Conditions: Myelodysplastic Syndromes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
Phase I: To investigate maximum tolerated dose (MTD), safety and tolerability, pharmacokinetics, exploratory biomarker and efficacy of BI 836858 monotherapy in patients with low or intermediate-1 risk myelodysplastic syndromes (MDS) with symptomatic anemia. Phase II: To investigate safety and efficacy of BI 836858 plus Best Supportive Care compared to Best Supportive Care alone in low or intermediate-1 risk MDS patients with symptomatic anemia.

Detailed description:

Arms:
arm 1: Best Supportive Care Alone arm 2: BI 836858 plus Best Supportive Care

Interventions: intervention 1: Best Supportive Care intervention 2: BI 836858
Intervention descriptions: intervention 1: At Discretion of the Investigator (Transfusions) intervention 2: Monotherapy with BI 836858

Protocol document:
Prot_001.pdf: 
    
  
Clinical Trial Protocol
Doc. No.: c02304070-07
EudraCT No.:
BI Trial No.:
2018-002177-21
1315.7
BI Investigational
Product(s):
BI 836858
Title:
A Phase I/II, Multicenter, Open-label, Dose Escalation and Randomized 
Trial of BI 836858 in Patients with Low or Intermediate-1 Risk 
Myelodysplastic Syndromes
Clinical Phase:
Phase I/II
Trial Clinical 
Monitor:
Telephone: 
Fax:
Co-ordinating 
Investigator:
Telephone:
Fax:
Status:
Final Protocol (Revised Protocol (based on Global amendment 4))
Version and Date:
Version: 5.0
Date: 11 SEP 2019
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TITLE PAGE


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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not Applicable
Name of active ingredient:
BI 836858
Protocol date:
Trial number:
Revision date:
11 SEP 2019
06 MAR 2014
1315.7
Title of trial:
A Phase I/II, Multicenter, Open-label, Dose Escalation and Randomized Trial of BI 
836858 in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes
Co-ordinating 
Investigator:
Trial site(s):
Multicenter trial
Clinical phase:
I/II
Objective(s):
Phase I: To investigate the maximum tolerated dose (MTD), safety and tolerability, 
pharmacokinetics, exploratory biomarker and efficacy of BI 836858 monotherapy in 
patients with low or intermediate-1 risk myelodysplastic syndromes (MDS) with 
symptomatic anemia.
Phase II: To investigate safety and efficacy of BI 836858 plus Best Supportive Care 
(BSC) compared to Best Supportive Care alone in low or intermediate-1 risk MDS
patients with symptomatic anemia.
Methodology:
Phase I: open label, single arm, dose escalation, Bayesian logistic regression model
(BLRM) with overdose control
Phase II: open label, two-arm, randomized, BI 836858 plus BSC vs. BSC Alone
No. of patients: 
total entered:
Approximately 200 patients
each treatment:
Phase I dose escalation: 21 patients
Phase I expansion: 6 patients
Recruitment in this trial was discontinued prematurely during the Phase I expansion  
cohort
Phase II: Approximately 150 patients, 75 patients each arm
Diagnosis :
Patients with MDS with symptomatic anemia due to low or intermediate-1 risk (i.e., 
International Prognostic Scoring System (IPSS) score 0-1) who have experienced 
Erythropoiesis-Stimulating Agent (ESA) treatment failure or low chance of response 
to ESAs and are refractory to or are not amenable or eligible for approved MDS 
therapy.  


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Main criteria
for inclusion:
Phase I: Adult patients with low or intermediate-1 risk MDS who, experienced ESA
treatment failure, except for those who have a low chance to respond to ESA 
treatment and are refractory to or are not amenable or eligible for approved MDS 
therapy.
Phase II: Adult patients with low or intermediate-1 risk MDS
Test product(s):
BI 836858
dose:
The Phase I starting dose is 20 mg.
Phase II: Recommended Phase II Dose (RP2D), based on the MTD determined in 
Phase I
mode of admin.:
Intravenous (i.v.) infusion on Days 1 and 15 of each 28-day cycle
Comparator products:
Phase II only: BSC per Investigator’s choice
mode of admin.:
NA
Duration of treatment:
Patients with clinical benefit, PR or CR after the 4th (or 6th) Cycle will receive 
repeated cycles until relapse after Complete Response (CR), Partial Response (PR), 
erythroid response (HI-E), Red Blood Cell transfusion independency or Marrow 
Complete Response (mCR), Progressive Disease (PD), or unacceptable adverse 
event(s), in the absence of other withdrawal criteria.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not Applicable
Name of active ingredient:
BI 836858
Protocol date:
Trial number:
Revision date:
11 SEP 2019
06 MAR 2014
1315.7
Criteria for efficacy:
Primary endpoints (Phase II): 

RBC transfusion independency
Secondary endpoints (Phase I): 

RBC transfusion independency
Secondary endpoints (Phase I and II):

Hematologic improvement neutrophils (HI-N)

Hematologic improvement platelets (HI-P)

Hematologic improvement erythroid (HI-E)

Time to HI-E response

Mean hemoglobin increase ≥ 1.5 g/dL

Duration of response (RBC Transfusion Independency, HI-N,  HI-P, 
HI-E or Objective Response)

Overall Response (CR, PR and HI)
Criteria for safety:
Primary endpoints (Phase I):

Maximum Tolerated Dose (MTD)

Occurrence of Dose Limiting Toxicity (DLT) 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not Applicable
Name of active ingredient:
BI 836858
Protocol date:
Trial number:
Revision date:
11 SEP 2019
06 MAR 2014
1315.7
Statistical methods:
Phase I: Descriptive statistics will be used for toxicity, PK parameters, biomarkers
and responses. A Bayesian two-parameter logistic regression model (BLRM) with 
overdose control will be fitted to binary toxicity outcomes.  The estimate of 
parameters will be updated as data are accumulated using the BLRM. At the end of 
the Phase I trial, the toxicity probability at each dose level will be calculated to 
determine the MTD.
Phase II: Efficacy and safety evaluation of BI 836858 compared to investigator’s 
choice of BSC based on the binary endpoint response. The analysis will be 
exploratory; no confirmatory statistical tests are planned for this study.


Boehringer Ingelheim                                                                                                       
                  
      11 SEP 2019
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Doc. No.: c02304070-07                                                                        Trial Protocol
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FLOW CHART 1 – INTRODUCTION TREATMENT
Trial Periods
Screen
Introduction Study Treatment
FU
Screen
Cycles 1 - 4 
(1 Cycle = 28 days)       
EOC4 
Cycles 5 & 6**
EOT
FU (No further visits 
after EoR period upon 
implementation 
approval of CTP version
5.0)
Visit
1
Cx
V1
Cx
V2
Cx
V3
Cx 
V4
C4 
V5
Cx
V1
Cx
V2
Days (in respective cycle)* 
-21 to -1
1
8 ± 11
15
22 ±11
28 +2
1
15
Informed consent 
x
Demographics and baseline 
conditions
x
Medical history
x
Review of in-/exclusion 
criteria
x
x 2
Dose assignment (Phase I) 
x 3
Randomization (Phase II) 
x3
LABS/SAFETY ASSESSMENTS
Safety laboratory parameters 
incl. urinalysis4
x
x
x1
x
x1
x
x20
X20
x20
Physical examination
ECOG performance status
x
x5
x
x5, 20
X20
Vital signs, height6, weight
x
x
x
x
x
x
x20, 21
x20, 21
x20, 21
Serum pregnancy test 7
x
x
x
x
x
12 lead-ECG
x
x
x
X20
x8, 20
Adverse events
x
x
x
x
x
x
x
x
x
x9
Concomitant therapy
x
x
x
x
x
x
x22
x22
x22
x9, 22
DISEASE ASSESSMENTS
Number of transfusions 
received
x
x20      k


Boehringer Ingelheim                                                                                                       
                  
      11 SEP 2019
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Doc. No.: c02304070-07                                                                        Trial Protocol
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FLOW CHART 1 – INTRODUCTION TREATMENT (cont.)
Trial Periods
Screen
Introduction Study Treatment
FU
Screen
Cycles 1 - 4 
(1 Cycle = 28 days)       
EOC4 
Cycles 5 & 6**
EOT
FU No further visits 
after EoR period upon 
implementation 
approval of CTP version 
5.0)
Visit
1
Cx
V1
Cx
V2
Cx
V3
Cx 
V4
C4 
V5
Cx
V1
Cx
V2
Days (in respective cycle)* 
-21 to -1
1
8 ± 11
15
22 ±11
28 +2
1
15
Bone marrow aspiration10
x
x11
x10, 20
x8, 11, 20
Cytogenetics and molecular 
genetics of MDS12
x
x13
x13, 20
Clinical disease assessment14
x
x14, 20
TRIAL MEDICATION
Drug Administration (BI 
836858)
x 
x
x
x
Best Supportive Care (Phase 
II Arm B only)
x
Eligibility for subsequent 
cycles of study treatment
x18
x18
x18, 19
x18
x18
End of trial treatment
x20
Other therapies for MDS 
(Phase II Only)
Vital Status
x20
EOC4: 
End of Cycle 4. Patients with clinical benefit, PR or CR after the 4th Cycle and who are tolerating the study treatment may continue on and into the maintenance 
treatment cycles until PD or other withdrawal criteria are met as noted in Section 3.3.4.1.  For patients who have received 8 administrations of BI 836858, this visit will 


Boehringer Ingelheim                                                                                                       
                  
      11 SEP 2019
BI Trial No.: 1315.7
Doc. No.: c02304070-07                                                                        Trial Protocol
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be performed 14 days (±2 days) after the 8th administration of BI 836858.  For those patients who received less than 8 administrations, but still in remission, this visit is 
to be performed 4 months (±2 days) after Cycle 1 Visit 1. Phase II: For patients randomized to BSC, this visit is to be completed 4 months (±2 days) after Cycle 1 Visit 
1.
EOT:
End of Treatment.  The EOT visit is to occur 30 days (+7 days) after the last administration of BI 836858. Patients who permanently discontinue study treatment will 
complete the EOT and complete Follow-up visits.  Refer to Section 3.3.4 for treatment discontinuation criteria. After implementation of CTP version 5.0, no 
further follow-up visits after End of Residual Effect (EoR), unless follow-up is for S(AE) that occurred before EoR period.
FU: 
Follow-up starts 4 weeks after the EOT visit; Phase I patients: visits or telephone calls will occur at least every 4 weeks for 6 months.  After the 6th follow-up visit, the 
patient will be considered off trial.  Phase II patients: visits or telephone calls will occur at least every 4 weeks until 12 months after the last administration of BI 836858, 
after which these visits will occur every 6 months until the end of the trial. After implementation of CTP version 5.0, no further follow-up visits after EoR, unless 
follow-up is for S(AE) that occurred before EoR period.
*     The planned duration of a treatment cycle is 28 days; there will be two administrations of BI 836858 per cycle, on Days 1 and 15.   All assessments should be performed prior 
to dose administration on dosing days, unless otherwise specified.
**  These visits are only for those patients who have received BI 836858 that are non-PD and equivocal as to if clinical benefit has been established, per investigator judgment,
after 4 Cycles; up to 2 additional introduction cycles allowed prior to end of introduction treatment.
1
Visit window of +1 day only allowed beginning in Cycle 3 and for all subsequent cycles.  In Cycles 1 and 2 visit window not allowed d
 
2
Review of inclusion/exclusion criteria during screening and again on day of first administration. 
3
After informed consent and review of inclusion/exclusion criteria (timing described in footnote 2).  For phase II, randomization should be performed as close to the first 
treatment dose as possible. It may be performed on the day of the first administration (Cycle 1 day 1) prior to patient treatment, but no later than 21 days after patient 
signs informed consent.
4
For details refer to Section 5.2.3.1. Urine has to be measured only at screening, EOC4 and EOT.  Safety laboratory assessments may be completed up to 2 days prior to 
administration, or BSC treatment on trial (Phase II). An additional safety lab will be collected on day 2 (i.e., 24 hours after the first administration of BI 836858) and 24 
hours after the first higher dose for patients who participate in intra-patient dose escalation. Other lab tests to be included: haptoglobin, direct Coombs test, and bilirubin 
(direct and indirect).
5
Only every second cycle (i.e. before cycle 1, 3, 5) Physical examination may be completed up to 2 days prior to administration.  Eastern Cooperative Oncology Group 
(ECOG) must be completed on the day of the administration. If the first administration of BI 836858, or BSC treatment on trial (Phase II), occurs within 3 days of the 
screening visit, these examinations do not need to be repeated.
6
Height required only in screening. 
7
For women of childbearing potential only.  Serum pregnancy test completed at Screening, Visit 1 of each Cycle, EOC4 and EOT. After implementation of CTP version 
5.0, pregnancy test results will not be documented by default in the eCRF. Only positive pregnancy tests will be documented via the Pregnancy Monitoring Form (and 
reported as an AE if applicable).


Boehringer Ingelheim                                                                                                       
                  
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Doc. No.: c02304070-07                                                                        Trial Protocol
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8
ECG and bone marrow aspiration will be performed at EOT only if the patient has completed at least 2 cycles (e.g. received 4 administrations) since the EOC4 visit (or 
additional introduction cycle 5 and 6). After implementation of Protocol version 5.0, ECG and bone marrow sampling is no longer mandatory at defined visits but is 
performed at the investigator’s discretion. Bone Marrow samples should not be shipped to the biomarker lab.
9
Follow-up of AEs not recovered since the EOT.  Concomitant therapy during FU is collected only if indicated for treatment of adverse event.
10
Bone marrow aspirate to assess efficacy at EOC4 and at disease progression/relapse or EOT, whichever occurs first. (Refer to Section 5.1.2).  Bone marrow aspirate for 
biomarker analysis at time points are noted in Table 4 (Section 5.6.1). After implementation of Protocol version 5.0, bone marrow sampling for response assessment is 
no longer mandatory at defined visits (except EOC4) but is performed at the investigator’s discretion. Bone Marrow samples should not be shipped to the biomarker lab.
11
Only one sample to be collected at the time of PD or the time of initiation of other MDS therapy, which may be at the EOC4/EOT, if PD or initiation of other MDS 
therapy occurs during treatment, or during follow-up. After implementation of Protocol version 5.0, bone marrow sampling for response assessment is no longer 
mandatory at defined visits (except EOC4) but is performed at the investigator’s discretion. Bone Marrow samples should not be shipped to the biomarker lab.
12
Data from initial diagnosis can be used if available; otherwise will be collected for this study (Section 5.6.3).
13
Phase II assessments only.
14
Clinical disease assessments can be performed up to 2 days prior to this visit to evaluate if patients are experiencing clinical benefit, PR or CR after the 5th and 6th Cycles
and tolerating the study treatment well, based on investigator judgement.  These patients who meet these criteria may continue on treatment in the maintenance cycles 
until PD or other withdrawal criteria are met as noted in Section 3.3.4.1.
18
Can be performed up to 2 days prior to this visit.
19
At the EOC4, patients will be evaluated to determine if they have clinical benefit, as defined by IWG objective response (PR or CR) or subjective response (in the 
absence of objective response) and are tolerating the infusions well and who would like to continue to receive infusions until PD or other criteria for withdrawal are met 
as noted in Section 3.3.4.1.  For each infusion past the 4th cycle, patients will continue to be assessed after each cycle for clinical benefit (objective or subjective 
response), and that they are tolerating the infusions well and would like to continue until PD or other criteria for withdrawal are met as noted in Section 3.3.4.1.
20
Procedures/assessments not mandatory after implementation of CTP version 5.0, but assessments (e.g. hematology & biochemistry laboratory tests, bone marrow 
aspirates) should be performed at the investigator’s discretion, based on standard medical care. Findings are documented in the eCRF only if qualifying for and (S)AE.
21
After implementation of CTP version 5.0, vital signs are mandatory only at the day of administration of BI 836858, results will be documented in the eCRF only if 
qualifying for an adverse event.
22
After implementation of Protocol version 5.0, Collection of Concomitant Therapy information only if the indication is treatment of an Adverse Event.


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FLOW CHART 2 – MAINTENANCE
Trial Periods
Maintenance Study Treatment**
FU
Maintenance Cycles X 
(1 Cycle = 28 days)       
EOT
FU (No further  
FU visits after 
EoR period upon 
implementation 
approval of CTP 
version 5.0)
Visit
MCx12
V1
Days (in respective cycle)* 
1
LABS/SAFETY ASSESSMENTS
Safety laboratory parameters incl. 
urinalysis1
x12
x12
Physical examination
ECOG performance status
x2, 12
x12
Vital signs, weight
x12, 13
x12, 13
Serum pregnancy test 3
x
x
12 lead-ECG
x4, 12
Adverse events
x
x
x5
Concomitant therapy
x14
x14
x5, 14
DISEASE ASSESSMENTS
Number of transfusions received
x12
Bone marrow aspiration6,7
x4, 7, 12
Cytogenetics and molecular genetics of 
MDS8
Clinical Disease Assessment 9
x12
TRIAL MEDICATION
Drug Administration (BI 836858)
x
Best Supportive Care (Phase II Arm B 
only)
x
Eligibility for subsequent cycles of study 
treatment11
x
End of trial treatment
x12
Other therapies for MDS (Phase II Only)
Vital Status
x12
EOT:
End of Treatment.  The EOT visit is to occur 28 days (+7 days) after the last administration of BI 836858. 
Patients who permanently discontinue study treatment will enter into Follow-up phase after EOT visit.  Refer to
Section 3.3.4 for treatment discontinuation criteria.  After implementation of CTP version 5.0, no further follow-
up visits, unless follow-up is for S(AE) that occurred before EoR period.
FU: 
Follow-up starts 4 weeks after the EOT visit; Phase I patients: visits or telephone calls will occur at least every 4 
weeks for 6 months.  After the 6th follow-up visit, the patient will be considered off trial.  Phase II patients:  visits 
or telephone calls will occur at least every 4 weeks until 12 months after the last administration of BI 836858, 
after which these visits will occur every 6 months until the end of the trial. After implementation of CTP version 
5.0, no further follow-up visits, unless follow-up is for S(AE) that occurred before EoR period.
*   The planned duration of a treatment cycle is 28 days; there will be one administration of BI 836858 per maintenance 
cycle, on Day 1.
** These visits are only for those patients with clinical benefit, PR or CR after 4 (or 6) Cycles and who are tolerating the 
infusions well, may continue until PD or other criteria for withdrawal are met as noted in Section 3.3.4.1.  


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1
For details refer to Section 5.2.3.1. Urine has to be measured only at EOT.  Safety laboratory assessments may be 
completed up to 2 days prior to administration.
2
Only every second cycle (i.e. at Maintenance Cycle 1, 3, 5, 7 etc. Visit 1) Physical examination may be 
completed up to 2 days prior to administration.  Eastern Cooperative Oncology Group (ECOG) assessment must 
be completed on the day of the administration. 
3
For women of childbearing potential only.  Serum pregnancy test completed at Visit 1 of each Cycle. After 
implementation of CTP version 5.0, pregnancy test results will not be documented by default in the eCRF. Only 
positive pregnancy tests will be documented via the Pregnancy Monitoring Form (and reported as an AE if 
applicable).
4
ECG and bone marrow aspiration will be performed at EOT only if the patient has completed at least 2 cycles 
(e.g. received 2 administrations) since the EOC4 visit (or additional introduction cycle 5 and 6). After 
implementation of Protocol version 5.0, ECG and bone marrow sampling for response assessment is no longer 
mandatory at defined visits but is performed at the investigator’s discretion. Bone Marrow samples should not be 
shipped to the biomarker lab.
5
Follow-up of AEs not recovered since the EOT.  Follow-up of new AEs that occurred during REP. Concomitant 
therapy during FU is collected only if indicated for treatment of adverse event.
6
Bone marrow aspirate to assess efficacy at disease progression/relapse or EOT, whichever occurs first. (Refer to 
Section 5.1.2). After implementation of Protocol version 5.0, bone marrow sampling for response assessment is 
no longer mandatory at defined visits but is performed at the investigator’s discretion. Bone Marrow samples 
should not be shipped to the biomarker lab.
7
Only one sample to be collected at the time of PD or the time of initiation of other MDS therapy, which may beat 
the EOT, if PD or initiation of other MDS therapy occurs during treatment, or during follow-up. After 
implementation of Protocol version 5.0, bone marrow sampling for response assessment is no longer mandatory 
at defined visits but is performed at the investigator’s discretion.
8
Phase II assessment only.
9
Clinical disease assessments can be performed up to 2 days prior to this Maintenance Cycle 1 Visit 1 to evaluate 
if patients experienced clinical benefit, PR or CR after the 6th Cycle and are tolerating the study treatment well, 
based on investigator judgement.  These patients who meet these criteria may continue on treatment in the 
maintenance cycles until PD or other withdrawal criteria are met as noted in Section 3.3.4.1.
11
Can be performed up to 2 days prior to this visit.
12
Procedures/assessments not mandatory after implementation of CTP version 5.0, but assessments (e.g. 
hematology & biochemistry laboratory tests, bone marrow aspirates) should be performed at the investigator’s 
discretion, based on standard medical care. Findings are documented in the eCRF only if qualifying for and 
(S)AE.
13
After implementation of CTP version 5.0, vital signs are mandatory only at the day of administration of BI 
836858, results will be documented in the eCRF only if qualifying for an adverse event.
14
After implementation of Protocol version 5.0, collection of Concomitant Therapy information only if the 
indication is treatment of an Adverse Event.


