Clinical trial NCT02624492
Conditions: Lymphoma, Large B-Cell, Diffuse
Sponsor: Boehringer Ingelheim
Start date: 2016-01-28; Completion date: 2018-03-16
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Part 1 (Phase Ib)

Primary objective:

To establish the maximum tolerated dose (MTD) of BI 836826 in combination with GemOx.

Secondary objectives:

To evaluate pharmacokinetics of BI 836826 when given in combination with GemOx and to investigate preliminary efficacy in terms of the overall response rate based on investigator's assessment.

Part 2 (Phase II randomized)

Primary objective:

To investigate the efficacy by means of the overall response rate (PR+ CR) based on central review assessment in patients with relapsed DLBCL treated with BI 836826-GemOx compared to R-GemOx.

Secondary objective:

To investigate the efficacy by means of the complete remission rate based on central review assessment in patients with relapsed DLBCL treated with BI 836826-GemOx compared to Rituximab + gemcitabine + oxaliplatin (RGemOx).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 836826 intervention 2: GemOx intervention 3: Rituximab intervention 4: GemOx
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_001.pdf: 
001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
CLINCAL TRIAL PROTOCOL
Document Number:
c02102551-08
EudraCT No.:
2014-004794-16
BI Trial No.:
1270.11
BI Investigational 
Product(s):
BI 836826
Title:
An open label multicenter Phase Ib/II trial to determine the dose of 
BI 836826 in combination with gemcitabine and oxaliplatin 
(GemOx) and the efficacy of BI 836826-GemOx versus rituximab 
(R)- GemOx (R-GemOx) in patients with relapsed/ refractory 
diffuse large B-cell lymphoma (DLBCL) who are not eligible for, 
or have relapsed/progressed after autologous/allogeneic stem cell 
transplant
Lay Title:
To determine the dose of BI 836826-GemOx and the efficacy of 
BI 836826-GemOx versus R-GemOx in patients with 
relapsed/refractory DLBCL
Clinical Phase:
Ib/II
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating
Principal
Investigator:
Phone:
 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 5))
Version and Date:
Version: 6.0
Date:14 September 2017
Page 1 of 118
Proprietary confidential information.
! 2017 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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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
not applicable
Name of active ingredient:
BI 836826
Protocol date:
11 Jun 2015
Trial number:
1270.11
Revision date:
14 September 2017
Title of trial:
An open label multicenter Phase Ib/II trial to determine the dose of BI 
836826 in combination with gemcitabine and oxaliplatin (GemOx) 
and the efficacy of BI 836826-GemOx versus rituximab (R)- GemOx 
(R-GemOx) in patients with relapsed/ refractory diffuse large B-cell 
lymphoma (DLBCL) who are not eligible for, or have 
relapsed/progressed after autologous/allogeneic stem cell transplant
Coordinating
Investigator< for multi-
center trial if 
applicable >:
Phone: 
 
Fax: 
Trial site(s):
Multicenter trial in two parts
∀
Part 1 (Phase Ib dose escalation) 12-14 sites mainly in Europe
∀
Part 2 (randomized Phase II) 35-40 sites in Europe and rest of 
the world
Clinical Phase:
Phase Ib/ II
Objective(s):
Part 1 (Phase Ib)
Primary objective: 
To establish the maximum tolerated dose (MTD) of BI 836826 in 
combination with GemOx
Secondary objective:
To evaluate pharmacokinetics of BI 836826 when administered in 
combination with GemOx
To evaluate preliminary efficacy in terms of the overall response rate
(ORR) based on investigator’s assessment.
Part 2 (Phase II randomized)
Primary objective: 


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BI Trial No.: 1270.11
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Trial Protocol
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001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
Name of company:
Boehringer Ingelheim 
Name of finished product:
not applicable
Name of active ingredient:
BI 836826
Protocol date:
11 Jun 2015
Trial number:
1270.11
Revision date:
14 September 2017
To investigate the efficacy by means of the overall response rate
(PR+ CR) based on central review assessment in patients with 
relapsed DLBCL treated with BI 836826-GemOx compared to R-
GemOx
Secondary objective:
To investigate the efficacy by means of the complete remission rate 
based on central review assessment in patients with relapsed DLBCL 
treated with BI 836826-GemOx compared to R-GemOx
Methodology:
Part 1: Open-label dose finding of BI 836826-GemOx
Part 2: Open-label randomized trial of BI 836826-GemOx versus
R-GemOx
No. of patients: 
up to 153
total entered:
Part 1 and Part 2 = Up to 153 
each treatment:
Part 1: Up to 33 patients treated with BI 836826-GemOx
Part 2: 120 patients; 60 patients randomized to BI 836826-GemOx 
and 60 patients randomized to rituximab-GemOx (R-GemOx)
Diagnosis :
Relapsed/ refractory diffuse large B-cell lymphoma 
Main criteria
for inclusion:
1. Age 18 years or older
2. Patients with histologically confirmed, relapsed/refractory, 
diffuse large B-cell lymphoma (including transformed 
follicular lymphoma)
•
who have received an anti-CD20-supplemented, 
anthracycline-containing chemotherapy 
and
•
are not eligible for high dose therapy followed by an 
autologous stem cell transplant, or have 
relapsed/progressed after autologous/ allogeneic stem
cell transplant
Allogenic stem cell transplant performed at least 6 months prior 
to study entry is allowed if patients do not require 


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001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
Name of company:
Boehringer Ingelheim 
Name of finished product:
not applicable
Name of active ingredient:
BI 836826
Protocol date:
11 Jun 2015
Trial number:
1270.11
Revision date:
14 September 2017
immunosuppressive treatment and have no evidence of active 
graft-versus-host disease
3. Patient has not received anti-lymphoma treatment prior to the 
first dose of trial medication: 
•
within past 14 days 
or 
•
within time that is shorter or equal to 5 half-lives of 
the drug  if the last anti-lymphoma treatment contained 
an investigational agent 
4. Screening computer tomography (CT) scan with involvement 
of at least 1 bi-dimensional lesion/node >1.5 cm
5. Screening #18F∃flourodeoxyglucose (FDG)- positron emission 
tomography (PET) scans must demonstrate positive lesion 
compatible with computer tomography (CT) defined 
anatomical tumor sites
6. ECOG performance status 0, 1, 2, see Table 5.2.3:1
7. Written signed informed consent consistent with ICH GCP and 
local legislation 
8. Patients must have an acceptable organ function defined as in 
Table 3.3.2.1 : 
9. 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. A list of contraception methods 
meeting these criteria is provided in the patient information.
Non-vasectomized male patients having a female sexual 
partner of childbearing potential must ensure their partner is 
using a highly effective method of birth control as described 
above, during the trial and for at least 12 months after the end 
of the trial. (See section 4.2.2.3 for details).
Test product(s):
BI 836826 
dose:
Part 1: Five dose levels of BI 836826 (25mg, 50mg, 100mg, 150mg 


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001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
Name of company:
Boehringer Ingelheim 
Name of finished product:
not applicable
Name of active ingredient:
BI 836826
Protocol date:
11 Jun 2015
Trial number:
1270.11
Revision date:
14 September 2017
and 200mg) will be administered intravenous (i.v.) on day 8 of each 
cycle. 
An additional intermediate dose might be tested.
GemOx (gemcitabine 1000mg/m2 plus oxaliplatin 100mg/m2) will be 
administered i.v. on day 1 of each cycle. Each cycle is 14 days. 
Part 2: 
BI 836826-GemOx arm: Recommended dose of BI 836826 as 
identified in Part 1 in combination with GemOx.
GemOx will be administered i.v on day 1 of each cycle.
BI 836826 will be administered i.v. on day 8 of each cycle.
Each cycle is 14 days
mode of 
administration:
Treatment arm with BI 836826-GemOx:
BI 836826 i.v.
Gemcitabine i.v. 
Oxaliplatin i.v.
Comparator products:
Part 2: Rituximab
dose:
Rituximab 375mg/m2 i.v. on day 1 of every cycle. GemOx
(gemcitabine 1000mg/m2 plus oxaliplatin 100mg/m2) i.v. on day 2 of 
each cycle. Each cycle is 14 days.
mode of 
administration:
Treatment arm with Rituximab and GemOx (R-GemOx):
Rituximab i.v.
Gemcitabine i.v.
Oxaliplatin i.v. 
Duration of treatment:
Six cycles
Endpoints
Primary endpoints:
Part 1
The number of patients with DLTs in cycle 1.
The MTD of BI 836826 with GemOx based on the number of patients 
with DLTs in cycle 1. The MTD of BI 836826 with GemOx is 
defined as the highest dose studied for which the number of patients 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
not applicable
Name of active ingredient:
BI 836826
Protocol date:
11 Jun 2015
Trial number:
1270.11
Revision date:
14 September 2017
with dose-limiting toxicity is 17% or less (i.e., 0-1/6 patients) during 
cycle 1.
Part 2 
Overall response (OR) by central review assessment, i.e. partial 
response (PR) and complete remission (CR) by central review 
assessment, analyzed by the overall response rate (ORR) and 
compared between the two treatment arms. 
Secondary endpoints:
Part 1
The secondary endpoints will be pharmacokinetic parameters: AUCt
and Cmax of BI 836826 when administered in combination with 
GemOx and the overall response based on investigator’s assessment.
Part 2
The CR by central review assessment will be the secondary endpoint, 
and will be compared between the two treatment arms. 
Safety criteria:
Incidence and intensity of adverse events graded according to 
common terminology criteria for Adverse Events (CTCAE) version 
4.0. Changes in laboratory parameters.
Statistical methods:
Part 1: 3+3 design to evaluate the dose of BI 836826 in combination 
with GemOx.
Part 2: Efficacy evaluation of BI 836826-GemOx compared to R-
GemOx will be based on the binary endpoint for overall response 
(OR) analyzed by overall response rate. Suissa-Shuster exact test 
(including the Berger-Boos modification) will be used to compare the 
OR for the treatment groups. 
All analyses are descriptive and explorative. 


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FLOW CHART 1 
PART 1: Dose Finding
Procedures/Cycles1)
screen
Cycle 1
Cycle 2
Cycle 3
Cycle 4-6
EOT2)
FU3) 
AEs
FU4)
Day of cycle
-14 to <1
1
85)
9
11
(- 1)
1
8
(+3)
1
8
(+3)
1
8
(+3)
30-42
days 
after 
last 
dose
Visit6)
Screen
C1D1
C1D8
C1D9 C1D11
C2D1
C2D8
C3D1
C3D8
C4D1
C4D8
EOT
FU
Informed consent Part1
X
Demographics
X
Height
X
Weight
X
X
X
X
X
X
ECOG
X
X
X
X
X
X
Physical exam 
(incl. evaluation of B symptoms)
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
Medical History 
X
In- and exclusion criteria review
X
12-Lead ECG7)
X
X
X
Tumor tissue biopsy8)
X


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Procedures/Cycles1)
screen
Cycle 1
Cycle 2
Cycle 3
Cycle 4-6
EOT2)
FU3) 
AEs
FU4)
Day of cycle
-14 to <1
1
85)
9
11
(- 1)
1
8
(+3)
1
8
(+3)
1
8
(+3)
30-42
days 
after 
last 
dose
Visit6)
Screen
C1D1
C1D8
C1D9 C1D11
C2D1
C2D8
C3D1
C3D8
C4D1
C4D8
EOT
FU
Safety labs
Hematology 
X
X
X
X
X
X
X
X
X
X
X
X
Reticulocytes
X
X
X
X
X
X
Biochemistry
X
X
X
X
X
X
Serum β2–microglobulin
X
Immunoglobulins
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
Urine
X
X
X
X
X
X
Serum pregnancy test
X
X
Screening for tumor lysis syndrome 
(TLS) 10)
X
Virology testing 11)
X
CMV viral load monitoring 12)
X
X
X
X
X
Flow cytometry 13)
X
X
X
Pharmacokinetics14)
X
X
X
X
X
X
X
X
X
X
X
 


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Procedures/Cycles1)
screen
Cycle 1
Cycle 2
Cycle 3
Cycle 4-6
EOT2)
FU3) 
AEs
FU4)
Day of cycle
-14 to <1
1
85)
9
11
(- 1)
1
8
(+3)
1
8
(+3)
1
8
(+3)
30-42
days 
after 
last 
dose
Visit6)
Screen
C1D1
C1D8
C1D9 C1D11
C2D1
C2D8
C3D1
C3D8
C4D1
C4D8
EOT
FU
IRT/ Dose assignment 16)
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
PET/CT scan 17)
X
X
X
Eligibility for continuation
X
X
X
Premedication for BI 836826
X
X
X
X
Administration of BI 836826
X
X
X
X
Antiemetics  prior to GemOx
X
X
X
X
Administration of Gemcitabine
X
X
X
X
Administration of Oxaliplatin
X
X
X
X
Disease assessment /vital status  
(remission/progression/death/new 
anti-lymphoma treatment) 18)
X
X
X
X
X


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1)
The planned duration of a treatment cycle is 14 days; and up to 17 days from Cycle 2, in case the D8 is delayed by maximum 3 days. In case of toxicity, the start of the 
next cycle maybe delayed by maximum of 14 days to allow for recovery.
2)
EOT is the End of treatment visit and should be done at the earliest 30 days and no later than 42 days after the last dose for those patients completing all 6 cycles 
according to protocol. If a patient is prematurely withdrawn from treatment (i.e. earlier than the end of the 6th cycle), an EOT visit should be performed within 14 days 
after last dose (last administration of Gemcitabine, Oxaliplatin or BI836826, whichever is the latest).
3)
FU AEs visit: The information collected at this visit should include all new AEs that occurred after the last dose and a follow-up of adverse events ongoing at the time of 
the last dose. If a patient has been prematurely withdrawn from treatment, the FU for AEs visit must be performed on site 30-42 days after the last dose. If a patient 
completes the 6 cycles according to the protocol the FU for AEs visit can be scheduled at the same time point as EOT visit. 
4)
Follow-up visits (FU) see section 6.2.5: After the FU for AEs, the patient will be followed for disease assessment/vital status (remission/progression/death/new anti-
lymphoma treatment) and drug related SAEs and AESIs. These FU visits should take place every 3 months for the first year after FU for AEs visit, and then every 6 
months until death, patient is lost to follow-up, patient withdraws consent for further follow up or the end of trial is reached. FU may be performed by telephone interview 
in case the patient is unable to visit the investigator.
5)
In cycle 1, during the first infusion of BI 836826 the patients are required to be hospitalized for at least 24hrs under close surveillance with access to intensive care.
6)
The naming of the visit follows the cycle number and day of treatment, i.e. Day 1 cycle 1 will read C1D1 and Day 8 cycle 2 will read C2D8.
7)
Single electrocardiogram (ECG) to be performed before any blood sampling at screening, day 8 in cycle 4 (C4D8) and EOT. Please note that on C4D8, ECG has to be 
performed before the infusion and immediately after the end of the infusion of BI 836826.
8)
Confirm availability of archival tissue. If the required amount of tumor tissue is not available, fresh biopsy is mandatory. Sample must be shipped to central laboratory.
See Section 5.5.1.1
    
10) Screening for TLS has to be performed within 24hrs of first dose of BI 836826 in patients at risk of TLS (high tumor burden) see section 5.3.3.2.
11) Mandatory tests at screening: see 5.3.3.3 virology: HIV antibody, CMV- Ig G, CMV-IgM, HbsAg, anti-HBc, anti-HCV. If patient is positive for anti-HCV during 
screening, the HCV-RNA test can be performed to exclude false positive results. If HCV-RNA test is negative, patient may be enrolled
 
13) Flow cytometry: quantitative assessment of: B cells, T cells, NK cells required at C1D1, C4D1 and EOT visit. Blood samples to be sent to a Central laboratory.
14) Pharmacokinetics for dosing times and cycles see Appendix 10.1, Table 10.1:1
 
16) Patients will be registered via interactive response technology (IRT) at screening and at each time-point trial medication is dispensed as well as at EOT. 
17) PET/CT Scan of neck, thorax, abdomen, and pelvis to be performed at each time.  
a)
Baseline PET/CT scan: up to 28 days prior to C1D1
b)
Interim PET/CT scan: after C3, i.e. prior to C4D1
c)
Final PET/CT scan: 3-6 weeks after the last dose if 6 cycles have been completed.
18) Disease assessment/vital status is collected at baseline, after the interim PET/ CT scan, i.e. after the end of cycle 3 and before C4D1 at EOT and during follow up visits.


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FLOW CHART 2
Part 2: BI 836826-GemOx arm
Procedures/Cycles1)
screen
Cycle 1
Cycle 2-6
EOT2)
FU3)
AEs
FU4)
Day of cycle
-14 to 
<1
1
85)
9
11 (-1)
1
8
(+3 )
30-42
days 
after 
last 
dose
Visit6)
screen
C1D1 C1D8 C1D9 C1D11
C2D1 C2D8
EOT
FU
Informed consent  Part 2
X
Demographics
X
Height
X
Weight
X
X
X
X
ECOG
X
X
X
X
Physical exam (incl. evaluation of B symptoms)
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Medical History
X
In- and exclusion criteria review
X
12-Lead ECG 7)
X
X
X
 


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Procedures/Cycles1)
screen
Cycle 1
Cycle 2-6
EOT2)
FU3)
AEs
FU4)
Day of cycle
-14 to 
<1
1
85)
9
11 (-1)
1
8
(+3 )
30-42
days 
after 
last 
dose
Visit6)
screen
C1D1 C1D8 C1D9 C1D11
C2D1 C2D8
EOT
FU
 
Safety labs
Hematology 
X
X
X
X
X
X
X
X
Reticulocytes
X
X
X
X
Biochemistry
X
X
X
X
Serum β2–microglobulin
X
Immunoglobulins
X
X
X
X
Coagulation
X
X
X
X
Urine
X
X
X
X
Serum pregnancy test
X
X
Screening for tumor lysis syndrome ( TLS) 10)
X
Virology testing 11)
X
CMV viral load monitoring 12)
X
X
X
X
)
Flow cytometry 13)
X
X
X
Pharmacokinetics14)
X
X
X
X


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Procedures/Cycles1)
screen
Cycle 1
Cycle 2-6
EOT2)
FU3)
AEs
FU4)
Day of cycle
-14 to 
<1
1
85)
9
11 (-1)
1
8
(+3 )
30-42
days 
after 
last 
dose
Visit6)
screen
C1D1 C1D8 C1D9 C1D11
C2D1 C2D8
EOT
FU
IRT/ Randomization 16)
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
PET/CT scan17)
X
X
X
Eligibility for treatment continuation
X
X
Premedication for BI 836826
X
X
Administration of BI 836826
X
X
Antiemetics  prior to  GemOx
X
X
Administration of Gemcitabine
X
X
Administration of Oxaliplatin
X
X
Disease assessment/ vital status 
(remission/progression/death/new anti-lymphoma 
treatment) 18)
X
X
X
X
X


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1)
The planned duration of a treatment cycle is 14 days; and up to 17 days from Cycle 2, in case the D8 is delayed by maximum 3 days. In case of toxicity, the start of the 
next cycle maybe delayed by maximum of 14 days.
2)
EOT is the End of treatment visit and should be done at the earliest 30 days and no later than 42 days after the last dose for those patients completing all 6 cycles 
according to protocol. If a patient is prematurely withdrawn from treatment (i.e. earlier than the end of the 6th cycle), an EOT visit should be performed within 14 days 
after last dose (last administration of Gemcitabine, Oxaliplatin or BI836826, whichever is the latest)
3)
FU AEs: The information collected at this visit should include all new AEs that occurred after the last dose and a follow-up of adverse events ongoing at the time of the 
last dose. If a patient has been prematurely withdrawn from treatment, the FU for AEs visit must be performed on site 30-42 days after the last dose. If a patient 
completes the 6 cycles according to the protocol the FU for AEs visit can be scheduled at the same time point as EOT visit. 
4)
Follow-up visits (FU) see section 6.2.5: After the FU for AEs, the patient will be followed for disease assessment/ vital status (remission/progression/death/new anti-
lymphoma treatment) and drug related SAEs and AESIs. These FU visits should take place every 3 months for the first year after FU for AEs visit, and then every 6 
months until death, patient is lost to follow-up, patient withdraws consent for further follow up or the end of trial is reached. FU may be performed by telephone interview 
in case the patient is unable to visit the investigator
5)
In cycle 1, during the first infusion of BI 836826 the patients are required to be hospitalized for at least 24hrs under close surveillance with access to intensive care.
6)
The naming of the visit follows the cycle number and day of treatment, i.e. Day 1 cycle 1 will read C1D1 and Day 8 cycle 2 will read C2D8
7)
Single electrocardiogram (ECG) are to be performed before any blood sampling at screening, day 8 in cycle 4 (C4D8) and EOT. Please note that on C4D8, ECG has to be 
performed before the infusion and immediately after the end of the infusion of BI 836826.
    
10) Screening for TLS has to be performed within 24hrs of first dose of BI 836826 in patients at risk of TLS (high tumor burden) see section 5.3.3.2.
11) Mandatory tests at screening: see 5.3.3.3 virology: HIV antibody, CMV- Ig G, CMV-IgM, HbsAg, anti-HBc, anti-HCV. If patient is positive for anti-HCV during 
screening, the HCV-RNA test can be performed to exclude false positive results. If HCV-RNA test is negative, patient may be enrolled.
12) Quantitative Cytomegalovirus (CMV), Deoxyribonucleic acid (DNA), polymerase chain reaction (PCR) to be performed at screening, C1D1,C2D1, C4D1, C6D1 and 
EOT. 
13) Flow cytometry: quantitative assessment of: B cells, T cells, NK cells required at C1D1 C4D1 and EOT visit. Blood samples to be sent to a Central laboratory.
14) Pharmacokinetics for dosing times, days and cycles see Appendix 10.1, Table 10.1.2.
 
16) Patients will be registered via interactive response technology (IRT) at screening and at each time-point trial medication is dispensed as well as at EOT.
17) PET/CT Scan of neck, thorax, abdomen, and pelvis to be performed at each time.
a)
Baseline PET/CT scan : up to 28 days prior to C1D1
b)
Interim  PET/CT scan : after C3, i.e. prior to C4D1
c)
Final PET/CT scan: 3-6 weeks after the last dose if 6 cycles have been completed.
18) Disease assessment/vital status is collected at baseline, after the interim PET/ CT scan, i.e. after the end of cycle 3 and before C4D1, at EOT and during follow up visits.


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FLOW CHART 3
Part 2: R-GemOx arm
Procedures/Cycles1)
screen
Cycle 1-6
EOT2)
FU3)
AEs
FU4)
Day of cycle
-14 to 
<1
1
25)
30-42
days 
after 
last 
dose
Visit6)
screen
C1-C6 
D1
C1-C6 
D2
EOT
FU
Informed consent  Part 2 
 
X
Demographics
X
Height
X
Weight
X
X
X
ECOG
X
X
X
Physical exam 
(incl. evaluation of B symptoms)
X
X
X
Vital signs
X
X
X
X
Medical History
X
In- and exclusion criteria review
X
12-Lead ECG 7)
X
X
X
 
Safety labs
     Hematology 
X
X
X
     Reticulocytes
X
X
X
     Biochemistry
X
X
X
     Serum β2–microglobulin
X
     Immunoglobulin
X
X
X
     Coagulation
X
X
X
     Urine
X
X
X


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Procedures/Cycles1)
screen
Cycle 1-6
EOT2)
FU3)
AEs
FU4)
Day of cycle
-14 to 
<1
1
25)
30-42
days 
after 
last 
dose
Visit6)
screen
C1-C6 
D1
C1-C6 
D2
EOT
FU
     Serum pregnancy test
X
X
Testing for tumor lysis syndrome ( TLS) 10)
X
     Virology testing 11)
X
     CMV viral load monitoring 12)
X
X
X
     Flow cytometry 13)
X
X
IRT/ Randomization 14)
X
X
X
X
Adverse events
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
PET/CT scan 15)
X
X
X
Eligibility for treatment continuation
X
Premedication for rituximab
X
Administration of rituximab
X
Antiemetics  prior to GemOx
X
Administration of Gemcitabine
X
Administration of Oxaliplatin
X
Disease assessment/ vital status 
(remission/progression/death/new anti-
lymphoma treatment) 16)
X
X
X
X
X


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1)
The planned duration of a treatment cycle is 14 days. In case of toxicity, the start of the next cycle maybe delayed 
by maximum of 14 days.
2)
EOT is the End of treatment visit and should be done at the earliest 30 days and no later than 42 days after the last 
dose for those patients completing all 6 cycles according to protocol. If a patient is prematurely withdrawn from 
treatment (i.e. earlier than the end of the 6th cycle) an EOT visit should be performed within 14 days after last dose
(last administration of Gemcitabine, Oxaliplatin or Rituximab, whichever is the latest)
3)
FU AEs: The information collected at this visit should include all new AEs that occurred after the last dose and a 
follow-up of adverse events ongoing at the time of the last dose. If a patient has been prematurely withdrawn from 
treatment, the FU for AEs visit must be performed on site 30-42 days after the last dose. If a patient completes the 
6 cycles according to the protocol the FU for AEs visit can be scheduled at the same time point as EOT.
4)
Follow-up visits (FU) see section 6.2.5: After the FU for AEs, the patient will be followed for disease 
assessment/vital status (remission/progression/death/new anti-lymphoma treatment) and drug related  SAEs and 
AESIs. These FU visits should take place every 3 months for the first year after FU for AEs visit, and then every 6 
months until death, patient is lost to follow-up, patient withdraws consent for further follow up or the end of trial is 
reached. FU may be performed by telephone interview in case the patient is unable to visit the investigator
5)
Day 2 is an outpatient visit. Patients do not need to stay overnight from day 1- day 2. 
6)
The naming of the visit follows the cycle number and day of treatment, i.e. Day 2 cycle 1 will read C1D2 and Day 
2 cycle 2 will read C2D2.
7)
Single electrocardiogram (ECG) is to be collected before any blood sampling at screening, on day 2 in cycle 4 
(C4D2) and EOT. Please note that on C4D2, ECG to be performed before the infusion and immediately after the 
end of the infusion of GemOx.
 
