients.
Rationale for change
Phase II of the study will not be conducted.
Section to be changed
Throughout the document
Description of change
Extended Follow up period removed. Study will be 
completed once all patients complete REP. 
Rationale for change
Extended Follow up period will not be necessary, 
since further analysis of trial data will not be 
completed. 
Section to be changed
Throughout the document 
Description of change
. 


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Rationale for change
 
 
Section to be changed
Flowchart- Screening to Cycle 12 and Cycle 13-
Cycle 24 and associated footnotes
Description of change
Trial medication listed separately as BI 836826 
investigational drug and backbone therapy, 
ibrutinib
Rationale for change
Ibrutinib is a non-investigational medicinal product 
in this trial and therefore does not qualify as trial 
medication.
Section to be changed
Flowchart-Screening to Cycle 12 and Cycle 13-
Cycle 24
Description of change
Assessments have been reduced. Footnotes updated 
to match the flowchart
Rationale for change
Phase II of the study will not be conducted. Trial 
data will not be analysed. Hence assessments have 
been reduced.
Section to be changed
Flowchart- Day 1and Day 15  of Cycle 2 to Cycle 
12, Response evaluation at the end of cycle 3,6,9 
and 12 and Day 1 of Cycle 13-cycle 24 
Description of change
A -2/ +14 day window has been added to day I of 
cycles 2-12 and cycles 13-24. 
Rationale for change
Broader window period provided to make it less 
stringent for the patient and site.
Section to be changed
Footnotes 20 and 21 in flowchart for Cycle 1 to 
Cycle 12, throughout the document where PK 
sampling and pharmacogenetics sampling is 
referenced, and footnote in Table 10.3.1
Description of change
 
 
Rationale for change
 
Section to be changed


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Description of change
Rationale for change
Section to be changed
Section 4.2.1.2
Description of change
Deleted sentence “After the REP, only concomitant 
therapy indicated for treatment of a BI 836826 
related SAE or Adverse Event of Special Interest 
(AESI) has to be reported.”
Rationale for change
Once REP is completed the patient will end the 
study per the amendment. No data will be collected 
after REP.
Section to be changed
Section 4.2.1.2.2 
Description of change
Cairo- Bishop Classification has been removed
Rationale for change
This classification and methodology was planned 
but not implemented in the trial. 
Section to be changed
Section 5.1, 
 7.3 and throughout the 
document
Description of change
Rationale for change
Section to be changed
Section 5.2.1 
Description of change
Sentence deleted-“The next scheduled disease 
assessment time point may be used for response 
confirmation.”
Rationale for change
With the termination of the trial, confirmatory 
disease assessments for response are no longer 
needed.
Section to be changed
Section 5.2.4 
Description of change
Following sentences have been deleted from this 
section-Physical examination with clinical 
assessment of all nodal disease locations amenable 
to clinical examination. The size of the liver and 
spleen, as assessed by palpation, should be 
documented in cm below costal margin if enlarged. 
Liver and spleen are not considered enlarged if 
palpation below costal margin is not possible. Now 
reads as:  “At Day 1 of each treatment cycle, a 
physical examination will be performed to assess 