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TABLE OF CONTENTS
TITLE PAGE .................................................................................................... 1
CLINICAL TRIAL PROTOCOL SYNOPSIS .............................................. 2
FLOW CHART 1 – INTRODUCTION TREATMENT............................... 6
FLOW CHART 2 – MAINTENANCE ......................................................... 10
TABLE OF CONTENTS ............................................................................... 15
ABBREVIATIONS......................................................................................... 20
1.
INTRODUCTION................................................................................... 23
1.1
MEDICAL BACKGROUND..........................................................................23
1.2
DRUG PROFILE.............................................................................................24
1.2.1
BI 836858 .............................................................................................24
1.2.2
Best Supportive Care (BSC) ..............................................................26
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ........................................................................................ 27
2.1
RATIONALE FOR PERFORMING THE TRIAL......................................27
2.2
TRIAL OBJECTIVES.....................................................................................28
2.3
BENEFIT – RISK ASSESSMENT.................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION............. 30
3.1
OVERALL TRIAL DESIGN AND PLAN ....................................................30
3.1.1
Administrative structure of the trial.................................................33
3.1.1.1
Phase I....................................................................................33
3.1.1.2
Phase II...................................................................................34
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)...................................................................................34
3.3
SELECTION OF TRIAL POPULATION ....................................................35
3.3.1
Main diagnosis for study entry..........................................................35
3.3.2
Inclusion criteria.................................................................................35
3.3.3
Exclusion criteria ................................................................................36
3.3.4
Removal of patients from therapy or assessments...........................38
3.3.4.1
Removal of individual patients..............................................38
3.3.4.2
Discontinuation of the trial by the sponsor............................39
4.
TREATMENTS....................................................................................... 40
4.1
TREATMENTS TO BE ADMINISTERED..................................................40
4.1.1
Identity of BI investigational product and comparator product(s)40
4.1.2
Method of assigning patients to treatment groups ..........................41


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4.1.3
Selection of doses in the trial..............................................................41
4.1.4
Drug assignment and administration of doses for each patient .....43
4.1.5
Blinding and procedures for unblinding ..........................................44
4.1.5.1
Blinding..................................................................................44
4.1.5.2
Procedures for emergency unblinding ...................................44
4.1.6
Packaging, labelling, and re-supply ..................................................44
4.1.7
Storage conditions...............................................................................45
4.1.8
Drug accountability ............................................................................45
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT..................................................................................................46
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) .........................................................................................46
4.2.2
Restrictions..........................................................................................46
4.2.2.1
Restrictions regarding concomitant treatment .......................46
4.2.2.2
Restrictions on diet and life style...........................................47
4.3
TREATMENT COMPLIANCE.....................................................................47
5.
VARIABLES AND THEIR ASSESSMENT ........................................ 48
5.1
EFFICACY – PHARMACODYNAMICS.....................................................48
5.1.1
Endpoints of efficacy...........................................................................48
5.1.2
Assessment of efficacy.........................................................................49
5.1.2.1
Bone marrow aspirate and peripheral blood ..........................49
5.1.2.3
Assessment and definition of response criteria......................49
5.2
SAFETY............................................................................................................53
5.2.1
Endpoint(s) of safety...........................................................................53
5.2.1.1
Dose limiting toxicity (DLT).................................................53
5.2.1.2
Maximum Tolerated Dose (MTD).........................................54
5.2.1.3
Recommended Phase 2 Dose (RP2D)....................................54
5.2.2
Assessment of adverse events.............................................................55
5.2.2.1
Definitions of adverse events.................................................55
5.2.2.2
Adverse event and serious adverse event reporting...............56
5.2.3
Assessment of safety laboratory parameters....................................59
5.2.3.1
General safety laboratory parameters ....................................59
5.2.3.2
Cytogenetics and molecular genetics.....................................60
5.2.4
Electrocardiogram..............................................................................60
5.2.5
Assessment of other safety parameters.............................................60
5.2.5.1
Vital signs ..............................................................................60
5.2.5.2
Physical examination .............................................................60


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5.4
APPROPRIATENESS OF MEASUREMENTS...........................................61
6.
INVESTIGATIONAL PLAN................................................................. 67
6.1
VISIT SCHEDULE..........................................................................................67
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ..............67
6.2.1
Screening and run-in period(s)..........................................................67
6.2.1.1
Re-screening ..........................................................................68
6.2.2
Treatment period(s)............................................................................68
6.2.2.1
Visit 1 and Visit 3 – day of BI 836858 administration..........68
6.2.2.2
Visit 2 and Visit 4  ( + 1 day window allowed beginning in 
Cycle 3)..................................................................................69
6.2.2.3
End of Cycle 4 (EOC4)..........................................................70
6.2.2.4
Cycles 5 and 6 (additional Introduction Treatment Cycles 
Visits 1 and 2)........................................................................70
6.2.2.5
Maintenance Cycles (Visit 1).................................................71
6.2.3
End of treatment and follow-up period ............................................72
6.2.3.1
End of treatment (EOT) .........................................................72
6.2.3.2
Follow-up...............................................................................72
6.2.3.3
End of the whole trial.............................................................73
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE.......................................................................................................... 74
7.1
STATISTICAL DESIGN - MODEL..............................................................74
7.2
NULL AND ALTERNATIVE HYPOTHESES ............................................78


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7.3
PLANNED ANALYSES..................................................................................78
7.3.1
Primary analyses.................................................................................78
7.3.1.1
Assessment of the MTD in phase I........................................78
7.3.1.2
Assessment of the primary endpoint in Phase II....................78
7.3.1.3
Statistical group comparison..................................................79
7.3.2
Secondary analyses .............................................................................79
7.3.3
Safety analyses.....................................................................................79
7.3.4
Interim analyses ..................................................................................80
7.3.4.1
Phase I....................................................................................80
7.3.4.2
Phase II...................................................................................80
7.4
HANDLING OF MISSING DATA ................................................................81
7.5
RANDOMIZATION........................................................................................82
7.6
DETERMINATION OF SAMPLE SIZE ......................................................82
7.6.1 Determination of the maximum tolerated dose................................82
7.6.2 Calculation of phase II sample size ...................................................82
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ............................................................................................... 84
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ........................................................................................................84
8.2
DATA QUALITY ASSURANCE ...................................................................85
8.3
RECORDS........................................................................................................85
8.3.1
Source documents ...............................................................................85
8.3.2
Direct access to source data and documents.....................................85
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS............................................................................................................85
8.4.1
Listedness.............................................................................................85
8.4.2
Expedited reporting to health authorities and IECs/IRBs..............85
8.5
STATEMENT OF CONFIDENTIALITY.....................................................86
8.6
COMPLETION OF TRIAL............................................................................86
9.
REFERENCES........................................................................................ 87
9.1
PUBLISHED REFERENCES.........................................................................87
9.2
UNPUBLISHED REFERENCES...................................................................90
10. APPENDICES ......................................................................................... 91
10.1
CLINICAL EVALUATION OF LIVER INJURY .......................................91


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10.1.1 Introduction.........................................................................................91
10.1.2 Procedures ...........................................................................................91
10.2
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ..........................................................................92
10.3
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS.............................................................................92
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................. 97
11.1 GLOBAL AMENDMENT 1 ...........................................................................97
11.2
GLOBAL AMENDMENT 2 ........................................................................120
11.3
GLOBAL AMENDMENT 3 ........................................................................131
11.4
GLOBAL AMENDMENT 4 .........................................................................143


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ABBREVIATIONS
5-aza
ADCC
AE
5-azacitidine
Antibody Dependent Cellular Cytotoxicity
Adverse Event
AESI
ALT
AML
ANC
AP
aPTT
AST
ATG
BI
BLRM
Adverse Event of Special Interest
Alanine Amino Transferase
Acute Myelogenous Leukemia
Absolute Neutrophil Count
Alkaline Phosphotase
Activated Partial Thromboplastin Time
Aspartate Amino Transferase
Anti-Thymocyte Globulin 
Boehringer Ingelheim
Bayesian two-parameter logistic regression model
BM
BSC
BUN
CA
CBC
CI
Bone Marrow
Best Supportive Care
Blood Urea Nitrogen
Competent Authority
Complete Blood Count
Confidence Interval/Coordinating Investigator
CML
Local Clinical Monitor 
CPPL
CR
CRA
Clinical Pharmacological Project Lead
Complete Response
Clinical Research Associate
CRF
Case Report Form
CRO
CTCAE
Contract Research Organization
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
DLT
Drug Induced Liver Injury
Dose Limiting Toxicity


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DMC
Data Monitoring Committee
DNA
DSB
EC
ECG
ECOG
eCRF
Deoxyribonucleic Acid
Data Safety Board
Ethics Committee
Electrocardiogram
Eastern Cooperative Oncology Group
Electronic Case Report Form
EMA
EOT
EPO
ESA
EudraCT
EWOC
European Medicines Agency
End of Treatment
Erythropoietin
Erythropoiesis-Stimulating Agents
European Clinical Trials Database
Escalation-with-overdose-control
FDA
FIH
FU
GCP
Food and Drug Administration
First In Human
Follow-up
Good Clinical Practice
G-CSF
HI
HI-E
HI-N
HI-P
HIV
HMA
HPC
granulocyte colony stimulating factor 
Hematologic Improvement
Hematologic Improvement -Achieve erythroid response
Hematologic Improvement - neutrophils
Hematologic Improvement - platelets
Human Immunodeficiency Virus
Hypomethylating Agents
Hematopoietic Progenitor Cells
IB
ICF
Investigator’s Brochure
Informed Consent Form
ICH
IEC
International Conference on Harmonization
Independent Ethics Committee
INN
INR
IPSS
IRB
International Nonpropriety Names
International Normalized Ratio
International Prognostic Scoring System
Institutional Review Board
ISF
IRT
Investigator Site File
Interactive Response Technologies
i.v.
IVRS/IWRS
IWG
LDH
mAb
Intravenous
Interactive Voice/Web Response System
International Working Group
Lactate Dehydrogenase
Monoclonal Antibody
mCR
MDSC
Marrow Complete Response
Myeloid derived suppressor cells
MDS
Myelodysplastic Syndromes


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MTD
NA
NC
NCI
NK
Maximum tolerated dose
Not Applicable
Not calculated
National Cancer Institute
Natural Killer
OPU
OR
PD
pd
PGx
PK
PLT
PR
PT
RBC
RDC
REP
Operative Unit
Objective Response
Progressive Disease
Pharmacodynamics
Pharmacogenomics
Pharmacokinetics
Platelet
Partial Response
Prothrombin Time
Red Blood Cell
Remote Data Capture
Residual Effect Period
RNA
RP2D
SAE
Ribonucleic Acid
Recommended Phase II Dose
Serious Adverse Event
SCT
SD
SOC
SOP
SUSAR
Stem Cell Transplantation
Stable Disease
Standard of Care
Standard Operating Procedure
Suspected Unexpected Serious Adverse Reactions
TCM
TD
Trial Clinical Monitor
Transfusion Dependent
TI
Transfusion Independence
TME
TMM
TPO
TransMed Expert
Team Member Medicine
Thrombopoietin
TSAP
ULN
WBC
Trial Statistical Analysis Plan
Upper Limit of Normal
White Blood Cell
WHO
World Health Organization


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders 
characterized by peripheral blood cytopenias and increased risk of transformation to acute 
myelogenous leukemia (AML) (R13-0382). 
MDS is primarily a disease of older adults with a median age at diagnosis of approximately 
70 years. MDS occurs in three to four individuals per 100,000 in the US population (R13-
0364). Prevalence increases with age, e.g. in individuals aged 60 and above, prevalence is 7 
to 35 per 100,000 (R13-0364). Due to advanced age, the MDS patient population is 
frequently affected by other co-morbidities, which often influence treatment decisions. 
Incidence of MDS is more frequent in males than females (R13-0364). Exposure to prior 
chemotherapy or radiation therapy is a risk for the development of MDS.
MDS is usually suspected by the presence of cytopenia on a routine analysis of peripheral 
blood. This prompts evaluation of bone marrow cell morphology (aspirate) and cellularity 
(biopsy). A manual count of bone marrow blasts is essential for risk assessment. 
Cytogenetic analysis will facilitate the identification of predictive risk and selection of
therapy. Once this information is collected, the risk of the patient may be evaluated based on 
the scoring system. The International Prognostic Scoring System (IPSS) (R13-0374) was 
introduced in 1997 and is still the most commonly used score.  In 2012, a revised IPSS score 
(IPSS-R) was introduced (R13-0375).  
A number of morphological classifications are in place to classify patients with MDS, the 
most recent one being the 2008 World Health Organization (WHO) by which MDS  are 
further categorized by their refractory cytopenias, karyotypic features, blast percentages, and 
number of dysplastic myeloid lineages. 
In MDS, cytogenetics is of major importance for prognosis. Clonal cytogenetic 
abnormalities can be identified in approximately 50% of cases. Patients with normal marrow 
karyotypes, del(5q) alone, del(20q) alone, and –Y alone have a relatively good prognosis 
whereas patients with complex abnormalities (three or more chromosome anomalies) or 
chromosome 7 anomalies have relatively poor prognoses. In addition, various gene 
mutations have been identified among patients with MDS that influence their prognosis. 
Such mutations may be present in a substantial proportion of newly diagnosed patients, 
including patients with normal cytogenetics. The most frequently occurring molecular 
genetic lesions are mutations in the TET2, ASXL1, RUNX1, TP53, EZH2, NRAS, KRAS, 
JAK2, ETV6, CBL, SF3B1, SRSF2, ZRSR2, U2AF35, FLT3, DNMT3A, IDH1 and IDH2
genes. Among these, TP53, RUNX1, EZH2, ETV6, and ASXL1 have been found to be 
independent predictors of decreased overall survival whereas mutations of TET2 appear to 
confer a more favorable prognosis compared to cases without TET2 mutations. This is an 
area of active research and during the course of the development of BI 836858 in MDS it is 
possible that a more detailed understanding of the role of these genetic lesions in disease 
outcome and drug response will become available. 


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Treatment of MDS is based on prognostic factors that predict survival and progression to 
AML. Currently, the treatment of patients with MDS is guided by the IPSS (R13-0374). 
This score divides patients into a lower risk subset (low and intermediate-1) and a higher 
risk subset (intermediate-2 and high), based on the number of cytopenias, percentage of 
bone marrow blasts, and karyotype. The survival of patients with higher-risk MDS is 
relevantly different than that of patients with lower-risk disease. Without intervention, 
median survival of higher-risk patients is close to 12 months (R13-0374). Survival of 
patients with lower-risk disease is more diverse and ranges from a few months (lower-risk 
disease with a poor-prognosis) to more than a decade (R13-0374, R13-0373). Therefore, the 
objectives of therapy are different in lower-risk versus higher-risk disease. While on 
higher-risk MDS, disease-modifying therapies are aiming at reduction of patients who 
progress to AML and by improving survival, the therapeutic goals in lower-risk MDS are
symptom relief, management of cytopenia, and minimizing the number of transfusions 
(R13-0377). Chronic anemia remains the most frequent clinical problem in lower-risk 
MDS, which alters quality of life in those elderly patients. Erythropoiesis-stimulating
agents (ESA) generally constitute the first-line treatment for anemia except, in patients with 
5q deletion, where lenalidomide brings superior outcomes. Major favorable prognostic 
factors for response to ESAs are low or no red blood cell (RBC) transfusion requirement (<2 
units per month) and baseline serum Erythropoietin (EPO) level <500 U/L. The addition of 
a myeloid growth factor such as granulocyte colony-stimulating factor (G-CSF) may raise 
the erythroid response rate. Second line treatments of anemia (including hypomethylating 
agents (HMA), lenalidomide in the absence of 5q deletion, and anti-thymocyte globulin 
(ATG)) are less satisfactory, yielding at best one-third of responses, so that many patients 
eventually require repeated RBC transfusions, a situation in which indications for iron 
overload prophylaxis are still somewhat disputed. In a minority of lower-risk MDS, 
thrombocytopenia is the predominating cytopenia, and Thrombopoietin (TPO) agonist 
receptors are currently being tested in this situation, whereas HMAs or ATG may be useful. 
Some patients with lower-risk MDS according to IPSS may, at diagnosis or during 
evolution, have features associated with poorer prognosis, based on new prognostic scoring 
systems (e.g., IPSS-R, M.D. Anderson score), presence of gene somatic mutations, or 
resistance to first-line treatment, that may qualify them for more intensive treatment, 
including in some cases allogeneic stem cell transplant (SCT).
The therapeutic goal in lower risk MDS is to alleviate the cytopenias, most importantly 
anemia. Therefore, red blood cell transfusions remain an important component of treatment, 
but exposes patients to insufficient correction of anemia, allo-immunization, and organ iron 
overload.
1.2
DRUG PROFILE
1.2.1
BI 836858
BI 836858 is a fully human IgG1 antibody specific for CD33.  
 


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CD33 is a myeloid differentiation antigen which is expressed on the cell surface of non-
malignant leukocytes of the myeloid lineage and with high frequency on malignant cells in 
AML, chronic myeloid leukemia and myelodysplastic syndrome (R11-1467, R11-1468, 
R11-1470, R11-2960). In addition to expression on malignant myeloid blast cells, CD33 
expression was reported for leukemic stem cells (R11-1469) and hematopoietic suppressive 
cells called immature myeloid-derived suppressor cells (MDSC) (R13-4724).  For normal 
leukocytes, CD33 expression was reported for monocytes, macrophages, dendritic cells, and 
to a lower extent, granulocytes (R11-1467), but not for CD34+CD38- hematopoietic stem 
cells in the bone marrow (R11-1469). 
 
The ADCC activity of BI 836858 was assessed on a panel of AML-derived cell lines and 
primary AML cells and compared to the ADCC activity of lintuzumab, a humanized CD33-
specific antibody which has been in clinical development for AML (R11-1471).  
 
Pre-clinical studies with BI 836858 were performed to assess BI 836858 for the MDS 
indication (P17-02032). 
 