 
 
10) Screening for TLS has to be performed within 24hrs of first dose of Rituximab in patients at risk of TLS (high 
tumor burden) see section 5.3.3.2  
11) Mandatory tests at screening: see 5.3.3.3 virology: HIV antibody, CMV- Ig G, CMV-IgM, HbsAg, anti-HBc, anti-
HCV. If patient is positive for anti-HCV during screening, the HCV-RNA test can be performed to exclude false 
positive results. If HCV-RNA test is negative, patient may be enrolled.
12) Quantitative Cytomegalovirus (CMV), Deoxyribonucleic acid (DNA), polymerase chain reaction (PCR) to be 
performed at screening , C1D1, C2D1,C4D1, C6D1, and EOT. 
13) Flow cytometry: quantitative assessment of: B cells, T cells, NK cells required at C1D1 C4D1 and EOT visit. 
Blood samples to be sent to a Central laboratory.
14) Patients will be registered via interactive response technology (IRT) at screening and at each time-point trial 
medication is dispensed as well as at EOT.
15) PET/CT Scan of neck, thorax, abdomen, and pelvis to be performed at each time.
a.
Baseline PET/CT scan : up to 28 days prior to C1D1
b.
Interim PET/CT scan : after C3, i.e. prior to C4D1
c.
Final PET/CT scan: 3-6 weeks after the last dose if 6 cycles have been completed.
16) Disease assessment/vital status is collected at baseline, after the interim PET/ CT scan, i.e. after the end of cycle 3 
and before C4D1, at EOT and during follow up visits.


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TABLE OF CONTENTS
CLINCAL TRIAL PROTOCOL............................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART 1.....................................................................................................................7
FLOW CHART 2...................................................................................................................11
FLOW CHART 3...................................................................................................................15
TABLE OF CONTENTS ......................................................................................................18
ABBREVIATIONS................................................................................................................22
1.
INTRODUCTION...............................................................................................26
1.1.
MEDICAL BACKGROUND.............................................................................26
1.2.
DRUGS PROFILE..............................................................................................27
1.2.1.
BI 836826 .............................................................................................................27
1.2.2.
Human experience with BI 836826....................................................................28
1.2.3.
Gemcitabine.........................................................................................................30
1.2.4.
For additional detailed information please refer to the summary of product 
characteristic (SmPC) located in the ISF. Oxaliplatin ....................................31
1.2.5.
Rituximab (only in Part 2)..................................................................................31
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....33
2.1.
RATIONALE FOR PERFORMING THE TRIAL.........................................33
2.2.
TRIAL OBJECTIVES........................................................................................34
2.3.
BENEFIT - RISK ASSESSMENT.....................................................................34
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................36
3.1.
OVERALL TRIAL DESIGN AND PLAN .......................................................36
3.1.1.
Administrative structure of the trial .................................................................38
3.2.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................39
3.3.
SELECTION OF TRIAL POPULATION .......................................................41
3.3.1.
Main diagnosis for trial entry ............................................................................41
3.3.1.1.
Patient population .................................................................................................41
3.3.2.
Inclusion criteria .................................................................................................41
3.3.3.
Exclusion criteria ................................................................................................42
3.3.4.
Removal of patients from therapy or assessments...........................................43
3.3.4.1.
Removal/Replacement of individual patients .......................................................43
3.3.4.2.
Discontinuation of the trial by the sponsor...........................................................44
3.3.4.3.
Trial stopping rules in case of unacceptable toxicities .........................................44
4.
TREATMENTS...................................................................................................45
4.1.
TREATMENTS TO BE ADMINISTERED.....................................................45
4.1.1.
Identity of BI investigational product(s) and comparator backbone 
product(s).............................................................................................................45


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4.1.2.
Method of assigning patients to treatment groups...........................................46
4.1.3.
Selection of doses in the trial..............................................................................46
4.1.4.
Drug administration of doses for each patient.................................................49
4.1.5.
Infusion schedules ...............................................................................................51
4.1.5.1.
BI 836826 infusion................................................................................................51
4.1.5.2.
Rituximab infusion................................................................................................52
4.1.5.3.
Gemcitabine and Oxaliplatin ................................................................................52
4.1.5.4.
Premedication for BI 836826 and Rituximab .......................................................52
4.1.6.
Blinding and procedures for unblinding...........................................................53
4.1.6.1.
Blinding.................................................................................................................53
4.1.6.2.
Un-blinding and breaking the code.......................................................................53
4.1.7.
Packaging, labelling, and re-supply...................................................................53
4.1.8.
Storage conditions...............................................................................................54
4.1.9.
Drug accountability.............................................................................................54
4.2.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT.....................................................................................................55
4.2.1.
Rescue medication, emergency procedures, and additional treatment(s) .....55
4.2.1.1.
Rescue medication ................................................................................................55
4.2.1.2.
Supportive care .....................................................................................................55
4.2.1.3.
Antibiotics and antivirals ......................................................................................55
4.2.1.4.
Concomitant treatments ........................................................................................55
4.2.2.
Restrictions ..........................................................................................................56
4.2.2.1.
Restrictions regarding concomitant treatment ......................................................56
4.2.2.2.
Restrictions on diet and life style..........................................................................56
4.2.2.3.
Restrictions regarding women of childbearing potential ......................................56
4.3.
TREATMENT COMPLIANCE........................................................................57
5.
VARIABLES AND THEIR ASSESSMENT ....................................................58
5.1.
TRIAL ENDPOINTS..........................................................................................58
5.1.1.
Primary Endpoints..............................................................................................58
5.1.2.
Secondary Endpoints..........................................................................................58
5.2.
ASSESSMENT OF EFFICACY........................................................................59
5.2.1.
Criteria for response...........................................................................................59
5.2.3.
ECOG Performance Status................................................................................61
5.3.
ASSESSMENT OF SAFETY.............................................................................62
5.3.1.
Physical examination & B symptoms................................................................62
5.3.2.
Vital Signs............................................................................................................62
5.3.3.
Safety laboratory parameters ............................................................................62
5.3.3.1.
General safety laboratory parameters ...................................................................62
5.3.3.2.
Screening for laboratory evidence of TLS............................................................63
5.3.3.3.
Screening for hepatitis B, hepatitis C, CMV and HIV..........................................63
5.3.3.4.
CMV monitoring...................................................................................................64
5.3.3.5.
Flow cytometry/quantitative lymphocyte phenotyping ........................................64
5.3.4.
Electrocardiogram ..............................................................................................64
5.3.5.
Other safety parameters.....................................................................................65


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5.3.6.
Assessment of adverse events.............................................................................65
5.3.6.1.
Definitions of AEs ................................................................................................65
5.3.7.
Adverse event collection and reporting.............................................................68
5.3.8.
Dose limiting toxicity for Part 1.........................................................................71
5.4.
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................72
5.4.1.
Assessment of pharmacokinetics .......................................................................72
5.4.2.
Methods of sample collection .............................................................................72
5.4.3.
Analytical determinations ..................................................................................73
5.6.
APPROPRIATENESS OF MEASUREMENTS..............................................76
6.
INVESTIGATIONAL PLAN.............................................................................77
6.1.
VISIT SCHEDULE.............................................................................................77
6.2.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................77
6.2.1.
Screening period..................................................................................................77
6.2.2.
Treatment period(s)............................................................................................78
6.2.2.1.
Criteria to continue next treatment cycle (C2-6) and guidance to dose 
reduction ..............................................................................................................78
6.2.2.2.
Monitoring for infusion-related reactions.............................................................81
6.2.2.3.
Handling of infusion-related reactions..................................................................81
6.2.2.4.
Laboratory analyses: .............................................................................................82
6.2.2.5.
Disease assessments (PET-CT).............................................................................82
6.2.2.6.
Tumor lysis syndrome (TLS)................................................................................82
6.2.3.
End of Treatment................................................................................................82
6.2.4.
Follow-Up for AEs ..............................................................................................83
6.2.5.
Follow Up Period and Trial Completion...........................................................83
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................84
7.1.
STATISTICAL DESIGN MODEL ...................................................................84
7.2.
NULL AND ALTERNATIVE HYPOTHESES ...............................................84
7.3.
PLANNED ANALYSES.....................................................................................84
7.3.1.
Primary endpoint analyses.................................................................................85
7.3.2.
Secondary endpoint analyses .............................................................................85
7.3.4.
Safety analyses.....................................................................................................86
7.3.5.
Pharmacokinetic analyses ..................................................................................87
7.3.5.1.
Plasma concentration - time profiles.....................................................................88


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7.3.5.2.
Pharmacokinetic assessment.................................................................................88
7.4.
INTERIM ANALYSES ......................................................................................89
7.5.
HANDLING OF MISSING DATA ...................................................................89
7.6.
RANDOMISATION ...........................................................................................89
7.7.
DETERMINATION OF SAMPLE SIZE .........................................................89
7.7.1.
Part 1....................................................................................................................89
7.7.2.
Part 2....................................................................................................................90
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........91
8.1.
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...........................................................................................................91
8.2.
DATA QUALITY ASSURANCE ......................................................................92
8.3.
RECORDS...........................................................................................................92
8.3.1.
Source documents ...............................................................................................92
8.3.2.
Direct access to source data and documents.....................................................92
8.3.3.
Storage period of records ...................................................................................93
8.4.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS93
8.4.1.
Listedness.............................................................................................................93
8.4.2.
Expedited reporting to health authorities and IEC / IRB...............................93
8.5.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........93
8.6.
END OF TRIAL..................................................................................................94
8.7.
PROTOCOL VIOLATIONS .............................................................................94
8.8.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY..............................................................................94
9.
REFERENCES....................................................................................................95
9.1.
PUBLISHED REFERENCES............................................................................95
9.2.
UNPUBLISHED REFERENCES....................................................................101
10.
APPENDICES...................................................................................................102
10.1.
BLOOD SAMPLING TIMES FOR PHARMACOKINETICS
.....................................................................................102
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................112


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ADCC
Antibody-dependent cell cytotoxicity
ALT
Alanine Amino Transferase
ANC
Absolute Neutrophil Count
anti-HBc
hepatitis B core antibody
anti-HBs
hepatitis B surface antibody 
anti-HCV
hepatitis C antibody 
AP
Alkaline Phosphatase 
aPTT
Activated Partial Thromboplastin Time 
AST
Aspartate Amino Transferase
AUCt
Area Under the Curve
BI
Boehringer Ingelheim
BI 836826-Gem
BI 836826+gemcitabine
BI 836826-
GemOx
BI 836826+gemcitabine + oxaliplatin
BLQ
Below The Limit of Quantification
BSA
Body Surface Area
CA
Competent Authority 
CDC
Complement dependent cytotoxicity
CHOP
cyclophosphamide, hydroxydaunorubicin, oncovin , and prednisolone
CLL
Chronic lymphocytic leukaemia
Cmax
maximum plasma concentrations 
CML
Local Clinical Monitor
CMV
Cytomegalovirus
CNS
Central nervous system
CR
Complete remission 
CRA
Clinical Research Associate
CRO
Clinical Research Organisation
CT
Computer Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DEDP
Drug Exposure During Pregnancy 
DILI
Drug-Induced Liver Injury
DLBCL
Diffuse Large B-cell lymphoma
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group


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e-CRF
Electronic Case Report Form
EDTA
Ethylendiaminetetraacetic acid
ELISA
Enzyme-Linked Immuno Assay
EMA
European Medicines Agency
EOT
End of Treatment
EudraCT
European Clinical Trials Database
FCGR
Immunoglobulin G fragment C receptors
FDA
Food and Drug Administration
FDG
#18F∃flourodeoxyglucose
FISH
Fluorescence in-situ Hybridization
FL
FU
Follicular Lymphoma
Follow-up
G1
Grade 1 CTCAE
G2
Grade 2 CTCAE
G3
Grade 3 CTCAE
G4
Grade 4 CTCAE
 
GCP
Good Clinical Practice
GemOx
Gemcitabine and Oxaliplatin
GFR
Glomerular Filtration Rate
Hb
Hemoglobin
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
HT
Human Immunodeficiency Virus
Histological Transformation
HMA CTFG
Heads of Medicines Agencies Clinical Trials Facilitation group
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
ICP-MS
Inductively Coupled Plasma Mass Spectrometry
IEC
Independent Ethics Committee
IgG
Immunoglobin G
IgM
Immunoglobin M
IgA
Immunoglobin A
INR
International Normalized Ratio 
IRB
Institutional Review Board
IRR
Infusion Related Reaction
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intravenous
LC-MS/MS
Liquid Chromatography-Tandem Mass Spectrometry
LDH
Lactate Dehydrogenase 
MedDRA
Medical Dictionary for Drug Regulatory Activities
mRNA
Messenger ribonucleic acid
MTD
Maximum Tolerated Dose
NC
Not Calculated


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NCI
National Cancer institute 
NHL
Non-Hodgkin’s lymphoma
NK cells
Natural killer cells
NIMP
Non-Investigational Product 
NOA
Not Analyzed
NOP
No peak detectable
NOR
No Valid Result
NOS
No Sample Available
OR
Overall Response
ORR
Overall Response Rate
OS
Overall Survival
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PET
Positron Emission Tomography
PFS
Progression Free Survival 
  
PI
Principal Investigator 
PK
Pharmacokinetics
PLT
Platelets 
p.o.
per os (oral)
PR
Partial Remission
5-PS
Five-point score
PT
Prothrombin Time 
RBC
Red Blood Cell Count
RDC
Remote Data Capture 
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamics effects still likely to be present
R-Gem
Rituximab- + gemcitabine
R-GemOx
Rituximab + gemcitabine + oxaliplatin
RNA
Ribonucleic acid
RP2
Recommended dose in Part 2
SAE
Serious Adverse Event
SCT
Stem Cell Transplant
SD
Stable Disease
SOP
Standard Operating Procedures 
SmPC
Summary of Product Characteristics
SPD
Sum of Product of Diameters
SUSAR
Suspected Unexpected Serious Adverse Reactions 
SUV
Standardized Uptake Value
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
THU
Tetrahydrouridine
TLS
Tumor Lysis Syndrome 
TMF
Trial Master File
TMM
Team Member Medicine


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TMDS
Team Member Drug Safety
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WBC
White Blood Cell Count
WHO-DD
World Health Organization Drug Dictionary 
WOCBP
Women of Childbearing Potential


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1. INTRODUCTION
1.1.
MEDICAL BACKGROUND
The Non-Hodgkin’s Lymphoma (NHL) encompass a number of subtypes with variable 
clinical course and outcome. Approximately 90% of NHL in western countries are of B cell 
origin NHL (R10-4834) and belong to mature B cell malignancies according to the World 
Health Organization (WHO) classification (R10-6296).The incidence of NHL of B cell origin 
is 15-20 per 100.000 (seer.cancer.gov). About 72,240 new cases of NHL were estimated for 
2017 and about 20,140 people will die (www.cancer.org) in the United States (US).
Historically, based on the clinical presentation, NHLs have been classified as indolent (low 
grade) lymphomas, or as (high grade) aggressive lymphomas. Most of the indolent types are 
nodular (or follicular) in morphology, and often with insidious presentation with slow 
growing lymphadenopathy, hepatomegaly, splenomegaly, and/or cytopenias. Early stages of 
indolent NHLs (stage I and stage II) can be effectively treated because the lymphomas are 
usually responsive to immunotherapy, radiation therapy, and chemotherapy. Patients with 
advanced stages cannot be cured (R15-0609), but have a relatively long median overall 
survival (up to 20 years) with a continuous rate of relapse over time, which can often be 
successfully re-treated as long as the disease histology remains low grade. The natural history 
and the clinical course of patients with B-cell indolent lymphomas are also characterized by 
the risk of histologic transformation (HT) to an aggressive lymphoma. This is a well-known 
phenomenon that has been extensively studied in terms of the incidence, risk factors, and
outcome in patients with follicular lymphoma (FL), which transforms to a Diffuse Large B 
cell Lymphoma (DLBCL); and, less commonly, to Burkitt lymphoma, or other types of 
aggressive lymphomas. HT has also been described in other subtypes of B-cell indolent 
lymphomas. Patients who present with, or convert to aggressive forms of NHL may have 
sustained complete remissions with combination chemotherapy regimens or aggressive 
consolidation with marrow or stem cell support.
Aggressive lymphomas commonly develop acutely or sub-acutely with a rapidly growing 
mass, systemic B symptoms (i.e., fever, night sweats, weight loss), and/or elevated levels of 
serum lactate dehydrogenase (LDH) and uric acid. Examples of lymphomas with this 
aggressive presentation include DLBCL, Burkitt lymphoma, adult T cell leukemia-
lymphoma, or precursor B and T lymphoblastic leukemia/lymphoma. Untreated aggressive 
lymphomas have very short natural history, but with progress in recent years a significant 
number of patients can be cured with intensive combination regimens. DLBCL is the most 
common lymphoma and accounts for approximately 25 percent of all NHLs in the developed 
world (R15-0608, R10-6296). Advanced stage DLBCL is treated primarily with systemic 
chemotherapy (CHOP regimen: Cyclophosphamide, Hydroxydaunorubicin, Oncovin , and
Prednisolone) with the addition of recombinant anti-CD20 antibody, rituximab. The addition 
of rituximab to CHOP-based therapy results in an approximately 10 to 15 percent overall 
increase in survival beginning at one year from initiation of therapy in patients of all ages 
with almost no increase in toxicity (R15-0607, R03-0720). The three year event free and 
overall survival for treated patients is 79 and 93% respectively (P12-05173). Unfortunately, a 
significant number of patients with DLBCL will not be cured with this approach, and will 
require subsequent treatments upon relapse. Relapsed or refractory DLBCL is treated with 
intense chemotherapy regiments with or without rituximab with plans to proceed to high-dose 


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chemotherapy and stem cell transplantation (SCT) in patients with chemotherapy-sensitive 
disease. The treatment of patients who (due to age and comorbidities) are not considered 
good candidates for SCT, who fail to respond to second-line chemotherapy regimens, or who 
relapse after SCT is generally palliative. In addition, patients with primary refractory disease 
rarely achieve a complete remission when treated with a second chemotherapy regimen. 
Recurrent or resistant DLBCL in patients ineligible for transplantation are particularly 
difficult to treat and have markedly reduced survival (P15-01473, P15-01472).
Therefore, the need to develop more efficacious treatments for relapsed/refractory DLBCL 
patients who are not eligible for SCT is apparent. Since monoclonal anti CD20 antibodies 
have demonstrated utility in lymphoma treatment as part of chemoimmunotherapy approach, 
it is reasonable to assume that further combinations with other monoclonal antibodies
targeting antigens present on tumor cells might also prove useful. While initial reports on the 
use of single agent rituximab for relapsed DLBCL demonstrated response rates of 
approximately 30 percent, the rate of response among patients who received rituximab as part 
of their initial treatment regimen is expected to be significantly lower. Therefore, rituximab 
may be of limited utility in these patients (P15-01471). Given that rituximab has become an 
inherent part of the standard first lane treatment in DLBCL, it is reasonable to expect that 
virtually all relapsed/refractory patients will have been pre-exposed to anti CD 20 antibody at 
some time in the past.  Using a different then CD20 target seems particularly attractive as it 
may allow overcoming resistance to CD20 antibody in those patients. 
CD37, a member of the tetraspanin superfamily, is a glycosylated cell surface protein which 
is predominantly expressed on normal B cells, with highest expression levels on mature 
peripheral blood B cells. The CD37 antigen is also expressed on the majority of malignant 
cells in patients with NHL and chronic lymphocytic leukaemia (CLL) (R08-2979, R08-2943, 
R08-2981, R08-2945, R08-2942, R14-3568, R14-3569). The physiological function of CD37 
in humans remains unknown (R08-2979, R08-2946). Mice deficient for CD37 display no 
changes in development and cellular composition of lymphoid organs but have reduced levels 
of IgG1 and attenuated T-cell mediated immune reactions (R09-5412). Studies with CD37-/-
T cells suggest a role for CD37 in T cell proliferation and regulation of immunoglobin A
(IgA) response (R09-4740, R09-5414).
1.2.
DRUGS PROFILE
1.2.1.
BI 836826
BI 836826 is a mouse-chimeric antibody of the IgG1 isotype, directed against human CD37.
BI 836826 has been investigated pre-clinically and in Phase 1 dose escalation trials in chronic 
lymphocytic leukemia and NHL. 
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 antibody-
dependent cell cytotoxicity (ADCC) in vitro, but lacks complement-dependent cytotoxicity
(CDC) activity. 
In vivo testing in nude mouse lymphoma xenograft models (Ramos DOHH2 cell lines) 
showed a statistically significant growth retardation of treated tumors with single agent BI 
836826 and in combination with chemotherapy (R11-4834, n00232742, n00232752). The 
combination of BI 836826 with chemotherapeutics (bendamustine, chlorambucil, 


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fludarabine) or with the CD20 antibody rituximab in vitro results in additive or synergistic 
apoptosis induction on lymphoma cell lines and primary CLL cells (R12-4648).
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 exposure to BI 
836826 in HuCD37 mice and to the surrogate BI 836847 (an antimacque 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 natural killer cells (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. Further details regarding the full safety profile from toxicological studies in 
animals can be found in the Investigator’s Brochure (IB). 
1.2.2.
Human experience with BI 836826
Preliminary data from two ongoing Phase 1 monotherapy trials are available, one in relapsed 
CLL (study 1270.1, 37 patients) and the other in relapsed NHL (study 1270.2, 45 patients).
Two different treatment schedules were used: 
∀
in patients with r/r CLL (study 1270.1), BI 836826 was administered every 2 weeks 
until disease progression; 
∀
in relapsed NHL (study 1270.2), BI 836826 was administered weekly in 3 courses of 
treatment with a total of up to 12 injections.
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In summary, based on the experience with BI836826 monotherapy in CLL at doses up to 
800mg and in NHL at doses up to 200mg, two (2) MTDs have been established: 400mg in 
monotherapy for CLL and 100mg for NHL. The MTD in the NHL study (1270.2) was 
determined based on DLTs seen at 150mg (asymptomatic laboratory abnormalities that 
resolved within 48 hours). Therefore, in the ongoing study (1270.11) in combination with 
GemOx, and using a different treatment schedule, it is legit to consider that a different dose 
of BI 836826 might be possible and might be higher than the 100mg defined as MTD in 
monotherapy in NHL.
For a more detailed description of the drug profile refer to the current IB which is included in 
the Investigator Site File (ISF).
1.2.3.
Gemcitabine
Gemcitabine (dFdC), is a pyrimidine antimetabolite, which exerts its cytotoxic effect by 
inhibition of DNA synthesis. Gemcitabine shows significant cytotoxic effects against a 
variety of cultured murine and human tumor cells. Its action is phase-specific such that 
gemcitabine primarily kills cells that are undergoing DNA synthesis (S phase) and, under 
certain circumstances, blocks the progression of cells at the junction of the G1/S phase 
boundary. In vitro, the cytotoxic effect of gemcitabine is dependent on both concentration 
and time.
Gemcitabine is mostly used for treatment of variety of solid tumors as monotherapy, or in 
combinations with other chemotherapeutic agents. Recent studies in lymphoma indicate that 
gemcitabine in combination with oxaliplatin and rituximab (R-Gem-Ox regimen) can be 
considered as a salvage regimen for elderly patients with DLBCL because of its high clinical 
activity and relatively safe toxicity profile, (P13-00889, R14-2111)
The most common (in >10% of treated patients) adverse effects of gemcitabine include. 
∀
Leukopenia, including G3-4 neutropenia 
∀
Nausea and/or vomiting
∀
Elevation in liver enzymes (aspartate amino transferase (AST), alanine amino transferase
(ALT) and alkaline phosphatase (AP))
∀
Hematuria and mild proteinuria 
∀
Allergic skin reactions 
∀
Dyspnea 
∀
Influenza-like symptoms


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On rare occasions a discontinuation of treatment with gemcitabine should be considered: 
Rare AEs requiring permanent discontinuation of Gemcitabine: 
∀
Severe pulmonary toxicity 
∀
Severe hepatic toxicity 
∀
At first evidence of microangiopathic hemolytic anemia or Hemolytic-Uremic Syndrome 
1.2.4.
For additional detailed information please refer to the summary of product 
characteristic (SmPC) located in the ISF. Oxaliplatin 
Oxaliplatin is an antineoplastic drug belonging to a new class of platinum-based compounds
which interact with DNA to form both inter and intra-strand cross-links, resulting in the 
disruption of DNA synthesis and leading to cytotoxic and antitumor effects. Oxaliplatin 
exhibits a wide spectrum of both in vitro cytotoxicity and in vivo antitumor activity in a 
variety of tumor model systems including human colorectal cancer models. A synergistic 
cytotoxic action has been observed in combination with 5-fluorouracil both in vitro and in 
vivo. Oxaliplatin is indicated for treatment in combination with 5-Fluorouracil and folinic 
acid for treatment in patients with colorectal cancers. 
Recent studies in lymphoma indicate that oxaliplatin in combination with gemcitabine and 
rituximab (R-Gem-Ox regimen) can be considered as a salvage regimen for elderly patients 
with DLBCL because of its high clinical activity and relatively safe toxicity profile (P13-
00889, R14-2111),
Most common adverse effects reported for oxaliplatin are 
∀
Neurological symptoms and peripheral neuropathy 
∀
Thrombocytopenia, anemia, and neutropenia
∀
Infections
∀
Nausea, vomiting and diarrhea
∀
Infusion reactions with flushing, headache, dyspnea and/or hypotension. 
∀
Grade 3/4 hypersensitivity, including anaphylactic/anaphylactoid reactions, to oxaliplatin has 
been observed. These allergic reactions which can be fatal, can occur within minutes of 
administration and at any cycle, and were similar in nature and severity to those reported with 
other platinum-containing compounds, such as rash, urticaria, erythema, pruritus, and, rarely, 
bronchospasm and hypotension. Re-challenge is contraindicated in those patients.
For additional information please refer to the SmPC located in the ISF.
1.2.5.
Rituximab (only in Part 2)
Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody 
representing a glycosylated immunoglobulin with human IgG1 constant regions and murine 
light-chain and heavy chain variable region sequences. The antibody is produced by 
mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity 
chromatography and ion exchange, including specific viral inactivation and removal 
procedures.