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disease progression. In case Progressive Disease 
(PD) is suspected based on physical examination, 
imaging should be performed.”
Rationale for change
With the termination of the trial, clinical disease 
assessments for response are no longer needed.
Section to be changed
Section 5.3.6.1 AEs considered “Always serious”
Description of change
Added “Note: Every new occurrence of cancer of 
new histology must be classified as serious event 
regardless of the time since the discontinuation of 
the trial medication and must be reported as 
described in  5.3.7 , subsections “AE collection” 
and “AE reporting to sponsor and timelines”.
Rationale for change
Updated to reflect BI’s reporting requirement that 
cancer of new histology should always be reported 
regardless of time since discontinuation of trial 
medication.
Section to be changed
Section 5.3.6.1 Causal relationship of AEs
Description of change
Updated sentence to remove the backbone 
medication ibrutinib as an IMP and the requirement 
to provide causal relationship of SAEs .for this 
treatment.
Rationale for change
Modified to show ibrutinib is a non-investigational 
medicinal product in this trial and therefore does 
not require reporting of causal relationship 
assessment for SAEs.
Section to be changed
Section 5.3.7 
Description of change
Under AE collection-Modified section to read as 
all AEs (non-serious and serious), and all AESIs 
will be collected and documented on the 
appropriate eCRF from signing the informed 
consent onwards through REP, until individual 
patient’s end of trial. After the individual patient’s 
end of trial:  the investigator does not need to 
actively monitor the patient for new AEs. Word 
“new” added.  Deleted second bullet “From the end 
of the REP until the last visit of the extended 
follow-up, all BI 836826 related SAEs and BI 
836826 related AESIs
Rationale for change
Updated as per BI reporting requirements. Deleted
second bullet since extended follow up period is no 


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longer required as per the amendment.
Section to be changed
Section 5.3.7 
Description of change
Schematic representation of study deleted.
Deleted sentences- “BI 836826 related events 
which occurred after the REP will be considered as 
post treatment events. Events attributed to ibrutinib 
only or not-related events will not be reported after 
the REP.”
Modified paragraph on Information required to
read as “For each AE, the Investigator should 
provide the information requested on the 
appropriate (e)CRF pages and the BI SAE form (if 
applicable)” and deleted the remainder of the 
paragraph.
Paragraph on exemptions to SAE reporting: 
However, when there is evidence suggesting a 
causal relationship between the study drug and the 
progression of the underlying malignancy, the 
event must be reported as an (S)AE on the SAE 
form and on the (e)CRF.
Rationale for change
Since there is no extended follow up period after 
the REP, section has been updated. Section on “ 
AE collection”, “Information required” and 
“exemptions to SAE reporting” has been updated 
to reflect current BI reporting practices.
Section to be changed
 
Section to be changed
Section 5.5.1.1 
Description of change
 
 
Rationale for change
Deleted to mirror the flow chart.
Section to be changed
Section 5.5.2 modified and 5.5.3 deleted
Description of change
 
 


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Rationale for change
 
Section to be changed
Section 6.2.3 and 6.2.3.2
Description of change
Trial completion for an individual patient has been 
clarified.
Rationale for change
Extended Follow up period has been removed. 
Section clarified to indicate criteria for trial 
completion.
Section to be changed
Section 7.3
Description of change
Removal of the sub-group analysis 
Rationale for change
Since the trial is being stopped prior to reaching the 
MTD, the subgroup analysis will not be performed.
Section to be changed
Section 7.4 
Description of change
Sentence deleted- “In addition, after determination 
of the RP2D in the Phase Ib part of this trial, s 
synoptic interim report will be written to justify the 
RP2D”.
Rationale for change
Since Phase II of the trial will not be conducted, an 
interim report will not be prepared.
Section to be changed
Section 8.4.2
Description of change
Expedited Reporting of Adverse Events section 
updated.
Rationale for change
Section updated to reflect current BI reporting 
requirements.
Section to be changed
Section 8.6
Description of change
Last patient last visit primary endpoint: Section 
modified to delete first bullet point-“ All patients 
without PD have completed the 1st follow up visit 
(of the follow-up for PD). Second bullet point 
modified to delete “with PD” from sentence “all 
patients with PD have completed the REP” 
Rationale for change
Follow up visit has been deleted from the protocol. 
Study will end once all patients complete the REP.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03032933
2.0
clinical-trial-protocol-version-02
A Phase Ib, Open label, Single Arm, Multi-center, Dose Escalation Trial of
Intravenous BI 836826 in Combination with ibrutinib in Patients with
Relapsed/Refractory Chronic Lymphocytic Leukemia
Author-Trial Clinical Monitor
24 Jul 2018 16:13 CEST
Author-Pharmacokinetics
24 Jul 2018 16:30 CEST
Approval-Team Member Medicine
24 Jul 2018 16:53 CEST
Author-Trial Statistician
24 Jul 2018 17:04 CEST
Approval-Therapeutic Area 
25 Jul 2018 08:42 CEST
Verification-Paper Signature
Completion
26 Jul 2018 00:21 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03032933
2.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c08764221-02
BI Trial No.:
1270.15
Title:
A phase Ib, Open label, Single Arm, Multi-center, Dose Escalation 
Trial of Intravenous BI 836826 in Combination with ibrutinib in 
Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia
Including protocol amendment 1 (c03032933-02)
Investigational
Product(s):
BI 836826
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
30 JUL 2018 SIGNED
Version:
FINAL
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2018 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 ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Other secondary endpoints ..................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................18
6.1
TREATMENTS...................................................................................................18
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................18
6.3
PATIENT SETS ANALYSED...........................................................................19
6.5
POOLING OF CENTRES .................................................................................20
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................20
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................21
7.
PLANNED ANALYSIS......................................................................................22
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........22
7.1.1
Disposition of patients.........................................................................................22
7.1.2
Important protocol violations ............................................................................22
7.1.3
Demographic and other baseline characteristics .............................................23
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................23
7.3
TREATMENT COMPLIANCE........................................................................23
7.4
PRIMARY ENDPOINTS...................................................................................23
7.5
SECONDARY ENDPOINTS.............................................................................24
7.5.1
Key secondary endpoints....................................................................................24
7.5.2
Other Secondary endpoints................................................................................24