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1.2.2
Best Supportive Care (BSC)
Best supportive care for MDS includes red blood cell transfusion, platelet transfusion and 
iron chelation therapy. Initiation of transfusion therapy should be based on clinical 
evaluation of anemia-related symptoms and co-morbid illness rather than on a defined 
hemoglobin level, especially because optimal hemoglobin levels are difficult to define for 
the elderly population. In clinical practice, pre-transfusion hemoglobin levels in MDS are 
generally maintained between 8 and 10 g/dL.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
MDSCs have recently been recognized as a subset of innate immune cells that can alter 
adaptive immunity and produce immunosuppression (R13-4724).  Human MDSC comprise 
a heterogeneous population of immature myeloid (CD33+) cells consisting of dendritic cell, 
macrophage, and granulocyte progenitors that lack lineage maturation markers. It is 
published that MDSCs, classically linked to immunosuppression, inflammation and cancer, 
are markedly expanded in the bone marrow of MDS patients and play a pathogenetic role in 
the development of ineffective hematopoiesis. Characterized by a LIN-HLA-DR-CD33+
phenotype, these clonally distinct MDSC overproduce hematopoietic suppressive cytokines, 
and function as potent apoptotic effectors targeting autologous hematopoietic progenitors.
Preclinical experiments have yielded evidence that depletion of MDSC with BI 836858 in 
bone marrow from MDS patients ex vivo can effectively improve hematopoiesis. Based on 
these results, it is hypothesized that BI 836858 may improve hematopoiesis in MDS patients 
by reduction of CD33-positive MDSC in the bone marrow and, in consequence, support the 
assumption that treatment with BI 836858 can lead to independency of red blood cell 
transfusion in patients with lower risk MDS (P17-02032).
It has been described that previous treatments with HMAs or lenalidomide reduce the 
number and activity of NK cells. [R17-1502, R17-1503, R17-1510].  BI 836858 mediated 
ADCC depends on functional NK cells. Therefore, it is hypothesized that Lower-Risk MDS 
patients it without previous HMA or lenalidomide treatments may respond better to BI 
836858, providing the rationale for an MTD expansion cohort targeting this group of 
patients.
Low to intermediate-1 risk MDS patients comprise around 70% of the entire MDS 
populations. In clinical practice, lower-risk patients are those with expected median survival 
measured in years, and those who have a lower chance to progress to AML. The main 
clinical burden in this group of patients is symptomatic cytopenias and their associated 
complications, such as bleeding, risk of infection and iron overload. The goal of treatment is 
to alleviate symptomatic cytopenias and abrogate or reduce RBC transfusion requirements
leading to better quality of life.
This rationale is supported by FDA and EMA approval of lenalidomide in MDS patients 
with a del 5q.
Overall treatment options for patients with lower risk MDS, especially for those without a 
5q deletion, are limited and benefit to available treatment is not satisfactory. Rates of RBC 
TI for at least 8 weeks for patients with Low to Intermediate-1 risk MDS with treatment of 
HMAs or lenalidomide are 15 to 30% without improvement in overall survival.
Furthermore the outcomes for those patients who failed treatment with HMAs or 
lenalidomide are poor with an estimated 3 year overall survival rate of 27% [R11-1106, 
R17-1501, R17-1504, R17-1505, R17-1506, R17-1507, R17-1508, R17-1509, R17-1521 ]. 
  


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2.2
TRIAL OBJECTIVES
The trial will be performed in two parts: Phase I and Phase II.
The Phase I primary objectives of the trial are to determine the maximum tolerated dose 
(MTD) and the Recommended Phase II Dose (RP2D) to be used in the Phase II. Secondary 
objectives include safety, pharmacokinetics, exploratory biomarkers and efficacy of BI 
836858 monotherapy. The trial will enroll patients with low or intermediate-1 risk MDS 
with symptomatic anemia, who at a minimum, experienced ESA treatment failure or do not 
qualify (serum erythropoietin level > 500 U) for ESA treatment and are refractory to or are 
not amenable or eligible for approved MDS therapy in the dose escalation phase and for one 
of the MTD expansion cohorts.  The second MTD expansion cohort will enroll patients with 
low or intermediate-1 risk MDS with symptomatic anemia, who experienced ESA treatment 
failure or do not qualify (serum erythropoietin level > 500 U) for ESA treatment and who 
have not received prior HMA and/or lenalidomide (this cohort is referred to as “untreated”). 
Patients with a deletion 5q cytogenetic abnormality will be allowed in Phase I who do not 
qualify for lenalidomide treatment (Absolute Neutrophil Count (ANC) < 500/µL or platelets 
<50,000/µl) or who experience primary lenalidomide failure (not for untreated expansion 
cohort).  Lenalidomide failure is defined as lack of hematological improvement after 4 
months of therapy, or secondary failure defined as loss of prior lenalidomide response at any 
time point.
In the randomized Phase II, primary objectives are to investigate the efficacy of BI 836858
plus Best Supportive Care (BSC) vs. Best Supportive Care alone, in low or intermediate-1 
risk MDS patients with symptomatic anemia who progressed/became resistant following
ESA, and are refractory to or are not amenable or eligible for approved MDS therapy.
Secondary objectives include the investigation of safety and tolerability of BI 836858 in this 
patient population.
2.3
BENEFIT – RISK ASSESSMENT
MDS are a heterogeneous group of clonal neoplasms with a patient median age at diagnosis 
of
>70 years.  ESA remain the first-line treatment of anemia in most lower-risk MDS patients 
without del 5q. Responses to ESA treatment is transient, but interestingly, approximately 
70% of the relapses of anemia after initial response to EPO are not associated with 
progression to higher-risk MDS but simply to loss of sensitivity of erythroid progenitors to 
EPO. Despite considerable progress in understanding the etiology and biologic behavior of 
lower risk MDS, BSC is still the standard of care for patients progressing after treatment 
with EPO or Hypomethylating Agents (HMA) in countries where it is available.
BI 836858 is a monoclonal antibody, which specifically targets CD33. Targeting CD33 in 
patients with MDS may potentially offer a benefit; since CD33 is expressed on MDSCs 
suppressing the bone marrow function (see Section 1.2). In addition, BI 836858 is a potent 
inducer of ADCC, which results in reduction of MDSCs in MDS-derived bone marrow 
samples.


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CD33 is not known to be expressed outside of the hematopoietic system. The anticipated 
side effect profile of BI 836858 based on the CD33 expression profile comprises 
predominantly hematologic adverse events such as neutropenia. These hematological 
adverse events are frequently reported in patients with hematological diseases and may be 
due to the underlying disease, the treatment or both. The preclinical safety assessments for 
BI 836858 have revealed TNF-alpha and IFN-gamma release, suggesting a potential for 
infusion reactions.
Considering these data and the experience with other monoclonal antibodies in hemato-
oncology indications, infusion-related reactions are likely. Prophylactic measures will be 
stipulated for primary prevention, and supportive treatments are available (Section 4.1.4).  
Although rare, a potential for drug-induced liver injury is under constant surveillance by
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´
safety.  A Phase I safety analysis report will be prepared based on the Phase I data and made 
available to regulatory authorities, ethics committees/IRBs and all investigators, and the 
protocol will be amended prior to initiating Phase II as defined in detail in Section 3.1.1.1.   
In addition, this study will utilize a Data Safety Board to oversee safety, review dose 
limiting toxicities and determine dose escalations.
Patients with lower risk MDS with limited or no standard treatment options may benefit 
from reduction of MDSCs suppressing the bone marrow function.
The benefits of 
participation in this trial and receiving BI 836858 may include response of the disease to 
the study treatment, better disease control, and improvement of MDS-related symptoms, 
resulting in better quality of life. Safety will be ensured by monitoring the patients for AEs 
both clinically and by laboratory testing. The potential benefit of therapy with BI 836858 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
The trial will be performed according to an open-label design. The data obtained from the 
trial will determine the MTD and RP2D based on a Bayesian logistic regression model with 
overdose control.  Furthermore, this trial will allow an exploratory efficacy analysis of BI 
836858 compared to BSC. The results of the trial will aid in the decision-making on the 
further development program of BI 836858 in MDS.
The overall structure of the study is described in Figure 3.1: 1.
Figure 3.1: 1
Structure of the 1315.7 Phase I/II
Phase I:
In Phase I dose escalation part, patients with low to intermediate-1 risk MDS, who have
experienced ESA treatment failure, except for patients who do not qualify for ESA 
treatment and are refractory to or are not amenable or eligible for approved MDS therapy
will be assigned to a dose cohort under investigation. After determination of the 
MTD/RP2D the same group of patients as for the dose escalation will be enrolled in the first 
expansion cohort (referred to as “pre-treated” patients). The second expansion cohort will 
enroll patients with low or intermediate-1 risk MDS with symptomatic anemia, who 
experienced ESA treatment failure or do not qualify (serum erythropoietin level > 500 U)
for ESA treatment and who have not received prior HMA and/or lenalidomide (referred to 
as “untreated” patients). Treatment failure on ESAs is defined as 1) failure or ceasing to 


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show hematologic response after at least 8 weeks of 40,000 to 60,000 IU/week of 
erythropoietin (EPO) or equivalent or 2) low chance/response to ESA with endogenous 
serum EPO>500.  It is expected that approximately 50 patients will be enrolled. 
The Phase I dose-escalation will be guided by a Bayesian logistic regression model with 
overdose control (refer to Section 7). At any time in the trial, it will not be permitted to 
escalate to a dose which does not fulfil the escalation with overdose control (EWOC)
criterion (refer to Section 7). Dose-escalation will be restricted to a maximum of 100% from 
the previous dose. 
For any dose-escalation cohort, at least 3 patients will be required (refer to Section 7). 
However, in the case that only 2 patients are evaluable and neither has experienced a dose-
limiting toxicity within the first cycle (2 administrations – 28 days), then dose-escalation 
can occur based on these 2 patients. After all patients in a cohort have either experienced a 
DLT or have been observed for at least one cycle (2 administrations – 28 days) without 
experiencing a DLT, the Bayesian model will be updated with the newly accumulated data. 
The overdose risk will then be calculated for each dose, and escalation will be permitted to 
all doses which fulfil the EWOC criterion and the additional 100% escalation rule. 
If DLTs are observed in the first two consecutive patients of a previously untested dose 
level, subsequent enrollment to that cohort will be stopped. The Bayesian logistic regression 
model will be re-run to confirm that the dose-level still fulfils the EWOC criterion. Based on 
this information, the Data Safety Board (DSB) will evaluate whether the next patients will 
be enrolled on the same dose level, or if they will be enrolled to a lower dose level.
The DSB may recommend stopping the dose finding phase after the criterion for MTD
(Section 5.2.1.2) is fulfilled. Further patients may be included to confirm the MTD.
If no DLT is observed at a dose of which the efficacy is considered sufficient, the DSB may 
decide to include an additional number of patients at the same dose level and to declare this 
dose as the RP2D.  Before the conclusion of Phase I and prior to initiating the Phase II, two 
expansion cohorts (untreated and pre-treated with HMA and/or lenalidomide) will recruit up 
to 12 patients per cohort.   Overall a minimum of 12 patients (including both expansion 
cohorts and the last escalation cohort) will receive treatment at RP2D. Patients who show 
clinical benefit, complete response (CR) or partial response (PR) after 4 cycles and who are 
tolerating the infusions well may continue to receive additional cycles upon agreement with 
Investigator and Sponsor until the patient meets any of the criteria for withdrawal as 
outlined in Section 3.3.4.1.
Recruitment in this trial was discontinued prematurely during the Phase I expansion cohort.
Phase II:
In Phase II, patients will be enrolled in a randomized manner to investigate efficacy and 
safety of BI 836858 at RP2D in patients who have experienced treatment failure on ESAs, 
except for patients who do not qualify for ESA treatment. As defined above, treatment 
failure on ESAs is defined as 1) failure or ceasing to show hematologic response after at 
least 8 weeks of 40,000 to 60,000 IU/week of erythropoietin (EPO) or equivalent or 2) low 
chance/response to ESA with endogenous serum EPO>500.  For further details regarding 


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inclusion of patients in phase II please see inclusion criteria (section 3.3.2). Randomization 
will be stratified by number of previous lines of MDS therapy (0, 1, >=2), where previous 
MDS therapy also includes previous ESA therapy (refer to Section 7.5).  A total of 150 
patients, 75 each arm, will be enrolled in Phase II.
In case there is no evidence of disease progression to high risk MDS or AML after 4 months 
of treatment (at EOC4), patients randomized to Arm B may cross-in and receive BI 836858 
study drug at the discretion of the investigator, providing these patients fulfill all 
inclusion/exclusion criteria. Alternatively, these patients may continue on in the trial 
receiving BSC until PD or criteria for withdrawal are met (refer Section 3.3.4.1).
Patients who show clinical benefit, complete response (CR) or partial response (PR) after 4 
cycles and who are tolerating the infusions well may continue to receive additional cycles 
any of the criteria for withdrawal as outlined in Section 3.3.4.1.
The overall treatment structure of the study is described in Figure 3.1: 2.
Figure 3.1: 2 Treatment Structure of the 1315.7 Phase I/II study


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3.1.1
Administrative structure of the trial
Boehringer Ingelheim is the Sponsor of this trial. The Coordinating Investigator (CI) will be
and participating Investigators will be 
physicians experienced and specialized in the treatment of MDS and in the conduct of Phase 
I and Phase II trials.
3.1.1.1
Phase I
Adult patients with low to intermediate-1 risk MDS, according to International Working 
Group (IWG) criteria, who experienced ESA treatment failure, except for patients that do 
not qualify for ESA treatment and are refractory to or are not amenable or eligible for 
approved MDS therapy, will be enrolled for the Phase I dose escalation part. After 
determination of the MTD/RP2D, the same group of patients as for the dose escalation will 
be enrolled in the first expansion cohort (referred to as “pre-treated” patients). The second 
expansion cohort will enroll patients with low or intermediate-1 risk MDS with 
symptomatic anemia, who experienced ESA treatment failure or do not qualify (serum
erythropoietin level > 500 U) for ESA treatment and who have not received prior HMA 
and/or lenalidomide (referred to as “untreated” patients). Approximately three Phase I sites 
in the United States will participate in the dose escalation portion of Phase I. An additional 
2-3 sites in the United States and/or European country(ies) are expected to participate during 
the cohort expansion portion of Phase I.
The Phase I dose-escalation will be guided by a Bayesian logistic regression model (BLRM)
with overdose control (refer to Section 7).  The DSB will consist of the Phase I 
investigators, Team Member Medicine (TMM), Trial Clinical Monitor (TCM), Project 
Statistician, Clinical Pharmacological Project Lead (CPPL) and TransMed Expert (TME).  
The information on the overdose risk will be presented by the trial statistician to the DSB. 
Additional information, such as lower grade adverse events, pharmacokinetics (PK), if 
available, progressive disease (PD), individual patient profiles and other relevant 
information will also be presented. Based on this information, the members of the DSB will 
reach a joint decision on the next dose level to be investigated. This dose level may be 
above, below or identical to the currently investigated dose level. The DSB will also 
recommend the size for the next cohort. However, the final decision on the next cohort size 
will be made by a mutual decision between the TMM and the Coordinating Investigator
(CI).  Minutes of the DSB meetings and recommendations will be documented and archived 
by the TCM.  Two expansion cohorts (untreated or pre-treated with HMA and/or 
lenalidomide) will recruit up to 12 patients per cohort and receive treatment at the RP2D 
prior to start of Phase II.
Prior to the initiation of Phase II, a Phase I safety analysis report will be prepared and the 
protocol will be amended based on Phase I results to update the benefit-risk assessment, 
stipulate the BI 836858 dose to be used in the Phase II part and define details of the patient 
population to be enrolled in phase II.  A summary of safety and efficacy from the dose 
escalation cohorts and from the expansion cohorts and RP2D will be included in the Phase I 
safety analysis report.  The Phase I safety analysis report and amended protocol will be 
made available for Health Authority and Ethics Committee/IRB review and approval (where 


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applicable) and to all investigators who participate in Phase II. Phase II is not allowed by 
regulatory authority yet, and Phase II will not be started prior to regulatory approval as 
required in attending countries. Patients must not be recruited to Phase II until local Health 
Authority and ethics committee/IRB approvals (where applicable) are granted.
All safety laboratory analyses will be performed locally at each clinic site in the schedule 
outlined in the Flow Chart.  
 
    
3.1.1.2
Phase II
Adult patients with low to intermediate-1 risk MDS, who received no prior treatment or 
progressed/become resistant after ESA and/or approved MDS drugs, such as HMAs will be 
included in the Phase II.  Approximately 20 sites from United States and select European 
countries will participate in the Phase II.
During this phase, using Interactive Response Technologies (IRT), patients will be 
randomized in a 1:1 ratio either to arm A (BI 836858 plus BSC) or arm B (BSC alone, per 
Investigator’s choice) to compare the efficacy of BI 836858 to investigator’s choice for the 
treatment of patients with MDS. An internal Data Monitoring Committee (DMC) will be 
implemented for the Phase II of this trial.
All safety laboratory analyses will be performed by local labs per the schedule outlined in 
the Flow Chart. 
 
 
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The Phase I is designed to determine the dose of BI 836858 monotherapy in patients with 
low to intermediate-1 MDS with symptomatic anemia. The study will be conducted in an 
open label, single arm dose escalation trial design. Dose escalation and cohort size will be 
determined based on the recommendation by the DSB, according to a Bayesian Model with 
overdose control. An escalation with overdose control design will increase a chance of 
treating patients at efficacious doses while reducing the risk of overdosing. This design is 
based on practical experience and is a preferable algorithmic method due to its superior 
ability to identify the dose with the desired toxicity rate and its allocation of a greater 
proportion of patients to doses at, or close to, that dose (R13-4802, R13-4804, R13-4805). 
Expansion cohorts will enroll at the RP2D defined during the dose escalation portion of 
Phase I.
The Phase II of the trial will be conducted as a randomized, open label trial. Patients will be 
randomized in a 1:1 ratio either to Arm A (BI 836858 + BSC) or Arm B (BSC alone, per 
Investigator’s choice). Due to the fact that the study drug is given via i.v., and that placebo 
infusions are ethically not acceptable in this context, the trial is performed open-label.  
Treatment Arm B with BSC will be determined per Investigator’s current Standard of Care 
(SOC) practice.  


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Single intra-patient dose escalation will be permitted.  See Section 4.1.4 for details. Each 
patient will be monitored closely for infusion-related reactions, as this is a potential side-
effect for monoclonal antibodies (mAb).
Safety 
 will be performed at all visits 
during treatment.
The trial shall allow the investigation of BI 836858 in MDS with regard to safety and 
efficacy and the definition of optimal dose for the further clinical development program in 
this disease.
3.3
SELECTION OF TRIAL POPULATION
Phase I will enter approximately 50 patients from approximately 3-7 sites in the United 
States and/or European country(ies).  In the Phase I dose escalation part, the trial will recruit 
patients with lower risk MDS who were either previously untreated or progressed/became 
resistant following ESA treatment. After determination of the MTD/RP2D, the same group 
of patients as for the dose escalation will be enrolled in the first expansion cohort. The 
second expansion cohort will enroll patients with low or intermediate-1 risk MDS with 
symptomatic anemia, who experienced ESA treatment failure or do not qualify for ESA 
treatment and who have not received prior HMA and/or lenalidomide.
Phase II will enter approximately 150 patients.  Approximately 20 sites from United States 
and European countries are expected to participate in Phase II. 
A log of all patients who signed the informed consent will be maintained in the Investigator 
Site File (ISF) at the investigational site irrespective of treatment assignment.
3.3.1
Main diagnosis for study entry
Patients with documented diagnosis of MDS according to World Health Organization 
(WHO) criteria that meets International Prognostic Scoring System (IPSS) classification of 
low or intermediate-1 risk disease will be eligible for this trial.
3.3.2
Inclusion criteria
1. Documented diagnosis of MDS according to World Health Organization (WHO) 
criteria that meets International Prognostic Scoring System (IPSS) classification of 
low or intermediate-1 risk disease at screening as determined by microscopic and 
standard cytogenetic analyses of the bone marrow and peripheral complete blood 
count (CBC).