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Rituximab targets CD20, a specific B-cell surface antigen. The binding of rituximab to the 
CD20 located on B lymphocytes results in cell destruction via three potential mechanisms: 
antibody-dependent cell cytotoxicity (ADCC), CDC and modest, if any, induction of 
apoptosis. This drug is administered intravenously, and is indicated for treatment of patients 
with various NHLs, CLL, and autoimmune diseases. Rituximab is also frequently used in 
clinical practice for treatment of patients with relapsed/refractory NHL either as part of multi-
drug regimens, or less frequently, as monotherapy.
Rituximab is contraindicated in patients who are hypersensitive to the active substance or to 
murine proteins, or to any of the other excipients, in patients with active, severe infections, 
and in patients with severe immunosuppression.
The most common adverse events (>10% of treated patients) reported for treatment with 
rituximab are:
∀
Infections: bacterial and viral
∀
Hematologic toxicities: neutropenia, leucopenia,  febrile neutropenia,  and   
thrombocytopenia
∀
IRR, including angioedema
∀
nausea
∀
skin reactions: pruritus, rash, alopecia
∀
fever, chills, asthenia, headache
∀
decreased IgG levels
Special warnings and precautions for use of rituximab include: 
∀
IRR
∀
skin reactions including toxic epidermal necrolysis (Lyell’s syndrome) and Stevens-
Johnson syndrome, some with fatal outcome, 
∀
serious infections, including hepatitis B reactivation 
∀
rare, but fatal progressive multifocal leukoencephalopathy. 
Tumor lysis syndrome and IRR usually occur in patients with high numbers of circulating 
tumor cells and in patients with high tumor burden, particularly if rituximab is administered 
in combination with chemotherapy. Angina pectoris, cardiac arrhythmias such as atrial flutter 
and fibrillation, heart failure and/or myocardial infarction are also reported. Therefore 
patients with a history of cardiac disease and/or cardio toxic chemotherapy should be 
monitored closely.
For additional information please refer to the SmPC located in the ISF.


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2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT
2.1.
RATIONALE FOR PERFORMING THE TRIAL
A substantial number of patients relapse after first line therapy for DLBCL and many of them 
will not be good candidates for intensive treatment with curative intent due to age or co-
morbidities (R10-4775, P12-05173). These patients will rather receive palliative treatment 
with the aim to control the disease, while maintaining reasonable quality of life. There are 
different options of combination chemotherapy in relapsed/refractory DLBCL setting, but
none has proven superior, and there is no approved standard treatment in this group of 
patients. Treatment regimens used in elderly patients with relapsed/refractory DLBCL are 
reported to achieve response rates in the range of 50-70%, however many of those are partial 
responses and rather of short duration (P14-08836, P10-10101, R14-2310). The progression 
free survival and overall survival are generally short (P14-08836, P10-10101). One of the 
regimens used in patients ineligible for intensive therapy is a combination of rituximab, 
gemcitabine and oxaliplatin (R-GemOx) (R13-0204, P13-00889, R13-0203 and R14-2111). 
So far limited numbers of patients have been included in trials with this triple combination, 
but the results from Phase 2 multicenter trial with 48 patients are encouraging. The trial 
demonstrated an overall response rate (ORR (CR+PR)) of 61% after 4 cycles of treatment
(R13-0204, P13-00889, R13-0203 and R14-2111). The 5 years progression free survival 
(PFS) and overall survival (OS) were 12.8 and 13.9% respectively. In addition, the R-GemOx 
regimen is relatively well tolerated with reversible hematologic toxicity and infections being 
the most frequent adverse events. Interestingly, prior exposure to rituximab seems to 
negatively affect responses in these patients (23 vs 65%). Emerging data from other trials in 
similar patient populations indicate that upon re-treatment with rituximab patients who 
received rituximab in their first line therapy have lower response rates and shorter event free 
survival compared to those who first received rituximab at relapse (R11-2236, P10-10101, 
R14-2111). Considering that rituximab became standard of care in western countries and 
almost all DLBCL patients receive rituximab as part of the initial therapy, it is concerning 
that combinations containing rituximab may not be the best treatment choice for those 
patients at relapse. One approach to avoid cross-resistance could be through targeting a 
different than CD20 antigen on the surface of tumor cells.
The majority of malignant cells in patients with NHL of B cell origin express the CD37 
antigen, so targeting CD37 in malignancies may offer a valid treatment option (R08-2979, 
R08-2943, R08-2981, R08-2945, R08-2942, R14-3568, R14-3569). BI 836826 targets an 
epitope on the tumor cells which has not previously been therapeutically targeted, thus
offering an advantage of avoiding cross-resistance with prior monoclonal antibody based 
therapies, The addition of BI 836826 to chemotherapy backbone in patients progressing after 
rituximab (or another anti-CD20 targeting mAb) offers a potential to overcome resistance to 
anti-CD20 monoclonal antibody and may improve the response rate and prolong survival in 
patients who are not eligible for high dose therapy. 
The preliminary clinical experiences with targeting CD37 with MB-1, a radio-immuno-
conjugate and TRU-016, a small modular immuno-pharmaceutical support the assumption 


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that targeting CD37 in man leads to lymphocyte reduction and consecutive lymph node 
shrinkage with an acceptable side effect profile (R10-2734, R10-2735, R10-6640).
The purpose of Part 1 (dose-escalation) of the trial is to establish the recommended dose of 
BI 836826 in combination with GemOx, based on safety profile. The purpose of Part 2 
(randomized part) of the trial is to compare the overall response rate (ORR) of BI 836826-
GemOx vs R-GemOx. An increase in ORR, especially in complete remission (CR) rate is 
considered a pre-requisite for improvement in PFS. Using the same chemotherapy backbone
in both arms the trial will assess whether the preclinical superiority of BI 836826 to rituximab 
also translates into a clinical setting and results in improvement in efficacy.
2.2.
TRIAL OBJECTIVES
Part 1 (Phase Ib)
Primary objective: 
To establish the maximum tolerated dose (MTD) of BI 836826 in combination with GemOx.
Secondary objectives:
To evaluate pharmacokinetics of BI 836826 when given in combination with GemOx and to 
investigate preliminary efficacy in terms of the overall response rate based on investigator’s 
assessment.
Part 2 (Phase II randomized)
Primary objective: 
To investigate the efficacy by means of the overall response rate (PR+ CR) based on central 
review assessment in patients with relapsed DLBCL treated with BI 836826-GemOx 
compared to R-GemOx.
Secondary objective:
To investigate the efficacy by means of the complete remission rate based on central review 
assessment in patients with relapsed DLBCL treated with BI 836826-GemOx compared to R-
GemOx.
2.3.
BENEFIT - RISK ASSESSMENT
In preclinical studies, BI 836826 induced marked apoptosis and ADCC activity resulted in 
depletion of normal and neoplastic B cells. It is expected that these findings will translate into 
clinical setting, and will result in antitumor activity of BI 836826.
Targeting CD37 may potentially offer a benefit to patients with NHL, because BI 836826 is 
directed against an epitope on the tumor cells which has not previously been targeted by other 
drugs (for example rituximab), and therefore cross-resistance with prior therapies is not 
expected. In the preclinical settings the combination of BI 836826 with chemotherapy shows 
additive cytotoxic effect (R12-4648).
CD37 is not expressed outside of the hematopoietic and lymphatic system. The anticipated 
side effect profile of BI 836826 based on preclinical studies and initial clinical experience 


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comprises predominantly hematologic AEs and IRRs. The hematologic events are 
leukopenia, such as lymphocytopenia, neutropenia and thrombocytopenia. Lymphocytopenia 
and neutropenia may predispose to infections, including opportunistic infections. These 
adverse events are frequently reported in patients with hematological diseases and may be 
due to the underlying disease, previous and current treatment or combination of these. The 
neutropenia associated with BI 836826 is frequently immediate (within hours), and recovers
few days after the administration. Hematologic toxicity has also been reported with GemOx 
combination with neutrophil nadir frequently reached around day 8 after administration. In 
order to avoid long lasting neutropenia the administration schedule in this trial has been 
structured in a way that the BI 836826 infusion is scheduled on day 8, when patients may 
already be neutropenic from the GemOx treatment received on day 1. We hypothesize that 
neutropenia resulting from BI 836826 administration will fall into nadir. While it is 
conceivable that further decrease in neutrophil counts may be observed, the overall duration 
of neutropenia should be affected minimally or, not at all. Accepting shorter periods of 
neutropenia with rapid recovery is considered safer then prolonged periods with low 
neutrophil counts when infections tend to develop. Together with adjustments of
administration schedule, treatment and prophylaxis recommendations are provided in this 
protocol to ensure patients’ safety see section 4.2.1.2. and 4.2.1.3. The allowance to use 
growth factors will further allow managing neutropenia in patients on this trial. 
Severe neutropenia has rarely been observed with treatment with rituximab, therefore the 
administration schedule for R-GemOx arm will adhere to previously described dosing of 
Rituximab on day 1 and GemOx on day 2 of each cycle.
To mitigate IRRs the protocol specified precautions must be adhered to, i.e. rate controlled 
infusion schedule, premedication, monitoring of vital signs and access to intensive care 
facilities (see section 4.1.5). With the specified precautions IRRs have been manageable and 
no patient has been discontinued from BI 836826 due IRR.
There is an added risk associated with procedure of tumor tissue biopsy for patients who do 
not have archival tumor tissue available at screening and for whom a new tumor biopsy will 
be required. Those risks include: pain, swelling bleeding, and infection.
Although rare, a potential for drug-induced liver injury (DILI) 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 5.3.3.1.
In summary, the prophylactic measures and guidance to investigators have been implemented 
in this protocol to protect patient’s safety. In Part 1 the safety review team will analyze data 
after each cohort has been completed and decide whether dose escalation to the next level is 
safe. In Part 2, the internal Data Monitoring Committee (DMC) will be appointed for this trial 
to provide additional safety oversight. Considering the advanced stage of the underlying 
malignant disease in patients on this trial the potential benefit of therapy is expected to 
outweigh the treatment-related risks.


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3. DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1.
OVERALL TRIAL DESIGN AND PLAN
Population:
The trial will be conducted in patients with relapsed/refractory diffuse large B-cell lymphoma 
(including transformed follicular lymphoma) who have been previously treated with an anti-
CD20 monoclonal antibody (e.g. rituximab) in combination with an anthracycline containing 
chemotherapy and who are not eligible for, or have relapsed/progressed after autologous/ 
allogeneic stem cell transplant.
Part1 (Phase I dose escalation)
This trial consists of two parts. The Part 1 is an open-label (Phase Ib), dose-escalation 
according to a standard 3+3 design to determine the MTD of BI 836286 in combination with 
gemcitabine and oxaliplatin. The dose escalation phase will be followed by an extension 
cohort of 6 patients to be treated at the established MTD, so that a total of 12 patients will be
treated at this established MTD.
Patients will receive maximum of 6 treatment cycles. Each cycle is 14 days (it can be up to 
17 days from Cycle 2, in case the D8 is delayed by maximum 3 days). In order to continue 
trial treatment, patients must fulfill all criteria as outlined in section 6.2.2.1. In case of 
toxicity, the start of the next cycle can be delayed by up to 14 days. 
Following doses of BI 836826 will be tested in combination with GemOx: 25mg, 50mg, 
100mg, 150mg and 200mg. An additional intermediate dose might be tested.
Table 3.1:1 Rules for dose escalation (for DLT definition see section 5.3.8)
Number of patients with DLT/dose level
Action
0/3
Proceed to the next dose level
1/3
Enroll additional 3 patients (up to 6 total) 
at the same dose
1/6
Proceed to the next dose level
>2/6
Dose is exceeding MTD- stop escalation or 
examine lower, intermediate dose
Cycle duration= 14 days, MTD will be defined on the basis of DLT observed during the first cycle, i.e. the first
14 days of C1.


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Figure 3.1:1 Part 1: Dose finding
Part 2 (open label randomized Phase II)
After the determination of the recommended dose of BI 836826 in combination with 
gemcitabine and oxaliplatin in Part 1, the randomized Part 2 of the trial will be initiated.
Patients who have participated in Part 1 will not be eligible to participate in Part 2.
Patients will be randomized (1:1) to one of the two treatment arms: BI 836826-GemOx or R-
GemOx.
∀
R-GemOx arm
The treatment administration schedule for R-GemOx is in line with previously published 
regimen (R13-0204, P13-00889, R13-0203, R14-2111). Patients in R-GemOx arm will 
receive rituximab at 375mg/m2 on day 1, and gemcitabine 1000mg/m2 followed by 
oxaliplatin 100mg/m2 on day 2 of each cycle. One cycle is 14 days, and treatment will be 
repeated on day 15 (i.e. D1 of the next cycle). Maximum number of treatment cycles is 6.
In order to continue trial treatment, patients must fulfill all criteria as outlined in section 
6.2.2.1. In case of toxicity, the start of the next cycle can be delayed by up to 14 days. 
∀
BI 836826-GemOx arm
Patients randomized to BI 836826-GemOx arm will receive: gemcitabine 1000mg/m2
followed by oxaliplatin 100mg/m2 on day 1, and BI 836826 at the recommended dose from 
Part 1 on day 8 of each cycle. One cycle is 14 days (it can be up to 17 days from Cycle 2, in 
case the D8 is delayed by maximum 3 days). Maximum number of treatment cycles is 6.
In order to continue trial treatment, patients must fulfill all criteria as outlined in section 
6.2.2.1. In case of toxicity, the start of the next cycle can be delayed by up to 14 days. 
Figure 3.1:2 Part 2: Randomized


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3.1.1.
Administrative structure of the trial
This is a multicenter trial sponsored by Boehringer Ingelheim (BI) which will be conducted 
in two parts, Part 1 (Phase Ib dose escalation) with 12-14 sites mainly in Europe and 
randomized Part 2 (Phase II randomized) with 35-40 sites in Europe and the rest of the world.
The Coordinating Principal Investigator will be nominated for the trial. 
 will be helping to 
provide an oversight to the execution of the trial at all centers, will be involved in dose 
escalation decisions in Part1. A Coordinating Investigator is responsible to coordinate 
investigators at different centres participating in this multicentre trial. Tasks and 
responsibilities of all investigators will be defined in a contract. Relevant documentation on 
the participating investigators (Principal) and other important participants, including their 
curricula vitae, will be filed in the ISF and Trial Master File.
The Principal Investigators (PIs) will be hematologists experienced and specialized in the 
treatment of DLBCL. The PI at each site will be responsible for the daily conduct of the trial, 
complying with scheduled patients’visits, electronic case report form (e-CRF) completion, 
and for assisting the Clinical Research Associates (CRAs) in site monitoring.
BI 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 (SOP)s,
∀
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
∀
insure appropriate training and information of Local Clinical Monitor (CML), Clinical 
Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and internal SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organize, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information 
can be found in the ISF.
In Part 1, a Safety Review Team consisting of the coordinating investigator, and principal 
investigators who have contributed by enrolling patients, Team member medicine (TMM), 
Team member drug safety (TMDS) and the TCM will review the clinical data regularly in 
order to assess safety (i.e. decide continuation, modification, or termination of the trial). The 
dose for the next cohort will be decided, based on the review of 3-6 patients in the same dose 
cohort, by the team.  
After completion of Part 1, enrollment to the trial will be temporary stopped to allow for 
additional assessment of benefit/risk profile. The Safety Review Team will perform careful 


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analysis of safety profiles at tested doses and confirm the recommendation of dose for Part 2 
of the trial. 
In Part 2, an internal DMC, independent of the trial team, will review the data in order to 
assess the safety and efficacy data from the trial. Assessment of the data will be performed at 
specified intervals to recommend whether to continue, modify or stop the trial. The tasks and 
responsibilities and scheduling of meeting for the DMC will be specified in a charter. The 
DMC will maintain written records of all its meetings.
The sponsor may outsource some responsibilities related to trial activities like: monitoring, 
trial medication supply logistics, or others.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in IRT Manual and Central Laboratory Manual, available in ISF.
In part 2, a vendor will be used for central review (response evaluation) and archiving of the 
PET/CT images collected in this trial. (See further details in sections 5.2.1. and 6.2.2.5).
Details on handling of the trial supplies are given in section 4 of this protocol.
3.2.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF
CONTROL GROUP(S)
The trial consists of two parts: Part 1, Phase Ib dose escalation and Part 2, a randomized 
Phase II. The MTD of BI 836826 established in Part 1 will be used to define the 
recommended dose for Part 2. The trial is designed as open label, since the administration 
schedule of the trial treatment is different in both arms, and blinding is not considered 
appropriate for this design. 
Part 1 
This is the first combination trial with BI 836826 and chemotherapy, therefore a careful dose 
escalation with starting dose below the MTD established for monotherapy is warranted. The 
starting dose has been selected at 25mg, which is two dose levels below the established 
monotherapy MTD of 100mg, and it is predicted to be safe. The planned 5 dose escalation 
levels should allow reaching the monotherapy MTD with the minimum required number of 
patients to gather safety data, while allowing the patients to be exposed to drug levels that 
might provide some clinical benefit.
From the definition of the MTD, and extension cohort will recruit 6 patients at that 
established MTD. The total number of patients treated at this MTD will be 12. 
Part 2
Once the MTD dose has been established in Part 1, and the recommended dose to be used is 
confirmed by the safety review team, Part 2 will be initiated. 
Patients will be randomized (1:1) to one of two treatment arms: BI 836826-GemOx, or R-
GemOx. The randomized design will allow exploring the clinical activity of BI 836826-
GemOx regimen versus R-GemOx and provide comparison data on safety for both arms. This 
randomized design will help to inform whether CD37 antibody is a valid target in this patient 


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population, and whether it has greater therapeutic potential than rituximab in setting of 
relapsed/refractory aggressive lymphomas in patients who are not eligible for stem cell 
transplant. 
Relapsed or refractory DLBCL is treated with systemic chemotherapy with or 
without rituximab with plans to proceed to high-dose chemotherapy and hematopoietic cell 
transplantation (HCT) in those with chemotherapy-sensitive disease. The treatment of 
patients who are not candidates for HCT, who fail to respond to second-line chemotherapy 
regimens, or who relapse after HCT is generally palliative. In the absence of HCT, 
conventional chemotherapy regimens provide only transient disease control for the majority 
of patients with relapsed or refractory DLBCL. Patients with primary refractory disease 
rarely achieve a complete remission when treated with a second chemotherapy regimen. 
Following relapse from a first complete remission, a subset of patients will achieve a second 
complete remission with chemotherapy; however, these remissions are generally not durable 
and long term disease-free survivors are rare (P15-01852). Patients that cannot tolerate the 
intensive standard chemotherapy followed by stem cell transplant are candidates for regimens 
designed for elderly patients. Examples of such regimens include: CEPP (P15-01777)
(cyclophosphamide, etoposide, prednisone, procarbazine), DA-EPOCH (P14-08837, P14-
08836) (dose-adjusted cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone), 
CEOP (P15-01909) (cyclophosphamide, etoposide, vincristine, prednisone), GDP (R15-
0717) gemcitabine, dexamethasone, cisplatin), or GemOx (R14-2111, R13-0203)
(gemcitabine, oxaliplatin). All of those regimens can be given with, or without addition of 
rituximab. Alternatively, single agent therapy with anthracyclines, cytarabine, or alkylating 
agents may be used for palliation of symptoms. None of the above combination regiments is 
clearly superior over the other, and in clinical practice the choice of treatment at relapse 
frequently relies on experience of treating physician, patient’s comorbidities and possible 
toxicities. The R-GemOx combination is one of possible treatments in this setting which has 
proven safe in patients with relapsed/refractory DLBCL who are not eligible for high dose 
chemotherapy (R14-2111).
It is controversial whether rituximab should be included in the treatment of all patients with
relapsed/refractory disease. This is partially because older studies that have demonstrated a 
benefit from rituximab in the setting of relapsed disease have included few patients who 
received rituximab as part of their initial treatment. It is important to note that according to 
newer emerging data patients who have received rituximab in their first line therapy have 
lower response rates and shorter event free survival compared to those who are rituximab-
naïve at time of their relapse (P10-10101, R14-2111). All patients enrolled into this trial will 
have been previously exposed to an anti-CD20 monoclonal antibody (see, section 3.3.2.
inclusion criterion #3). The trial will provide initial data on whether such pre-exposure limits
the beneficial effect of rituximab in the salvage regimen, when compared with novel anti 
CD37 antibody targeting another antigen on tumor cells. The trial will also provide initial 
data whether CD37 antibody can be effectively used in this setting, and how the activity of BI 
836826-GemOx compares to clinical activity to R-GemOx regimen.