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7.7
EXTENT OF EXPOSURE.................................................................................25
7.8
SAFETY ANALYSIS..........................................................................................25
7.8.1
Adverse events.....................................................................................................25
7.8.1.1
Maximum tolerated dose / RP2D and dose limiting toxicity................................25
7.8.1.2
Adverse events ......................................................................................................25
7.8.2
Laboratory data ..................................................................................................28
7.8.3
Vital signs.............................................................................................................30
7.8.4
ECG......................................................................................................................30
8.
REFERENCES....................................................................................................31
10.
HISTORY TABLE..............................................................................................34


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LIST OF TABLES
Table 6.2 : 1
Important protocol violations ...........................................................................18
Table 10: 1
History table .....................................................................................................34


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis Dataset
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALKP
Alkaline Phosphatase
ALT
Alanine Amino Transferase
AST
Aspartate Amino Transferase
ATC
Anatomic Therapeutic Classification
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
BMI
Body Mass Index
BSA
Body Surface Area
CLL
Chronic Lymphocytic Leukemia
CTCAE
Common Terminology Criteria for Adverse Events
CTh
Concomitant Therapies
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug-Induced Liver Injury
DLT
Dose Limiting Toxicity
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EOT
End Of Treatment
EWOC
Escalation With Overdose Control
ICH
International Conference on Harmonisation
IPV
Important Protocol Violation
IRR
Infusion Related Reaction


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Term
Definition / description
LDH
Lactate Dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum Tolerated Dose
PT
Preferred Term
REP
Residual Effect Period
RIS
Run-in Set
RNA
Ribonucleic Acid
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SCR
Screened Set
SOC
System Organ Class
SRC
Safety Review Committee
StD
Standard deviation
TLS
Tumour Lysis Syndrome
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UDAEC
User-Defined Adverse Event Category
ULN
Upper Limit of Normal
WHO-DD
World Health Organisation Drug Dictionary