Phase I dose escalation: patients who experienced ESA treatment failure or do 
not qualify (serum erythropoietin level > 500 U) for ESA treatment, and are 
refractory to or not amenable or eligible for established MDS therapy (HMA, 
lenalidomide)


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
Phase I expansion: 
-
Expansion cohort 1 (“pre-treated”): patients who experienced ESA 
treatment failure or do not qualify (serum erythropoietin level > 500 U)
for ESA treatment and are refractory to established MDS therapy (HMA 
and /or lenalidomide)
-
Expansion cohort 2 (“untreated”): patients who experienced ESA 
treatment failure or do not qualify (serum erythropoietin level > 500 U)
for ESA treatment and who have not received prior HMA and/or 
lenalidomide (because not amenable or eligible for these treatments)

Phase II: patients who experienced ESA treatment failure or do not qualify 
(serum erythropoietin level > 500 U) for ESA treatment. For definition of further 
details of the phase II patients to be included the protocol will be amended based 
on Phase I results.
2. Patient has the evidence of symptomatic anemia according to the following criteria:

Phase I only: patients must have mean hemoglobin concentration < 10.0 g/dL of 
2 measurements (not influenced by RBC transfusion within 7 days of 
measurement) and having received < 4 units of RBCs within 8 weeks prior to 
start of treatment OR,

Phase I/II: Patients must have received ≥ 2 units of RBCs for hemoglobin ≤ 9.0 
g/dL within 8 weeks prior to start of treatment.
3. Patient is non-responsive to, refractory to, or intolerant of ESAs, or ESAs are 
contraindicated or unavailable, or a documented serum erythropoietin level of > 500 
U/L.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2 (refer to 
Section 10.2) (R14-0080). 
5. Age ≥ 18 years.
6. Written informed consent which is consistent with International Conference on 
Harmonization – Good Clinical Practice (ICH-GCP) guidelines and local legislation.
3.3.3
Exclusion criteria
1. Patient with IPSS category of Int-2 or high-risk MDS.
2. Phase II only: Patients with a deletion 5q cytogenetic abnormality.
3. Treatment within 28 days prior to Cycle 1 Day 1 with: i) long acting erythropoiesis 
stimulating agents, ii) long acting Granulocyte colony-stimulating factor (G-CSF), iii) 
granulocyte- macrophage colony stimulating factor (GM-CSF), iv) 5-aza, 
lenalidomide or decitabine, or v) iron chelation and within 14 days prior to Cycle 1 
Day 1 with short acting erythropoiesis stimulating agents and short acting G-CSF.
4. Patient previously received allogeneic bone marrow or stem cell transplantation. 
5. Second malignancy currently requiring active therapy (except for hormonal/anti-
hormonal treatment, e.g. in prostate or breast cancer).
6. Neutrophils <1000 /μL (1.0 x 109/L).


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7. Aspartate amino transferase (AST) or alanine amino transferase (ALT) > 2.5 times 
the upper limit of normal (ULN).
8. Bilirubin >1.5 mg/dL, except for Gilbert’s Syndrome or hemolysis.
9. Serum creatinine >2.0 mg/dL.
10. Known human immunodeficiency virus (HIV) infection and/or active hepatitis B 
infection (defined as presence of Hep B DNA), active hepatitis C infection (defined 
as presence of Hep C RNA)
11. Presence of concomitant intercurrent illness, or any condition which in the opinion 
of the Investigator, would compromise safe participation in the study, e.g. active 
severe infection, unstable angina pectoris, new onset of exacerbation of a cardiac 
arrhythmia.
12. Psychiatric illness or social situation which in the opinion of the Investigator would 
limit compliance with trial requirements.
13. Patient receiving concomitant therapy, which in the opinion of the Investigator is 
considered relevant for the evaluation of the efficacy or safety of the trial drug (refer 
to Section 4.2.2).
14. Female patients of childbearing potential who are sexually active and unwilling to 
use a medically acceptable method of contraception during the trial and for 6 months 
after the last administration of BI 836858, i.e. combination of two forms of effective 
contraception (defined as hormonal contraception, intrauterine device, transdermal 
patch, implantable or injectable contraceptive, bilateral tubal ligation etc.).  

Women of childbearing potential are defined as females who:

Have experienced menarche  and

Are not postmenopausal (12 months with no menses without an alternative 
medical cause) and

Are not permanently sterilized (e.g. hysterectomy, bilateral oophorectomy or 
bilateral salpingectomy 
15. Male patients with partners of childbearing potential who are unwilling to use 
condoms in combination with a second effective method of contraception (defined as 
hormonal contraception, intrauterine device, condom with spermicide, etc.) during 
the trial and for 6 months after the last administration of BI 836858.
16. Pregnant or nursing female patients.
17. Treatment with another investigational agent under the following conditions:

Within two weeks (4 weeks for biologics) of first administration of BI 836858, 
or if the half-life of the previous product is known, within 5 times the half-life, 
whichever is longer.

Patient has persistent toxicities from prior MDS therapies which are determined 
to be relevant by the Investigator.

Concomitant treatment with another investigational agent while participating in 
this trial.


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18. Chronic use, as defined by > 2 weeks of a corticosteroid agent that is ≥20 mg/day of 
prednisone or its equivalent, within 4 weeks prior to first administration of BI 
836858.
19. Treatment with an immunomodulatory agent within 4 weeks prior to first 
administration of BI 836858.
20. Patient received prior treatment with a CD33 antibody.
21. In the opinion of the Investigator patient is unable or unwilling to comply with the 
protocol.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient is to be withdrawn from the trial treatment if:

The patient withdraws consent. Patients are free to discontinue their participation 
in this trial at any time without providing a reason to withdraw trial treatment.

The patient requires prohibited treatment as specified in Section 4.2.2 or 
concomitant drugs which in the opinion of the investigator may interfere with the 
investigational product.

Delay in start of subsequent treatment cycle of more than 8 weeks due to a drug-
related event (e.g. delay in recovery of blood counts). Refer to section 4.1.4.  

The patient is no longer able to participate for other medical reasons (e.g. 
adverse events unrelated to therapy or disease progression, concomitant 
diagnoses, pregnancy, surgery or administrative reasons). The Investigator may 
also stop a patient's participation if the patient is no longer able to complete trial 
visits or trial-required procedures.
A patient can be withdrawn from the trial after discussion between the Investigator and the 
Sponsor if eligibility criteria are violated and/or the patient fails to comply with the 
protocol.
All withdrawals will be documented and the reason for withdrawal recorded and discussed, 
as necessary, in the final report of the trial. If a patient is withdrawn from the trial treatment, 
the end of active treatment (EOT) visit will be performed. All patients who discontinue 
active treatment will continue and complete follow-up visits, after the EOT visit.  Every 
effort should be made to follow-up with patients in case an adverse event (AE) is still 
ongoing at the time of withdrawal.  If a patient is withdrawn from the trial due to consent 
withdrawal, no further visits will be completed.
A patient has to discontinue trial drug administration in case:

A DLT occurs which does not recover to a degree that allows treatment continuation 
(see Section 4.1.4).

Progressive disease (PD) or any other concomitant diagnosis/symptom develops 
resulting in an indication to start any other therapy for MDS, including deterioration 
of general condition.


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Patients who have not completed at least 2 administrations (1 cycle) of BI 836858 due to 
BI 836858 related toxicity will not be replaced; this will be considered as a DLT. However, 
patients who have not completed at least 2 administrations (1 cycle) of BI 836858 for 
reasons other than BI 836858 related toxicity will be replaced. 
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site,
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial, or
3. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract by a trial site or 
investigator, disturbing the appropriate conduct of the trial.
4. The investigator / the trial site will be reimbursed for reasonable expenses incurred in 
case of trial termination (except in case of the third reason).
Recruitment in this trial was discontinued prematurely during the Phase I expansion cohort.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
BI 836858 will be administered as rate-controlled intravenous infusion.  In case a patient 
experiences an adverse event during the infusion, the duration of the infusion may be 
expanded until the use-by date and use-by time indicated on the label is reached.  The actual 
duration of the infusion needs to be documented in the electronic case report form (eCRF) 
including actual start and end time, actual time points for interruption and restart of the 
infusion and the actual infusion rates.
Adverse events during the infusion will be thoroughly documented and characterized to 
allow differentiation between infusion-related reactions (R10-4428, R10-4517).
4.1.1
Identity of BI investigational product and comparator product(s)
The characteristics of the test product are below.

Substance (INN):
BI 836858

Pharmaceutical form:  
Concentrate for solution for infusion 

Source:
Boehringer Ingelheim Pharma GmbH & Co. KG

Unit strength: 
10 mg/mL (vials with 10mL)

Daily dose:
See Section 4.1.3

Duration of use:
Single administration every 14 days

Route of administration:
Intravenous

Posology:
Rate controlled infusion
(Volume:  250 mL)
All infusions will be started at a rate of 10 mL/h.  The infusion rate should be increased 
every 30 (+/-10) minutes by 10 mL/h to a maximum of 80 mL/h as long as tolerated by the 
patient. If considered safe by the Investigator, the stepwise increase of infusion rate during 
the third and subsequent infusions may be faster or steps may be omitted, but the maximum 
infusion rate must not exceed 120 mL/h. If symptoms of an infusion-related reaction occur, 
the infusion should be temporarily stopped. Upon recovery, it should be infused at 50% of 
the rate at which the reaction occurred and should not be dose escalated from this dose for at 
least 30 minutes. Lower rates may be selected if clinically indicated. Depending on the time 
of occurrence and the severity of the reaction, the investigator may consider administering 
additional supportive medication, e.g. corticosteroids. A stepwise re-increase of the infusion 
rate to a maximum of 80 mL/h is possible. For medical reasons, in case a patient 
experiences an adverse event during the infusion, the duration of the infusion may be 
expanded until the use-by date and use-by time indicated on the label is reached. The actual 
duration of the infusions and infusion steps need to be documented in the eCRF including 
actual start and end time, actual time points for interruption and restart of the infusion and 
the actual infusion rates. Infusions should not exceed 8 hours.  In cases where an infusion is 
ongoing at 8 hours from the time of the start of infusion, the infusion must be stopped and 
documented.  


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4.1.2
Method of assigning patients to treatment groups
In Phase I of the trial, patients will be assigned into escalating dose cohorts and Phase I 
Expansion cohorts using IRT. After determination of the MTD/RP2D, Phase I safety 
analysis report and protocol amendment (see section 3.1.1.1), Phase II enrollment will be 
initiated.  
In Phase II of the trial, utilizing IRT, patients will be randomized to a 1:1 ratio of either BI 
836858 plus BSC or BSC alone.  When a patient qualifies for the trial, randomization 
should be performed just prior to Cycle 1 Day 1, or as close to the first treatment dose as 
possible.  It may be performed on the day of the first administration prior to patient 
treatment, but no later than 21 days after patient signs informed consent.
To facilitate the use of IRT, the investigator will receive an IRT manual including all 
necessary instructions.  A copy of the manual will be available in the Investigator Site File.
4.1.3
Selection of doses in the trial
 The starting dose for this trial will be the confirmed safe dose tested in the FIH 
study of BI 836858 which is an anticipated fixed dose of 20mg of BI 836858.
A fixed dose regimen was chosen as opposed to the dose adjusted by Body Surface Area
based on a recent publication by Wang et al. The individual and population performance of 
body size-based and fixed dosing in adults were compared for 12 oncology approved mAbs 
(R10-6267). Although both dose regimens demonstrated similar performance, the fixed dose 
was recommended since it offered advantages in the ease of dose preparation and a lower 
chance of dosing errors.
Phase I:
The dose is planned to be escalated in cohorts at pre-defined dose levels based on a
maximum escalation of 100%. The provisional dose levels are 20mg, 40mg, 80mg, 160mg, 
and 320mg. Intermediate or lower dose levels, depending on the number of DLTs observed 
in the study, may be investigated if agreed upon between Investigator and Sponsor.
For any dose-escalation cohort, at least 3 patients will be required, but two out of those 
patients must be evaluable patients to escalate dose in next cohort. The DSB will also 
recommend the size for the next cohort between three to six patients. However, the final 
decision on the next cohort size will be made by a mutual decision between the TMM and 
the Coordinating Investigator (CI). After all patients in a cohort have either experienced a 
DLT or have been observed for at least one cycle (28 days – 2 administrations) without 
experiencing a DLT, the BLRM will be updated with the newly accumulated data and the 
overdose risk will be calculated. Based on the model and on additional information (PK, PD
patient profiles), the members of the DSB will reach a joint decision on the next dose level 
to be investigated.


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During the cohort dose escalation phase, entry into the initial 20mg dose cohort will be
allowed after a minimum of 7 days from the first administration of the first patient, and 
subsequently between patient 2 and 3. If the cohort expands to 6 patients, the 7-day 
observation period between the subsequent patients must be followed.  For subsequent 
cohorts, enrollment will be allowed after a minimum of 3 days from the first administration 
of each patient.
Enrollment into the next dose cohort is allowed after the previous dose cohort is found to be 
safe for all patients in this cohort (e.g. at least 28 days after the first administration of drug 
in the last patient entered into the cohort).  For the purposes of determining dose escalation,
Dose Limiting Toxicities will be assessed based on safety data from Cycle 1 (2 
administrations – 28 Days), however DLTs will be monitored beyond Cycle 1 and 
throughout the trial.
If no DLT is observed at a dose that efficacy is considered sufficient, the DSB may decide 
to include additional number of patients at the same dose level and to declare this dose level
as the RP2D.  Before the conclusion of Phase I and prior to initiating the Phase II, two 
expansion cohorts (untreated or pre-treated with HMA and/or lenalidomide) will recruit up 
to 12 patients per cohort (overall a minimum of 12 patients – inclusive of the last dose 
escalation cohort) and receive treatment at RP2D.  In the expansion cohorts new patients 
may be enrolled at any time without observation period.
Table 4.1.3: 1
Entry of patients into trial, by cohort
Cohort
Day first patient in 
cohort receives 
infusion
Earliest day next patient 
can be entered
Initial 20 mg
Day 1
Day 8
All other dose levels in cohort 
dose escalation
Day 1
Day 3
RP2D Expansion cohorts
Day 1
Any time
A one-week observation period must be followed between the first administration of BI 
836858 and the start of treatment of the subsequent patient for all patients in the 20 mg 
cohort. 
Phase II:
Patients will be randomized in a 1:1 ratio either to Arm A, to be treated at the RP2D of BI 
836858 plus BSC or Arm B, BSC alone, per Investigator’s choice.  Patients can be enrolled 
at any time during this trial without observation period.
Patients randomized to Arm B (BSC alone) have the opportunity to cross-in to receive BI 
836858 study drug after 4 months of treatment (EOC4) have elapsed since Cycle 1 Visit 1, 
following a disease assessment confirmation at this visit, if patients have not progressed to 
high-risk MDS or AML.  At the time-point of cross-in patients must meet all 


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inclusion/exclusion criteria, which includes stopping of any ESA and/or iron chelation 
therapies.
4.1.4
Drug assignment and administration of doses for each patient
Prior to inclusion of a new patient during the cohort dose escalation phase, the Investigator 
has to confirm the actual dose tier of BI 836858 for the patient with the Sponsor who 
oversees the cohort dose escalation steps and the safety data of patients from all trial sites.  
BI 836858 will be administered as an intravenous infusion every 14 days under the 
supervision of the Investigator or designated personnel.
BI 836858 may be administered at any time during the day.  
 
 it is recommended to 
start the infusion during the morning hours.  
Premedication to prevent infusion-related reactions is obligatory 30 minutes (up to 120 min 
before start of administration of BI 836858 is permissible) prior to the first and second 
administration of BI 836858, unless a contraindication for premedication exists, and should 
include:

Acetaminophen/Paracetamol 650 mg - 1000 mg p.o., or equivalent

Antihistamine p.o. or i.v., equivalent to Diphenhydramine 50 mg i.v.

Glucocorticoid i.v., equivalent to prednisolone 100 mg
If BI 836858 has been well tolerated without signs of infusion-related reactions in the first 
administration, glucocorticoid premedication may be reduced to a dose equivalent to 50 mg 
prednisolone for the second through fourth administrations, and in case this is well tolerated 
reduce the glucocorticoid with the 5th infusion (25 mg with the 5th and 0 mg with the 6th
infusion.) However, in case an administration of BI 836858 was not well tolerated the 
premedication with prednisolone can be re-escalated up to 100 mg.
Before the administration of BI 836858, adverse events and safety laboratory will be 
assessed.  To start or continue treatment with further administrations, all of the following 
criteria must be met:
(1)
Neutrophils ≥1000 /μL (1.0 x 109/L) 
(2)
Platelets ≥50,000 /μL (50 x 109/L), unless CTCAE Grade 3 or 4 
thrombocytopenia was preexistent prior to trial entry.  Patients who go from 
Grade 3 to Grade 4 thrombocytopenia after treatment may continue on study 
provided that post-transfusion platelet count is at least 20,000/uL before therapy 
is given.
(3)
Acceptable tolerability (in case of an AE at the planned start of a further 
administration, patients may continue therapy only after recovery to a level 
which would allow further therapy, i.e. CTCAE grade 1 or baseline value.)


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In case criterion 1 and 2 are not fulfilled, blood counts and/or the adverse event should be 
re-evaluated for up to three weeks and documented in the eCRF.  In case of a treatment 
delay, the Sponsor must be notified.  
Administration of the trial drug has to be stopped temporarily in case of a DLT (see 
Section 5.2.1.1).  Patients may continue therapy only after recovery from the DLT to a 
CTCAE level which allows further therapy based on Investigator assessment and only with 
a reduced dose of BI 836858.  The new dose of BI 836858 must be finally agreed on 
between the Sponsor and the Investigator.  The reduced dose will be valid for all following 
treatment cycles in the individual patient.  A reduction of the dose will be allowed only once 
for an individual patient during the whole trial.  In case a patient experiences a second 
episode of DLT with the reduced BI 836858 dose, the treatment has to be permanently 
discontinued.  Likewise, treatment has to be discontinued in case the DLT is not reversible.  
Patients who discontinue treatment will complete an End of Trial Visit and follow-up visits.
Intra-patient dose escalation may be considered after agreement between investigator and 
sponsor for selected patients. It is restricted to patients who have completed and received a 
minimum of 8 administrations of BI 836858 and tolerate the treatment well at the time of 
dose escalation. Intra-patient dose escalation can only be performed at a time when the next 
higher dose cohort has been reviewed and considered safe by the DSB. The dose escalation 
step is limited to the dose which has been administered to the next higher cohort.  Only one 
dose escalation will be permitted for a patient.  Dose escalations can only occur on Day 1, or 
Visit 1 of a cycle.  After the first dose at the higher dose level, patients have to be monitored 
for at least 24 hours after the end of the infusion, including a safety laboratory 24 hours after 
the first administration of the escalated dose of BI 836858. Patients who have escalated to a 
higher dose and who experience toxicities may be permitted to reduce back to a lower dose, 
following the criteria described above. A log of all patients pre-screened and enrolled into 
the study (i.e. having given informed consent) will be maintained in the Investigator Site 
File (ISF) at the investigational site irrespective of whether they have been treated with 
investigational drug or not.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The trial will be conducted in an open-label. Blinding is not applicable. However, to reduce 
bias, the BI study team will be blinded from the aggregated Phase II data at the treatment 
level until the primary analysis for Phase II.
4.1.5.2
Procedures for emergency unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
BI 836858 will be supplied in 10 mL vials containing 100 mg BI 836858.  For details of 
packaging and the description of the label, refer to the ISF.  Medication will be delivered to 


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the Investigator’s pharmacy where the total dose per patient will be prepared upon request 
from the Investigator.
For preparation of BI 836858 infusion solution, the content of the vial of BI 836858 will be 
diluted in 0.9% sodium chloride.  The content of several vials may be needed for 
administration of the requested dose.  For further details, please refer to the instructions 
included in the ISF. The full volume of the diluted compound will be 250 ml.
4.1.7
Storage conditions
BI 836858 has to be stored in a limited access area at the temperature indicated on the trial 
drug label.  Do not freeze.  If the storage conditions are found to be outside the specified 
range, immediately contact the local clinical monitor (CML) as provided in the list of 
contacts and reported in the ISF.  For more details on BI 836858, please refer to the 
Investigator’s Brochure (IB) and the ISF.
4.1.8
Drug accountability
Drug supplies, which will be provided by the Sponsor or a Clinical Research Organization 
(CRO) appointed by the Sponsor, must be kept in a secure, limited access storage area under 
the storage conditions defined by the Sponsor.  A temperature log must be maintained to 
make certain that the drug supplies are stored at the correct temperature.
Each Investigator and/or pharmacist will receive the investigational drugs delivered by the 
Sponsor when the following requirements are fulfilled:

approval of the study protocol by the Institutional Review Board (IRB) / 
Independent Ethics Committee (IEC), 

availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Center,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal Investigator,

availability of a signed and dated CTP or immediately imminent signing of the CTP,

availability of the proof of a medical licence for the principal investigator,

availability of the FDA Form 1572 if applicable.
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, 
and the unique code numbers assigned to the investigational product(s) and trial patients.  
The Investigator and/or pharmacist must maintain records of the product’s delivery to the 
trial site, the inventory at the site, the use for each patient, and the return to the Sponsor or 
alternative disposition of unused product.  The Investigator/pharmacist will maintain records 
that document adequately that the patients were provided these doses specified by the CTP 
and reconcile all investigational product received from the Sponsor. At the time of return to 
the sponsor, the investigator must verify that all unused or partially used drug supplies have 
been either destroyed or returned by the investigational site, and that no remaining supplies 
are in the investigator’s possession.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medication to reverse the action of BI 836858 is not available.  Potential side effects 
of BI 836858 have to be treated symptomatically.  Patients should receive supportive care 
according to the local guidelines regarding treatment of infusion-related reactions, blood 
product support, antibiotics, antivirals, analgesics, skin and mouth care, etc.  The use of 
growth factors such as granulocyte colony stimulating factor (G-CSF) will be allowed (other 
than ESAs), but growth factors should be avoided during the first four administrations (2 
cycles) for better assessment of safety and response parameters. G-CSF should not be given 
prophylactically.
Anti- bacterial and fungal prophylaxis should be given according to local standards or 
available guidelines.
All concomitant therapies to provide adequate care may be given as clinically necessary.  
All concomitant treatments will be recorded in the eCRF except for vitamins and 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 be 
specified in detail.  It should be indicated as ‘parenteral nutrition’.  If a patient needs 
anesthesia, it will be sufficient to indicate ‘anesthesia’ without specifying the details.
Concomitant therapy will be recorded in the eCRF during the screening and treatment 
period, starting at the date of signature of informed consent, and ending at the EOT-visit.  
After the EOT-visit, only concomitant therapy indicated for treatment of an adverse event 
needs to be reported.
After implementation of CTP version 5.0 collection of Concomitant Therapy information 
only if the indication is treatment of an (S)AE.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Patients must not be receiving any concurrent treatment for MDS while on study.  
Exceptions will be made for supportive therapies such as transfusions or use of growth 
factors.  The use of colony stimulating factor (G-CSF) will be allowed (other than ESAs), 
but growth factors should be avoided during the first four administrations (2 cycles) of BI 
836858 for better assessment of safety and response parameters.  G-CSF should not be 
given prophylactically.
Iron chelation therapy are permitted to those Phase II patients randomized to BSC only, 
however these treatments are not allowed for patients receiving BI 836858 in this study. 
Short term glucocorticoid medications may be used as clinically indicated to treat 
infusion-related reactions at any dose.  All other indications for steroids have to be 
discussed and agreed upon between Investigator and Sponsor.