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3.3.
SELECTION OF TRIAL POPULATION
3.3.1.
Main diagnosis for trial entry 
3.3.1.1.
Patient population
Patients with relapsed/refractory DLBCL (including transformed folicullar lymphoma) who 
have been pretreated with an anti-CD20 monoclonal antibody (e.g. rituximab) in combination 
with an anthracycline containing chemotherapy and who are not eligible for, or have 
relapsed/progressed after autologous/allogeneic stem cell transplant.
Number of patients to be enrolled: 
Part 1:
Up to 33 evaluable patients will be enrolled during dose escalation. Patients who received, 
full treatment in the first cycle, but did not complete the 14 days observation period (D1 to 14 
of the first cycle) for reasons other than a DLT, will be replaced at the same dose level. 
Part 2: 
A total of 120 patients will be randomized (1:1) to either of two treatment arms: R-GemOx, 
or BI 836826-GemOx, see section 4.1.2.
Patients participating in Part 1 will not be eligible for Part 2 of this trial.
3.3.2.
Inclusion criteria
1. Age 18 years or older
2. Patients with histologically confirmed, relapsed/refractory, diffuse large B-cell 
lymphoma (including transformed follicular lymphoma)
∀
who have received an anti-CD20-supplemented, anthracycline-containing 
chemotherapy 
and
∀
are not eligible for high dose therapy followed by an autologous stem cell 
transplant, or have relapsed/progressed after autologous/ allogeneic stem cell 
transplant
Allogenic stem cell transplant performed at least 6 months prior to study entry is 
allowed if patients do not require immunosuppressive treatment and have no evidence of 
active graft-versus-host disease.
3. Patient has not received anti-lymphoma treatment prior to the first dose of trial 
medication: 
∀
within past 14 days
or 
∀
within time that is shorter or equal to 5 half-lives of the drug if the last anti-
lymphoma treatment contained an investigational agent
4.
Screening computer tomography (CT) scan with involvement of at least 1 bi-
dimensional lesion/node >1.5 cm


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5. Screening #18F∃flourodeoxyglucose (FDG)- positron emission tomography (PET) scans 
must demonstrate positive lesion compatible with computer tomography (CT) defined 
anatomical tumor sites. 
6. ECOG performance status 0, 1, 2, see Table 5.2.3:1
7. Written signed informed consent consistent with ICH GCP and local legislation 
8. Patients must have an acceptable organ function defined as in Table 3.3.2.1 :
Table 3.3.2:1 Definition of acceptable organ function 
Laboratory investigation
Value required at screening
Hb1)
≥ 8g/dL
Absolute neutrophil count (ANC)1)
≥ 1000/μL
Platelets (PLT)
≥ 75000/μL
Glomerular filtration rate (GFR) 2)
≥ 45mL/min
Serum creatinine
≤ 2xULN
AST and ALT
≤ 3xULN
Bilirubin (total)
(Exceptions: patients with diagnosed 
Gilbert’s syndrome)
≤ 1.5xULN
International Normalized Ratio (INR)
(If treated with anticoagulants prolonged 
INR is acceptable) 
≤ 1.5XULN
1)
growth factor support and transfusions are allowed
2)
GFR calculated based on local practices
9. 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. Non-vasectomized male patients having a 
female sexual partner of childbearing potential must ensure their partner is using a 
highly effective method of birth control as described above, during the trial and for at 
least 12 months after the end of the trial. (See section 4.2.2.3 for details)
3.3.3.
Exclusion criteria
1. Eligible for curative salvage high dose therapy followed by stem cell transplant
2. Primary central nervous system lymphoma or known Central nervous system (CNS)
involvement
3. Prior history of malignancy other than DLBCL except basal cell or squamous cell 
carcinoma of the skin, or carcinoma in situ of the uterine cervix or breast which has 
been treated with curative therapy. Other prior malignancies are allowed only if patient
has been free of disease and without treatment other than hormones for at least past 
three years. 
4. Refractory to gemcitabine and/or oxaliplatin 


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5. Contraindications for gemcitabine, oxaliplatin and/or rituximab as judged by the 
investigator. Hypersensitivity to oxaliplatin.
6. Unresolved toxicity of CTCAE grade > 1from prior anti-lymphoma therapy (except 
alopecia) 
7. Significant concurrent medical disease or condition which according to the investigators 
judgment would either compromise patient safety or interfere with the evaluation of the 
safety of the test drug. e.g. symptomatic congestive heart failure, unstable angina 
pectoris, cardiac arrhythmia requiring therapy with the exception of extra systoles of 
minor conduction abnormalities
8. An infection requiring treatment at the start of the trial medication. 
9. Active hepatitis B or hepatitis C, or laboratory evidence for a chronic infection or HIV 
infection (test results done in routine diagnostics are acceptable if done within 14 days 
before the first study treatment dose)
10. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
This includes the female sexual partners of a male participant.
11. Known alcohol or drug abuse which could potentially interfere with trial participation 
according to investigator’s judgment 
12. Prior treatment with CD37 antibody
3.3.4.
Removal of patients from therapy or assessments
3.3.4.1.
Removal/Replacement of individual patients
An individual patient is to be withdrawn from trial treatment if:
∀
The patient withdraws consent for trial treatment or trial participation, without the need to 
justify the decision.
∀
The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy)
∀
Occurrence of toxicity other than lymphopenia which does not recover to Grade 1 or less 
within 14 days after the end of the 14-days cycle (meaning not recovered at D28 of cycle 
1 and maximum D31 from cycle 2 in case the D8 was delayed by maximum 3 days), or to
a degree that allows treatment continuation (see section 6.2.2.1)
∀
Progressive disease 
∀
Development of any other concomitant disease/symptom, including deterioration of 
general condition, which results in patient’s inability to continue trial treatment.
The patient will undergo the procedures for premature treatment discontinuation and follow 
up as outlined in the Flow Chart 1, 2, 3.
For all patients who discontinue or withdraw from the study, the reason must be recorded in 
the eCRFs. At the time of discontinuation of the study treatment, the next scheduled visit
assessments and the EoT visit assessments will be performed whenever possible, as described 
in the study procedures (see section 6.2.3), and the information will be recorded in the eCRF. 
Although treatment is discontinued, patients who do not withdraw consent for follow-up, nor 
die, nor become lost to follow-up will enter the follow-up period (see section
6.2.4 and 6.2.5). The data will be recorded in the trial database and will be reported.


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If a patient or patient’s partner should become pregnant during the trial, all trial treatment 
must immediately be stopped, and this female patient is not allowed to receive trial 
medication from that point onward. The female patient or patients’ partner will be followed 
up until delivery or termination of pregnancy (see section 5.3.7). The data of the female 
patient or patients’ partner 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.
Patients who have not received BI 836826 on D8 in cycle 1 will be replaced. Patients who 
received, full treatment in the first cycle, but did not complete the 14 days observation period 
(D1 to 14 of the first cycle) for reasons other than DLT, will be replaced at the same dose 
level. Patients who experienced a DLT prior to BI 836826 infusion will be replaced.
3.3.4.2. 
Discontinuation of the trial by the sponsor
BI 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,
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 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 
termination of the trial (except in case of the third reason).
3.3.4.3. 
Trial stopping rules in case of unacceptable toxicities
All AEs, including Serious Adverse Event (SAEs) and deaths will be carefully analyzed.
Unacceptable toxicity will be defined as:
∀Clinically relevant adverse events that are unexpected considering the mode of action, 
and are not manifestations of underlying disease or background events typical of the trial
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 adverse event
∀Higher than expected frequency of specific events (such as known consequences of the 
underlying disease or other events that commonly occur in the trial population 
independent of drug therapy) that indicates those events occur more frequently in the drug 
treatment group than would be expected in the trial population.
If one or both of the above criteria are met, the enrolment to the trial will be stopped for in-
depth analysis of the safety profile of BI 836826-GemOx. The risk-benefit profile of BI 
836826-GemOx will be re-assessed by the sponsor’s trial team, coordinating investigator and
internal DMC (in Part 2). The outcome of the analysis and the recommendations will be 
shared with all involved regulatory health authorities prior to a possible re-start of enrolment.
In case the benefit/risk assessment is no longer considered to be positive, the trial will be
stopped.


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4. TREATMENTS
4.1.
TREATMENTS TO BE ADMINISTERED
All drug products listed in section 4.1.1 will be provided by Boehringer Ingelheim Pharma 
GmbH & Co. KG.
4.1.1.
Identity of BI investigational product(s) and comparator backbone
product(s)
Table 4.1.1:1 BI 836826
Substance:
BI 836826
Pharmaceutical formulation:
Concentrate for solution for infusion
Strength:
100mg/vial
Posology
Rate controlled infusion
Route of administration:
Intravenous
Doses
25, 50, 100, 150, 200mg*
* An additional intermediate dose level might be tested.
Table 4.1.1:2 Gemcitabine
Substance:
Gemcitabine
Pharmaceutical formulation:
Concentrate for solution for infusion
Strength:
1000mg/vial
Posology
Rate controlled infusion
Route of administration:
Intravenous
Dose
1000mg/m2
Table 4.1.1:3 Oxaliplatin
Substance:
Oxaliplatin
Pharmaceutical formulation:
Concentrate for solution for infusion
Strength:
100mg/vial
Posology
Rate controlled infusion
Route of administration:
Intravenous
Dose
100mg/m2


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Table 4.1.1:4 Rituximab
Substance:
Rituximab
Pharmaceutical formulation:
Concentrate for solution for infusion
Strengths:
500mg/vial
Posology
Rate controlled infusion
Route of administration:
Intravenous
Dose
375mg/m2
4.1.2.
Method of assigning patients to treatment groups
The treatment group will be assigned via Interactive Response Technology (IRT). The IRT 
will be used to register the patient at screening and at all time-points trial medication is 
dispensed as well as at EOT visit. The time points for accessing the IRT system are shown in 
the Flow chart 1, 2, 3.
The complete trial medication, including BI 836826, rituximab, gemcitabine and oxaliplatin 
will be supplied by BI and managed through the IRT system. Please note that the medication 
number is the trial medication identification and is different from the patient number.
An IRT manual, describing how to access and use the IRT, will be distributed to the 
investigator, pharmacist and site personnel prior to start of the trial. 
Part 1
All patients enrolled in Part 1 will receive BI 836826 in combination with GemOx. The 
following dose levels of BI 836826 will be tested in cohorts of 3-6 patients: 25-50-100-150-
200mg (an additional intermediate dose level might be tested). The assignment to a cohort 
/dose level will be facilitated by the IRT system. 
Part 2
In Part 2, patients will be randomized in a 1:1 ratio to BI 836826-GemOx, or R-GemOx. 
Patients who have participated in Part 1 will not be eligible for Part 2. Randomization will be 
carried out centrally using IRT. The company that provides the IRT will receive the 
randomization list from Boehringer-Ingelheim Clinical Trial Support Group or a Clinical 
Research Organisation (CRO) appointed by the sponsor. The BI standard validated random 
number generating system will be used to generate the randomization schedules which will 
be verified by an independent statistician who is not involved in the trial. The access to the 
randomization code will be supervised by the Clinical Trial Support Group. People who are 
directly involved in the conduct and analysis of the trial will have no access to the 
randomization schedule.
4.1.3.
Selection of doses in the trial
BI 836826 will be given as a flat dose i.e. without any adjustment for body surface area
(BSA) or weight, in a biweekly dosing schedule (every 2 weeks). The starting dose has been 
selected at 25mg, which is two dose levels below the established monotherapy MTD of 
100mg, and it is predicted to be safe. During the dose escalation, the dose will be doubled in 
the 2 first subsequent cohorts (next dose levels: 50 and 100mg) and then escalate to 150 and 


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200mg cohorts. This approach was selected because it is to be safe and allows the 
achievement of an efficacious dose with minimum number of patients treated below MTD. 
The patients in a cohort will be evaluated for occurred DLTs during the 14 days observation 
period (D1 to 14 of the first cycle). Any patient withdrawing from study participation before 
D15, for reasons other than DLT, will be replaced in the cohort by a new patient, as the 
withdrawn patient is considered not evaluable. The safety profile of the cohort has to be 
assessed as tolerable by the safety review team before the next cohort can be opened for 
enrolment. The IRT system will be closed during this evaluation and it will not be possible to 
enter a patient in the trial. The investigators will be able to obtain the information about the 
next dose level from the IRT system.
The doses of gemcitabine (1000mg/m2) and oxaliplatin (100mg/m2) in a biweekly dosing 
schedule were selected based on tolerability and efficacy data from the literature (R13-0203). 
Both, gemcitabine and oxaliplatin are dosed by BSA. Patient’s weight from C1D1 should be 
used or initial calculation of BSA and the same value can be used throughout the trial as long 
as patient’s weight does not change by 10% or more. If body weight changes by >10% the 
BSA needs to be recalculated and doses of both: gemcitabine and oxaliplatin need to be 
adjusted accordingly. 
One cycle is 14 days (it can be up to 17 days from Cycle 2, in case the D8 is delayed by 
maximum 3 days), and repeated cycle starts on day 15 (or D18 in case of D8 delayed by 
maximum 3 days). In case of toxicity, the next cycle start might be delayed by a maximum of 
14 days. Patients who do not recover from toxicity within 14 days will be removed from the 
trial for toxicity reasons, and will not be allowed to re-enter the trial treatment.
Part 1
Table 4.1.3:1 Part 1 Doses and administration of BI 836826-GemOx  
Trial Medication
Dose levels
Administration
BI 836826 1)
25mg-50mg-100-150-200mg iv
in 250mL normal saline 
at rate controlled infusion
for details see Table 4.1.5.1:1
Day 8 of each cycle
(up to 6 cycles)
Gemcitabine
1000mg/m2 iv
in 500mL normal saline
at 10mg/m2/min
Day1 of each cycle
(up to 6 cycles)
Oxaliplatin
100mg/m2 iv
in 5% glucose solution administered after 
Gemcitabine as 2hrs infusion
Day1 of each cycle
(up to 6 cycles)
1)
An additional intermediate dose level might be tested.


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Part 2
BI 836826-GemOx arm
BI 836826 will be given as a flat dose, i.e. without any adjustment for body surface area or 
weight.
The recommended BI 836826 dose in combination with GemOx will be based on the 
observed AEs of the combination with GemOx from cycle 1 in Part 1 and on all additional 
safety data available from subsequent treatment cycles in Part 1. The recommended dose in 
Part 2 may be equal or lower than the MTD determined in Part 1. 
Table 4.1.3:2 Part 2 Doses and administration of BI 836826–GemOx
Trial Medication
Dose levels
Administration
BI 836826
Recommended dose iv from Part 1
in 250mL normal saline 
at rate controlled infusion
for details see Table 4.1.5.1:1
Day 8 of each cycle
(up to 6 cycles)
Gemcitabine
1000mg/m2 iv
in 500mL normal saline 
at 10mg/m2/min
Day1 of each cycle
(up to 6 cycles)
Oxaliplatin
100mg/m2 iv
in 5% glucose solution  administered after 
Gemcitabine as 2hrs infusion
Day1 of each cycle
(up to 6 cycles)
R-GemOx arm
The rituximab dose will be given at the approved dose of 375mg/m2. Rituximab will be given 
in combination with GemOx as documented in the literature (R13-0203).
Table 4.1.3:3 Part 2 Doses and administration of R–GemOX 
Medication
Dose levels
Administration
Rituximab
375mg/m2 iv
in 500mL normal saline 
at rate controlled infusion
for details see section 4.1.5.2.
Day 1 of each cycle
(up to 6 cycles)
Gemcitabine
1000mg/m2 iv
in 500mL normal saline 
at 10mg/m2/min
Day 2 of each cycle
(up to 6 cycles)
Oxaliplatin
100mg/m2 iv
in 5% glucose solution administered 
after Gemcitabine as 2hrs infusion
Day 2 of each cycle
(up to 6 cycles)


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4.1.4.
Drug administration of doses for each patient
Standard or routine prophylactic measures (including antiemetic’s and hydration) should be 
used prior to administration of GemOx chemotherapy to reduce the incidence of adverse 
events from these infusions. 
For premedication before antibody infusion see section 4.1.5.4. 
For handling of IRRs see section 6.2.2.3, and for tumor lysis syndrome (TLS), see section 
6.2.2.6. 
The use of transfusions and growth factors is allowed throughout the trial as clinically 
indicated.
A cycle is 14 days in length (it can be up to 17 days from Cycle 2, in case the D8 is delayed 
by maximum 3 days). The repeat cycle starts on day 15 (= day 1 of the next cycle; up to D18 
in case D8 is delayed by maximum 3 days). Up to 6 cycles can be administered, if the
treatment is well tolerated and the patient has no clinical and/or radiologic signs of 
progression, as judged by the investigator.
Before the initiation of each subsequent cycle, each patient has to be evaluated for eligibility 
to receive further treatment. If the patient does not fulfill all criteria to continue treatment as 
outlined in section 6.2.2.1, the start of the next cycle can be delayed by a maximum of 14 
days to allow recovery. Patients who do not recover during those additional 14 days will be 
withdrawn from the trial for toxicity reasons. 
The actual duration of all the infusions need to be documented in the e-CRF including actual 
start and end time, actual time points for interruptionand restart of the infusion and the actual 
infusion rates, including all steps in rate changes.
Part 1 
Gemcitabine and oxaliplatin (GemOx) will be administered as intravenous infusions on day 
1of each cycle (see section 4.1.5.3). BI 836826 will be administered as an intravenous 
infusion, on day 8 of each cycle under the supervision of the investigator or designated 
personnel.


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Figure 4.1.4:1 BI 836826-GemOx arms Part 1 and 2
In order to facilitate blood sampling for pharmacokinetic (PK) 
analyses, it is recommended to start the BI 836826 infusion during the morning, preferably 
before 12 noon.
Part 2 
BI 836826-GemOx
Gemcitabine and oxaliplatin (GemOx) will be administered as intravenous infusions on day 
1of each cycle (for details see section 4.1.5.3). BI 836826 will be administered as an 
intravenous infusion on day 8 of each cycle under the supervision of the investigator or 
designated personnel. For administration scheme see Figure 4.1.4:1
R-GemOx
Rituximab will be administered on day 1 of each cycle and gemcitabine and oxaliplatin 
(GemOx) will be administered as intravenous infusions on day 2 of each cycle (see section
4.1.5.3). For administration scheme see Figure 4.1.4:2 


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Figure 4.1.4:2 Rituximab-GemOx arm Part 2
4.1.5.
Infusion schedules 
All patients (Part 1 and Part 2) need to fulfil criteria to continue treatment prior to starting the 
next cycle (C2-6), for details see section 6.2.2.1. The initiation of the next cycle may be 
postponed for up to 14 days to allow patients to fulfil these criteria (meaning the next cycle 
has to be started at the latest on D29, or maximum on D32 from cycle 2 and in case the D8 
was delayed by maximum 3 days).
For dose adjustment recommendations please see details below and see Table 6.2.2.1:1.
4.1.5.1.
BI 836826 infusion
BI 836826 is to be diluted into 250mL of normal saline. Premedication is mandatory (see 
section 4.1.5.4). All patients have to be hospitalized for at least 24hrs after the first infusion
of BI 836826. Please refer to table 4.1.5.1:1 for the first infusion schedule.
Table 4.1.5.1:1 Infusion schedule for BI 836826:
Time (+/- 10min)
Rate mL/h in 250mL
Total Volume (ml) infused
0-29 min
10
5
30-59 min
20
15
60-89 min
30
30
90-119 min
40
50
120-149 min
50
75
150-179 min
60
105
180-209 min
70
140
210-293 min
80
250
Subsequent infusions may be faster or steps maybe omitted if considered safe. The maximum 
speed of infusion should not exceed 120mL/h.


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The total duration of the infusion may not extend 24 hours. If interruptions are necessary for 
IRR treatment, the time from the initial start of infusion until the end of infusion must be
≤ 24 hours. Any remaining solution needs to be discarded after this time.
No dose reduction or dose delay of BI 836826 is allowed in cycle 1. From Cycle 2, the D8 
can be delayed by maximum 3 days.
Only one dose of BI 836826 may be omitted from cycle 2.
4.1.5.2.
Rituximab infusion
The rituximab dose of 375mg/m2 is to be diluted into 500mL normal saline. Premedication is 
mandatory, see section 4.1.5.4. The first dose of rituximab should be given cautiously, 
starting at a slow rate and increased slowly. As recommended in the SmPC of rituximab, the 
initial rate for infusion should be a maximum of 50mg/h. After 30 minutes, the infusion rate 
can be escalated in 50mg/h increments every 30 minutes, to a maximum rate of 400mg/h.
No dose reduction or skipped dose of rituximab is allowed.
4.1.5.3.
Gemcitabine and Oxaliplatin
Gemcitabine 1000mg/m2 (diluted into 500mL of normal saline) is administered at a fixed 
dose rate of 10mg/m2/min on:
∀
day 1 if patients are participating in Part 1 or, are randomized to the BI 836826-
GemOx treatment arm in Part2 
or
∀
day 2 if patients are randomized to R-GemOx arm in Part2.
This prolonged administration schedule has been shown to achieve superior intracellular drug 
concentrations than the standard 30 min i.v. schedule (R14-4504). 
No dose reduction or skipped dose of gemcitabine is allowed.
Oxaliplatin 100 mg/m2 is to be administered after gemcitabine in a 2hrs infusion on: 
∀
day 1 if patients are participating in Part 1 or are randomized to the BI 836826-
GemOx treatment arm in Part2
or
∀
day 2 if patients are randomized to R-GemOx arm in Part 2.
Only one dose of oxaliplatin may be omitted during the trial.
Reduction of dose is allowed as per events described in table 6.2.2.1:1.
4.1.5.4.
Premedication for BI 836826 and Rituximab 
Premedication and close monitoring of the rate of infusion are the main precautions to 
minimize infusion related reactions. Premedication is mandatory and has to be administered 
30-120 minutes prior to the administration of monoclonal antibody, i.e. BI 836826 or 
rituximab. The premedication in the first and second cycle should include:


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∀
Acetaminophen/paracetamol 1000 mg per os (p.o.), or equivalent
∀
Antihistamine p.o. or i.v., equivalent to diphenhydramine 50mg i.v.
∀
Glucocorticoid i.v., equivalent to prednisolone 100mg
If patients tolerate the infusions with BI 836826 or rituximab well during the first 2 cycles,
the dose of glucocorticoid premedication may be reduced by:
∀
50% at the third cycle, (i.e. glucocorticoid i.v., equivalent to 50mg prednisolone)
∀
75% at the fourth and subsequent cycles (i.e. glucocorticoid i.v., equivalent to 25mg 
prednisolone)
4.1.6.
Blinding and procedures for unblinding
4.1.6.1.
Blinding
This is an open label trial. Blinding is not applicable, see section 3.2. However, to reduce 
bias, the BI trial team will be blinded for the aggregated data in Part 2 until the database has
been locked.
4.1.6.2.
Un-blinding and breaking the code
This is an open label trial. Procedures for emergency un-blinding are not applicable.
4.1.7.
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP).
Boxes and vials of BI 836826, rituximab, gemcitabine and oxaliplatin will be labelled 
according to local regulations and will include the following as a minimum:
∀
The trial number (1270.11)
∀
Product name
∀
Contents of the bottle/carton box
∀
Strength
∀
Batch number
∀
Use-by date
∀
Storage information
∀
Instructions for use
∀
Sponsor name and address
∀
A statement indicating that the medication is for clinical trial use only
∀
A caution statement
Examples of the labels will be filed in the ISF.
The BI 836826, rituximab, gemcitabine and oxaliplatin drug supply will be managed
through IRT by the trial sites and BI personnel.


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Re-supply to the sites will be managed via an IRT system, which will also monitor expiry 
dates of supplies available at the sites.
Refer to the ISF for details of packaging and the description of the label as well as the
process for resupply of trial drug.
4.1.8.
Storage conditions
All trial medication will be kept in original packaging in a secure limited access storage area 
according to the recommended storage conditions on the label. 
Temperature logs must be maintained to make certain that the drug supplies are stored at the 
correct temperature. In case temperature would be out of range, the sponsor has to be 
notified.
For a more detailed description of the BI 836826 drug profile refer to the current IB which is 
included in the ISF.
For gemcitabine, oxaliplatin and rituximab please refer to SmPC in ISF.
4.1.9.
Drug accountability
The investigator or the pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:
∀
Approval of the trial protocol by the Institutional Review Board (IRB) / ethics committee/ 
/ Health Authority (HA)
∀
Availability of a signed and dated clinical trial contract between the sponsor and the Head 
of Trial Centre
∀
Approval/notification of the regulatory authority, e.g. competent authority
∀
Availability of the curriculum vitae of the principal investigator
∀
Availability of a signed and dated clinical trial protocol or immediately imminent signing 
of the clinical trial protocol
∀
If applicable, availability of the proof of a medical license (e.g. Form 1572 in US) for the 
principal investigator
The investigator or pharmacist must maintain records of the 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 disposition of unused products.
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the medication kit numbers assigned to the investigational products and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational product(s) received from the sponsor. 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.


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Any opened vials of BI 836826, rituximab, gemcitabine and oxaliplatin should be discarded 
after use following local regulations and local hospital practices. 
4.2.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
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.
4.2.1.2.
Supportive care
Patients should receive supportive care according to local guidelines regarding treatment of 
any AEs, IRRs (section 6.2.2.3), TLS (section 6.2.2.6), blood product support, growth factor 
support, analgesics, skin and mouth care, etc.
4.2.1.3.
Antibiotics and antivirals
Prophylactic antibiotics, antivirals, and antifungals are allowed. For patients who are 
considered to have an increased risk for herpes and/or pneumocystis jiroveci infections, the 
prophylaxis is mandatory. For patients who are considered to have an increased risk for other 
infections, prophylactic therapy is recommended.
Prophylactic antiviral therapy is recommended for patients with a history of recurrent herpes 
virus infections, herpes infection during previous anti-lymphoma therapy e.g. acyclovir 400 
mg three times a day orally.
CMV reactivation during treatment should be treated according to institutional standards.
4.2.1.4.
Concomitant treatments
All concomitant therapies to provide adequate care may be given as clinically necessary. Any 
other anti-lymphoma therapy besides trial treatment is not allowed. All concomitant 
treatments should be recorded in the e-CRF 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 
anesthesia, it will be sufficient to indicate ‘general anesthesia’ without specifying the details.
Systemic immune-suppressive therapy other than corticosteroids is not allowed during 
treatment. Short term pulsatile glucocorticoid medications may be used as clinically indicated 
to treat IRRs or autoimmune phenomena, at any dose. Long term (>5 days) daily oral steroid 
treatment may be administered at doses equivalent to prednisolone 20mg per day or below. 
Higher doses of daily steroid treatment should be discussed and agreed upon between 
investigator and sponsor.