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3.
INTRODUCTION
As per International Conference on Harmonisation E9 (ICH E9) the purpose of this document 
is to provide a more technical and detailed elaboration of the principal features of the analysis 
described in the protocol, 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 Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification 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 and definition of measurements and variables.
The study was initially planned to be a single arm, open label trial consisting of two parts: a 
Phase Ib dose escalation part and a Phase II part investigating one expansion cohort. 
Approximately 60 chronic lymphocytic leukaemia (CLL) patients who qualify for treatment 
with ibrutinib were to be treated with a combination of BI 836826 and ibrutinib in this trial. 
Approximately 20 patients were intended to be enrolled in Phase Ib and 40 patients were
intended to be enrolled in the Phase II part of this study.
Dose-escalation of BI 836826 is guided by a Bayesian Logistic Regression Model (BLRM) 
with overdose control. The BLRM estimates the maximum tolerated dose (MTD) by updating 
estimates of the probability of observing a dose limiting toxicity (DLT) in the MTD 
evaluation period for each dose level in the study as patient information becomes available. At 
any time in the trial, it is not permitted to escalate to a dose which does not fulfil the 
escalation with overdose control (EWOC) criterion. Dose-increments are ≤100% of the 
previous dose level tested in the previous cohort.
Due to the strategical decision to stop the project, the Phase II part of the trial will not be 
conducted. Therefore, this TSAP only describes the analysis of the Phase Ib part of the trial, 
based on CTP amendment 1 which reflects this change in the study set-up. The decision was 
made that an abbreviated clinical trial report (CTR) will be written for this trial instead of a 
full CTR. Therefore, only analyses mandatory to be reported and additional analyses deemed 
necessary by the trial are described in this TSAP and will be included in the abbreviated CTR. 
In the following, study medication always refers to either BI 836826 or ibrutinib.
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
Clarifications:
 
 
 
 
 
 
 
 
 
  
 
 
Changes:
 
 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary endpoints of the trial are: 

Recommended Phase II dose (RP2D) of BI 836826 in combination with ibrutinib. If a 
MTD can be determined based on the criteria as described in Section 7 of the CTP, the 
RP2D will be either the MTD or a lower dose. The RP2D will be determined by the 
safety review committee (SRC) based on safety and efficacy considerations.

Number of patients with DLTs during the MTD evaluation period (starting at the day 
of first administration of BI 836826, lasting until 14 days after the Day 15 
administration of BI 836826 in the first cycle)
For definition of DLT, refer to CTP Section 5.3.6.2.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Other secondary endpoints
The secondary endpoint is the MTD. The MTD may be considered reached if the posterior 
probability that the true DLT rate is in the target interval [0.16, 0.33) is larger than 0.5 or if at 
least 15 patients have been treated in the Phase Ib part, of which at least 6 at the MTD. 
Patients who have been replaced are not considered evaluable for MTD determination. Only 
DLTs occurring in the MTD evaluation period will be considered for the determination of the 
MTD


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
In this trial, treatments are not randomized (open-label, dose-escalation). Different dose levels 
of BI 836826 in combination with ibrutinib are being administered. All planned analyses will 
be presented by initial treatment group, i.e. for all dose cohorts separately and in total over all 
dose cohorts.
To justify the RP2D / MTD determination, DLTs occurring during the MTD evaluation 
period will be presented separately from those occurring during the whole on-treatment 
period. Patients where treatment group assignment has not been followed will be handled on a 
case-by-case basis and will be agreed upon latest at the report planning meeting before 
database lock.
For safety summaries events that start from first administration of BI 836826 and last until 30 
days (residual effect period (REP)) after the last administration of BI 836826 will be 
considered as having occurred “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, run-in,
or post-study period will be displayed in separate listings from those occurred during the on-
treatment period (refer to Section 7.8.1.2 for details). 
Labels of each analysis treatment period, analysis numbers, the labels used for displays in the 
tables and listings in the CTR, as well as codes, decodes, sort order and labels for each trial 
medication are provided in the TSAP technical document analysis dataset (ADS) plan. 
6.2
IMPORTANT PROTOCOL VIOLATIONS
No per protocol set analysis will be performed for this study, hence no patient will be 
excluded from the analyses. However, patients with important protocol violations (IPVs) will 
be documented. The following table defines the different categories of IPVs.
Table 6.2 : 1
Important protocol violations
Category / 
Code
Description
Example/Comment
Excluded 
from
A
Entrance criteria not met
A1a
Patient has condition that may 
cause additional risk from study
medication
Check Inclusion/Exclusion criteria:
In6, In8
Ex4, Ex9, Ex10, Ex11, Ex12, Ex13, Ex16, 
Ex17, Ex18, Ex19
None
A2a
Patient has laboratory assessments 
that may cause additional risk
Check whether baseline laboratory data 
comply with thresholds as defined by In7 and 
check that In7 = “Yes”
None
A3a
Patient is unable to comply with 
the protocol
Check Ex20
None
A4a+m
Patient does not have trial 
diagnosis or is not part of the 
target population
Check Inclusion/Exclusion criteria:
In1, In2, In3, In4, In9, In10
Ex1, Ex3, Ex5, Ex6, Ex7
None
B
Informed consent