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4.2.2.2
Restrictions on diet and life style
No restrictions apply with regard to diet, water intake or life style.
4.3
TREATMENT COMPLIANCE
BI 836858 will be administered as a single intravenous infusion under supervision of the 
Investigator or dedicated clinic personnel.  Compliance may also be verified by 
pharmacokinetic assessment.  Any discrepancies will be explained in the eCRF by the 
Investigator or designee.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY – PHARMACODYNAMICS
5.1.1
Endpoints of efficacy
The efficacy endpoints will be assessed at the time points specified in the Flow Chart.
For definition of response criteria please refer to Section 5.1.2.3.
Primary Endpoint: (Phase II)

RBC Transfusion Independency  
Secondary endpoints: (Phase I)

RBC Transfusion Independency  
Secondary endpoints: (Phase I and II)

Hematologic improvement neutrophils (HI-N)

Hematologic improvement platelets (HI-P)

Hematologic improvement erythroid (HI-E)

Time to HI-E response

Mean hemoglobin increase ≥ 1.5 g/dL 

Duration of Response (RBC Transfusion Independency, HI-N, HI-P, HI-E or Objective 
Response)

Overall Objective Response (OR) [Complete Response (CR), Partial Response (PR),  
and Hematologic Improvement (HI)]


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5.1.2
Assessment of efficacy
5.1.2.1
Bone marrow aspirate and peripheral blood
Response will be assessed in bone marrow (BM), peripheral blood and clinically as 
specified in the Flow Chart. 
The investigator’s overall assessment of the disease and confirmation of non-PD/non-
relapse status will be required for the decision to continue with the next cycle of study 
treatment.
At baseline a BM aspirate is required. A BM biopsy will be required if aspiration is 
inadequate. During response assessment after treatment initiation, a BM aspirate will be 
sufficient and no BM biopsy will be required unless the aspirate results in a punctio sicca
(dry tap) in which case a BM biopsy will be performed. The first scheduled bone marrow 
sample for response assessment will be performed at the end of Cycle 4.  The BM aspirate 
(or biopsy if aspirate is inadequate) will be scheduled for response assessment at the EOC4 
and at the time of disease progression/relapse or EOT, whichever occurs first. The 
classification of response is defined in Section 5.1.2.3.
An unscheduled BM examination should be performed as soon as possible when 
progression or relapse of MDS is suspected (based on clinical or laboratory findings) 
irrespective of the next scheduled BM assessment.
5.1.2.3
Assessment and definition of response criteria
Response to treatment will be evaluated according to the International Working Group
(IWG) 2006 criteria (R13-0369).  The evaluation period for transfusion independence and 
response will last from randomization (for phase II / first administration for phase I) until 
discontinuation of treatment.


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Transfusion independence (TI)

Red blood cell (RBC) transfusion independence and platelet transfusion 
independence will be evaluated in patients who are transfusion dependent at 
baseline. Percentages will be calculated using all treated patients as the denominator.

A patient is considered transfusion independent at baseline if the patient has had no 
transfusions during the 56 days prior to and including the first day of treatment. 
Otherwise, the patient is considered to be transfusion dependent.

A patient is considered transfusion independent if the patient has had no transfusions 
over the course of ≥ 56 consecutive days.
Hematologic improvement (HI)
The HI will be evaluated in patients with abnormal pretreatment values defined as follows:

Erythroid response (HI-E):  Patients with a pretreatment hemoglobin <11 g/dL 
demonstrate erythroid response if their hemoglobin increases by ≥1.5 g/dL for at 
least eight weeks, and there is a reduction in the units of red cell transfusions by an 
absolute number of at least four red cell transfusions per eight weeks compared with 
the pretreatment transfusion number in the previous eight weeks. Only red cell 
transfusions given for a hemoglobin ≤9 g/dL pretreatment will count in the red cell 
transfusion response evaluation. 

Platelet response (HI-P) — Patients with a pretreatment platelet count <100 x 109/L 
demonstrate a platelet response if there is an absolute platelet increase of ≥30 x 
109/L for patients starting with >20 x 109/L platelets. For those with an increase from 
10 x 109/L to >20 x 109/L must have an increase of at least 100 percent. 

Neutrophil response (HI-N) — Patients with a pretreatment neutrophil count <1 x 
109/L demonstrate a neutrophil response if they have an at least 100 percent increase 
and an absolute increase >0.5 x 109/L.

Mean hemoglobin increase ≥ 1.5 g/dL  — Time Frame: Up to approximately 48 
weeks.  Proportion of subjects achieving hemoglobin (Hgb) increase from baseline ≥ 
1.5 g/dL over any consecutive 56-day period in absence of Red blood cell (RBC) 
transfusions.
Duration of Response

Response duration analysis is defined only for patients who achieve CR or mCR or 
RBC Transfusion Independency and is measured from the first date of achieving a 
response until the date of relapse. The date of relapse will be the earliest of the dates 
of the disease assessment (blood sample, bone marrow sample, or clinical 
assessment) in which the relapse was observed. For patients who die or are lost to 
follow-up without documented relapse, response duration will be censored, 
respectively, on the date of death, regardless of cause, or on the date of last disease 
assessment for the patients who are alive when lost to follow-up.
Complete Response (CR)


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
Bone marrow: <5 % blasts with normal maturation of all cell lines*

Persistent dysplasia will be noted*

Peripheral blood:
o Hgb > 11 g/dL
o Platelets >100 x 109/L
o Neutrophils > 1.0 x 109/L
o Blasts 0 %
*Dysplastic changes should consider the normal range of dysplastic changes
Partial Response (PR)

All CR criteria if abnormal before treatment except:
o Bone marrow blasts decreased by >50 % to pre-treatment but still >5 %
o Cellularity and morphology not relevant
Marrow Complete Response (mCR)

Bone marrow: < 5 % blasts and decrease by >50 % over pretreatment

Peripheral blood: if HI responses, they will be noted in addition to marrow CR
Stable Disease (SD)

Failure to achieve at least PR, but no evidence of progression for >8 weeks
Relapse after CR or PR 

At least 1 of the following:
o Return to pre-treatment bone marrow blast percentage
o Decrement of >50 % from maximum remission/response levels in 
granulocytes or platelets
o Reduction in Hgb concentration by > 1.5 g/dL or transfusion dependence
after a period of RBC transfusion independence
Progressive disease (PD)

Patient with less than 5 % blasts: > 50 % increase in blasts to > 5 % blasts

Patient with 5 %-10 % blasts: >50 % increase to > 10 % blasts

Patient with 10 %-20 % blasts: > 50 % increase to >20 % blasts

Patients who meet any of the following criteria:
o
At least 50 % decrement from maximum remission/response in granulocytes or 
platelets;


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o
Reduction in Hgb by >2 g/dL;
o
Transfusion dependence after a period of RBC transfusion independency; or


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5.2
SAFETY
Recruitment in this trial was discontinued prematurely during the Phase I expansion cohort.
With the aim to minimize the burden for trial participants, after approval of CTP version 
5.0, the mandatory protocol procedures described below in sections 5.2.2 Assessment of 
adverse events, 5.2.3 Assessment of safety laboratory parameters 5.2.4, Electrocardiogram, 
5.2.5 Assessment of other safety parameters, and 5.3.1 Physical Examinations are reduced 
for all patients who continue to receive trial medication in treatment cycles ≥5. Instead, 
safety assessments should be performed at the investigator’s discretion, based on standard 
medical care. For details refer to Flow Chart.
Findings are documented in the eCRF only if qualifying for an adverse event (see section 
5.2.2, which remains unchanged).
5.2.1
Endpoint(s) of safety
Primary Endpoints: (Phase I)

Maximum Tolerated Dose (MTD)

Occurrence of Dose Limiting Toxicity (DLT)
Other Endpoints: (Phase I and II)

Incidence and intensity of treatment related adverse events according to CTCAE 
Version 4.0 (R09-2850)
The primary objective of the Phase I part is to assess the safety of the drug in humans and to 
determine the MTD of BI 836858. For details on determination of MTD, please refer to 
sections 3.1, 5.2.1.2 and 7.3.1.
The safety of BI 836858 in the Phase I and II will be assessed by a descriptive analysis of 
incidence and intensity of adverse events graded according to CTCAE (version 4.0), the 
incidence of non disease-related adverse events qualifying for dose limiting toxicity (DLT), 
laboratory data and results of physical examination.
5.2.1.1
Dose limiting toxicity (DLT)
The Dose Limiting Toxicity is defined as follows:

Grade ≥ 3, according to CTCAE version 4.0, non disease-related, non-hematologic 
adverse events, with the following exceptions:
–
Any laboratory abnormality, which is not considered clinically significant by 
the investigator or resolves spontaneously or can be recovered with 
appropriate treatment within 5 days


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–
For patients with neutrophils <500 /µL (0.5 x 109/L) at start of treatment 
febrile neutropenia with neutrophils <500 /µL (0.5 x 109/L) or infection with 
neutrophils <500 /µL (0.5 x 109/L) will not constitute a DLT if they can be 
recovered with appropriate treatment within 14 days.

Inability to deliver the full dose of the study drug according to the assigned dose 
level within cycle 1 due to drug-related adverse events.

Absence of hematological recovery as following: 
–
Neutrophils: Grade 4 (if Grade 0/1 at baseline) OR < 100 /µL (0.1 x 109/L) 
and decrease of > 75% from baseline (if Grade  ≥ 2 at baseline) for > 7 days
–
Platelets: Grade 4 (if Grade 0/1 at baseline) OR < 10000/µL (10 × 109/L) for 
> 7 days and decrease of > 75% from baseline (if Grade ≥ 2 at baseline) 

Treatment delay of ≥ 4 weeks of the start of Cycle 2 
–
If Cycle 2 is not started until 57th day from Day 1 of Cycle 1 as a result of 
drug related AE, it is considered as DLT.
Infusion-related reactions associated with the administration of BI 836858 will not be 
regarded as a DLT. The exception is anaphylaxis which occurs despite premedication with 
glucocorticoid or which does not resolve with glucocorticoid.
5.2.1.2
Maximum Tolerated Dose (MTD)
The MTD may be considered reached if the probability that the true DLT rate in the target 
interval (16%-33%) is sufficiently large. For detailed definition see Section 7.1. 
The DSB may recommend stopping the dose finding phase after the criterion for MTD is 
fulfilled. Further patients may be included to confirm the MTD. If no DLT is observed at a 
dose of which the efficacy is considered sufficient, the DSB may decide to include 
additional number of patients at this dose level and to declare this dose as the MTD and 
RP2D.  
5.2.1.3
Recommended Phase 2 Dose (RP2D)
Before the conclusion of Phase I and prior to initiating the Phase II, two expansion cohorts 
(untreated or pre-treated with HMA and/or lenalidomide) will recruit up to 12 patients per 
cohort  (overall minimum of 12 patients – inclusive of the last dose escalation cohort) and 
receive treatment at RP2D.
Based on the Phase I data, the DSB will make a final determination of the RP2D, which 
must not exceed the MTD. The Phase I safety analysis report, including the rationale of 
RP2D determination will be prepared prior to the initiation of Phase II as described in detail 
in 3.1.1.1.


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5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received 
a pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or 
prolongs patient hospitalization, is a congenital anomaly / birth defect, or is to be deemed 
serious for any other reason if it is an important medical event when based upon appropriate 
medical judgement which may jeopardise the patient and may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definitions.
Intensity of adverse event
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 in the eCRF.
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms
(CRFs). 
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
If a SAE is reported from a still blinded trial, the causal relationship must be provided by the 
investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e. 
any active comparator or placebo according to the trial design).
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as 
an (S)AE in the eCRF.
Changes in vital signs, ECG, physical examination, and laboratory test results


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Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the eCRF , if they are judged clinically relevant by the investigator.
Protocol-specified Adverse Events of Special Interest (AESI)
The following are considered as Protocol-specified Adverse Events of Special Interest:

Infusion-related reactions (CTCAE grade 3 or higher)

Any event that qualifies for a dose limiting toxicity (refer to Section 5.2.1.1)

Drug Induced Liver Injury (DILI)
Hepatic injury defined by the following alterations of liver parameters:

For patients with normal liver function (ALT, AST and bilirubin within normal 
limits) at baseline an elevation of AST and/or ALT ≥3 fold ULN combined with 
an elevation of total bilirubin ≥2 fold ULN measured in the same blood draw 
sample. 
o
Patients showing these lab abnormalities need to be followed up 
according to Section 10.1.2 of this clinical trial protocol (CTP) and the 
"DILI checklist" provided in the ISF.

For patients with impaired liver function at baseline an elevation of AST and/or 
ALT ≥5 fold ULN combined with an elevation of total bilirubin≥2 fold ULN 
measured in the same blood draw sample. 
o
Patients showing these lab abnormalities need to be followed up 
according to Section 10.1.2 of this clinical trial protocol and the “DILI 
checklist” provided in ISF.
AESI are to be reported in an expedited manner similar to Serious Adverse Events (within 
24 hours), even if they do not meet any of the seriousness criteria - for details please see 
Section 5.2.2.2.
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the residual effect period (REP)
(30 days after the last drug administration, Table 5.2.2.2: 1)) will be collected, documented 
and reported to the sponsor by the investigator on the appropriate CRF(s) / eCRFs / SAE 
reporting forms. Reporting will be done according to the specific definitions and 
instructions detailed in the ‘Adverse Event Reporting’ section of the Investigator Site File. 
For each adverse event, the investigator will provide the onset date, end date, 
intensity/CTCAE grade (according to CTCAE, version 4.0, R09-2850), treatment required, 
outcome, seriousness, and action taken with the investigational drug or BSC treatment(s). 
The investigator will determine the relationship of the investigational drug to all AEs as 
defined in Section 5.2.2.1. 


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The Residual Effect Period (REP) for BI 836858 is 30 days.  Therefore all events reported 
within 30 days after the last trial medication will be considered on drug. All adverse events 
will be reported up until the last per protocol visit (EOT) which is 30 days after the last dose 
of trial medication. The investigator does not need to actively monitor patients for adverse 
events once the clinical trial has ended. However, if the investigator becomes aware of an 
SAE(s) that occurred after the patient has completed the clinical trial (including any 
protocol required REP and / or follow-up), it should be reported by the investigator to the 
sponsor if considered relevant by the investigator.  
Table 5.2.2.2: 1
AE/SAE reporting requirements
Time Period
Reporting Requirements
From signature of informed consent 
until 30 days after last 
administration of study drug
Report all AEs, SAEs regardless of relatedness. 
This includes all events leading to death.
Post treatment (>30 days after last 
administration of study drug) until 
end of follow-up 
Report AEs and SAEs which are considered related 
to study drug, study design / procedures or if 
considered relevant by the investigator.
Please note: The event(s) leading to death (other 
than progressive disease) should always be reported 
as SAE in this trial
During and after post treatment 
(after the patient has completed the 
clinical trial)
If the investigator becomes aware of an SAE(s) it 
should be reported by the investigator to the 
sponsor if considered relevant by the investigator
The investigator must report the following events if using paper process SAE form via fax 
immediately (within 24 hours) to the sponsor: SAEs and non-serious AEs relevant to the 
SAE(s), and AESI.   
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non-serious
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event.  If the event description is correct, the 
item “serious” needs to be ticked and an SAE has to be reported in expedited fashion 
following the same procedure as above.  The list of these adverse events can be found via 
the RDC-system.
The SAE form is to be forwarded to the defined unique entry point identified for the BI 
OPU (country-specific contact details will be provided in the Investigator Site File). This 
immediate report is required irrespective of whether the investigational product has been 
administered or not and irrespective of causal relationship. It also applies if new information 
to existing SAEs or AESIs becomes available. 
Exemption to SAE Reporting


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Disease progression/relapse of the underlying condition is a study endpoint for analysis of 
efficacy. Disease progression/relapse is exempted from reporting as a (S)AE. 
Progression/relapse of the subject's underlying condition will be recorded in the appropriate 
pages of the (e)CRF as part of efficacy data collection. Death due to disease 
progression/relapse is to be recorded on the appropriate (e)CRF page and not on a SAE 
form.
Examples of exempted events of disease progression/relapse are:

Progression/relapse of underlying condition (Progressive disease PD): if PD is 
clearly consistent with the suspected progression as defined by the respective 
response criteria.

Hospitalization/Procedures due solely to the progression/relapse of underlying 
condition Clinical symptoms and/or signs of progression/relapse (with or without 
confirmation by objective criteria), if the symptom can exclusively be determined to 
be due to the progression/relapse of the underlying condition  and meets the 
expected pattern of progression/relapse for the disease under study.
If the observed event is not unequivocally due to progression/relapse of the underlying
condition and there is a reasonable possibility for a causal relationship to administration of
study medication, the event must be reported as (S)AE on both the SAE form and the 
(e)CRF.
Exempted events are collected and tracked following the protocol-specified monitoring plan.  
Exempted events are monitored at appropriate intervals preferably by an independent 
committee such as a Data Monitoring Committee.
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours or next business day 
whichever is shorter) to the defined unique entry point for SAE forms of the respective BI 
OPU (country-specific contact details will be provided in the Investigator Site File). The 
outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical 
Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).
After implementation of CTP version 5.0, pregnancy test results will not be documented by 
default in the eCRF. Only positive pregnancy tests will be documented via the Pregnancy 
Monitoring Form (and reported as an AE if applicable).