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Concomitant therapy should be recorded in the e-CRF during the screening and treatment 
period, starting at the date of signature of informed consent, and ending at FU for AEs visit.
(i.e. this is equivalent to the Residual Effect Period (REP) 30-42 days after the last dose). 
If new anti-lymphoma therapy is administered during this period, it will be captured on a 
separate follow up therapy e-CRF page. 
4.2.2.
Restrictions
4.2.2.1.
Restrictions regarding concomitant treatment
∀
No concomitant anti-neoplastic therapies are allowed during the trial
∀
No other investigational therapy is allowed
∀
Additional glucocorticoid medications may be used as clinically indicated only to treat 
IRRs at any dose
4.2.2.2.
Restrictions on diet and life style
No restrictions apply with regard to diet or life style exception the contraception rules see 
section 3.3.2., (inclusion criterion 9) and section 4.2.2.3.
4.2.2.3.
Restrictions regarding women of childbearing potential 
Women of childbearing potential* (WOCBP) must be ready and able to use highly effective 
methods of birth control per ICH M3 (R2) and in accordance with the recommendations 
related to contraception and pregnancy testing in clinical trials by Heads of Medicines 
Agencies Clinical Trials Facilitation Group (HMA CTFG) [R16-0373] that result in a low 
failure rate of less than 1% per year when used consistently and correctly, and this during the 
trial and for at least 12 months after the end of the trial.
*Women of childbearing potential (WOCBP) are defined as:
∀
A woman is considered of childbearing potential, i.e. fertile, following menarche and 
until becoming post-menopausal unless permanently sterile, which also includes the 
female sexual partner of a male patient.
∀
Women who underwent tubal ligation/occlusion, a highly effective method of 
contraception but not a method of permanent sterilisation, are still considered of 
childbearing potential, which means that they must be tested for pregnancy during the 
study period [R16-0373].
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. hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
Highly effective methods of birth control for WOCBP are: 
∀
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation, taken as oral, intravaginal or transdermal formulation.
∀
Progestogen-only hormonal contraception associated with inhibition of ovulation, 
taken as oral, injectable or implantable formulation.


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∀
Intrauterine device (IUD) or Intrauterine hormone-releasing system (IUS).
∀
Surgical sterilisation (vasectomy) of the sexual male partner.
∀
Complete sexual abstinence: a preferred or usual life-style where you refrain from any 
sort of sexual activity that could involve the spill of an ejaculate, even if the spill does 
not occur.
An explanation is also provided in the patients informed consent information form.
4.3.
TREATMENT COMPLIANCE
BI 836826- GemOx and R-GemOx will be administered as intravenous infusions at the 
investigational site under supervision of authorized personnel. Any discrepancies in drug 
accountability are to be documented in the e-CRF by the investigator or his/her deputy.


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5. VARIABLES AND THEIR ASSESSMENT 
5.1.
TRIAL ENDPOINTS
5.1.1.
Primary Endpoints 
Part 1
∀
The number of evaluable patients with DLTs in cycle 1.
∀
The MTD of BI 836826 with GemOx based on the number of evaluable patients with
DLTs in cycle 1. The MTD of BI 836826 with GemOx is defined as the highest dose 
studied for which the number of evaluable patients with dose-limiting toxicity is 17% or 
less (i.e., 0-1/6 patients) during cycle 1.
∀
The observation time for both endpoints is 14 days from first trial medication 
administration. 
Part 2
∀
Overall response (OR) by central review assessment, i.e. partial response (PR) and 
complete remission (CR) by central review assessment, analyzed by the ORR and 
compared between the two treatment arms.
∀
The observation time for OR is up to 32 weeks from first trial medication administration.
5.1.2.
Secondary Endpoints
Part 1
∀
Pharmacokinetic parameters: AUCt and Cmax of BI 836826 when administered in 
combination with GemOx.
∀
Overall response based on investigator’s assessment
∀
The observation time for all secondary endpoints is up to 32 weeks from first trial 
medication administration. 
Part 2
∀
The CR by central review assessment will be the secondary endpoint, and will be 
compared between the two treatment arms.
∀
The observation time for this endpoint is up to 32 weeks from first trial medication 
administration. 
 
 
 
 
 


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5.2.
ASSESSMENT OF EFFICACY
5.2.1.
Criteria for response
Response will be evaluated using PET/CT scan. Scans will be performed locally and in Part 2 
images will be sent for central reading. The response evaluation criteria will follow the 
criteria for NHL as published in the literature in 2007 (R10-1462) and with refined evaluation 
for the PET scan introducing the 5-PS score in 2014 (R14-3387) see Table 5.2.1:1.
Table 5.2.1:1 Criteria for Response
Response
Definition
Nodal disease
Spleen, Liver
Bone marrow
Complete 
remission
Disappearance 
of all evidence 
of disease
a) FDG-avid or PET + 
prior to therapy; mass of 
any size permitted if PET 
negative
b) Variable FDG-avid or 
PET negative; regression 
to normal* size on CT
Not palpable, 
nodules 
disappeared
Infiltrates cleared on 
repeat biopsy; if 
indeterminate by 
morphology, immuno-
histochemistry should 
be negative
Partial 
remission
Regression of 
measurable 
disease and no 
new sites
%50% decrease in SPD of 
up to 6 largest dominant 
masses; no increase in 
size of other nodes
a) FDG-avid or PET + 
prior to therapy; one or 
more PET + at previously 
involved site
b) Variably FDG-avid or 
PET negative; regression 
on CT
%50% decrease in 
SPD of nodules 
(for single nodule 
in greatest 
transverse 
diameter); no 
increase in size of 
spleen or liver
Irrelevant if positive 
prior to therapy, cell 
type should be 
specified


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Table 5.2.1:1 Criteria for Response (cont’d)
Response
Definition
Nodal disease
Spleen, Liver
Bone marrow
Stable 
disease
Failure to attain:
Complete 
remission
Partial remission 
Or 
Progressive 
disease
a) FDG-avid or PET + prior to 
therapy; PET + at prior sites of 
disease and no new sites on CT 
or PET
b) Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT
Relapsed 
disease or 
progressive 
disease**
Any new lesion or 
increase by %50% 
of previously 
involved sites from 
nadir
Appearance of new lesion(s) 
>1.5 cm in any axis, %50% 
increase in SPD of more than 
one node, or %50% increase in 
longest diameter of a 
previously identified node >1 
cm in short axis
Lesions PET + if FDG-avid 
lymphoma or PET+ prior to 
therapy
>50% increase 
from nadir in the 
SPD of any 
previous lesions
New or 
recurrent 
involvement
FDG = #18F∃flourodeoxyglucose; PET = positron emission tomography; CT = computer tomography; SPD = sum of product 
of diameters
*Normal size of lymph nodes and nodal masses on CT scan is defined as ≤1.5 cm in their 
greatest transverse diameter for nodes >1.5 cm before therapy. For previously involved nodes 
that were 1.1 to 1.5 cm in their long axis and more than 1.0 cm in their short axis before 
treatment must have decreased to ≤1.0 cm in their short axis after treatment. 
**For relapsed disease or progression, lymph nodes should be considered abnormal if the 
long axis is more than 1.5 cm regardless of the short axis. If a lymph node has a long axis of 
1.1 to 1.5 cm, it should only be considered abnormal if its short axis is more than 1.0 cm. 
Lymph nodes ≤1.0 x ≤1.0 cm will not be considered as abnormal for relapse or progressive 
disease.
The PET scan should be evaluated in accordance with recent guideline (R14-3383). The 
PET/CT scan should use a fixed display and color table scaled to standardized uptake value 
(SUV). The focal uptake in aggressive DLBCL is sensitive to bone marrow involvement and 
may make the need for a bone marrow biopsy unnecessary.
The PET scan should be evaluated with the use of the 5-PS which has been validated for use 
both as an interim and as end of treatment.
The 5-PS scores the most intense uptake in a site of initial disease, if present, as follows: 
1. No uptake 
2. Uptake ≤ mediastinum
3. Uptake > mediastinum but ≤ liver
4. Uptake moderately higher than liver
5. Uptake markedly higher than liver and/or new lesions


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In addition, as written in the published reference (R14-3383) new areas of uptake, unlikely to 
be related to lymphoma, are marked by (X).
If the PET scan performed after 3 cycles, demonstrates a disease progression the patient has 
to be withdrawn from the trial treatment.
 
 
 
 
 
 
5.2.3.
ECOG Performance Status
The ECOG performance status is a scale used to assess how a patient’s disease affects daily 
living abilities. Performance status is graded using the following scale from 0 to 5:
Table 5.2.3:1 ECOG performance status
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


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5.3.
ASSESSMENT OF SAFETY
5.3.1.
Physical examination & B symptoms
A physical examination including height (only at screening), weight and ECOG performance 
score as well as the tumor size determination (by palpation) will be performed at screening 
and at the time points specified in the Flow Chart 1, 2, 3. During the physical examination, 
the patient should be assessed for possible adverse events.
Patients may present with constitutional symptoms at baseline, which may improve on 
treatment, or may develop constitutional symptoms in the context of progression which may 
indicate the need for a subsequent therapy. 
All patients will be evaluated for lymphoma related B symptoms at the same time points 
when a physical examination is indicated in the Flow Charts 1, 2, 3. 
An evaluation of B symptoms will be based on the following parameters which have to be 
reported in the e-CRF:
∀
Weight loss ≥10% in 6 months or less
∀
Fever higher than 38.0°C
∀
Night sweats.
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 clinical 
procedure and after at least 5 minutes of rest. Additional measures of vital signs need to be 
collected at the time of trial drug administration in order to detect possible IRRs which must 
be reported as AEs. In case of IRR, the investigator should decide whether to intensify or 
prolong the monitoring of vital signs and to adapt patient’s surveillance during subsequent 
infusions.
5.3.3.
Safety laboratory parameters
5.3.3.1.
General safety laboratory parameters
Blood samples and urine have to be collected at the time points specified in the Flow Chart 1,
2, 3 and before the infusion of trial medication, and will include the following analysis:


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Hematology
Reticulocytes
At each study visit: Hemoglobin, red blood cell count (RBC), 
white blood cell count (WBC) with differential count
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), 
PLT.
At screening, D1 of each cycle and at the EOT.
Biochemistry
Immunoglobulins
Serum β2–microglobulin
At screening, D1 of each cycle and EOT: Glucose, sodium, 
potassium, calcium, inorganic phosphate, creatinine, AST, ALT, 
alkaline phosphatase (AP), lactate dehydrogenase (LDH), total 
bilirubin (if elevated provide direct bilirubin), total protein, 
albumin, uric acid
At screening, D1 of each cycle and EOT: IgG, IgM, IgA, direct 
antiglobulin test are to be measured.
At screening visit only
Coagulation
At screening, D1 of each cycle and EOT: Activated partial 
thromboplastin time (aPTT), prothrombin time (PT)/international 
normalized ratio (INR).
Urine
At screening, D1 of each cycle and EOT: pH, glucose, 
erythrocytes, leukocytes, protein, nitrite will be analyzed by 
dipstick and reported as semi-quantitative measurements. 
Pregnancy test
A serum pregnancy test needs to be obtained at screening and at 
EOT in female patients of childbearing potential. 
5.3.3.2.
Screening for laboratory evidence of TLS
To allow for early treatment in case TLS develops, vigilant monitoring after the first dose of 
BI 836826 or rituximab is recommended. During the first 24 hours after the start of the first 
dose of BI 836826 or rituximab the following laboratory parameters need to be checked at 
least once in patients who considered at risk for TLS, (e.g. large tumor burden, leukemic
manifestation of the lymphoma). The actual date and time of the blood samples should be 
recorded in the e-CRF. 
Testing for tumor lysis 
syndrome
Uric acid, potassium, sodium, calcium, inorganic phosphate, 
LDH, creatinine.
5.3.3.3.
Screening for hepatitis B, hepatitis C, CMV and HIV
At the time points indicated in the Flow Charts 1, 2, 3 local laboratory will be used. 
For HIV, HBV, HCV, test results done in routine diagnostics are acceptable if done within 14 
days before C1D1.
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.


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The following laboratory parameters have to be determined at the screening visit and reported
in the eCRF: Hepatitis B Surface Antigen (HBsAG), 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:
9 9 HBV DNA negative
9 9 HCV RNA negative
9 9 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.
CMV monitoring
Monitoring of CMV has to be performed at the time points indicated in the Flow Chart 1, 2, 3
according to local standards. Cytomegalovirus serology (CMV, Ig G and Ig M) should be 
included in screening assessment to allow for differentiation between a primary CMV 
infection and reactivation of CMV during the trial. Quantitative polymerase chain reaction
(PCR) assays to detect CMV DNA are considered acceptable for the purpose of this trial. The 
same method should be used for all treated patients in the same investigational site. Results 
have to be reported in the e-CRF.
5.3.3.5.
Flow cytometry/quantitative lymphocyte phenotyping
At the time points indicated in the Flow Chart 1, 2 and 3, lymphocyte sub-populations (B 
cells, CD4+ T cells, CD8+ T cells, NK cells) will be quantitatively analyzed by a standard 
flow cytometry protocol in a central laboratory. Detailed instructions are included in the 
laboratory manual in the ISF.
Table 5.3.3.5:1 Lymphocyte surface markers
B cells
CD19
T cells
CD3+
CD4+
CD8+
NK cells
CD56+
5.3.4.
Electrocardiogram
Single 12-lead ECG will be performed in all patients as specified in the Flow Chart 1, 2, 3. 
Please note ECG to be performed before any blood sampling. 
The ECG time-points for the Part 1 are defined as the following:

Screening


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∀
On trial: C4D8 (-60 min. to -5 min. prior to administration of BI 836826) and
immediately after the end of infusion
∀
EOT visit 
The ECG time-points for Part 2 are defined in BI 836826-GemOx Treatment arm:
∀
Screening
∀
On trial: C4D8 (-60 min. to -5 min. prior to administration of BI 836826) and
immediately after the end of infusion
∀
EOT visit 
The ECG time-points for Part 2 are defined in R-GemOx Treatment arm:
∀
Screening
∀
On trial: C4D2 (-60 min. to -5 min. prior to administration of GemOx) and immediately
after the end of infusion
∀
EOT visit 
The ECGs will be recorded using calibrated equipment 12-lead ECGs at site. The ECG
recordings must also be reviewed and checked for abnormality by the investigator. Any ECG
findings that are clinically significant should be reported as AE. Any QT prolongation not 
related to a baseline condition must be followed up sufficiently as deemed by the investigator. 
Additional ECGs should be done whenever the investigator deems necessary.
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 adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable 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
A SAE is defined as any AE which:
∀
results in death,
∀
is life-threatening,
∀
requires inpatient hospitalization or prolongation of existing hospitalization,
∀
results in persistent or significant disability or incapacity,
∀
is a congenital anomaly/birth defect,
or


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∀
is 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.
Every new occurrence of cancer will be reported as a SAE regardless of the duration between 
discontinuation of the drug and the occurrence of the cancer.
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 as described in section 5.3.6.1.
Adverse events of special interest (AESIs)
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 are considered AESIs in this trial:
∀
DLT
Any event that qualifies for DLT refer to section 5.3.8.
∀
IRR
IRRs CTCAE grade 3 -5 are defined to be AESIs.
∀
Late onset infections
Infections occurring during the “extended follow-up” period see Figure 5.3.7:1, which are 
clinically relevant and considered related to BI 836826 by the investigator, are to be 
reported as AESIs. 
∀
Hepatic injury  
Drug-induced liver injury (DILI) is under constant surveillance by sponsors and 
regulators and is considered an AESI in this trial. Timely detection, evaluation, and 
follow-up of laboratory alterations of selected liver laboratory parameters, is necessary to 


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distinguish an effect of the underlying malignancy on liver function from other causes. 
This is 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 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.
Work-up as outlined in the “Drug-Induced Liver Injury (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 
judgment, 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 possible as part of the 
adverse event reporting process and/or on the respective CRF pages. In the event the 
aetiology 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 haemochromatosis 
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 trial drug, the administration of the 
trial drug must be managed according to Table 6.2.2.1:1.


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Any elevation of ALT and/or AST and total bilirubin qualifying as laboratory hepatic 
injury alert should lead to reflex testing on the initial blood sample. The reflex testing 
should include (if appropriate specimen is available):
∀
direct bilirubin
∀
acetaminophen level
∀
lactate dehydrogenase
∀
haptoglobin
∀
additional single PK sample should be drawn
∀
liver imaging should be performed within 48 hours of identifying a liver event
If the reflex testing at the local laboratory is initiated by the investigator the results 
need to be entered in the e-CRF.
Severity of AEs
The severity of adverse events should be classified and recorded in the e-CRF according to 
the CTCAE version 4.0 (R10-4848)
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.
Every adverse event must be assessed for causal relationship by the investigator. The 
investigator needs to determine according to their best ability whether given adverse event is 
related to BI 836826, rituximab and/or GemOx.
The causal relationship needs to be documented on the SAE form. The causal relationship 
also needs to be documented in the patient’s source data.
5.3.7.
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate e-CRF by the 
investigator:


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Figure 5.3.7:1 AE Collection
∀
From signing the informed consent onwards until FU for AEs visit all AEs (non-serious 
and serious), and AESIs ( this is the REP period).
∀
After the FU for AEs visit until the last per protocol contact, all those SAEs and AESIs 
which are considered related to trial medication .
∀
However, if only vital status information is collected for a patient after PD and/or new 
anti-lymphoma treatment, from then on until the patient’s participation in the trial ends,
the investigator does not need to actively monitor the patient for AEs.  Fatal AEs, relevant
SAEs and relevant AESIs, which the investigator may become aware of, should be
reported.
The FU for AEs / (end of REP) is scheduled 30-42 days after the last dose of trial medication
(last administration of Gemcitabine, Oxaliplatin, Rituximab or BI836826, whichever is the 
latest).All AEs which occurred during treatment up until FU for AEs visit are considered as 
“on treatment” AEs. Please see section 7.3.4. Events which occurred after the FU for AEs 
visit are considered “ post- treatment” AEs.
After the last per protocol contact, the investigator does not need to actively monitor patients 
for AEs. However, if the investigator becomes aware of SAEs or AESIs that occurred after 
the last per protocol contact, the SAEs and AESIs should be reported by the investigator to 
the sponsor if considered relevant by the investigator. The rules for AE reporting exemptions 
still apply.
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.


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Information required
For each AE, the investigator should provide the information requested on the appropriate e-
CRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, outcome, 
seriousness, and action taken with the investigational drug(s). The investigator should 
determine the causal relationship to the trial medication, and any possible interactions 
between the investigational drug(s) and a non-investigational product (NIMP) 
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 subject 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 drug exposure during pregnancy 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
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 e-CRF page and not on a SAE form.
Examples of exempted events of PD are:
•
Progression of underlying malignancy (Progressive disease PD): if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by the 
respective response criteria. 


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•
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.
When there is evidence suggesting a causal relationship between the drug and the event of 
progression of the underlying disease, the event must be reported as (S)AE in the eCRF and 
on the SAE form.
5.3.8.
Dose limiting toxicity for Part 1
The MTD will be defined on the basis of DLT observed during the first cycle, i.e. the first 14 
days of C1.
Any patient who has been replaced will not be considered evaluable for MTD determination.
The following adverse events will qualify as DLT:
∀
Any ≥G3 non hematologic adverse event considered related to any trial medication with 
the following exceptions:
•
Laboratory abnormalities that can be corrected with treatment within 48 
hours (for example: electrolyte abnormalities).
•
nausea, vomiting, diarrhea which resolve within 48hrs with adequate 
treatment
•
neuropathy considered related to oxaliplatin
•
IRR
∀
Any hematologic adverse event related to any trial medication defined as follows:
•
G4 neutropenia lasting >7 days despite growth factors support
•
Any febrile neutropenia which does not resolve within 48 hours with 
appropriate treatment (antibiotics, antifungal, antiviral agents and growth 
factors )
•
G4 thrombocytopenia lasting >7 days, or G3-4 thrombocytopenia with 
clinically significant bleeding
•
Failure to recover platelets (PLT) ≥ 75 x 109/L by 4 weeks after start of the 
cycle (meaning by D28 of the cycle)
•
Failure to recover neutrophils (ANC) ≥1.0 x 109/L by 4 weeks after start of 
the cycle (meaning by D28 of the cycle)
A DLT has to be reported as Adverse Event of Special Interest (AESI) section 5.3.6.1 .
The MTD will be defined on the basis of DLT observed during the first treatment cycle (D1 
to 14). However, for those patients who receive more than one cycle of BI 836826 plus 
gemcitabine and oxaliplatin, all adverse events corresponding to the above definition of DLT 
as well as other adverse events and laboratory assessments will be considered for the purpose 


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of confirming the selection of the recommended dose for BI 836826 with GemOx in Part 2 of 
the trial. 
5.4.
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.4.1.
Assessment of pharmacokinetics
Blood samples will be collected for determining the pharmacokinetic parameters of BI 
836826 and exposure of gemcitabine and oxaliplatin in plasma. Oxaliplatin exposure will be 
assessed by means of the free platinum concentrations in plasma.
In addition samples will be collected for determining potential immunogenicity of BI 836826. 
The dates and the “start and stop” times of infusions along with additional information on 
respective infusion conditions, e.g. total dose and interruptions of infusion, should be 
documented for BI 836826, gemcitabine and oxaliplatin on all days of PK sampling.
These actual administration and sampling times will be used for determination of 
pharmacokinetic parameters.
Concentrations will be used for graphs and calculations in the format that is reported in the
bio-analytical report.
If data allow, the following pharmacokinetic parameters of BI 836826 will be evaluated using
noncompartmental analysis methods according to the internal BI Standard Operating
Procedure:
∀
Maximum measured plasma concentration of the analyte (Cmax)
∀
Area under the plasma concentration-time curve over the time interval from 0 to the 
time of the last quantifiable data point after drug administration (AUC0-tz)
∀
Area under the plasma concentration-time curve over the time interval from zero
extrapolated to infinity (AUC0-∞)
Others pharmacokinetic parameters can be calculated if considered relevant considering the 
available data.
5.4.2.
Methods of sample collection
For quantification of BI 836826 plasma concentrations, 3mL blood will be taken in an 
ethylendiaminetetraacetic acid (EDTA) anticoagulant blood drawing tube at the time points 
specified in Appendix 10.1. For the early time points on the day of drug administration the 
sample has to be taken from the opposite arm to the one where the infusion is/was 
administered in order to prevent contamination of blood samples with the infusion solution.


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For quantification of gemcitabine and free platinum plasma concentrations, 3mL blood will 
be taken in an EDTA blood drawing tube at the time points specified in Appendix 10.1. For 
the early time points on the day of drug administration the sample has to be taken from the 
opposite arm to the one where the infusion is/was administered in order to prevent 
contamination of blood samples with the infusion solution. Since gemcitabine is highly 
unstable in blood and plasma, blood samples have to be stabilized with tetrahydrouridine
(THU) immediately after collection. To accurately determine free platinum concentrations, 
the blood samples have to be immediately centrifuged after collection. The resulting plasma 
has to be subsequently ultra-filtrated before freezing. The details are described in the ISF and 
it is important note that the ultra-filtration process must be started less than 20 minutes after 
blood draw. 
Correct, complete and legible documentation of drug administration and blood sampling 
times as well as adequate handling and identification of PK samples is mandatory to obtain 
data of adequate quality for the pharmacokinetic analysis.
Details about sample collection, preparation, required cryovials, labels, storage and shipment 
are described in the laboratory manual included in the ISF.
5.4.3.
Analytical determinations
BI 836826 will be determined using a validated enzyme-linked immuno assay (ELISA). 
Plasma concentrations of oxaliplatin will be determined as free platinum by a validated 
inductively coupled plasma mass spectrometry (ICP-MS) assay and gemcitabine 
concentrations will be determined by a validated liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) assay. The procedures and specifications of the analytical 
methods are available at the determination site.
A detailed description of the assays will be available prior to the start of sample analysis.
 
 
 
 
 
 
 
 


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5.6.
APPROPRIATENESS OF MEASUREMENTS
Determination of MTD of BI 836826 is based on toxicities graded according to CTCAE
version 4.0 (R10-4848). The CTCAE criteria are commonly used for the assessment of 
adverse events in cancer patients. In the randomized part of the trial the response is assessed 
according to the International recommendation for lymphoma which is well established (R10-
1462, R14-3383, R14-3387).   