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Table 6.2 : 1
Important protocol violations (cont.)
B1a
Informed consent not given or too 
late
Check In12
Check date of IC against date of Screening 
visit
All
C
Trial medication and 
randomisation
C1a+m
Drug not administered according 
to protocol
Infusion schedule followed = “No” and 
medical review of associated comments
None
C2a
Drug administration not according 
to schedule
Ibrutinib not administered continuously from 
start of Run-in period 
Cycle 1: pre-dose of 10 mg of BI836826 not 
administered on Day 1 and 50% of target dose 
on Day2 and Day 8 and 100% of target dose 
on Day 15.
Cycles 2-4: 100% of target dose of BI836826 
not administered on days 1 and 15 of each 
cycle
Cycles 5-24: 100% of target dose of BI836826  
not administered on day 1 of each cycle
None
C3a
Incorrect treatment taken
Study drugs dispensing error leading to 
change in actual treatment
None
D
Concomitant medication
D1a+m
Prohibited medication 

anti-neoplastic therapy

long-term use (>7 days)of strong 
CYP3A inhibitor (check also Ex15)

Oral anti-coagulants (check also 
Ex14)
ongoing systemic immunosuppressive therapy 
other than corticosteroids (check also Ex8)
None
D2a+m
Pre-medication not administered 
according to protocol
Did the subject receive standard pre-
medication = “No” to any standard pre-
medication and medical review of associated 
comments – only until cycle 6, afterwards pre-
medication according to investigator 
judgement
None
a = automated IPV; m = manual IPV; In = Inclusion criterion; Ex = Exclusion criterion
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.
The Run-In Set (RIS) includes all patients who received at least one dose of ibrutinib. The 
RIS will be used for the analysis of exposure to ibrutinib. 
The Treated Set (TS): consists of all patients who received at least one administration of 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 BI 836826 and were not replaced for the MTD evaluation. The 
MTD evaluation set will be used for the primary analyses of DLTs and MTD determination.


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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 (TCM) no later than the last 
blinded report planning meeting (BRPM) and will be stored in the TMF.
 
6.5
POOLING OF CENTRES
This section is not applicable since there will not be any inferential statistical analysis. Thus, 
no statistical model in which centre or country is included as factor is applied.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates are imputed according to BI standards (3).
In general, missing data not discussed in (3) will not be imputed unless required for the 
following analyses and definitions. Then the rules as described below apply.
1) Change of laboratory values from baseline
Laboratory values at baseline: For missing laboratory data at visit 1 (before the first 
administration of BI 836826) the data of preceding visits will be used. 
2) Definition of on-treatment period and actual treatment 
Date of permanent discontinuation of last study medication: All reasonable efforts 
should be undertaken during the study to obtain the dates of permanent 
discontinuation of last study medication. However, if the date of the very last 
administration is missing this will be imputed with:

If only month and year are given, the last day of the month will be used for 
imputation

If only the year is given, the 31st of December of this year will be used for 
imputation
If the imputed date leads to a date that is later than the date of the end of treatment
(EOT) visit, then the imputed date is the date of the EOT visit. If the imputed date 
leads to a date that is later than the death date, then the imputed date is the date of 
death.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study days and visits will be labelled according to the flow chart of the CTP.
Unless otherwise specified, baseline is defined as the time-point closest to but prior to first 
administration of BI 836826. 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 the very first 
administration of BI 836826. 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 administration of BI 836826 is considered 
as baseline value if and only if the time of laboratory value is before or the same as the time 
of BI 836826 administration.