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5.2.3
Assessment of safety laboratory parameters
5.2.3.1
General safety laboratory parameters
Blood samples and urine have to be collected at the time points specified in the Flow Chart.  
Safety laboratory examinations will include hematology, biochemistry, coagulation and 
qualitative urine analysis:
Hematology
Hemoglobin, red blood cell count (RBC), white blood cell 
count (WBC) with differential (neutrophils, basophils
lymphocytes, monocytes, eosinophil),  platelets (PLT)
Reticulocytes have to be measured only at Visit 1 of every 
second cycle, EOC4, EOT.
Biochemistry
Glucose, sodium, potassium, calcium, inorganic phosphate, 
creatinine, AST, ALT, alkaline phosphatase (AP), lactate 
dehydrogenase (LDH), bilirubin, urea (preferred) or BUN, 
total protein, albumin, uric acid
Serum immunoglobulin levels (IgG, IgM, IgA) and direct 
antiglobulin (direct Coombs) test have to be measured only 
every 2 cycles, EOC4 and EOT.
Coagulation
Activated partial thromboplastin time (aPTT), prothrombin 
time (PT), international normalised ratio (INR) where 
indicated (e.g. treatment with vitamin K antagonists)
Urine
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be 
analysed by dipstick and reported as semiquantitative 
measurements. In case of pathological findings, further 
evaluation should be performed and results documented.
Pregnancy test
A serum pregnancy test needs to be obtained at the time 
points indicated in the Flow Chart in patients of childbearing 
potential. 
Additional safety labs will be collected on day 2 of Cycle 1 (i.e., 24 hours after the first 
administration of BI 836858) and after the first infusion of a higher dose, following intra-
patient dose escalation (i.e. 24 hours after the first administration of the higher dose). Other 
lab tests to be included for these visits: haptoglobin, direct antiglobulin/Coombs test, 
bilirubin (direct and indirect) and free hemoglobin. Non pre-existing abnormal laboratory 
values (CTCAE Grade 3 or higher) will be followed up every 48 hours until these laboratory 
values are back to at least CTCAE Grade 1 or baseline.
In case an administration is delayed due to an AE, the patient should visit the site at least 
once a week for assessment of safety laboratory and AEs. More frequent visits may be 
appropriate as assessed by the Investigator.


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5.2.3.2
Cytogenetics and molecular genetics
The results of molecular genetic testing undertaken at the time of initial diagnosis will be 
entered into the eCRF. This includes karyotyping (chromosomal banding), the testing of 
specific cytogenetic alterations by in-situ hybridization and the detection of somatically-
acquired mutations.
5.2.4
Electrocardiogram
A 12-lead resting ECG will be performed in all patients according to the schedule in the 
Flow Chart.  The ECG will be assessed for pathological results (to be recorded as either 
concomitant disease or AE) by the Investigator or qualified individual delegated by the PI.  
Additional examinations should be done whenever the Investigator deems necessary.
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Vital signs (blood pressure, heart rate and body temperature) will be recorded at every visit 
during screening, treatment, EOC4 and EOT. Additional time points for blood pressure and 
heart rate at the day of administration of BI 836858 are: prior to the start of premedication, 
prior to the start of BI 836858 infusion, and in 30 (±10) minute intervals throughout the 
course of the infusion of BI 836858 and 60 (±10) minutes after the end of the infusion, 
thereafter every 4-8 hours until at least 24 hours after start of the infusion. In case of an 
infusion-related reaction, the Investigator should decide whether to intensify or prolong 
monitoring of vital signs of the patient. 
Beginning with infusion 2, blood pressure and heart rate will be assessed at the same time 
points as during infusion 1 with the exception that they will not be assessed every 4-8 hours 
until at least 24 hours after the start of the infusion.
After implementation of CTP version 5.0 the vital signs are mandatory only at the day of 
administration of BI 836858 (see above). Results will be documented in the eCRF only if
qualifying for an adverse event.
5.2.5.2
Physical examination
A physical examination including height, weight and ECOG performance score will be 
performed at screening and at the time points specified in the Flow Chart. During the 
physical examination, the patient should be assessed for possible AEs.


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5.4
APPROPRIATENESS OF MEASUREMENTS
Determination of MTD is based on toxicities graded according to CTCAE version 4.0 (R09-
2850).  The CTCAE criteria are commonly used in the assessment of AEs in oncology and 
hemato-oncology patients. The criteria to be used for evaluation of MDS are internationally 
accepted as standard of practice for haematologists worldwide.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
During the introduction treatment phase, patients will receive administration with BI 836858 
every 14 days.  Patients are required to be hospitalized under close surveillance with access 
to intensive care for at least 24 hours after the first administration of BI 836858 to allow 
close monitoring for infusion-related reactions or other AEs.  After good tolerability of the 
first administration of BI 836858, the Investigator may evaluate the risk for an infusion-
related reaction and other AEs in view of relevant comorbidities or MDS-related symptoms, 
and as a result, the patient may receive subsequent infusions in the out-patient setting.  
In case a patient misses a visit within one treatment cycle and the patient comes to the clinic 
between the missed and the next scheduled visit, the delayed visit should be scheduled as 
soon as possible and documented with the actual date and the reason for the delayed visit. 
However, in case the day of treatment administration (Visit 1 of a cycle) is delayed, all 
subsequent visits of a cycle will be recalculated based on the actual date of Visit 1 of the 
delayed cycle.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations as outlined in the Flow Chart will be performed at the respective visits as 
described in detail in the following sections.  All assessments should be performed prior to 
dose administration on dosing days, unless otherwise specified.
With the aim to minimize the burden for trial participants, after approval of CTP version 5.0, 
the mandatory protocol procedures are reduced for all patients who continue to receive trial 
medication in treatment cycles ≥5. Instead, safety assessments should be performed at the 
investigator’s discretion, based on standard medical care. Refer to updated Flow Chart for 
specific requirements during treatment period.
Findings during safety assessments are documented in the eCRF only if qualifying for an 
adverse event (see sections 5.2.2, which remain unchanged).
6.2.1
Screening and run-in period(s)
The screening period (Visit 1), i.e. the phase after informed consent and before the first 
administration of the trial drug, may be as long as 21 days. The site should call Interactive 
Response Technologies (IRT) after informed consent is signed to register the patient as 
enrolled.
The patient will be officially entered (randomized for Phase II) via IRT after all the 
eligibility criteria are met.
The following parameters and investigations will be obtained and / or performed:

Informed consent

Demographics (sex, birth date, race) and baseline conditions


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
Medical history

Review of inclusion and exclusion criteria (patient eligibility)

Dose assignment (during cohort dose escalation of Phase I only, before the first 
administration of the trial drug and after informed consent and review of in- and 
exclusion criteria)

Safety laboratory (hematology, biochemistry including serum immunoglobulin levels 
and direct antiglobulin test, coagulation, urine; for details please refer to Section 5.2.3.1)

Physical examination, height, weight, vital signs and ECOG performance score

Serum pregnancy test in women of childbearing potential

12-lead ECG

Adverse Events

Concomitant therapy

Bone marrow aspiration for disease assessment 

Molecular genetics and cytogenetics of MDS (Historical/available data for Phase I 
patients and required at screening for Phase II patients)

Number of transfusions (up to 3 months prior to start of treatment)

Phase II: Randomization may be at the latest performed on Cycle 1 Visit 1, but before 
start of therapy
6.2.1.1
Re-screening
Sites will be allowed to re-screen patients after 1 week from when they screen failed. If 
more than 4 weeks have elapsed prior to re-screening, all screening procedures must be 
repeated.
6.2.2
Treatment period(s)
6.2.2.1
Visit 1 and Visit 3 – day of BI 836858 administration 
Phase II: these visits will also occur for BSC patients, 
The first dose of study medication should occur no later than 21 days after the informed 
consent is signed.  
On the treatment days, the following parameters and investigations will be obtained and / or 
performed:

Review of inclusion and exclusion criteria (patient eligibility), in the first administration 
only

Safety lab parameters before trial drug administration as specified in Section 5.2.3.1

Physical examination and ECOG performance score completed Day 1 of every second 
cycle beginning with cycle 1. Physical exam may be completed up to 2 days prior to
administration and ECOG must be completed on the day of the administration. Height 
only at Day 1 of first cycle.  If the first administration of BI 836858, or BSC treatment 


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on trial (Phase II) is completed within 3 days of the screening visit, these examinations 
do not need to be repeated

Vital signs at time points specified in Section 5.2.5.1 and weight

Serum pregnancy test in women of childbearing potential (Day 1 of every Cycle)

12-lead ECG (required at Visit 1 of each cycle)

Adverse events (AEs)

Changes in concomitant therapies

Number of transfusions

Administration of BI 836858 after final confirmation of dose tier 

Eligibility for further administration may be performed up to 2 days prior to this visit (at 
administration 2 and beyond)
Phase II only: Patients randomized to BSC should be treated on BSC, as indicated by 
investigator, throughout Introduction Treatment Cycles
6.2.2.2
Visit 2 and Visit 4 ( + 1 day window allowed beginning in Cycle 3)                          
Phase II: these visits will also occur for BSC patients, 
In Cycles 1 and 2, visits will occur at Day 8 and Day 22.  Beginning in Cycle 3 and 
thereafter, patients will come to the clinic only for infusions and will not be required to 
complete the visits on Day 8 and Day 22 unless medically indicated.  On the Visit 2 and 
Visit 4 days, the following parameters and investigations will be obtained and / or 
performed:

Safety lab parameters before trial drug administration as specified in Section 5.2.3.1

Vital signs at time points specified in Section 5.2.5.1 and weight

Adverse events (AEs)

Changes in concomitant therapies

Number of transfusions
Phase II only: Patients randomized to BSC should be treated on BSC, as indicated by 
investigator, throughout Introduction Treatment Cycles


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6.2.2.3
End of Cycle 4 (EOC4)
This visit includes an evaluation for further treatment.  Those patients with clinical benefit, 
CR or PR and who are tolerating the infusions well may continue until PD or other criteria 
for withdrawal are met as noted in Section 3.3.4.1.  For those patients who have received 8 
administrations, this visit is to be performed 14 days (+ 2 days) after the 8th administration 
of BI 836858.  For those patients who have received < 8 administrations, who are still in 
remission, this visit is to be performed 4 months (±2 days) after Cycle 1 Visit 1.  Phase II: 
For patients randomized to BSC, this visit to be completed 4 months (±2 days) after Cycle 1 
Visit 1.
The following parameters and investigations will be obtained and /or performed:

Safety lab parameters and urine analysis as specified in Section 5.2.3.1

Physical examination, weight and ECOG performance score  

Vital signs at time points specified in Section 5.2.5.1

Serum pregnancy test in women of childbearing potential

12-lead ECG

Adverse events (AEs)

Changes in concomitant therapies

Bone marrow aspiration

Molecular genetics and cytogenetics of MDS (Phase II patients only)

Number of transfusions

Clinical disease assessment - Eligibility for further administration may be performed up 
to 2 days prior to this visit
Phase II: For patients that are randomized to Arm B (BSC), following disease assessment 
confirmation at this visit, if patients have not progressed to high-risk MDS or AML, there is 
the opportunity to cross-in and receive BI 836858 study drug, providing they fulfil all 
inclusion/exclusion criteria.  Alternatively, these patients may continue on in the 
Maintenance Cycles receiving BSC treatment until PD or other criteria for withdrawal are
met.
6.2.2.4
Cycles 5 and 6 (additional Introduction Treatment Cycles Visits 1 and 2)
These visits are only for those patients who have received BI 836858 that are non-PD and 
equivocal as to if clinical benefit has been established, per investigator judgement after 4 
Cycles.  Two additional introduction treatment cycles are allowed prior to end of 
introduction treatment.
The Day 1 of Cycle 5 and Visit 5 of Cycle 4 may occur on the same day.  Tests that are 
done on both Visit 5 of Cycle 4 and Visit 1 of the Cycle 5 do not need to be repeated.  Refer 
to the CRF instructions on data entry.  In case the Cycle 5 Day 1 is delayed pending 


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retreatment eligibility, the Cycle 5 Day 1 will be calculated based on the actual day of the 
treatment.
Prior to each infusion, the following parameters and investigations will be obtained and /or 
performed:

Safety lab parameters before trial drug administration as specified in Section 5.2.3.1

Physical examination and ECOG performance score completed every second cycle 
beginning with cycle 1. Physical exam may be completed up to 2 days prior to
administration and ECOG must be completed on the day of the administration

Vital signs at time points specified in Section 5.2.5.1 and weight

Serum pregnancy test in women of childbearing potential (Day 1 of every Cycle)

12-lead ECG (required at Visit 1 of each cycle)

Adverse events (AEs)

Changes in concomitant therapies

Bone marrow aspiration (at the discretion of the Investigator).

Number of transfusions

Administration of BI 836858

Clinical disease assessment

Eligibility for further administration may be performed up to 2 days prior to this visit
6.2.2.5
Maintenance Cycles (Visit 1)
These visits are only for those patients with clinical benefit, CR or PR.  Procedures already 
done at EOC4 or at end of Cycle 6, for patients who completed the additional Introduction 
Treatment Cycles, (i.e., safety lab, pregnancy test) do not need to be repeated at 
Maintenance Cycle 1 Visit 1 if this visit is within 7 days from EOC4 (or at end of Cycle 6).  
The patients will receive monthly infusions until PD or other criteria for withdrawal are met 
as noted in Section 3.3.4.1.  
Prior to each infusion, the following parameters and investigations will be obtained and /or 
performed:

Safety lab parameters before trial drug administration as specified in Section 5.2.3.1

Physical examination every other cycle starting with cycle 1 (may be completed up to 
2 days prior) and ECOG performance score  

Vital signs at time points specified in Section 5.2.5.1 and weight

Serum pregnancy test in women of childbearing potential (Day 1 of every Cycle)

Adverse events (AEs)

Changes in concomitant therapies

Bone marrow aspiration (at the discretion of the Investigator).

Number of transfusions


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
Administration of BI 836858

Clinical disease assessment - Eligibility for further administration may be performed up 
to 2 days prior to this visit
Phase II only: Patients randomized to BSC, who choose not to cross-in, may continue on in 
the Maintenance Cycles receiving BSC treatment until PD or other criteria for withdrawal 
are met.
6.2.3
End of treatment and follow-up period
6.2.3.1
End of treatment (EOT)
The EOT visit is to occur 30 days (+7 days) after the last administration of BI 836858.  
The following parameters and investigations will be obtained and /or performed:

Safety lab parameters and urine analysis as specified in Section 5.2.3.1

Physical examination including weight  and ECOG performance score  

Vital signs at time points specified in Section 5.2.5.1

Serum pregnancy test in women of childbearing potential 

12 lead ECG (completed only in patients who receive at least 2 Cycles since EOC4 visit)

Adverse events (AEs)

Changes in concomitant therapies

Number of transfusions

Bone marrow aspirate (completed only in patients who receive at least 2 Cycles since 
EOC4 visit)

Molecular genetics and cytogenetics of MDS (Phase II patients only)

End of trial treatment.  This will include the reason for conclusion of treatment if 
applicable, premature discontinuation of treatment, and date of last administration of the 
trial drug  
6.2.3.2
Follow-up
Follow-up visits or telephone calls will be performed after the patient has completed or 
discontinued treatment according to protocol or is not eligible for further treatment cycles.  
Follow-up visits or telephone calls will begin 4 weeks after the EOT visit.  Follow-up will 
end in case the patient is lost to follow-up or in case the Investigator and Sponsor agree not 
to pursue further follow-up visits.  In Phase I, Follow-up visits should be performed at 4 
week intervals for 6 months. After the 6 month assessment, patients will be considered off 
trial.  In Phase II, Follow-up visits should be performed at 4 week intervals for the first 12 
months or earlier if appropriate as determined by the Investigator, and thereafter in 6 month 
intervals.


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At the last follow-up visit (Phase I and Phase II), an end of trial assessment will be 
performed and documented in the eCRF.  For follow-up of patients with adverse events 
which have not recovered at the last planned follow-up visit please refer to Section 5.2.2.2.
The following will be obtained and / or performed:

AEs since last visit/contact in case they occurred during the residual effect period (30 
days after the last trial drug administration) or are considered drug-related (see 
Section 5.2.2.1)

Follow-up of AEs in case they were not yet recovered at EOT

Concomitant therapy indicated for treatment of an AE

Number of transfusions

Treatment with any other MDS therapy (report date of treatment and drug)

Vital status evaluated at each follow-up visit
After implementation of CTP version 5.0, no further follow-up visits after EoR, unless 
follow-up is for S(AE) that occurred before EoR period.
6.2.3.3
End of the whole trial
The end of the trial will be defined as when the following have occurred:
1. All entered and treated patients have discontinued study drug
2. The last patient has completed the EoR visit
In the case that the trial is ended by the Sponsor when patients are still being treated and the 
final report of the trial is being prepared, the patients will either be included in a follow-up 
trial or alternatively kept on treatment in this trial provided that treatment continuation is in 
the best interest of the patient, based on clinical trial results and the investigator´s benefit 
risk assessment for an individual patient. Those patients will then be reported in a revised 
report and it will be noted in the original report that such a revised report will be written. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
Phase I Dose Finding 
The objective of the design is to determine the MTD defined as the highest dose with less 
than 25% risk of the true DLT rate being above 33%. The phase I dose-finding will be 
guided by a Bayesian 2-parameter logistic regression model with overdose control (R13-
4806; R13-4803). These designs have been shown to be superior regarding the precision of 
MTD determination compared to 3+3 designs and have been particularly endorsed by the 
FDA (R13-4881). 
The model is formulated as follows:
logit(p(d)) = log(α) + β*log(d/d*),
where logit(p) = log(p/(1-p)). 
p(d) represents the probability of having a DLT in the first cycle at dose d, d* = 160mg is 
the reference dose, allowing for the interpretation of α as the odds of a DLT at dose d*, 
and θ = (log(α), log(β)) with α, β > 0 is the parameter vector of the model.
Since a Bayesian approach is applied, a prior distribution π(θ) for the unknown parameter 
vector θ needs to be specified. This prior distribution will be specified as a mixture of three 
multivariate normal distributions, i.e.
π(θ) = φ1π1(θ) + φ2π2(θ) + φ3π3(θ)
with 
φi, i = 1, 2, 3 the prior mixture weights (φ1+ φ2+ φ3 = 1)
and 
πi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and 
covariance matrix Σi, with








2
22
,
22
,
11
,
22
,
11
,
2
11
,
i
i
i
i
i
i
i
i
i








Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust. 
Prior derivation


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For the current study, no relevant information in the form of human data was available, 
since no study in a comparable population has been conducted. Therefore, the three mixture 
components were established as follows:
1. A weakly informative prior was derived reflecting the a priori assumption that the 
median DLT rate at the starting dose of 20mg would equal 1%, and the median DLT 
rate at the anticipated MTD of 320mg would equal 20%. This yields μ1 = (-2.189,
0.146). The standard deviations were set such that large uncertainty about the 
parameter means is reflected, and the correlation was set to 0, thus yielding σ1,11 = 2, 
σ1,22  = 1 and ρ1 = 0, respectively. The prior weight φ1 for the first component was 
chosen as 0.9.
2. A high-toxicity weakly informative prior was derived reflecting the case that the 
compound would be much more toxic than expected. For this prior component, it 
was assumed that the median DLT rate at the starting dose of 20mg would equal 
10%, and the median DLT at the anticipated MTD of 320mg would equal 50%. 
These assumptions yield μ2 = (-0.549, -0.233). The standard deviations and 
correlations were set identical to the weakly informative prior, i.e. σ2,11 = 2, σ2,22  = 1 
and ρ2 = 0, respectively. The prior weight φ2 for the second component was chosen 
as 0.05.
3. A low-toxicity weakly informative prior was derived reflecting the case that the 
compound would be much less toxic than expected. For this prior component, it was 
assumed that the median DLT rate at the starting dose of 20mg would equal 1%, and 
the median DLT at the anticipated MTD of 320mg would equal 2%. These 
assumptions yield μ3 = (-4.068, -1. 372), i.e. basically a flat curve. The standard 
deviations and correlations were set to σ3,11 = 5, σ3,22  = 0.01, therefore almost fixing 
the slope parameter to its mean. The correlation was set to 0, i.e. ρ3 = 0. The prior 
weight φ3 for the third component was chosen as 0.05.
A summary of the prior distribution is provided in Table 7.1: 1. Additionally, the prior 
probabilities of DLT at different doses, as well as the corresponding probability of under-, 
targeted and overdosing, are shown in Table 7.1: 2. Graphically, the prior medians with 
accompanying 95% credible intervals are shown in Figure 7.1. As can be seen from both, 
the Table and the Figure, the prior medians of the DLT probabilities are in-line with the 
prior medians derived from the weakly informative prior, and the uncertainty around the 
medians is large, showing the low amount of information this prior provides. This is also 
supported by the prior sample size, i.e. the information contained in the prior. This is 
approximately equal to 1.5 patients, i.e. about half the weight the first cohort in the study 
will have.