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6. INVESTIGATIONAL PLAN
6.1.
VISIT SCHEDULE
The allowable time windows for visits are included in the Flow Charts 1, 2, 3.
∀
Screening period is 14 days to 1 day prior C1D1.
∀
The planned duration of a treatment cycle is 14 days (+ maximum 3 days from cycle 2 
in case of delayed D8). In case of toxicity, the start of the next cycle may be delayed 
by maximum of 14 days to allow for recovery.
∀
Day 1, 2 and 8 of cycle 1 must be strictly respected. Only C1D11 can be done with -1 
day window (applicable only with BI 836826-GemOx). From Cycle 2, D8 can be 
delayed by maximum 3 days.
∀
EOT:
o
If a patient has been prematurely withdrawn from treatment (i.e. earlier than 
the 6th cycle), EOT must be performed within 14 days after last dose (last 
administration of Gemcitabine, Oxaliplatin, Rituximab or BI 836826, 
whichever is the latest).
o
If a patient completed all 6 cycles according to protocol, EOT must be 
performed at the earliest 30 days and no later than 42 days after the last dose
(last administration of Gemcitabine, Oxaliplatin, Rituximab or BI836826, 
whichever is the latest).
∀
FU AEs visit: The information collected at this visit should include all new AEs that 
occurred after the last dose and a follow-up of adverse events ongoing at the time of 
the last dose or EOT visit. 
o
If a patient has been prematurely withdrawn from treatment, the FU for AEs 
visit can be performed on site 30-42 days after the last dose. 
o
If a patient completed the 6 cycles according to the protocol, the FU for AEs 
visit can be scheduled at the same time point as EOT visit. 
∀
Follow-up visits (FU): After the FU for AEs, the patient will be followed for disease 
assessment/vital status (remission/progression/death/new anti-lymphoma treatment) 
and drug related SAEs and AESIs. These FU visits should take place every 3 months 
for the first year after FU for AEs visit, and then every 6 months until death, patient is 
lost to follow-up, patient withdraws consent for further follow up or the end of trial is 
reached. FU may be performed by telephone interview in case the patient is unable to 
visit the investigator
6.2.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1.
Screening period
Patients who failed screening may repeat the screening once after discussion between the 
investigator and sponsor providing that reasons for screening failure were reversible and have 
been resolved.
SAEs and /or AESI occurring in patients who are classed as screening failures, ( i.e. those  
patients who did not receive any trial medication), are to be reported if the Investigator 


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considers the SAEs and /or AESI to be related to the screening procedure. SAEs and /or 
AESI during the screening period are to be reported according to standard procedures.
A log of all patients 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
6.2.2. 
Treatment period(s)
A treatment cycle is defined as 14 days, with the start of next cycle on day 15 (from cycle 2, 
D8 can be delayed by maximum 3 days, meaning that the cyle could be up to 17 days, with 
the start of the next cycle on day 18). However if it is medically indicated a cycle may be 
postponed by maximum of 14 days due to toxicity reasons. Any additional visits (not 
foreseen by flow charts) will be recorded in the e-CRF.
In Part I, Cycle 1, no dose reduction or dose skipped is allowed.
In Part 1 and 2 in Cycle 1, there is the need for hospital stay for a minimum of 24 hours for 
PK sampling and safety monitoring. Please see Flowchart 1and2 and Appendix 10.1.
Patients may continue trial medication for maximum of 6 cycles. Patients who develop PD, or 
toxicity or who are considered intolerable, or withdraws consent, are to discontinue the trial 
according to the discontinuation rules described in section 3.3.4.
Please refer to section 4.1.4for drug administration.
6.2.2.1. 
Criteria to continue next treatment cycle (C2-6) and guidance to dose 
reduction 
The following criteria need to be fulfilled on D1 of each treatment cycle for Cycles 2-6:
∀no active infection
∀no evidence of progressive disease 
∀recovery from any AE except lymphopenia to ≤ G1, or to baseline
∀peripheral blood counts recovery defined as: 
PLT ≥ 75 x 10
9/L
ANC ≥1.0 x 109/L
Patients who experienced toxicity suspected as DILI need to demonstrate recovery of 
AST/ALT/bilirubin values as defined in section 5.3.6.1.
Guidance for dose reduction:
∀BI 836826:
The following criteria need to be fulfilled on D8 of each treatment cycle for Cycles 2-6, prior 
to start of the infusion with BI 836826:
In case elevations of AST and or ALT > 3 x ULN are considered drug related 
or related to a hepatic injury, a decline to ≤ 3 x ULN has to be documented 
prior to administration of the next dose of BI 836826. In case an elevation of 
bilirubin to >1,5 x ULN is considered drug related or related to a hepatic 


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injury, a decline to ≤ 1.5 x ULN or baseline (for patients with elevated levels 
at trial entry) has to be documented prior to administration of the next dose of 
BI 836826. 
From cycle 2, the infusion can be delayed by maximum 3 days, until D11. In that case, the 
next cycle should not start before at least 7 days between the BI 836826 infusion and the next 
D1.
If needed, the dose of BI 836826 should be omitted. If more than one dose of BI 836826 is 
skipped, the patient must be removed from the study.
Reduction of dose is allowed as per events described in table 6.2.2.1:1.
∀
Rituximab:
No dose reduction or skipped dose of rituximab is allowed.
∀
Oxaliplatin:
Only one oxaliplatin dose can be omitted for toxicity reasons during the duration of the trial
(6 cycles). If due to toxicity, related to oxaliplatin (Table 6.2.2.1:1), a patient is unable to 
receive oxaliplatin, the treatment can continue with BI 836826-Gem, or R-Gem for one cycle. 
If at the time of the next cycle the patient still cannot receive oxaliplatin due to oxaliplatin 
related toxicities, this patient needs to be withdrawn for toxicity reasons, and will not be 
allowed to re-enter the trial.
Reduction of dose is allowed as per events described in table 6.2.2.1:1.
∀
Gemcitabine:
No dose reduction or skipped dose of gemcitabine is allowed.
The criteria below are serving as basic guidance to investigators. They should not replace a 
sound clinical judgment in case of occurrence of other serious toxicities not listed in the table 
below.
Table 6.2.2.1:1 Criteria for dose reduction and treatment discontinuation
Finding
Recommended action
Hepatitis B or C reactivation
Withdraw patient from trial
Serum creatinine >2xULN
Reduce* Oxaliplatin dose to 75mg/m2
G2 neurosensory AEs lasting ≤ 14days
Reduce* Oxaliplatin dose to 75mg/m2
G2 neurosensory AEs lasting > 14days:
Omit one Oxaliplatin dose
G3 neurosensory AEs 
(single occurrence)
Omit one Oxaliplatin dose
G3 neurosensory  AEs 
(prolonged >14 days, or recurrent)
Withdraw patient from trial
Hypersensitivity to oxaliplatin
Withdraw patient from trial


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Finding
Recommended action
CMV reactivation:
  -with clinical signs of infection
  -raising CMV viral load without clinical     
signs
Withdraw patient from trial, implement 
treatment according to local standards
Continue following viral load bi-weekly
(every 2 weeks), and monitor patient for 
clinical signs of infection. If viral load 
continues to rise on two consecutive 
assessments consider pre-emptive antiviral 
treatment and withdrawal from trial
Hepatic injury fulfilling DILI criteria see 
section 5.3.6.1
Consider delaying next cycle or dose 
reduction of BI 836826 by 25%  
Recurrent febrile neutropenia 
Primary prophylaxis with colony-
stimulating factors is not permitted, but if a 
chemotherapy cycle is delayed, then 
filgrastim [granulocyte colonystimulating
factor (G-CSF)] is administered with 
subsequent cycles to aid maintenance of the 
dose intensity. Use of filgrastim is also 
recommended if febrile neutropenia had 
been observed during a previous treatment 
cycle.
Infusion related reactions (IRR) (see 
6.2.2.3) to BI 836826:
∀
Grade 1 
∀
Grade 2-3
Grade 4
∀
G1: Reduce BI 836826 infusion rate by 
50%, or temporarily interrupt and restart 
infusion when considered clinically 
manageable
∀
G2-3: Stop infusion until all symptoms 
are resolved. Resume BI 836826 at lower 
infusion rate, e.g. to 50%, and increase 
infusion rate as tolerated to the target 
rate.
∀
G4: Stop infusion immediately and do 
not re-expose to B 836826 after the 
event.
*Dose adjustment of oxaliplatin was carried out in the event of peripheral neuropathy. The 
oxaliplatin dose was to be reduced to 75 mg/m² in the event of significant paresthesia lasting 
between 7 and 13 days after each administration. In the event of abnormal results by 
neurological examination or if a patient experienced significant paresthesia lasting for 14 


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days or more, oxaliplatin was to be stopped until symptoms improved and then restarted at a 
dose of 75 mg/m². In the event of pharyngolaryngeal dysesthesia, the duration of the 
oxaliplatin infusion was to be prolonged from 2 to 6 h.
6.2.2.2.
Monitoring for infusion-related reactions
Close monitoring of the patients during and after the infusions of BI 836826 or rituximab in 
combination with GemOx is required for the evaluation of IRR. The monitoring includes:
∀
During the first infusion of BI 836826 the patients are required to be hospitalized under 
close surveillance with access to intensive care for at least 24 hours.
∀
Subsequent infusions of BI 836826 may be administered in outpatient facilities with 
access to intensive care unit.
∀
The infusions of rituximab can be administered in an outpatient setting if well tolerated.
∀
Frequent measurements and documentation of blood pressure and heart rate (see section 
5.3.2.
6.2.2.3.
Handling of infusion-related reactions
In case of an IRR, the infusion has to be stopped immediately for ≥ G2 reactions. Appropriate 
actions depending on the type and severity of the reaction should be taken according to best 
medical judgment and local guidelines. Supportive therapy including steroids may be used as 
clinically indicated. If IRR has been managed successfully, and if in the investigators’ 
judgment the infusion can be re-started at lower rate, the total time between original start and 
end of infusion cannot exceed 24 hrs. If infusion cannot be completed within 24 hours the 
remaining solution needs to be discarded, and the total dose received appropriately 
documented in e-CRF.
IRR should be reported as other AEs according to CTCAE version 4.0 with the term infusion 
related reaction. Together with this term the individual symptom, e.g. chills should also be 
grade according to CTCAE. IRRs are defined to be AESIs if they are classified CTCAE 
grade 3-5. AESIs have to be reported in an expedited manner according to SAE-reporting 
(see section 5.3.7).
The following recommendations for the management of IRRs may be considered by the 
investigator as guidance (see also table 6.2.2.1:1):
∀
In the case of G1 IRR, the infusion rate of BI 836826 should be reduced, e.g. to 50% of 
the target rate, or the infusion should be temporarily interrupted and resumed as soon as 
considered clinically manageable by the investigator.
∀
In the case of G2-3 IRR, the infusion with BI 836826 should be stopped immediately. 
Only in case all symptoms have resolved, administration of BI 836826 may be resumed at 
a slower infusion rate, e.g. of 50% of the target rate, and increase the infusion rate as 
tolerated to the target rate.
∀
In the case of G4 IRR, the infusion has to be stopped immediately. These patients should 
not be re-exposed to BI 836826 after the event.


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6.2.2.4.
Laboratory analyses:
The safety laboratory analyses (see section 5.3.3) will be performed at the investigator’s site, 
i.e. local hospital laboratories. The certification/accreditation for each laboratory or evidence 
that it participates in an established quality program must be provided by the investigator and 
filed in the sponsor’s and in the local ISF. The normal ranges of each test performed are to be 
documented in e-CRF.
Blood samples for pharmacokinetic analyses (PK), and flow cytometry (lymphocyte immune-
phenotyping) 
 will be shipped to a central laboratory in both 
Part 1 and 2.
 
 
6.2.2.5.
Disease assessments (PET-CT) 
PET/CT Scan of neck, thorax, abdomen, and pelvis has to be performed at:
∀
Baseline PET/CT scan : up to 28 days prior to C1D1
∀
Interim  PET/CT scan : after end of C3, i.e. prior to C4D1 infusion
∀
Final PET/CT scan: 3-6 weeks after the last dose if 6 cycles have been completed.
In Part 1, image acquisition and readings will be performed locally, and appropriate data and 
measurements will be entered into e-CRF. 
In Part 2 image acquisitions will be performed locally, however the images will be sent to an 
appointed vendor for central readings, and central archiving. A copy of the images are to be 
retained at the site. Local readings should be used for treatment decisions (i.e. discontinuation 
from trial participation due to PD) local results are to be entered in e-CRF.
6.2.2.6.
Tumor lysis syndrome (TLS)
During the first 24 hours after the start of the first dose of BI 836826 or rituximab, laboratory 
parameters need to be checked at least once in patients who considered at risk for TLS (e.g. 
large tumor burden, leukemic manifestation of the lymphoma) (see section 5.3.3.2). 
In case of clinical or laboratory signs of TLS appropriate treatment and hydration needs to be 
instituted immediately according to local standards.
6.2.3.
End of Treatment
For patients completing all 6 cycles: the end of treatment visit and should be done at the 
earliest 30 days and no later than 42 days after the last dose (last administration of 
Gemcitabine, Oxaliplatin, Rituximab or BI836826, whichever is the latest).
If a patient is prematurely withdrawn from treatment (i.e. earlier than the 6th cycle) an EOT 
visit should be performed within 14 days after last dose (last administration of Gemcitabine, 
Oxaliplatin, Rituximab or BI836826, whichever is the latest).


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6.2.4.
Follow-Up for AEs
A Follow up visit for AEs collection needs to be performed between 30- 42 days after the last
dose (last administration of Gemcitabine, Oxaliplatin, Rituximab or BI836826, whichever is 
the latest). The information collected at this visit should include all new AEs that occurred 
after the last dose and a follow-up of adverse events ongoing at the time of the last dose.
If a patient completes the 6 cycles according to the protocol the FU for AEs visit can be 
scheduled at the same time point as EOT visit. 
If a patient has been prematurely withdrawn from treatment, the FU for AEs visit can be 
performed on site 30-42 days after the last dose. 
6.2.5.
Follow Up Period and Trial Completion
After the FU for AEs, the patient will be followed for disease assessment/vital status 
(remission/progression/death/new anti-lymphoma treatment) and drug related SAEs and 
AESIs. These FU visits should take place every 3 months for the first year after FU for AEs 
visit, and then every 6 months until death, patient is lost to follow-up, patient withdraws 
consent for further follow up or the end of trial is reached. FU may be performed by 
telephone interview in case the patient is unable to visit the investigator
If patient progresses or relapses, only data on the new anti-lymphoma treatment and survival 
will be collected.
Prior to primary and final analyses, all applicable patients will be contacted for vital status  
regardless of whether the next FU visit is due or not.
The end of the trial is defined as when the last ongoing patient has completed treatment and 
has been followed for at least a year or when at least 50% of the patients have died, 
whichever occurs last.


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7. STATISTICAL METHODS AND DETERMINATION OF SAMPLE
SIZE
7.1.
STATISTICAL DESIGN MODEL
This trial will be conducted as an open-label trial in two parts. The primary objective of the 
Part 1 (Phase Ib) is to determine the dose of BI 836826 for the combination with GemOx 
using the classical 3+3 design (R04-0569) based on the number of patients with DLTs and 
the resulting MTD. 
In the second randomized part of the trial safety and efficacy of the combination BI 836826-
GemOx vs. R-GemOx will be evaluated. The primary endpoint for efficacy is OR by using 
PR+CR rates, analyzed when the last patient in the trial has completed 6 cycles of trial 
medication, or has been withdrawn for other reasons. 
Only descriptive and exploratory analyses are planned and no formal statistical testing will be 
performed.
7.2.
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing is planned in this trial. This is an exploratory Phase Ib/II trial 
with the main objective of treatment effect estimation. The primary endpoint for Part 2 will 
be overall response analyzed by PR+CR rate. All analysis and p-values provided need to be 
understood in an exploratory way.
7.3.
PLANNED ANALYSES
All patients who have received any amount of trial drug of BI 836826 or rituximab or 
gemcitabine or oxaliplatin will be included into safety analyses. All patients randomized for 
the Part 2 of the trial will be included in all efficacy analyses, using the intent-to-treat 
approach. Every effort will be made to evaluate response and progression for all patients who 
receive treatment, including those who discontinue prematurely.
During Part 1, cohorts of patients treated with BI 836826 in combination with GemOx will be 
evaluated continuously based on the totality of the safety data in order to determine the 
recommended BI 836826 dose for Part 2 of the trial. Results from data snapshots will be 
provided as needed to the trial team and involved investigators to support the determination 
of the dose for the randomized Part 2 of the trial. 
Summary outputs of efficacy analyses will include all patients entered in Part 2 of the trial. 
Both treatment arms in Part 2 will be compared.
Safety analyses will be summarized separately for patients treated in Part 1 and Part 2 of the 
trial.
No per protocol set will be used in the analyses. However potential important protocol 
violations will be summarized and violations of inclusion and exclusion criteria will be 


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provided in a subject data listing. The Core Trial Statistical Analysis Plan will specify the 
potential important protocol violations in detail.
The analyses of all primary, secondary and further endpoints in Part 1 and  Part 2 will be 
performed when the last patient entered in Part 2 has completed 6 cycles of trial medication 
or has been withdrawn for other reason; a CTR will be written at this time point.
The final CTR will be written at the end of the trial.
7.3.1.
Primary endpoint analyses
Part 1: The primary endpoint of the Phase Ib is to determine the MTD of BI 836826 in 
combination with GemOx analyzed via the number of patients with DLTs during the MTD 
evaluation period. In order to identify the MTD, the number of patients with DLTs at each 
dose level will be presented.
Part 2: The primary endpoint of the randomized Phase II is overall response analyzed by the 
PR+CR rate. The 95% confidence interval will be provided for the PR and CR rate in each 
arm. Comparisons between treatment groups will be performed using the Suissa-Shuster 
exact test (including the Berger-Boos modification), for which an exploratory p-value will be 
provided.
7.3.2.
Secondary endpoint analyses
Part 1: PK endpoints will be analysed as described in Section 7.3.5. Overall response by 
investigator’s assessment will be analysed descriptively in terms of the OR rate.
Part 2:
Complete remission
Best overall response is the best response (CR, PR, stable disease (SD) or PD) with respect to 
all time points. Complete remission is defined as CR and will be analyzed descriptively and 
compared between the two treatment arms.
Frequency distributions and other descriptive statistical measures will be used to examine this 
endpoint.
 
 
 
 


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7.3.4.
Safety analyses
All patients who have received any amount of trial drug will be included in the safety 
analysis. The number of patients with dose limiting toxicity (during the MTD observation 


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period in the Part 1 as well as during the on-treatment period in Part 1) as well as the 
incidence and intensity of adverse events, graded according to CTCAE version 4.0 and 
reported according to BI standards, laboratory parameters and vital signs will be evaluated. 
The safety analysis will be descriptive and exploratory and results for the Part 1 and Part 2 
will be presented separately. No hypothesis testing is planned. 
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced.
The overall incidence and intensity of adverse events, as well as relatedness of adverse events 
to treatment with BI 836826 will be reported for all dose cohorts in Part 1 and for both 
treatment arms in Part 2. SAEs, fatal AEs and AESIs will be tabulated. In addition, events 
leading to treatment discontinuation will be examined.
Events that start from any administration of trial medication until 30 days after the last 
administration of any trial medication will be considered as having occurred “on treatment” 
see section 5.3.8.
In general, adverse events occurring after the FU for AEs visit (after REP) will be attributed 
to the post-treatment period and will be presented separately. However, post-treatment events 
will be examined to determine whether they need to be combined with on-treatment events in 
an additional table.
Descriptive statistics will be used to describe changes in laboratory tests over time. In 
addition, all abnormalities of potential clinical significance will be reported. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
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.
7.3.5.
Pharmacokinetic analyses
Refer to Section 5.5.1 for PK parameters to be calculated.
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the
drug plasma concentration-time tables. For the presentation of the mean profiles, the 
arithmetic and geometric mean and the planned blood sampling times will be used. If the 
actual sampling time deviates significantly from the planned time, the corresponding plasma
concentration will be excluded from the calculation of descriptive statistics.
The following descriptive statistics will be calculated for analytic concentrations as well as 
for all pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, 
median, maximum, arithmetic coefficient of variation, geometric mean, and geometric 
coefficient of variation. The data format for descriptive statistics of concentrations will be 
identical with the data format of the respective concentrations. The descriptive statistics of 
pharmacokinetic parameters will be calculated using the individual values with the number of 


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decimal places as provided by the evaluation program. Then the individual values as well as 
the descriptive statistics will be reported with three significant digits in the clinical trial 
report.
7.3.5.1.
Plasma concentration - time profiles
Concentration data identified with no sample available (NOS), no valid result (NOR), not 
analyzed (NOA), and below the limit of quantification (BLQ) will be ignored and not 
replaced by zero at any time point (applies also to the lag Phase including the pre-dose 
value). Descriptive statistics of concentrations at specific time points will be calculated only 
when at least 2/3 of the individuals have concentrations within the validated concentration 
range. The overall sample size to decide whether the “2/3 rule” is fulfilled will be based on 
the total number of samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS, 
NOA are included).
7.3.5.2.
Pharmacokinetic assessment
In the non-compartmental analysis, concentration data identified with NOS, NOR, and NOA 
will not be considered. All other BLQ values of the profile will be ignored.
If the pre-dose concentration before the first dose is less than or equal to 5% of Cmax value in 
that subject, the subject’s data without any adjustments can be included in all 
pharmacokinetic measurements and calculations (i.e. the pre-dose value will not be changed 
to zero). If the pre-dose value is greater than 5% of Cmax, the subject should be dropped from 
all statistical evaluations. The individual pharmacokinetic parameters can be calculated and 
listed separately. 
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis. 
∀
If a concentration is only excluded from half-life determination, it will be used for all 
other calculations (e.g. descriptive statistics) and for graphical presentation.
∀
If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter 
determination. However the excluded concentration itself will be listed in the clinical trial 
report associated with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not 
be recorded or will be missing for a certain time point, the planned time will generally be 
used for this time point instead. Pharmacokinetic parameters which cannot be determined will 
be identified by "not calculated" (NC).


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7.4.
INTERIM ANALYSES
The dose selection for Part 2 will be based on the safety and PK data after the last patient in 
Part1 has completed cycle 1. After the discussion with the treating investigators the decision 
will be documented and shared with the investigators.
Details for the evaluations to be performed will be outlined in the trial statistical analysis plan
(TSAP).
During Part 2 of the trial regular monitoring by the internal DMC will be performed to ensure 
the positive benefit-risk for the patients. See section 3.1.1
7.5.
HANDLING OF MISSING DATA
In general, missing data will not be imputed. Every effort will be undertaken to obtain the 
date of progression or remission for patients known to have progressed or experienced a 
remission 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.
7.6.
RANDOMISATION
Part 1:
No randomization will be performed. Patients will be assigned into escalating dose groups by 
order of admission into the trial.
Part 2:
In the second part of the trial patients will be randomized in a 1:1 ratio to BI 836826-GemOx 
or R-GemOx.
Patients will be randomized in blocks to one of the treatment groups. Approximately equal 
numbers of patients will be randomized to each treatment group. Randomization will be 
performed using IRT. BI, Clinical Trial Support Group or a CRO appointed by the sponsor 
will provide the randomization lists using a validated randomization number generating 
system, which involves a pseudo-random number generator so that the resulting treatment 
will be both reproducible and non-predictable. The block size will be documented in the 
CTR. Access to the codes will be controlled and documented.
7.7.
DETERMINATION OF SAMPLE SIZE
7.7.1.
Part 1
In the first part (Phase Ib) of the trial the classical 3+3 design will be used. The overall 
number of the patients for the 3+3 design is not fixed. 
Up to-33 will be enrolled. The classical 3+3 design allows for flexibility and additional 
patients might be recruited to determine the BI 836826 dose to be used in the combination BI 
836826-GemOx.


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7.7.2.
Part 2
For the determination of sample size in the second part we assume as a best case scenario a 
target ORR of the BI 836826-GemOx combination of 81% and for the reference combination 
R-GemOx an ORR of 61%. In this case the true treatment difference is 20%. Due to 
stochastic nature of the process the true treatment difference is usually not the same as the 
treatment difference observed in the trial. Therefore we evaluate the probability to observe a 
difference of at least 10% under the assumption that the true difference lies somewhere 
between 0% and 20% (see table 7.7.2:1).
Table 7.7.2:1
Evaluation of probabilities to observe a treatment difference in OR-
rate dependent on true difference and sample size.
Number of 
patients per arm
True treatment 
difference
Treatment 
difference at least 
observed in the trial
Probability to observe a 
treatment difference of at 
least 10%
30
0 %
10 %
17.7%
30
10 %
10 %
44.6%
30
15%
10 %
61.3%
30
20 %
10 %
76.8%
60
0 %
10 %
11.2%
60
10 %
10 %
46.3%
60
15%
10 %
69.2%
60
20 %
10 %
87.2%
Results are based on 1000000 simulations in SAS version 9.2.
If the true difference is 20%, the probability to observe a treatment difference of at least 10% 
should be above 80% in order to provide sufficient credibility for the trial results. This 
probability is 87.2% with 60 patients per arm. At the same time if there is no difference in 
ORR between the treatments, the probability to observe a treatment difference of at least 10% 
by chance in the trial with 60 patients per arm is very low (11.2%).
The sample size of 60 patients per arm and the requirement that the observed treatment 
difference is at least 10% allows clear differentiation between these two scenarios and 
therefore is considered adequate for efficacy evaluation in the second part of this trial.


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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 Standard Operating Procedures (SOPs), the EU regulation 536/2014.
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 subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following
web page: http://trials.boehringer-ingelheim.com. 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. As a rule, no trial results should be published prior to finalization of the Clinical 
Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF 
8.1.
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective 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 after confirming that the patient understands the 
contents. The investigator must sign (or place a seal on) and date the informed consent form. 
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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Re-consenting may become necessary when new relevant information becomes available and
should be conducted according to the sponsor’s instructions. The consent and re-consenting 
process should be properly documented in the source documentation.
8.2.
DATA QUALITY ASSURANCE
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.
8.3.
RECORDS
Electronic case report forms (e-CRF) for individual patients will be provided by the sponsor.
For drug accountability, refer to section 4.1.9.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the trial master file 
(TMF). Coding of the data obtained will be done by using the MedDRA and the World health 
organization drug dictionary (WHO-DD).
Changes in laboratory parameters and adverse events will be graded according to US 
National Cancer Institute (NCI) CTCAE version 4.0 (R10-4848).
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 e-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 e-CRF, all data need to be derived from source documents.
8.3.2.
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data / documents. e-CRF 
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 Research Associate 
(CRA), auditor and inspection by health authorities (e.g. Food and Drug Administration 
(FDA)). The Clinical Research Associate (CRA) / on site monitor and auditor may review all 
e-CRF, and written informed consents. The accuracy of the data will be verified by reviewing 
the documents described in section 8.3.1. The sponsor will also monitor compliance with the 
protocol and ICH GCP.