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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. For tables that are provided for endpoints with some extreme data, 
median, quartiles and percentiles should be preferred to mean, StD, min, and max. Efficacy 
data are presented by dose cohort. Displays of safety data will be presented by dose cohort 
and in total. 
For time-to-event analysis tables, the set of statistics is: number of patients [N(%)], Number 
of patients with event [N(%)], <Time to event> [months] followed by P25 (25th percentile), 
median, P75 (75th percentile), Number of patients censored [N(%)]. If not specified otherwise, 
the duration as well as the time to event will be displayed in days.
If not otherwise specified, the abbreviation Pxx should be used for displaying the xxth
percentile. 
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.
Abbreviations (e.g. Wors.) should not be displayed without any explanations. They will be 
either spelled out in the table or explained in footnotes (whatever is more reasonable from the 
programming point of view).
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
Descriptive statistics are planned for this section.
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) will be provided.
7.1.2
Important protocol violations
The number of patients with important protocol violations will be displayed.


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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, oncology history, virology, physical examination (including 
constitutional symptoms), eastern cooperative oncology group (ECOG) performance score,
tumour size, previous therapies and previous stem cell transplantations.
7.2
CONCOMITANT DISEASES AND MEDICATION
Descriptive statistics are planned for this section of the report.
Concomitant diseases will be coded similarly as adverse events based on the most current 
MedDRA version. Concomitant therapies (CTh) will be coded according to the 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 BI 836826. Transfusions will be 
displayed separately.
7.3
TREATMENT COMPLIANCE
Compliance will be evaluated by whether or not the medication was always administered 
according to protocol for BI 836826.
For patients where the infusion schedule was not followed a listing with comments will be 
presented.
Furthermore, a listing will show all administrations of BI 836826 including also the 
administration of premedication Analgesic/Antipyretic, Glucocorticoid and Antihistamine as 
well as the dose changes and interruptions of ibrutinib.
7.4
PRIMARY ENDPOINTS
The primary endpoints are the RP2D and the number of patients with DLTs in the MTD 
evaluation period. The number of patients with DLTs at each dose level will be presented for 
the MTD evaluation period for the MTD evaluation set and for the whole on-treatment period 
for the treated set separately.
The RP2D will either be the MTD or any lower dose, examined based on safety and efficacy 
criteria. The analysis of the MTD is based on a BLRM guided by the EWOC principle. 
Estimation of the MTD during the dose escalation phase of the study will be based upon the 
estimation of the posterior probability of the incidence of DLT in toxicity categories during 
the MTD evaluation period for all evaluable patients. The model to be used is specified in 
CTP Section 7.


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The posterior probabilities that the toxicity rates of each dose level fall into the categories 
specified in CTP Section 7 estimated from the BLRM will be displayed graphically as well as 
in a table. This will be done for the MTD evaluation period as well as for the complete on-
treatment period.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
Not applicable.
7.5.2
Other Secondary endpoints
The secondary endpoint is the MTD. This will analysed analogously to the primary endpoint 
RP2D. Only patients evaluable for MTD determination will be used for the analysis of the 
MTD, i.e. patients, if any, who were replaced during the MTD evaluation period will be 
excluded from the analysis of the MTD. 


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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 frequencies and percentages, as well as summary statistics.
7.8
SAFETY ANALYSIS
If not specified otherwise, all safety analyses will be performed on the treated set.
7.8.1
Adverse events
7.8.1.1
Maximum tolerated dose / RP2D and dose limiting toxicity
A summary of the number of patients with DLTs within the MTD evaluation period will be 
displayed for the MTD evaluation set. This table will also be created for all treatment courses 
of the on-treatment period by initial treatment for the treated set.
Patients who were replaced within the MTD evaluation period will be excluded from the 
determination of the MTD but will be considered for all other safety evaluations. A listing of 
replaced patients will be provided. 
Refer to Section 7.4 for more details on the analysis of the MTD and the RP2D.
7.8.1.2
Adverse events
Unless otherwise specified, adverse events analyses will be performed for the on-treatment 
period. Selected analyses will be repeated for the MTD evaluation period and for the run-in 
period. 
The analyses of AEs will be descriptive in nature and will follow the standard procedure laid 
down in (4). All analyses of AEs will be based on the number of patients with AEs and NOT 
on the number of AEs.
AEs will be coded with the most recent version of MedDRA. The version number will be 
displayed as a footnote in the respective tables and listings. The severity of AEs will be scaled 
according to CTCAE version 4.0.