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Table 7.1: 1
Summary of prior distribution
Prior Component
Mixture Weight
Mean vector
SD vector
Correlation
1: Weakly inf.
0.900
-2.189  0.146
2.000, 1.000
0.000
2: High Tox
0.050
-0.549 -0.233 2.000, 1.000
0.000
3: Low Tox
0.050
-4.068 -1.372
5.000, 0.010
0.000
Table 7.1: 2
Prior probabilities of DLT at selected doses
Dose
Probability of true DLT rate in
Quantiles
[0–0.16)
[0.16–0.33)
[0.33–1]
Mean
SD
2.5%
50%
97.5%
20
0.873
0.059
0.069
0.072
0.161
<0.001
0.007
0.641
40
0.829
0.080
0.091
0.094
0.181
<0.001
0.015
0.721
80
0.752
0.109
0.138
0.133
0.208
<0.001
0.036
0.802
160
0.596
0.159
0.244
0.215
0.253
0.001
0.103
0.894
320
0.400
0.159
0.441
0.365
0.329
0.002
0.257
0.992
Doses printed in bold face meet the overdose criterion (P(overdose) < 0.25))


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Figure 7.1
Prior medians and 95% credible intervals
The MTD may be considered reached if one of the following criteria is fulfilled
1. The posterior probability of the true DLT rate in the target interval (16%-33%) is 
above 50%, OR
2. At least 12 patients have been treated at MTD, including the two expansion cohorts.
The DSB may recommend stopping the dose finding phase after the criterion for MTD is 
fulfilled. Further patients may be included to confirm this MTD estimate. If no DLT is 
observed at a dose of which the efficacy is considered sufficient, the DSB may decide to 
include additional number of patients at this dose level and to declare this dose as the 
recommended dose for phase 2 (RP2D).
Recruitment in this trial was discontinued prematurely during the dose expansion cohort.
Statistical model assessment
The model was assessed using two different metrics:
1. Hypothetical data scenarios: for various potential data constellations as they could 
occur in the actual trial, the maximal next doses as allowed by the model and by the 


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100% escalation limit are investigated. Data scenarios thus provide a way to assess 
the “on-study” behaviour of the model.
2. Simulated operating characteristics: these illustrate for different assumed true dose-
toxicity relationships, how often a correct dose would be declared as MTD by the 
model. They are a way to assess the “long-run” behaviour of the model.
In summary, the model showed very good behaviour as assessed by these metrics. More 
details can be found in Section 10.3. 
Phase II efficacy comparison
In the phase II part the efficacy of the two arms (BI 836858 vs. investigator’s choice) will be 
compared in an exploratory manner.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing is planned in this trial. This is an exploratory Phase I/II study 
with the main objective of dose finding (Phase I) and treatment effect estimation (Phase II). 
7.3
PLANNED ANALYSES
Two analysis populations are defined for efficacy and safety analyses. For the Phase I the 
full analysis set (Phase I) is defined, in analogy to the intention to treat population as the 
treated set with respect to Phase I; i.e. all patients of Phase I who have received at least one 
single dose of BI 836858 will be considered, including the patients who have been replaced 
for any reason (refer to Section 3.3.4.1). For the Phase II the full analysis set (Phase II) is 
defined, in analogy to the intention to treat population as the randomized set with respect to 
Phase II; i.e. all patients randomized.  No per protocol population will be used for analyses. 
However protocol violations will be described.
7.3.1
Primary analyses
7.3.1.1
Assessment of the MTD in phase I
In order to determine the MTD the occurrence of a DLT in the first cycle will be assessed on 
an individual patient level. The MTD will be determined as described in Section 7.1.
Based on the data observed in the trial other models might be considered either additionally 
or replacing the primary model. For feasibility or other reasons a different dose might be 
considered as the recommended dose for Phase II. 
7.3.1.2
Assessment of the primary endpoint in Phase II
The primary endpoint for efficacy in Phase II is RBC transfusion independency derived 
from the data of all cycles. The primary analysis will be done for all patients of the full 
analysis set (Phase II). Each patient will be assigned to RBC transfusion independency 
yes/no based on the criteria described in Section 5.1.1. Analyses for the primary endpoint
will be performed both pooled as well as separately for the two strata (see Section 7.5).


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7.3.1.3
Statistical group comparison
All statistical group comparisons will be performed with respect to the full analysis set 
(phase II). Odds ratios, confidence intervals, and chi-square test will be used to compare 
treatments in an exploratory manner if appropriate. The exploratory nature of these analyses 
will be considered when interpreting the significance levels. P-values derived from
statistical tests smaller than 5% will only be reported as nominally significant regarding the 
small sample size in each treatment schedule.
7.3.2
Secondary analyses
Secondary time-to-event endpoints will be analyzed by using Cox proportional hazard 
models and Kaplan-Meier curves. Hazard ratios will be derived for the phase II part. 
Secondary endpoints that are binomial (like response rates) will be analyzed similarly to the 
primary endpoint for Phase II.
Secondary endpoints in phase I will be listed only. If considered useful, aggregated tables 
will be provided where different dosages might be grouped.
Details of the primary as well as the secondary analyses will be specified in the trial 
statistical analysis plan (TSAP).
7.3.3
Safety analyses
All treated patients (both Phase I and Phase II) will be included in the safety analyses. Two 
analyses will be performed. The first analysis of safety will be performed for the first part of 
the trial (determination of the MTD, first cycle only, treatment regimen = initial dose at the 
start of the treatment, treated set (Phase I only)). This descriptive analysis will evaluate the 
MTD for the monotherapy of BI 836858 in MDS patients. The second analysis will be 
performed with respect to all cycles and will act as a support for the determination of the 
MTD (treated set (both Phase I and Phase II)). In addition a sensitivity analysis for the 
second expansion cohort will be conducted. Further details will be described in the TSAP.
Events that started within the period starting with the first administration of the treatment 
and ending four weeks (30 days) after the last administration of treatment will be considered 
as having occurred on treatment. In general, later events will be attributed to the post-study 
period and will be presented separately. However, post-study events will be examined to 
determine whether they need to be combined with on-treatment events in an additional table.
Adverse events will be graded according to CTCAE Version 4.0 (R09-2850) and reported 
according to BI standards. Frequency, severity, and causal relationship of adverse events 
will be tabulated by system organ class and preferred term after coding according to the 
current version of the Medical Dictionary for Drug Regulatory Activities (MedDRA).
Serious adverse events will be tabulated. In addition, events leading to dose reduction or 
treatment discontinuation will be examined, but may not be reported as individual tables, 
depending upon the extent of overlap. Descriptive statistics will be used to describe changes 
in laboratory tests over time. In addition, all abnormalities of potential clinical significance 


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will be reported. In general, potential clinical significance is defined as at least CTCAE
Grade 2 and an increase in CTCAE classification from baseline. 
 
7.3.4
Interim analyses
7.3.4.1
Phase I
In the Phase I, interim safety evaluations will be performed as considered necessary. In 
particular safety evaluations will be performed after each dose cohort by the DSB consisting 
of the investigators and representatives of the sponsor (refer to Section 3.1.1). Based on this 
the DSB will recommend the next dose level as well as the corresponding cohort size. DSB 
meeting minutes and outputs provided for these DSB meetings will be documented and 
archived in the clinical trial master file (CTMF).
A Phase I safety analysis report will be prepared prior to the initiation of Phase II. A 
summary of safety and efficacy from the dose escalation cohorts and from the expansion 
cohorts will be included in the Phase I safety analysis report. Results of this evaluation will 
be documented, archived and made available for Health Authority and Ethics 
Committee/IRB review and approval (where applicable) and to all investigators who 
participate in the Phase II. Such an analysis will be defined in more detail in the TSAP.
7.3.4.2
Phase II
After approximately 100 patients are evaluable for the primary endpoint, an internal DMC
consisting of representatives of the sponsor will perform an interim analysis for internal 
project purposes. At this time point it will be evaluated whether the results so far necessitate 
adjustments in the total sample size. Results of this analysis will be kept confidential and 
will not be communicated to the trial team and the investigators. No interim Clinical Trial 
Report (CTR) will be provided. Further details of these analyses will be specified in the 
statistical analysis plan and the DMC charter.


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7.4
HANDLING OF MISSING DATA
No imputation will be performed on missing efficacy data.


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Missing baseline laboratory values will be imputed by the respective values from the 
screening visit. No other imputations will be performed on missing data although every 
effort will be made to obtain complete information on all adverse events and to follow-up 
the patients for efficacy data.
7.5
RANDOMIZATION
Randomization will be performed in the phase II part of this trial only. In Phase I, doses will 
be assigned based on the decision made by the DSB (see Section 7.3.4.). In Phase II, the 
randomization ratio is 1:1 for the two treatment arms, i.e. BI 836858 plus BSC vs. BSC 
alone, per investigator’s choice. Randomization will be stratified by number of previous 
lines of MDS therapy (0, 1, ≥ 2), where previous MDS therapy also includes previous ESA 
therapy. Randomization will be performed using IVRS/IWRS. Boehringer Ingelheim 
Pharma GmbH & Co. KG, Clinical Trial Support Group or a CRO appointed by the Sponsor 
will provide the randomization lists using a validated randomization number generating 
system. Access to the randomization codes will be controlled and documented.
7.6
DETERMINATION OF SAMPLE SIZE
7.6.1 
Determination of the maximum tolerated dose
A maximum of 50 patients (including patients at MTD) will be expected for the dose 
finding part. Fewer patients might be needed based on the recommendation of the DSB and 
the criteria specified (see Section 7.1)
7.6.2 
Calculation of phase II sample size
For the estimation of patient number in the second part we assume a RBC transfusion 
independency rate in the BI 836858 arm of 35% compared to a RBC transfusion 
independency rate in the BSC arm of 5%. Based on these assumptions and a sample size of 
2x75=150 patients overall the probability of observing an unadjusted difference in RBC 
transfusion independency rates of more than 25% is approximately 81%. On the other hand, 
if the true RBC transfusion independency rates are assumed to be 35% both in the BI 
836858 arm and the BSC arm, the probability for observing a difference in RBC transfusion 
independency rate between the two arms of more than 25% is smaller than 1%. Different 
scenarios and resulting probabilities for observing a difference in RBC transfusion 
independency rates of more than 25% are given in Table 7.6.1.
In summary, a sample size of 2x75=150 patients is considered to be sufficient to clearly 
differentiate between the two treatment arms in case that a pronounced treatment benefit of 
BI 836858 exists. On the other hand, if there is no or only a small benefit for BI 836858 
compared to the BSC arm, the sample size is large enough such that the probability for 
falsely observing a beneficial outcome for the BI 836858 arm is sufficiently small.


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Table 7.6: 1
Evaluation of the probabilities of observing a treatment difference in RBC 
transfusion independency rate depending on assumed response rate and sample size.
Assumed 
RBC 
Transfusion 
Independency 
Rate BI
836858
Assumed RBC 
Transfusion 
Independency 
Rate Inv. 
Choice, BSC
Sample 
Size BI 
836858
Sample Size Inv. Choice, 
BSC
Probability observing 
difference in RBC 
Transfusion 
Independency Rate
bigger than 25%
0. 35
0.05
75
75
0.81
0. 30
0.05
75
75
0.52
0. 40
0.05
75
75
0.95
0. 35
0.35
75
75
<0.01
0. 35
0.25
75
75
0.02
0. 35
0.15
75
75
0.25
0.2
0.05
75
75
0.03
Probabilities based on simulations (n= 100000 iterations) using SAS v.9.3.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study patients against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should 
be published prior to finalisation of the Clinical Trial Report.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of 
the informed consent and any additional patient information must be given to each patient or 
the patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML), Clinical Research Associates (CRA) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB / IEC members, and by 
inspectors from regulatory authorities.


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8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients may be provided by the sponsor, either on 
paper or via remote data capture (RDC). For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the trial; also 
current medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory 
and medical test results must be available at all times for review by the sponsor’s clinical 
trial monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents 
described in Section 8.3.1.
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. 
The current version of the Investigator’s Brochure (U11-2766) for BI 836858 and reference 
documents are filed in the Investigator Site File (ISF). No AEs are classified as listed for 
matching placebo, study design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 


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regulatory requirements. Further details regarding this reporting procedure are provided in 
the Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified
about the end of the trial (last patient/patient out, unless specified differently in Section
6.2.3 of the CTP) or early termination of the trial. 


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P17-02032
Eksioglu, E A, Chen, X, Heider, K-H, Rueter, B, McGraw, K L, Basiorka, A 
A, et al. Novel therapeutic approach to improve hematopoiesis in low risk 
MDS by targeting MDSCs with the Fc-engineered CD33 antibody BI 
836858.  Leukemia 2017; 31(10), 2172-2180.
R09-2850
Common terminology criteria for adverse events (CTCAE) version 4.0 (NHI 
Publication NO. 03-5410, publish date: May 28, 2009). U.S.Department of 
Health and Human Services, National Institutes of Health, National Cancer 
Institut; 2009
R10-4428
Chung CH. Managing premedications and the risk for reactions to infusional 
monoclonal antibody therapy. Oncologist 13, 725 - 732 (2008)
R10-4517
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the 
management of pediatric and adult tumor lysis syndrome: an evidence-based 
review. J Clin Oncol 26 (16), 2767 - 2778 (2008)
R10-6267
Wang DD, Zhang S, Zhao H, Men AY, Parivar K.  Fixed dosing versus body 
size-based dosing of monoclonal antibodies in adult clinical trials. J Clin 
Pharmacol 49, 1012 - 1024 (2009)
R11-1106
Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, 
Odchimar-Reissig R, et al. Randomized controlled trial of azacitidine in 
patients with the myelodysplastic syndrome: a study of the Cancer and 
Leukemia Group B. J Clin Oncol 2002; 20 (10):2429-2440.
R11-1467
Crocker PR, Zhang J. New I-type lectins of the CD33-related siglec subgroup 
identified through genomics. Biochem Soc Symp 69, 83 - 94 (2002)
R11-1468
Scheinberg DA, Tanimoto M, McKenzie S, Strife A, Old LJ, Clarkson BD.  
Monoclonal antibody M195: a diagnostic marker for acute myelogenous 
leukemia. Leukemia 3 (6), 440 - 445 (1989)
R11-1469
Hauswirth AW, Florian S, Printz D, Sotlar K, Krauth MT, Fritsch G, et.al. 
Expression of the target receptor CD33 in CD43+/CD38-/CD123+ AML 
stem cells. Eur J Clin Invest 37 (1), 73-82 (2007)
R11-1470
Plesa C, Chelghoum Y, Plesa A, Elhamri M, Tigaud I, Michallet M, 
Dumontet C, Thomas X Prognostic value of immunophenotyping in elderly 
patients with acute myeloid leukemia: a single-institution experience. Cancer 
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R11-1471
Raza A, Jurcic JG, Roboz GJ, Maris M, Stephenson JJ, Wood BL, et al. 
Complete remissions observed in acute myeloid leukemia following 
prolonged exposure to lintuzumab: a phase 1 trial. Leuk Lymphoma 50 (8), 
1336 - 1344 (2009)
R11-2960
Webber BA, Cushing MM, Li S. Prognostic significance of flow cytometric 
immunophenotyping in acute myeloid leukemia. Int J Clin Exp Pathol. 2008. 
1(2): 124-133.
R13-0364
Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, et al.
Epidemiology of myelodysplastic syndromes and chronic myeloproliferative 
disorders in the United States, 2001 - 2004, using data from the NAACCR 
and SEER programs. Blood 112 (1), 45 - 52 (2008)
R13-0369
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, 
Nimer SD, et al. Clinical application and proposal for modification of the 
International Working Group (IWG) response criteria in myelodysplasia.  
Blood 108 (2), 419 - 425 (2006)
R13-0373
Garcia-Manero G, Shan J, Faderl S, Cortes J, Ravandi F, Borthakur G, et al. 
A prognostic score for patients with lower risk myelodysplastic syndrome.  
Leukemia 22, 538 - 543 (2008)
R13-0374
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al.
International scoring system for evaluating prognosis in myelodysplastic 
syndromes. Blood 89 (6), 2079 - 2088 (1997)
R13-0375
Greenberg PL, et al.  Revised International Prognostic Scoring System for 
myelodysplastic syndromes.  Blood 120 (12), 2454 - 2465 (2012)
R13-0377
Komrokji RS, Sekeres MA, List AF. Management of lower-risk 
myelodysplastic syndromes: the art and evidence. Curr Hematol Malign Rep 
6, 145 - 153 (2011)
R13-0382
Nimer SD. Myelodysplastic syndromes. Blood 111 (10), 4841 - 4851 (2008)
R13-4724
Chen X, Eksioglu EA, Zhou J, Zhang L, Djeu J, Fortenbery N, et al. 
Induction of myelodysplasia by myeloid-derived suppressor cells. Journal of
Clinical Investigaton, Published October 15, 2013, doi: 10.1172/JCI67580; 
(2013)
R13-4802
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a 
comparison of trial designs. Cancer Chemother Pharmacol 71, 1107 - 1114 
(2013)
R13-4803
Neuenschwander B, Branson M, Gsponer T.  Critical aspects of the Bayesian 
approach to phase I cancer trials.  Stat Med 27, 2420 - 2439 (2008)


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R13-4804
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A.  
Translation of innovative designs into phase I trials.  J Clin Oncol 25 (31), 
4982 - 4986 (2007)
R13-4805
Tourneau C le, Gan HK, Razak ARA, Paoletti X.  Efficiency of new dose 
escalation designs in dose-finding phase I trials of molecularly targeted 
agents. Plos One 7 (12), e51039 (2012)
R13-4806
Babb J, Rogatko A, Zacks S.  Cancer phase I clinical trials: efficient dose 
escalation with overdose control.  Stat Med 17, 1103 - 1120 (1998)
R13-4881
FDA’s critical path initiative (page last updated: 12/28/2012). 
http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/uc
m07668 9.htm (access date: 8 November 2013); Silver Spring: U.S. Food and 
Drug Administration (2012)
R14-0080
Eastern Cooperative Oncology Group (ECOG) ECOG performance status 
(revised: July 27, 2006). http://ecog.dfci.harvard.edu/general/perf_stat.html 
(access date: 7 January 2014); Eastern Cooperative Oncology Group (ECOG) 
(2006)
R17-1501
Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ, et al. 
Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and 
intermediate-1-risk myelodysplastic syndromes with karyotypes other than 
deletion 5q. Blood 2008; 111 (1): 86-93. 
R17-1502
Gang AO, Frosig TM, Brimmes MK, Lyngaa R, Treppendahl MB, Gronbaek 
K, et al. 5 –Azacytidine treatment sensitizes tumor cells to T-cell mediated 
cytotoxicity and modulates NK cells in patients with myeloid malignancies. 
Blood Cancer J 2014; 4:e197. 
R17-1503
Gao X, Lin J, Wang Ll, Yu L. Demethylating treatment suppresses natural 
killer cell cytolytic activity. Mol Immunol 2009; 46: 2064-2070. 
R17-1504
Jabbour EJ, Garcia-Manero G, Strati P, Mishra A, Ali NH al, Padron E, et al. 
Outcome of patients with low-risk and intermediate-1-risk myelodysplastic 
syndrome after hypomethylating agent failure: a report on behalf of the MDS 
Clinical Research Consortium. Cancer 2015; 121 (6):876-882. 
R17-1505
List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, et al. Efficacy 
of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352 
(6):549-557. 
R17-1506
Park S, Hamel JF, Toma A, Kelaidi C, Thepot S, Diez Campelo M, et al. 
Outcome of lower-risk patients with myelodysplastic syndromes without 5q 
deletion after failure of erythropoiesis-stimulating agents. Journal of Clinical 
Oncology, published online before print March 28, 2017, doi: 
10.1200/JCO.2016.71.3271; 2017.