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8.3.3.
Storage period of records
Trial site(s):
The trial site(s) must retain the source documents and essential documents for a period 
defined in the trial site’s contract with the sponsor.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
When it is no longer necessary for the trial site to retain the source documents and essential 
documents, the sponsor must notify the head of trial site.
8.4.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1.
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For BI 836826 this is the current version of the Investigator’s Brochure. 
For the comparator, rituximab, the SmPC of the originator Mabthera will be used. For the 
non-investigational trial medication, gemcitabine and oxaliplatin, the  SmPCs of the 
originator products GEMZAR and Eloxatin will be used will be used. The current versions of 
these reference documents are to be provided in the ISF. 
8.4.2.
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local 
regulatory requirements.
8.5.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
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.
Data protection and data security measures are implemented for the collection, storage and
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP
handbook.
Treatment data may be given to the patient’s personal physician or to 
∀
 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.


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8.6.
END OF TRIAL
The end of the trial is defined as when the last ongoing patient has completed treatment and 
has been followed for at least a year or when at least 50% of the patients have died, 
whichever occurs last.
The IEC / competent authority in each participating EU member state needs to be notified 
about the end of the trial or early termination of the trial.
When the trial is completed, the investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
sponsor of the completion in writing.
8.7.
PROTOCOL VIOLATIONS
The investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.
8.8.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9. REFERENCES
9.1.
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Crump M, Baetz T, Couban S, Belch A, Marcellus D, Howson-Jan K, Imrie K, 
Myers R, Adams G, Ding K, Paul N, Shepherd L, Iglesias J, Meyer R
Gemcitabine, dexamethasone, and cisplatin in patients with recurrent or 
refractory aggressive histology B-cell non-Hodgkin lymphoma: a phase II 
study by the National Cancer Institute of Canada Clinical Trials Group 
(NCIC-CTG). Cancer 101 (8), 1835 - 1842 (2004)
P15-01777
Chao NJ CEPP(B): an effective and well-tolerated regimen in poor-risk, 
aggressive non-Hodgkin's lymphoma. Blood 76 (7), 1293 (1990)


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P15-01852
Singer CR, Goldstone AH. Clinical studies of ABMT in non-Hodgkin's 
lymphoma
P15-01909
Moccia AA, Schaff K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Gascoyne 
RD, Connors JM, Sehn LH R-CHOP with etoposide substituted for 
doxorubicin (R-CEOP): excellent outcome in diffuse large B cell lymphoma 
for patients with a contraindication to anthracyclines. 51st Ann Mtg of the 
American Society of Hematology (ASH), New Orleans, 5 - 8 Dec 2009
R16-0373
Recommendations related to contraception and pregnancy testing in clinical 
trials (2014-09-15)


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9.2.
UNPUBLISHED REFERENCES
n00232742
 Efficacy of BI 836826, a chimeric monoclonal antibody 
to CD37, in combination with bendamustine in a  subcutaneous xenograft 
model of the human follicular lymphoma DOHH2 in C.B-17 scid mice
BIRCV03-13 March,10 2014
n00232752
Efficacy of BI 836826, a chimeric monoclonal antibody to CD37, in 
combination with chlorambucilin a  subcutaneous xenograft model of the 
human follicular lymphoma DOHH2 in C.B-17 scid mice BIRCV05-13
March, 31 2014


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10.APPENDICES
10.1.
BLOOD SAMPLING TIMES FOR PHARMACOKINETICS
Table 10.1:1 Part 1, Cycle 1
Blood sampling times for Pharmacokinetics (PK) 
 
for BI 83682-GemOx arm
Procedures
screen
Cycle 1
Day of cycle
-14 to <1
1
82)
9
11(- 1)
Visit
Screen
C1D1
C1D8
C1D9
C1D11
Time point 
after dose
[h:min]
Up to 6hrs
before
gemcitabine
infusion
Shortly 
before end 
gemcitabine 
infusion 
Shortly 
before end 
oxaliplatin 
infusion 
8hrs
(+/-30 min)
after start 
gemcitabine
infusion
Up to 6hrs
before
BI 836826
infusion
Shortly 
before end 
BI 836826 
infusion 
8hrs
(+ /-30 min)
after start
BI 836826
infusion
23hrs
(+/- 2hrs)
after start
BI 836826
infusion
96hrs
(- 24hrs)
after start
BI 836826 
infusion
Write in 
e-CRF Actual 
date and time 
point
T0 (G) 
0:00
1:00*
3:00**
8:00
T0
(BI 836826)
0:00
4:00***
8:00****
23:00
96:00
BI 836826
analysis
X
X
X
X
X
Gemcitabine 
analysis
X
X
X
X
Oxaliplatin 
analysis
*This is an indication as the total duration of Gemcitabine infusion duration is based on BSA (10mg/m²/hour). The PK sample must be drawn shortly 
before the end of the Gemcitabine infusion.


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** This is an indication as the start of the Oxaliplatin infusion depends on the Gemcitabine infusion duration. The PK sample must be drawn shortly 
before the end of the Oxaliplatin infusion.
*** This is an indication, the PK sample must be drawn just before the end of the BI 836826 infusion, meaning if the infusion is longer than 4 hours, the
PK sample must be drawn later than 4 hours but shortly before the end of the infusion.
**** This is an indication; the post-infusion PK sample must be drawn 4 hours after the end of the infusion.
T0 (G) Time zero is when gemcitabine infusion starts
T0 (BI 836826) Time zero is when BI 836826 infusion starts 
2) Day 8, in cycle 1, the patient will stay over-night allowing a morning PK sample to be taken day 9
If the investigator determines a need for an unscheduled safety lab, a concomitant sampling of PK is required


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Table 10.1:1 Part 1, Cycle 3 cont`d
Blood sampling times for Pharmacokinetics (PK) 
for BI 836826 and GemOx arm
Procedures
Cycle 3
Day of cycle
1
8
Visit
C3D1
C3D8
Time point 
after dose
[h:min]
Up to 6hrs
before
gemcitabine
infusion
Shortly 
before end 
gemcitabine 
infusion 
Shortly 
before end 
oxaliplatin
infusion 
8hrs
(+/-30 min)
after start 
gemcitabine
infusion
Up to 6hrs
before
BI 836826
infusion
Shortly 
before end 
BI 836826
infusion 
8hrs
(+ /-30 min)
after start
BI 836826
infusion
Write in 
e-CRF Actual 
date and time 
point
T0 (G)
0:00
1:00*
3:00**
8:00
T0
(BI 836826)
0:00
4:00***
8:00****
BI 836826
analysis
X
X
X
X
Gemcitabine 
analysis
X
X
X
X
Oxaliplatin 
analysis
*This is an indication as the total duration of Gemcitabine infusion duration is based on BSA (10mg/m²/hour). The PK sample must be drawn shortly before 
the end of the Gemcitabine infusion.
** This is an indication as the start of the Oxaliplatin infusion depends on the Gemcitabine infusion duration. The PK sample must be drawn shortly before 
the end of the Oxaliplatin infusion.
*** This is an indication, the PK sample must be drawn just before the end of the BI 836826 infusion, meaning if the infusion is longer than 4 hours, the PK 
sample must be drawn later than 4 hours but shortly before the end of the infusion.
**** This is an indication; the post-infusion PK sample must be drawn 4 hours after the end of the infusion.


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T0 (G) Time zero when gemcitabine infusion starts
T0 (BI 836826) Time zero when BI 836826 infusion starts
 
If the investigator determines a need for an unscheduled safety lab, a concomitant sampling of PK is required


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Table 10.1:1 Part 1, Cycle 2,4,5,6 and EOT cont`d
Blood sampling times for Pharmacokinetics (PK) 
for BI 836826-GemOx arm
Procedures
Cycle 2, 4, 5, 6
EOT
Day of cycle
1
8
Visit
C2D1, C4D1, C5D1, C6D1
C2D8, C4D8, C5D8, C6D81)
Time point 
after dose
[h:min]
Up to 6hrs
before
gemcitabine
infusion
Up to 6hrs
before BI 836826
infusion
Shortly before end 
BI 836826 infusion 
Write in 
e-CRF Actual 
date and time 
point
T0 (G)
0:00
T0 (BI 836826)
0:00
4:00*
BI 836826
analysis
X
X
X
X
* This is an indication, the PK sample must be drawn just before the end of the infusion, meaning if the infusion is longer than 4 hours, the PK sample 
must be drawn later than 4 hours but shortly before the end of the infusion.
T0 (G) Time zero when gemcitabine infusion starts
T0 (BI 836826) Time zero when BI 836826 infusion starts 
 
If the investigator determines a need for an unscheduled safety lab, a concomitant sampling of PK is required


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Table 10.1:2 Part 2, Cycle 1
Blood sampling times for Pharmacokinetics (PK) 
for BI 836826-GemOx arm
Procedures
screen
Day of cycle
-14 to <1
1
82)
Visit
Screen
C1D1
C1D8
Time point
after dose
[h:min]
Up to 6hrs
before
gemcitabine
infusion
Shortly 
before end 
gemcitabine 
infusion
Shortly 
before end 
oxaliplatin
infusion
8hrs
(+/-30 min)
after start 
gemcitabine
infusion
Up to 6hrs
before
BI 836826
infusion
Shortly 
before end 
BI 836826
infusion
Write in 
e-CRF Actual 
date and time 
point
T0 (G)
0:00
1:00*
3:00**
8:00
T0
(BI 836826)
0:00
4:00***
BI 836826
analysis
X
X
*This is an indication as the total duration of Gemcitabine infusion duration is based on BSA (10mg/m²/hour). The PK sample must be drawn shortly 
before the end of the Gemcitabine infusion.
** This is an indication as the start of the Oxaliplatin infusion depends on the Gemcitabine infusion duration. The PK sample must be drawn shortly 
before the end of the Oxaliplatin infusion.
*** This is an indication, the PK sample must be drawn just before the end of the BI 836826 infusion, meaning if the infusion is longer than 4 hours, the 
PK sample must be drawn later than 4 hours but shortly before the end of the infusion.
**** This is an indication; the post-infusion PK sample must be drawn 4 hours after the end of the infusion.
T0 (G) Time zero when gemcitabine infusion starts
T0 (BI 836826) Time zero when BI 836826 infusion starts


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2) Day 8, in cycle 1, the patient will stay over-night allowing a morning PK sample to be taken day 9
If during an unscheduled visit the investigator determines a need for a safety lab a concomitant sampling of PK is required


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Table 10.1:2 Part 2, Cycle 3 cont`d
Blood sampling times for Pharmacokinetics (PK) 
for BI 836826-GemOx arm
Procedures
Cycle 3
Day of cycle
1
8
Visit
C3D1
C3D8
Time point 
after dose
[h:min]
Up to 6hr
before
gem-
citabine
infusion
Shortly 
before end 
gemcitabine 
infusion 
Shortly 
before end 
oxaliplatin
infusion 
8hrs
(+/-30 min)
after start 
gemcitabine
infusion
Up to 6hr
before
BI 836826
infusion
Shortly 
before end 
BI 836826
infusion 
Write in 
e-CRF Actual 
date and time 
point
T0 (G)
0:00
1:00*
3:00**
8:00
T0
(BI 836826)
0:00
4:00***
BI 836826
analysis
X
X
X
*This is an indication as the total duration of Gemcitabine infusion duration is based on BSA (10mg/m²/hour). The PK sample must be drawn shortly 
before the end of the Gemcitabine infusion.
** This is an indication as the start of the Oxaliplatin infusion depends on the Gemcitabine infusion duration. The PK sample must be drawn shortly 
before the end of the Oxaliplatin infusion.
*** This is an indication, the PK sample must be drawn just before the end of the BI 836826 infusion, meaning if the infusion is longer than 4 hours, the 
PK sample must be drawn later than 4 hours but shortly before the end of the infusion.
T0 (G) Time zero when gemcitabine infusion starts
T0 (BI 836826) Time zero when BI 836826 infusion starts
If during an unscheduled visit the investigator determines a need for a safety lab a concomitant sampling of PK is required


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Table 10.1:2 Part 2, Cycle 2,4,5,6 and EOT cont`d
Blood sampling times for Pharmacokinetics (PK) 
 
for BI 836826-GemOx arm
Procedures
Cycle 2, 4, 5, 61)
EOT
Day of cycle
1
8
Visit
C2D1, C4D1, C5D1 C6D1
C2D8,C4D8,C5D8,C6D8
Time point 
after dose
[h:min]
Up to 6hrs
before
gemcitabine
infusion
Up to 6hrs
before
BI 836826
infusion
Shortly before end 
BI 836826 infusion 
Write in 
e-CRF Actual 
date and time 
point
T0 (G)
0:00
T0 (BI 836826)
0:00
4:00*
BI 836826
analysis
X
X
X
X
ADA1)
analysis
X1)
X
* This is an indication, the PK sample must be drawn just before the end of the infusion, meaning if the infusion is longer than 4 hours, the sample must 
be drawn later than 4 hours but shortly before the end of the infusion.
T0 (BI 836826) Time zero when BI 836826 infusion starts
T0 (G) Time zero when gemcitabine infusion starts
 
If the investigator determines a need for an unscheduled safety lab, a concomitant sampling of PK is required


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11. DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
13 OCTOBER 2016
EudraCT number
2014-004794-16
BI Trial number
1270.11
BI Investigational Product(s)
BI 836826
Title of protocol
An open label multicenter Phase Ib/II trial to 
determine the dose of BI 836826 in combination 
with gemcitabine and oxaliplatin (GemOx) and the 
efficacy of BI 836826-GemOx versus rituximab 
(R)- GemOx (R-GemOx) in patients with relapsed/ 
refractory diffuse large B-cell lymphoma (DLBCL) 
who are not eligible for, or have 
relapsed/progressed after autologous/ allogeneic
stem cell transplant
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
X
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
Title, Protocol Synopsis, Flow chart, List of 
abbreviations, section 1.2.2, 1.2.4, 1.2.5, 3.3.2, 
3.3.3, 3.3.4, 4.1, 4.1.1, 5.3.3, 6.1, 6.2.
Description of change
- Clarification of the protocol Title, to match with 
inclusion criteria.
- Correction of the Protocol Synopsis to match with 
changes made in other sections.
- Flow chart: correction of the visit window 
allowed, blood safety tests added at C1D1 and 
EOT, Weight added at EOT, footers numbering 
corrected, rewording of the notes.
- List of abbreviations: some have been added.
- section 1.2.2: updated section with latest data


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- section 1.2.4 & 1.2.5: reference to SMPC located 
in the ISF rather than a specific version to avoid 
upcoming amendment in case of change in the 
referenced SMPC.
- section 3.1: clarifications and rewordings
- section 3.3.1: clarification of the observational 
period (D& to 14 Cycle 1)
- section 3.3.2: clarification of inclusion criteria 2.
- section 3.3.3: clarification of exclusion criteria 7 
& 9
- section 3.3.4: clarification of the removal of 
patients
- section 4.1.1: renaming of “comparator products” 
to “comparator backbone products”
- section 4.1.2 – 4.1.3- 4.1.4- 4.1.5- 4.1.7: 
clarifications and rewordings 
- section 4.2.2.3: correction of the section based on 
the recommendations to contraception and 
pregnancy testing in clinical trials (HMACTFG)
- section 5.3: rewording and clarifications within 
the section.
- section 6.1: clarifications and description added
- section 6.2: rewording and various clarifications 
within the section.
- section 8: some administrative changes
In general: Rewording of Administrative changes.
Corrections of unclear sentences, typos.
Rationale for change
Biochemistry test added on C1D1 is on request of 
Belgian HA.
Other changes are made to make the protocol more 
clear, correct some mistakes, unclarities, and add 
consistency.


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Number of global amendment
2
Date of CTP revision
03 November 2016
EudraCT number
2014-004794-16
BI Trial number
1270.11
BI Investigational Product(s)
BI 836826
Title of protocol
An open label multicenter Phase Ib/II trial to 
determine the dose of BI 836826 in combination 
with gemcitabine and oxaliplatin (GemOx) and the 
efficacy of BI 836826-GemOx versus rituximab 
(R)- GemOx (R-GemOx) in patients with relapsed/ 
refractory diffuse large B-cell lymphoma (DLBCL) 
who are not eligible for, or have 
relapsed/progressed after autologous/ allogeneic
stem cell transplant
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Flow chart, Sections 5.3.3.3 , 11
Description of change
Flow chart: Part 3: weight assessment moved to 
EoT.
Section 5.3.3.3: HBV tests described in more 
detail. 
Section11: tick box “to be implemented after..” is 
ticked: was missing for amendment 1
Rationale for change
Flow chart: Part 3: weight assessment was put on 
FU for AE in error
Section 5.3.3.3.: Regular HBV DNA tests is 
required in case HBsAg and/or anti-HBc are 
positive at screening.
Section11: tick box was not ticked in error


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Number of global amendment
3
Date of CTP revision
10 January 2017
EudraCT number
2014-004794-16
BI Trial number
1270.11
BI Investigational Product(s)
BI 836826
Title of protocol
An open label multicenter Phase Ib/II trial to 
determine the dose of BI 836826 in combination 
with gemcitabine and oxaliplatin (GemOx) and the 
efficacy of BI 836826-GemOx versus rituximab 
(R)- GemOx (R-GemOx) in patients with relapsed/ 
refractory diffuse large B-cell lymphoma (DLBCL) 
who are not eligible for, or have 
relapsed/progressed after autologous/ allogeneic
stem cell transplant
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
X
Section to be changed
3.3.4.1 & 5.1.1 & 5.3.8
Description of change
3.3.4.1: Clarification by addition of the sentence: 
“Patients who experienced a DLT prior to BI 
836826 infusion will be replaced.”
5.1.1: clarification about DLT and MTD 
determination based on “evaluable” patients.
5.3.8 Clarification by addition of the sentence: 
“Any patient who has been replaced will not be 
considered evaluable for MTD determination. “
Rationale for change
MTD can only be determined on “evaluable” 
patients.


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Number of global amendment
4
Date of CTP revision
09 June 2017
EudraCT number
2014-004794-16
BI Trial number
1270.11
BI Investigational Product(s)
BI 836826
Title of protocol
An open label multicenter Phase Ib/II trial to 
determine the dose of BI 836826 in combination 
with gemcitabine and oxaliplatin (GemOx) and the 
efficacy of BI 836826-GemOx versus rituximab 
(R)- GemOx (R-GemOx) in patients with relapsed/ 
refractory diffuse large B-cell lymphoma (DLBCL) 
who are not eligible for, or have 
relapsed/progressed after autologous/ allogeneic
stem cell transplant
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
Synopsis, Sections 1.1, 1.2.2, 2.2, 3.1, 3.2, 3.3, 4, 
5.1.2, 7.3.2, 7.3.2, 7.7.1
Description of change
Synopsis: 
- addition of a secondary endpoint (evaluate the 
preliminary efficacy in terms of the ORR based on 
investigator’s assessment)
-total number of patients entered increased in Part 1 
(from 12 to 18, to a total up to 33)
- addition of two dose cohorts: 150 & 200mg
Section 1.1.Introduction: update for number of 
NHLM cases in 2017, based on www.cancer.org.
Section 1.2.2: rationale for addition of 2 doses 
cohorts, and updated data.


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Section 2.2:  addition of a secondary endpoint: 
evaluate the preliminary efficacy in terms of the 
ORR based on investigator’s assessment
Section 3.1 & 3.2: addition of 6 to 9 patients will 
be recruit at the established MTD to have a total of 
12 patients treated at this MTD
Section 3.3: correction of the number of patients in 
Part 1: up to 33
Section 4: additional dose cohorts: 150 and 200mg
Section 5.1.2 & 7.3.2: addition of the secondary 
endpoint: ORR based on investigator’s assessment
Section 7.7.1: sample size adapted to new numbers
Section 7.3.2: addition of secondary endpoint part 
1
Rationale for change
Addition of 2 dose cohorts (150 and 200mg) and 
addition of patients to be treated at the established 
MTD.


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Number of global amendment
5
Date of CTP revision
14 Sep 2017
EudraCT number
2014-004794-16
BI Trial number
1270.11
BI Investigational Product(s)
BI 836826
Title of protocol
An open label multicenter Phase Ib/II trial to 
determine the dose of BI 836826 in combination 
with gemcitabine and oxaliplatin (GemOx) and the 
efficacy of BI 836826-GemOx versus rituximab 
(R)- GemOx (R-GemOx) in patients with relapsed/ 
refractory diffuse large B-cell lymphoma (DLBCL) 
who are not eligible for, or have 
relapsed/progressed after autologous/ allogeneic
stem cell transplant
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
Synopsis, Section 3.3.2
Description of change
Synopsis: 
Change of inclusion criteria 4 from two to at least 1 
bi-dimensional lesion/node >1.5 cm
Section 3.3.2: Change of inclusion criteria 4 from 
two to at least 1 bi-dimensional lesion/node >1.5 
cm
Rationale for change
The initial inclusion criteria did not allow patients 
with one large single lesion to participate to the 
study. This amendment will allow these patients to 
enter the study and to be treated


 
 
 
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SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c06878240-02
BI Trial No.:
1270.11
Title:
An open label multicenter Phase Ib/II trial to determine the dose of 
BI 836826 in combination with gemcitabine and oxaliplatin 
(GemOx) and the efficacy of BI 836826-GemOx versus 
rituximab (R)- in combination with GemOx (R-GemOx) in patients 
with relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) 
who are not eligible for, or have relapsed/ progressed after
autologous/ allogeneic stem cell transplant
  Including protocol amendments 1 to 5 (c02102551-08)
Investigational
Product(s):
BI 836826
Responsible trial 
statistician(s):
 
Phone: 
Fax:    
Date of statistical 
analysis plan:
30 JAN 2018 SIGNED
Version:
Final 
Page 1 of 34
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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
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
5.4.3
Pharmacokinetic parameters.............................................................................13
5.4.4
Adverse Events ....................................................................................................13
5.4.4.1
Adverse events of special interest.........................................................................13
 
5.4.4.3 
Other significant adverse events ...........................................................................13
5.4.5
Laboratory parameters ......................................................................................13
5.4.5.1
Laboratory values of special interest ....................................................................16
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................18
6.1
TREATMENTS...................................................................................................18
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................18
6.3
PATIENT SETS ANALYSED...........................................................................20
6.5
POOLING OF CENTRES .................................................................................21
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................21
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................22
7.
PLANNED ANALYSIS......................................................................................23
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........23
7.1.1
Disposition of patients.........................................................................................23
7.1.2
Important protocol violations ............................................................................24
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................24
7.3
TREATMENT COMPLIANCE........................................................................24
7.4
PRIMARY ENDPOINTS...................................................................................24
7.5
SECONDARY ENDPOINTS.............................................................................25
7.5.1
Key secondary endpoints....................................................................................25
7.5.2
Other secondary endpoints ................................................................................25


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7.7
EXTENT OF EXPOSURE.................................................................................25
7.8
SAFETY ANALYSIS..........................................................................................26
7.8.1
Adverse events.....................................................................................................26
7.8.1.1
Maximum tolerated dose and dose limiting toxicities ..........................................26
7.8.1.2
Adverse events ......................................................................................................26
7.8.1.3
Protocol-specified adverse events of special interest............................................27
7.8.1.5
Other significant AEs............................................................................................28
7.8.2
Laboratory data ..................................................................................................28
7.8.3
Vital signs.............................................................................................................31
7.8.4
ECG......................................................................................................................31
8.
REFERENCES....................................................................................................32
10.
HISTORY TABLE..............................................................................................34


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LIST OF TABLES
 
Table 5.4.5: 1 Primary laboratory parameters ........................................................................14
Table 5.4.5.1: 1 
Laboratory Signs of Cell Destruction.......................................................16
Table 6.2: 1
Important protocol violations ...........................................................................19
Table 10: 1
History table .....................................................................................................34


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALKP
Alkaline Phosphatase
ALT
Alanine Transaminase
AST
Aspartate Transaminase
ATC
Anatomical, Therapeutic, Chemical (Classification System)
AUC
Area Under the Curve
BI
Boehringer Ingelheim
BMI
Body Mass Index
BRPM
Blinded Report Planning Meeting
BS
Biomarker Set
BSA
Body Surface Area
Cmax
Maximum measured plasma concentration
CR
Complete Remission
CT
Computer Tomography
CTh
Concomitant Therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DILI
Drug-Induced Liver Injury
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
(e)CRF
(electronic) Case Report Form
EOT
End of Treatment
FISH
Fluorescence In Situ Hybridization
GemOx
Gemcitabine and Oxaliplatin


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Term
Definition / description
ICH
International Conference on Harmonisation
IPV
Important Protocol Violation
IRR
Infusion Related Reaction
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MTD
Maximum Tolerated Dose
NHL
Non-Hodgkin’s Lymphoma
OR
Objective Response
PET
Positron Emission Tomography
PK
Pharmacokinetics
PKS
Pharmacokinetic Set
PPS
Per Protocol Set
PR
Partial Remission
PT
Preferred Term
R
Rituximab
REP
Residual Effect Period
SCR
Screened Set
StD
Standard Deviation
SOC
System Organ Class
SOP
Standard Operating Procedure
SPD
Sum of Products of Diameter
TLS
Tumour Lysis Syndrome
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
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) (1) 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 is a multicentre study initially planned with two study parts. Part 1 is an open-label, 
(Phase 1b) dose-escalation according to a standard 3+3 design. Part 2 was to be a randomised 
parallel study comparing BI 836826 in combination with gemcitabine and oxaliplatin 
(GemOx) to rituximab (R-) in combination with GemOx.
The primary objective of part 1 of the study is to determine the maximum tolerated dose 
(MTD) of BI 836826 in combination GemOx. The secondary objective of part 1 is to evaluate 
the pharmacokinetics (PK) of BI 836826 when administered in combination with GemOx.
The primary objective of part 2 of the study was to investigate efficacy by means of the 
overall response rate based on central review assessment of BI 836826-GemOx compared 
with R-GemOx. The secondary objective was to compare the efficacy of the two 
combinations by means of the complete remission (CR) rate based on central review 
assessment.
Due to the strategical decision to stop the project, the part 2 of the trial will not be conducted. 
The trial will be stopped after the dose escalation phase (or earlier). Therefore, this TSAP 
only describes the analysis of part 1 of the trial. 
 