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The system organ classes (SOCs) will be sorted alphabetically. In tables displaying AEs by 
dose cohort, preferred terms (PTs) will be sorted by descending frequency of adverse events 
in the “Total” BI 836826 group.
Each patient can be observed during the trial under several doses. Analysing the AEs of all 
treatment courses will be carried out under the initial treatment. No formal statistical analysis 
is planned for the safety comparison. 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs occurring from the first administration of BI 836826 until 30 days after last 
administration of BI 836826 will be assigned to the on-treatment period. All AEs occurring 
before first administration of any trial medication will be assigned to “Screening”, all AEs 
occurring after the first administration of ibrutinib and before the first administration of BI 
836826 will be assigned to “Run-in” and all AEs occurring after last administration of BI 
836826 + 30 days will be assigned to “Post-study” (for listings only). The actual planned 
dosage of BI 836826 and ibrutinib 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 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 in Section 15 of the CTR is displayed as “all Grades”, 
“missing Grade”, “Grade 1”, “Grade 2”, “Grade 3”, “Grade 4” and “Grade 5”, but the 
“missing grade” column should only be displayed in case AEs with a missing CTCAE grade 
occurred. A separate table will show AEs leading to death. In this table no CTCAE grades 
will be shown. 
Frequencies of patients with AEs will be summarised by treatment, highest CTCAE grade, 
primary SOC and PT. Tables will be provided for patients with drug-related AEs, with serious 
AEs (SAEs), with drug-related SAEs, with AEs leading to discontinuation of last study 
medication (i.e. leading to discontinuation of the last administered study medication), with 
AEs leading to discontinuation of BI 836826, with AEs leading to discontinuation of 
ibrutinib, with AEs leading to dose reduction of BI 836826, with AEs leading to dose 
reduction of inbrutinib, with protocol-specified AEs of special interest (AESI), and with AEs 
leading to death.


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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 (2).  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 normalized laboratory values 
over time by dose cohort. The graphs may be truncated if sufficient data is not available. 
These graphs will be displayed in Section 16.1.13.1 of the CTR for the following parameters, 
using the BI normalised values for haematology and differentials, and the multiples of the 
ULN for enzymes.
Haematology: haemoglobin, white blood cell count 
Differentials: absolute lymphocyte count
Enzymes: LDH
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:

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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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.
Patients with hepatic enzyme elevation will be tabulated (drug-induced liver injury (DILI)
supporting table). In addition, a separate listing will be presented giving patients with missing 
parameter in the given time frame. 
For potential Hy’s law cases, possible clinically significant abnormal laboratory values and 
cases of TLS frequency tables will be provided. 


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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 separate analyses are planned. Newly emergent abnormalities will be recorded and 
analysed as AEs.
7.8.5
Others
Not applicable


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8.
REFERENCES
1
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; IDEA for 
CON.
2
001-MCG-157: “Handling, Display and Analysis of Laboratory Data”, current 
version; IDEA for CON.
3
001-MCG-156_RD-01: “Handling of missing and incomplete AE dates”, current 
version; IDEA for CON.
4
001-MCG-156: “Handling and summarization of adverse event data for clinical 
trial reports and integrated summaries”, 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). 
htts://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf2010


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial 
version
19-JUL-16
None
This is the initial version of the TSAP 
with necessary information for the trial 
conduct
Final
30-JUL-18
1-9
This is the final TSAP