 
 
 
 
 
In the following, study medication always refers to either BI 836826 or GemOx. 
SAS® Version 9.4 or higher will be used for all analyses.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints of this trial are: 

The number of evaluable patients with dose-limiting toxicities (DLTs) in the MTD 
evaluation period (cycle 1)

The MTD of BI 836826 with GemOx based on the number of evaluable patients with 
DLTs in cycle 1. The MTD of BI 836826 with GemOx is defined as the highest dose 
studied for which the number of evaluable patients with dose-limiting toxicity is 17% or 
less (i.e., 0-1/6 patients) during the MTD evaluation period.
For the definition of DLT, refer to CTP Section 5.3.8.
Patients who have been replaced are not considered evaluable for MTD determination.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Other secondary endpoints
The secondary endpoints are:

The pharmacokinetic parameters AUCt and Cmax of BI 836826 when administered in 
combination with GemOx.

OR by investigator assessment
 
 
 
 
 
 
 
 
 


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5.4.3
Pharmacokinetic parameters
The PK parameters will be calculated as defined in Section 5.5.1 of the CTP using the
processes detailed in (4).
5.4.4
Adverse Events
Severity of adverse events (AEs) is scaled according to Common Terminology Criteria of 
Adverse Events (CTCAE) version 4.03 (5).
5.4.4.1
Adverse events of special interest
DLTs, Infusion related reactions (IRRs), late onset infections and drug-induced liver injury
(DILI) are considered as adverse events of special interest (AESI) in this study, for details see 
CTP Section 5.3.6.1 and 5.3.8.
 
 
5.4.4.3 
Other significant adverse events
Other significant AEs are all serious and non-serious AEs leading to treatment discontinuation 
or dose reduction of any study medication.
5.4.5
Laboratory parameters
Original values will be converted into standard units and the CTCAE grades will be assigned 
to parameters which have a CTCAE definition.


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Primary List: Tables and figures for these laboratory values and urine measurement will be 
displayed in Section 15 of the clinical trial report (CTR). 
Table 5.4.5: 1
Primary laboratory parameters
Worsening direction
Laboratory
Measurement
low value
Haematology
white blood cell count (WBC, total leukocyte 
count)
platelets (thrombocytes, PLTCT)
Differentials
neutrophils (NEUABS)
Biochemistry
inorganic phosphate (P)
high value
Substrates
creatinine (CRE)
total bilirubin (TBILI)
Enzymes
aspartate transaminase (AST)
alanine transaminase (ALT)
Biochemistry
lactate dehydrogenase (LDH)
uric acid (URIC)
high and low value
Electrolytes
potassium (K)
calcium (CA)
Corrected calcium
Differentials
lymphocytes (lymphopenia) (LYMPABS)
Haematology
haemoglobin (HGB)
Flow cytometry
TBNK (CD3, CD4, CD8, CD19, CD56)
Corrected calcium: 
The grading of hypocalcemia is based on corrected calcium as calcium can be falsely low if 
hypoalbuminemia is present. The following corrective calculation will be performed:
Corrected calcium (mg/dL) = Total Calcium (mg/dL) – 0.8[Albumin (g/dL)-4)
No correction of the reference range has to be done. The reported reference range of total 
calcium should be used for analyses.
Corrected calcium can be only derived at a certain time point in case both laboratory values, 
total calcium and albumin, have been reported for the patient in the same laboratory sample. 


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5.4.5.1
Laboratory values of special interest
Potential Hy’s law cases
Special attention will be paid to patients fulfilling the criteria for potential Hy’s law cases.
These are defined as those cases where a combination of all of the following events occurred: 
any on-treatment value of ALT and/or AST > 3 times upper limit of normal (3 x ULN) with 
total bilirubin ≥ 2 x ULN and ALKP < 2 x ULN. The events can occur in any order, but must 
occur within 14 days of the previous event, i.e. the second event must occur within 14 days of 
the first event, and the third event must occur within 14 days of the second event.
Possible clinically significant abnormal lab values
Possible clinical significance based on CTCAE grading is defined as CTCAE grade 2 or 
higher with an increase of at least one CTCAE grade from baseline. If however the baseline 
value is missing, then all post-baseline values with CTCAE grade 2 or higher will be 
classified as possibly clinically significant. For the laboratory parameters recorded that do not 
have CTCAE criteria, the BI default rules for clinical significance should be applied (6).
Tumour lysis syndrome (TLS)/Laboratory signs of cell destruction
In patients with a high tumour burden who are exposed to a highly effective therapy, there is a 
risk of rapid tumour destruction resulting in TLS. The presence of TLS will be mainly 
investigated via adverse event reporting and the respective UDAEC. In addition, laboratory 
signs of cell destruction will be investigated based on the laboratory values uric acid, 
potassium, inorganic phosphate and creatinine. Laboratory signs of cell destruction may be 
considered present if within the time window of the day of BI 836826 infusion and the 
following 6 days, two or more of these laboratory parameters are considered abnormal 
simultaneously. Simultaneously means that abnormality of these ≥2 lab parameters occurs 
within 24 hours within the 7 day window after BI 836826 infusion. 
The definition of abnormal laboratory values is given in Table 5.4.5.1: 1 below. In addition, it 
will be investigated whether an adverse event episode of the UDAEC “Tumour lysis 
syndrome” started in the same time window in which potential laboratory signs of cell 
destruction have been observed. 
Table 5.4.5.1: 1
Laboratory Signs of Cell Destruction
Laboratory parameter
Abnormal value
Uric acid
≥476 µmol/L AND increase from relative baseline by 
≥25%
Potassium
Only if relative baseline is < 6.0 mmol/L: value  ≥ 6.0 
mmol/L 
Inorganic phosphate
≥1.45 mmol/L AND increase from relative baseline by 
by ≥25%
Creatinine
Absolute increase from relative baseline by 26.5 µmol/L 
AND increase from relative baseline by ≥50%


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Derivation of “relative baseline” for the laboratory values uric acid, potassium, inorganic 
phosphate and creatinine: relative baseline is derived for each BI 836826 infusion as the last 
respective value prior to BI 836826 infusion. Relative baseline will be derived independently 
for the four parameters, i.e. the four baseline values do not necessarily have to be derived 
from the same laboratory assessment.
Around each infusion of BI 836826, a time window is constructed. This time window starts at 
the day and start time of BI 836826 infusion until the end of the 6th day after BI 836826 
infusion (end of the day, i.e. 23.59h), i.e. the day of BI infusion and the following 6 days will 
be considered for evaluation of potential laboratory signs of cell destruction.
 
 
 
 
 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
In this trial, treatment is not randomised (open-label, dose-escalation). Different dose levels of 
BI 836826 in combination with GemOx can arise. 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 MTD determination of BI 836826 with GemOx, DLTs occurring during the
MTD evaluation period (first treatment cycle) will be presented separately from those 
occurring during the complete 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 last report planning meeting before DBL.
For safety summaries, events that start from the first administration of any trial medication 
until 30 days (residual effect period (REP)) after the last administration of any trial 
medication 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 or post-study period will be displayed in separate listings from those occurred 
during the on-treatment period. 
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 “ADS plan”. 
6.2
IMPORTANT PROTOCOL VIOLATIONS
No per protocol set (PPS) 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 potential IPVs. 


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Table 6.2: 1
Important protocol violations
Category/Code
Description
Requirement
Excluded from
A
Entrance criteria 
not met
A1*
Efficacy related 
entrance criteria 
not met
In4, In 5 
Missing bone marrow biopsy at 
screening
None
A2*
Patient has 
condition that may 
cause additional 
risk from study 
medication
In 9, 
Ex 6, Ex 7, Ex 8, Ex 9, Ex 10
None
A3*
Patient has 
laboratory 
assessments that 
may cause 
additional risk.
In 8
None
A4*
Patient is unable to 
comply with the 
protocol
Ex 11 
None
A5*
Patient does not 
have trial diagnosis 
or is not part of the 
target population
In1, In 2, In 3, In 6
Ex 1, Ex 2, Ex 3, Ex 4, Ex 5, Ex
12
None
B
Informed consent
B1*
Informed consent 
not given or too 
late
In 7
None
C
Trial medication 
and 
randomisation
C1*§
Incorrect treatment 
taken
Study drugs dispensing error 
leading to change in actual 
treatment
None
C2*§
Drug not 
administered 
according to the 
protocol
Infusion schedule 
followed=”No” and medical 
review of associated comments
(e.g. no IPV if volume and 
duration of infusion are 
according to local standards)
None


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Table 6.2: 1 
Important protocol violations (cont.)
Category/Code
Description
Requirement
Excluded from
None
D
Concomitant 
medication
D1 *§
Prohibited 
medication

Any other anti-
lymphoma therapy

Systemic immune-
suppressive therapy 
other than 
corticosteroids

Concomitant anti-
neoplastic therapy

Long term (>5 days) 
daily oral steroid 
treatment at doses 
higher to 
prednisolone 20mg 
per day
None
D2 *§
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 (e.g. no IPV if 
patient receives a 
combination of 
premedication according to 
local standards)
None
* Automatic IPV
§ Manual IPV
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 MTD evaluation set (MS) 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 analysis of DLTs and MTD determination.
Rules for replacement of patients are defined in the CTP. The list of replaced patients will be 
provided by the Trial Clinical Monitor no later than at the last report planning meeting and 
will be stored in the TMF.


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Treated set (TS) includes all patients who received at least one dose of any study medication. 
The TS will be used for all planned safety and efficacy analyses besides the MTD 
determination. 
Pharmacokinetic set (PKS) includes all patients in the TS who have at least one drug plasma 
concentration available. The PKS is used for the pharmacokinetic analyses.
No PPS will be used for analysis.
 
6.5
POOLING OF CENTRES
This section is not applicable because there are no inferential statistics, and therefore no 
statistical model in which centre/country could be included.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates are imputed according to BI standards (7).
Missing data and outliers of PK data are handled according to (4).
In general, missing data not discussed in (4, 7) 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 very first 
administration of any study medication) 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 intake is partially 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 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 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 will be 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 charts of the CTP.
Unless otherwise specified, baseline is defined as the latest time-point before the very first 
administration of any study medication in the first cycle. 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 any study medication. For laboratories where not only the examination date 
but also time are recorded, examination time has to be taken into account when defining 
baseline. That is, a laboratory value on the same date as the first study drug administration is 
considered as baseline value if and only if the time of laboratory value is before or the same 
as the time of first study drug administration.
If any of these times are missing and the date of laboratory value is equal to the date of first 
study drug administration, then the laboratory assessment will be considered as according to 
protocol, i.e. as prior to first study medication.


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7.
PLANNED ANALYSIS
For End-Of-Text tables, the set of summary statistics is: N / Mean / standard deviation [StD] / 
Minimum [Min] / Median / Maximum [Max]. Efficacy data are presented by dose cohort. 
Displays of safety data will be presented by dose cohort and in total. 
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, StD, Min and Max.
For time-to-event analysis tables, the set of statistics is: number of patients [N(%)], Number 
of patients with event [N(%)] < Time to event > [months] followed by P25 (25th percentile), 
median, P75 (75th percentile), Number of patients censored [N(%)]. If not specified otherwise 
the duration as well as the time to event will be displayed in months.
If not otherwise specified, the abbreviation Pxx should be used for displaying of the xxth
percentiles.
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, conversions 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
Only 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) together with the primary reason for 
exclusion will be provided. 


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7.1.2
Important protocol violations
A summary table (or listing) with the number of patients with protocol violations by initial 
treatment will be created in Section 15 of the CTR.
 
 
 
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant diseases will be coded similarly as adverse events based on the most current 
Medical Dictionary for Regulatory Activities (MedDRA) version.
Concomitant therapies (CTh) will be coded according to world health organisation drug 
dictionary (WHO DD). They will be classified according to the Anatomical, Therapeutic, 
Chemical (ATC) classification system. The third ATC level will be used to categorise CThs 
by therapy type. In situations where a medical product may be used for more than one equally 
important indication, there are often several classification alternatives. As appropriate, 
patients receiving CThs with more than one possible ATC level-three category will be 
counted more than once; footnotes will clarify this possible double counting in tables.
Summaries will be presented for previous and concomitant medications started at baseline and 
for CThs started after the administration of first trial medication. Transfusions will be 
displayed separately. Separate summaries will be presented for concomitant medications with 
missing or incomplete start dates.
7.3
TREATMENT COMPLIANCE
Compliance will be evaluated by whether or not the medication was always administered 
according to protocol for BI 836826.
A listing will show all administrations of trial drug including the comment if administration 
was not according to protocol and also the administration of premedication 
acetaminophen/paracetamol, antihistamine and glucocorticoid will be included.
7.4
PRIMARY ENDPOINTS
The primary endpoint of part 1 is the MTD of BI 836826 in combination with GemOx,
analysed via the number of patients with DLTs during the MTD evaluation period (for 
definition of DLT see CTP Section 5.3.8, for definition of the MTD evaluation period see 
Section 6.1). In order to identify the MTD, the number of patients with DLTs at each dose 
level will be presented.


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Patients in TS who were replaced during the MTD evaluation period will be excluded from 
the determination of the MTD, i.e. the MS will be used for the analysis of the primary 
endpoints.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Other secondary endpoints
The analysis of PK parameters AUCt and Cmax of BI 836826 when administered in 
combination with GemOx will be performed according to (4).
Further standard PK parameters will be evaluated if feasible.
OR by investigator assessment will be analysed descriptively for all patients in the TS in 
terms of the OR rate. 
 
 
 
7.7
EXTENT OF EXPOSURE
Standard descriptive analyses over all treatment courses will be performed. This will include a 
summary on the variables specified in Section 5.4.2. This descriptive analysis will comprise a 
mixture of frequencies and percentages, as well as summary statistics.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS besides the analysis of the MTD, this will be 
performed on the MS.
The primary analysis of the study is for determination of MTD. No statistical model is 
foreseen allowing assessment of MTD. Descriptive analysis is confined to a listing and 
descriptive table by dose group. The purpose of these tables is to summarize and document 
the data that led to the selection of the MTD.
7.8.1
Adverse events
7.8.1.1
Maximum tolerated dose and dose limiting toxicities
A table displaying DLTs by primary system organ class (SOC) and preferred term (PT) will 
be provided by initial treatment for the MTD evaluation period for the MS. The same table 
will additionally be displayed for all treatment courses of the on-treatment period for the TS.
A summary of the number of patients with DLT within the MTD evaluation period and within
the on-treatment period will be given by initial treatment for the TS.
7.8.1.2
Adverse events
Unless otherwise specified, adverse events analysis will be performed for the on-treatment 
period. 
The analyses of AEs will be descriptive in nature and will follow the standard procedure laid 
down in (9). 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 SOCs will be sorted alphabetically. In tables displaying AEs by dose cohort 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 between the first administration of BI 836826 and 30 days after last 
administration of BI 836826 will be assigned to the on-treatment period. All adverse events 
occurring before first administration of BI 836826 will be assigned to “Screening” and all 
adverse events occurring after last administration of BI 836826 + 30 days will be assigned to 
“post-study”. The actual planned dosages of BI 836826 and GemOx 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 


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maximum CTCAE grade will be assigned to episodes and records. CTCAE grade and DLT 
information will be displayed in AE listings. MedDRA levels for condensing will be SOC and 
PT.
An overall summary of adverse events will be presented.
Reporting of CTCAE grades
CTCAE grading within AE tables is displayed as “all Grades”, “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 related serious AEs, with AEs leading to treatment discontinuation, with 
AEs leading to dose reduction, with protocol-specified AESIs, with AEs leading to death, and 
with IRRs.
7.8.1.3
Protocol-specified adverse events of special interest
Protocol-specified AESIs are defined in the CTP, Section 5.3.6.1.
Any event that qualifies for DLT
Please refer to Section 5.3.8 of the CTP and to Section 7.8.1.1 of this TSAP.
Infusion-related reactions (IRR) 
IRRs will be analysed as AEs by UDAEC as defined in Section 7.8.1.4. To help analysing 
these terms, a by-patient listing with patients with an IRR as defined by the UDAEC 
categories will be produced. Additionally, IRRs will be analysed separately using the 
associated symptoms as indicated in the eCRF.
Frequency of patients with IRRs will be tabulated by treatment and infusion number. 
Summary statistics will be provided for the “Duration of IRR [h]” and the “Time since start of 
treatment (in the respective infusion) [min]” (until IRR). 
For the All Infusions column, “Duration of IRR [h]” and “Time since start of treatment (in the 
respective inf) [min]” will be based on all reported infusions and hence patients with more 
than one infusion accompanied by an IRR will contribute more than once.
Late onset infections
Frequencies of these AESIs will be displayed.
Hepatic injury
The frequency of this AESI will be displayed in the CTR.


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7.8.1.5
Other significant AEs
Frequency tables of patients with 

AEs leading to dose reduction of BI 836826

AEs leading to dose reduction of oxaliplatin

AEs leading to overall permanent discontinuation of last study medication

AEs leading to discontinuation of BI 836826

AEs leading to discontinuation of gemcitabine

AEs leading to discontinuation of oxaliplatin
will be provided by dose cohort and total, worst CTCAE grade, primary SOC and PT for the 
on-treatment period.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will follow (8).  Patients will 
be counted under the initial treatment. The analysis of laboratory data will use the same 
‘analysing treatments’ as described for the AEs, except for that the baseline laboratory value 
(as defined in Section 6.7) will be included in the ‘on treatment’ period. Patients having at 
least one post-baseline laboratory value will be displayed in the descriptive analyses. Patients 
with missing CTCAE grade at baseline or no baseline value but with post-baseline laboratory 
values will be displayed in the category “Missing CTCAE grade at baseline”
Single time courses by initial treatment will be used to display converted laboratory values 
over time by dose cohort. The graphs may be truncated if sufficient data is not available. 
These graphs will be displayed in Chapter 16.1.9.2 for the following parameters.
Haematology: haemoglobin, WBC count, CD4 T-cell count and platelets
Differentials: neutrophils (absolute count), and absolute lymphocyte count
Enzymes: LDH
Clinically relevant abnormalities (as defined in Section 5.4.5.1) will also be summarised.
Descriptive statistics, including change from baseline, frequency of patients with transitions 
relative to the references range, will be provided. No post-study laboratory values will be 


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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 parameters. 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.
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. Additionally, laboratory values of 
special interest as described in Section 5.4.5 will be analysed. 
Neutropenia and infections:
Special attention will be paid to neutropenia episodes of CTCAE grade 3/4 for ≥ 7 days as 
well as neutropenia episodes for CTCAE grade 4 for ≥ 7 days. The number of patients with 
such episodes, number of episodes, number of episodes per patient, duration of episodes as 
well as exposure adjusted number of durations (number of episodes per patient divided by 
number of infusions per patient), mean and median duration of episodes per patient will be 
summarised. 
An episode of low blood counts of grade 4 starts with the first occurrence of a CTCAE grade 
4 and lasts until the first time the CTCAE grade falls back to <=3 (analogously for an episode 
of CTCAE grade 3/4) .
In case the episode starts during the EOT or Follow-up, the duration of this episode is defined 
to be missing. The reason for this approach is that after the EOT laboratory data is only 
captured infrequently and therefore the duration of an episode would be overestimated due to 
lack of data.
If an episode starts before EOT and the CTCAE grade of the respective parameter does not 
fall back to the respective grade that ends the episode and the patient dies, the end of the 


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episode is defined by the date of death. If the episode starts before EOT and lasts during 
Follow-up, the episode is censored with the date of DBL.
Additionally, a frequency table displaying number of patients with episode of neutropenia 
Grade 4 and concomitant AEs in the UDAEC Infections (incl. respiratory infections and 
sepsis) of any grade as well as only for Grade 3 or 4 infections will be provided. In this 
context, concomitant AE is defined as AE with onset date within the neutropenia episode 
(same for neutropenia episode Grade 3 and 4 and concomitant infection). 
Time profiles for neutrophils will be prepared on patient level as well as displaying the mean 
and 95% CI for neutrophil counts over time for each cycle separately 
Thrombocytopenia and bleeding:
Thrombocytopenia based on low platelets counts will be analysed the same way as 
neutropenia. A frequency table displaying number of patients with episode of platelets Grade 
4 and concomitant AEs in the UDAEC Bleeding of any grade as well as only for Grade 3 or 4 
bleeding will be provided. In this context, concomitant AE is defined as AE with onset date 
within the thrombocytopenia episode (same for thrombocytopenia episodes of Grade 3 and 4 
and concomitant bleeding). 
Time profiles of platelets will be prepared as for neutrophils.
Low CD4+ T-cell count and infections:
Low CD4+ T-cell counts will be analysed the same way as neutropenia. A frequency table 
displaying number of patients with episode of low CD4+ T-cell counts Grade 4 and 
concomitant AEs in the UDAEC Infection of any grade as well as only for Grade 3 or 4 
infections will be provided. In this context, concomitant AE is defined as AE with onset date 
within the CD4+ T-cell episode (same for low CD 4+ T-cell count episodes of Grade 3 and 4 
and concomitant infections).
Laboratory signs of cell destruction: 
Potential laboratory signs of cell destruction may be considered present if two or more of the 
four laboratory parameters of interest are considered abnormal simultaneously. Abnormality 
is defined in Table 5.4.5.1: 1. Simultaneously means that abnormality of these ≥2 lab 
parameters occurs within 24 hours within the 7 day window described above.
In case a patient has potential laboratory signs of cell destruction as defined above observed, 
it will be checked whether a clinical symptom in terms of an AE episode from the UDAEC 
“Tumour lysis syndrome” has been reported within the same time window as the potential 
laboratory sign of cell destruction. Since only start dates but not start times of AEs are 
captured in the eCRF, the time window for UDAEC screening will be from the day of BI 
836826 infusion until the following 6 days.
A listing will show all four laboratory values for all patients, including a flag whether the 
value is considered abnormal with regard to the definitions from Table 5.4.5.1: 1. A second 
listing will show all patients who have potential laboratory signs of cell destruction and 


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indicate whether an AE episode from the UDAEC “Tumour lysis syndrome” has been 
reported in the same time window. The number of patients with laboratory signs of cell 
destruction and clinical symptoms will be also reported in a table.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
No separate analyses are planned. Newly emergent abnormalities will be recorded and 
analysed as AEs. 
 
 
 
 
 
 


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9, Note For Guidance on Statistical Principles for Clinical Trials, current 
version.
2
Cheson BD et al. Revised response criteria for malignant lymphoma. J Clin 
Oncol 2007; 25: 579-86 (BI literature database R10-1462)
3
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister 
TA Recommendations for initial evaluation, staging, and response assessment of 
Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 
32, 2014 (BI Literature database R14-3387)
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for 
CON.
5
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  (BI Literature database R10-4848)
6
001-MCG-157_RD-02: “Standard Clinical Evaluation Criteria”, current version; 
IDEA for CON.
7
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
8
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.
9
001-MCG-156: "Handling and summarization of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
10
Choi WWL, et al 
A new immunostain algorithm classifies diffuse large B-cell lymphoma into 
molecular subtypes with high accuracy. 
Clin Cancer Res 15 (17), 5494 - 5502 (2009)
BI Literature database P14-15474


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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
03-NOV-16
None
This is the initial TSAP with necessary 
information for trial conduct
Final
30-JAN-18
1-9
This is the final TSAP