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R17-1507
Santini V, Almeida A, Giagounidis A, Groepper S, Jonasova A, Vey N, et al. 
Randomized phase III study of lenalidomide versus placebo in RBC 
transfusion-dependent patients with lower-risk non del (5q) mylodysplastic 
syndromes and ineligible for or refractory to erythropoiesis-stimulating 
agents. J Clin Oncol 2016; 34 (25): 2988-2996.
R17-1508
Thepot S, Abdelali RB, Chevret S, Renneville A, Beyne-Rauzy O, Prebet T, 
et al, Groupe Francophone des Myelodysplasies (GFM). A randomized phase 
II trial of azacitidine +/- epoetin-beta in lower-risk myelodysplastic
syndromes resistant to erythropoietic stimulating agents. Haematologica 
2016; 101 (8):918-925.
R17-1509
Garcia-Manero G, Jabbour E, Borthakur G, Faderl S, Estrov Z, Yang H, et al. 
Randomized open-label phase II study of decitabine in patients with low- or 
intermediate-risk myelodysplastic syndromes. J Clin Oncol 2013:31 
(20):2548-2553. 
R17-1510
Imrichova D, Messingerova L, Seres M, Kavcova H, Pavlikova L, Coculova 
M, et al. Selection of resistant acute myeloid leukemia SKM-1 and MOLM-
13 cells by vincristine-, mitoxantrone- and lenalidomide-induced 
upregulation of P-glycoprotein activity and downregulation of CD33 cell 
surface exposure. Eur J Pharm Sci 2015:77:29-39.
R17-1521
Toma A, Kosmider O, Chevret S, Delaunay J, Stamatoullas A, Rose C, et al. 
Lenalidomide with or without erythropoietin in transfusion-dependent 
eythropoisesis-stimulating agent-refractory lower-risk MDS without 5q 
deletion. Leukemia 2016; 30:897-905.
9.2
UNPUBLISHED REFERENCES


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10.
APPENDICES
10.1
CLINICAL EVALUATION OF LIVER INJURY
10.1.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (AESI) are to be 
further evaluated using the following procedures: 
10.1.2
Procedures
Repeat the following lab tests: ALT, AST, and bilirubin (total and direct) - within 48 to 
72hours. If ALT and/or AST ≥3 fold ULN combined with an elevation of total bilirubin ≥2 
fold ULN (for normal values at baseline/screening) are confirmed, results of the laboratory 
parameters described below must be made available to the investigator and to BI as soon as 
possible.
In addition,

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF

obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets according to the “DILI checklist” provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the “DILI checklist” provided in the ISF;
and report these via the CRF.
Provide abdominal ultrasound or other appropriate imaging to rule out biliary tract, 
pancreatic or intrahepatic pathology, e.g. bile duct stones or neoplasm.
Clinical chemistry
alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferrin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (RNA), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-HCV, RNA), 
Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-
HEV IgM positive), Cytomegalovirus (repeat CMV DNA), Anti-Smooth Muscle antibody 
(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody
Hormone
Thyroid stimulating hormone


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Haematology
White blood count + differential, haemoglobin, thrombocytes
In case AST/ALT remain elevated and the previous testing does not provide a likely cause 
for the elevation, the following tests should be performed: Epstein Barr Virus (VCA IgG, 
VCA IgM), herpes simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), 
toxoplasmosis (IgG, IgM).
Initiate close observation of patients by repeat testing of ALT, AST, and total bilirubin (with 
fractionation by total and direct) at least weekly until the laboratory ALT and / or AST 
abnormalities stabilize or return to normal, then according to the protocol. Depending on 
further laboratory changes or additional parameters identified, follow-up should be based on 
medical judgement and Good Clinical Practice (GCP).
10.2
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS
ECOG PERFORMANCE STATUS
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair
5
Dead
10.3
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS
The model was assessed by two different metrics: hypothetical on-study data scenarios and 
long-run operating characteristics. 
Hypothetical data scenarios


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Hypothetical data scenarios are shown in Table 10.3: 1. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model and the 100% 
escalation limit. For each scenario, the probability of overdose for the current dose, as well 
as the next potential dose and related probabilities of under-dosing, target dose and over-
dosing are shown. 
For example, scenario 1 represents the case that no DLT is observed in three patients at the 
starting dose of 20mg. In this case, the next dose permitted by the model and by the 100% 
escalation rule is 40mg. Similarly, scenario 5 represents the case that no DLTs are observed 
in the first cohort of three patients at 20mg, and 1 DLT is observed in the second cohort of 3 
patients at 40mg. In this case, the model requires to re-enroll at the current dose level of 
40mg. Scenario 7 shows the case that 1 DLT is observed in three patients at the starting dose 
of 20mg and 1 DLT is observed in the second cohort of three patients at the same dose level 
of 20mg. The model then allows a de-escalation to 10mg.
Finally, scenario 8 and 9 illustrate a case where no DLTs are seen in the first four cohorts, 
and then 2 DLTs occur in 3 patients in the next cohort. Based on scenario 8, the model and 
the 100% escalation limit allow to escalate up to 320mg. In scenario 9, it is then assumed 
that 2 DLTs occur at this dose level. Despite the fact that no DLTs were seen in the previous 
four cohorts (12 patients in total), the model reacts immediately to the data observed at 
320mg and requires a de-escalation to 160mg. This case illustrates the adaptive behaviour of 
the model even in extreme situations.
Table 10.3: 1
Hypothetical data scenarios
Scenario
Dose 
(mg)
# DLT
# Pat
Current 
Dose: 
P(OD)
Next 
Dose
Next Dose
P(UD)
P(TD)
P(OD)
1
20
0
3
0.010
40
0.914
0.062
0.024
2
20
1
3
0.222
20
0.503
0.275
0.222
3
20
2
3
0.668
N/A
N/A
N/A
N/A
4
20
40
0
0
3
3
0.004
80
0.894
0.080
0.026
5
20
40
0
1
3
3
0.102
40
0.639
0.259
0.102
6
20
40
0
2
3
3
0.369
20
0.470
0.349
0.181
7
20
20
1
1
3
3
0.289
10
0.484
0.347
0.168
8
20
40
80
160
0
0
0
0
3
3
3
3
0.016
320
0.625
0.156
0.219


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Table 10.3: 1
Hypothetical data scenarios (cont.)
Scenario
Dose 
(mg)
# DLT
# Pat
Current 
Dose: 
P(OD)
Next 
Dose
Next Dose
P(UD)
P(TD)
P(OD)
9
20
40
80
160
320
0
0
0
0
2
3
3
3
3
3
0.709
160
0.688
0.259
0.053
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model. Under an 
assumed true dose-toxicity curve, metrics such as the probability of recommending a dose 
with true DLT rate in the target interval can be approximated via simulation. Table 10.3: 2
describes 5 assumed true dose-toxicity scenarios which were used to assess the operating 
characteristics of the model. These scenarios reflect a wide range of possible cases as 
follows:
- Scenario 1: aligned with prior means
- Scenario 2: high-toxicity scenario
- Scenario 3: low-toxicity scenario
- Scenario 4: non-logistic dose-toxicity scenario
- Scenario 5: low-tox followed by high-tox
Table 10.3: 2
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
10
20
40
80
160
320
1 (Prior)
P(DLT)
0.057
0.072
0.094
0.133
0.215
0.365
2 (High Tox)
0.120
0.20
0.320
0.440
0.550
0.680
3 (Low Tox)
0.020
0.040
0.080
0.100
0.140
0.250
4 (Non-Logistic)
0.050
0.080
0.130
0.280
0.320
0.380
5 (Low-High)
0.020
0.040
0.080
0.320
0.440
0.550
Bold numbers indicate true DLT rates in the target interval [0.16-0.33).


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For each of these scenarios, 1000 trials were simulated. It was then assessed how often a 
dose was declared as MTD with true DLT rate in the under-, targeted or over-dose range. 
Furthermore, the average, minimum and maximum number of patients per trial and the 
average number of DLTs per trial are reported. Results are shown in Table 10.3: 3.
Table 10.3: 3
Simulated operating characteristics
Scenario
% of trials declaring an MTD with true DLT 
rate in
# Patients
# DLT
underdose
target dose
overdose
STOPPED
Mean
(Min-Max)
Mean
(Min- Max)
1
45.1
42.5
10.7
1.7
23.05
(3 – 39)
3.674
(1 – 8)
2
3.7
62.6
10.4
23.3
15.61
(3 – 33)
4.384
(2 – 10)
3
68.3
31.3
0
0.4
24.74
(3 – 45)
3.169
(1 – 9)
4
34.5
59.5
3.5
2.5
20.99
(3 – 39)
4.162
(1- 10)
5
35.0
56.6
8.0
0.4
21.09
(3 – 39)
4.328
(1 – 11)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
42.5% of the simulated trials declared a dose as MTD with true DLT rate in the targeted 
dose range. Since 80mg has a DLT probability of 0.133 which is relatively close to the 
lower bound of the target interval (0.16), this dose was identified quite often as MTD,
namely in 36.1% of the simulated cases. When considering this as an MTD as well, the 
target rate would add up to 78.6%.
In Scenario 2 (high-toxicity scenario), the starting dose has already >10% probability of 
observing at least 2 DLTs in the first cohort. This contributes to the high percentage (23.3%) 
of all simulated trials for which the trial is stopped since none of the doses is considered 
tolerable anymore. This is an expected situation for a high-toxicity scenario.
Scenario 3 (low-toxicity scenario) shows a similar effect as for Scenario 1. The probability 
of observing a DLT at 160mg is 0.14 and therefore close to the lower bound of the target 
interval. Adding up the corresponding probability of declaring this dose as an MTD (45.0%) 
leads to a target rate of 76.2%.
In scenarios 4 and 5, more than 50% of the simulated trials declared a dose as MTD with 
true DLT rate in the targeted dose range.
The mean patient numbers range from 15.6 patients (high-toxicity scenario) to 24.7 patients 
(low-toxicity scenario) and the maximum number of patients was 45. Therefore, the patient 
numbers are as expected and increase when moving away from the high-toxicity scenario. 


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In summary, the considered data scenarios show a reasonable behavior of the model and the 
operating characteristics demonstrate a good precision of MTD determination. 


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1 
GLOBAL AMENDMENT 1
.
Number of global amendment
1
Date of CTP revision
20 AUG 2015
EudraCT number
N/A
BI Trial number
1315.7
BI Investigational Product(s)
BI 836858
Title of protocol
A Phase I/II, Multicenter, Open-Label, Dose 
Escalation and Randomized Trial of BI 836858 in 
Patients with Low or Intermediate-1 Risk 
Myelodysplastic Syndromes
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
Title Page
Description of change
Status has been updated:
“Trial Protocol” replaced with  “Revised 
Protocol (based on Global Amendment 01)”
Version and Date have been updated:
Version 1.0 replaced with Version 2.0; Date 
06Mar2014 to be replaced with 13Aug2015
Rationale for change
Update
Section to be changed
Headers
Description of change
Added the extension “-03” to the c02304070 
document number.


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Number of global amendment
1
Rationale for change
The “01” and “-02” version of the document 
number were inadvertently omitted in the 
previous version of the protocol.  The current 
amendment  reflects the new document number of 
“-03”.
Section to be changed
Synopsis -Diagnosis
Description of change
For Phase I and Phase II:  Further clarify patients 
eligible for this trial and added “are refractory to 
or are not amenable or eligible for approved MDS 
therapy”
Rationale for change
Revised entry criteria based on FDA feedback
Section to be changed
Synopsis – Main Criteria for Inclusion
Description of change
For Phase I and Phase II:  Further clarify patients 
eligible for this trial  and added “are refractory to 
or are not amenable or eligible for approved MDS 
therapy”
Rationale for change
Revised entry criteria based on FDA feedback
Section to be changed
Synopsis – Criteria for Efficacy
Description of change
Rationale for change
Clarification and Update
Section to be changed
Flow Chart – Introduction Treatment
Description of change
Clarified the collection of “other MDS therapies” 
during follow-up is for Phase II only.
Rationale for change
Updated 
Section to be changed
Flow Chart – Introduction Treatment
Description of change
Revised the timing of EOT visits from 28 days (+ 
7 days) to 30 days (+ 7 days) after last 
administration of BI 836858.
Rationale for change
Boehringer-Ingelheim Standards
Section to be changed
Flow Chart – Introduction Treatment
Description of change
Revised the Follow-up period for Phase I patients: 


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Follow-up starts 4 weeks after the EOT visit; 
Phase I patients: visits or telephone calls will 
occur at least every 4 weeks for 6 months.  After 
the 6th follow-up visit, the patient will be 
considered off trial.  Phase II patients: visits or 
telephone calls will occur at least every 4 weeks 
until 12 months after the last administration of BI 
836858, after which these visits will occur every 
6 months until the end of the trial
Rationale for change
Clarification and Update
Section to be changed
Flow Chart – Introduction Treatment
Description of change
Revised Footnote #4 to include an additional 
safety lab to be performed 24 hours after intra-
patinets dose esacaltion occurs:  “For details refer 
to Section 5.2.3.1. Urine has to be measured only 
at screening, EOC4 and EOT.  Safety laboratory 
assessments may be completed up to 2 days prior 
to administration, or BSC treatment on trial 
(Phase II). An additional safety lab will be 
collected on day 2 (i.e., 24 hours after the first 
administration of BI 836858) and 24 hours after 
the first higher dose for patients who participate 
in intra-patient dose escalation. Other lab tests to 
be included: haptoglobin, direct Coombs test, and 
bilirubin (direct and indirect)”
Rationale for change
Clarification and Update
Section to be changed
Flow Chart – Introduction Treatment
Description of change
Further clarified  Footnote #8 to note timing of 
EOT ECGs and Bone marrow aspirate to include 
reference to introduction Cycles 5 and 6 “ECG 
and bone marrow aspiration will be performed at 
EOT only if the patient has completed at least 2 
cycles (e.g. received 4 administrations) since the 
EOC4 visit” (or additional introduction cycle 5 
and 6).
Rationale for change
Clarification and Update
Section to be changed
Flow Chart – Introduction Treatment
Description of change
Updated Vital Assessment in flowchart to remove 
text on Overall survival.  Clarification on Phase I 
vs Phase II survival data collection covered under 
FU: Follow-up footnote. Updated Footnote #20 to 
clarify overall survival to be collected from Phase 
II patients only.  “Overall Survival for Phase II 
Patients only”
Rationale for change
Clarification and Update


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Section to be changed
Flow Chart – Maintenance
Description of change
Clarified the collection of “other MDS therapies” 
during follow-up is for Phase II only.
Rationale for change
Updated
Section to be changed
Flow Chart – Maintenance
Description of change
Revised the Follow-up period for Phase I patients:
Follow-up starts 4 weeks after the EOT visit; 
Phase I patients: visits or telephone calls will 
occur at least every 4 weeks for 6 months.  After 
the 6th follow-up visit, the patient will be 
considered off trial.  Phase II patients:  visits or 
telephone calls will occur at least every 4 weeks 
until 12 months after the last administration of BI 
836858, after which these visits will occur every 
6 months until the end of the trial Follow-up starts 
4 weeks after the EOT visit; visits or telephone 
calls will occur at least every 4 weeks until 12 
months after the last administration of BI 836858, 
after which these visits will occur every 6 months.
Rationale for change
Clarification and Update
Section to be changed
Flow Chart – Maintenance
Description of change
Further clarified Footnote #4 to note timing of 
EOT ECGs and Bone marrow aspirate to include 
reference to  introduction Cycles 5 and 6 ECG 
and bone marrow aspiration will be performed at 
EOT only if the patient has completed at least 2 
cycles (e.g. received 2 administrations) since the 
EOC4 visit (or additional introduction cycle 5 and 
6).
Rationale for change
Clarification and Update
Section to be changed
Flow Chart – Maintenance
Description of change
Clarified Footnote#5 and collection of AEs during 
REP: Follow-up of AEs not recovered since the 
EOT.  Follow-up of new AEs that occurred 
during REP.  Concomitant therapy during FU is 
collected only if indicated for treatment of 
adverse event.
Rationale for change
Clarification and Update
Section to be changed
Flow Chart – Maintenance
Description of change
Updated Footnote #12 to clarify overall survival 
to be collected from Phase II patients only.
Overall Survival for Phase II Patients only
Rationale for change
Clarification and Update
Section to be changed


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1
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Abbreviations
Description of change
Added one abbreviation to distinguish between 
Progressive Disease and Pharmacodynamics 
Added: pd: Pharmacodynamics
Rationale for change
Clarification
Section to be changed
2.2 Trial Objectives
Description of change
Added additional eligibility language: “The Phase 
I primary objectives of the trial are to determine 
the maximum tolerated dose (MTD) and the 
Recommended Phase II Dose (RP2D) to be used 
in the Phase II. Secondary objectives include 
safety, pharmacokinetics, exploratory biomarkers 
and efficacy of BI 836858 monotherapy in 
patients with low or intermediate-1 risk MDS 
with symptomatic anemia, who at a minimum, 
experienced ESA treatment failure or do not 
qualify (serum erythropoietin level > 500 U) for 
ESA treatment and are refractory to or are not 
amenable or eligible for approved MDS therapy.  


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Patients with a deletion 5q cytogenetic 
abnormality will be allowed in Phase I who do 
not qualify for lenalidomide treatment (Absolute 
Neutrophil Count (ANC) < 500/µL or platelets 
<50,000/µl) or who experience primary 
lenalidomide failure.  lenalidomide failure is 
defined as lack of hematological improvement 
after 4 months of therapy, or secondary failure 
defined as loss of prior lenalidomide response at 
any time point.”
And
In the randomized Phase II, primary objectives 
are to investigate the efficacy of BI 836858 plus 
Best Supportive Care (BSC) vs. Best Supportive 
Care alone, in low or intermediate-1 risk MDS 
patients with symptomatic anemia without a 
deletion 5q cytogenetic abnormality who are 
previously untreated or who progressed/became 
resistant following ESA, and are refractory to or 
are not amenable or eligible for approved MDS 
therapy. Secondary objectives include the 
investigation of safety and tolerability of BI 
836858 in this patient population.
Rationale for change
Revised entry criteria based on FDA feedback
Section to be changed
2.3 Benefit-Risk Assessment
Description of change
Clarified eligibility criteria by deleting 5-AZA 
and replacing with Hypomethylating Agents 
(HMA): MDS are a heterogeneous group of 
clonal neoplasms with a patient median age at 
diagnosis of  > 70 years.  ESA remain the first-
line treatment of anemia in most lower-risk MDS 
patients without del 5q. Responses to ESA 
treatment is transient, but interestingly, 
approximately 70% of the relapses of anemia 
after initial response to EPO are not associated 
with progression to higher-risk MDS but simply 
to loss of sensitivity of erythroid progenitors to 
EPO. Despite considerable progress in 
understanding the etiology and biologic behavior 
of lower risk MDS, BSC is still the standard of 
care for patients progressing after treatment with 
EPO or 5-azaHypomethylating Agents (HMA) in 
countries where it is available.
Rationale for change
Revised entry criteria based on FDA feedback
Section to be changed
3.1 Overall Trial Design and Plan


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Description of change
Added additional eligibility language 
Phase I:
In Phase I, patients with low to intermediate-1 
risk MDS, who have, at a minimum, experienced 
ESA treatment failure, except for patients who do 
not qualify for ESA treatment  and are refractory 
to or are not amenable or eligible for approved 
MDS therapy, will be assigned to a dose cohort 
under investigation.  Treatment failure on ESAs is 
defined as 1) failure or ceasing to show 
hematologic response after at least 8 weeks of 
40,000 to 60,000 IU/week of erythropoietin 
(EPO) or equivalent or 2) low chance/response to 
ESA with endogenous serum EPO>500.   It is 
expected that approximately 50 patients will be 
enrolled.
Rationale for change
Revised entry criteria based on FDA feedback
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
Updated stratification factor and stratification 
levels: Patients also must have experienced 
treatment failure on ESAs, except for patients 
who do not qualify for ESA treatment. As defined 
above, treatment failure on ESAs is defined as 1) 
failure or ceasing to show hematologic response 
after at least 8 weeks of 40,000 to 60,000 
IU/week of erythropoietin (EPO) or equivalent or 
2) low chance/response to ESA with endogenous 
serum EPO>500.  Randomization will be 
stratified by number of previous lines of MDS 
therapy (0, 1, >=2), where previous MDS therapy 
also includes previous ESA therapy (refer to 
Section 7.5).  A total of 150 patients, 75 each arm, 
will be enrolled in Phase II.
Rationale for change
Revised Phase II Stratification levels in response 
to FDA feedback on potential patients eligible for 
trial. 
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
Updated eligibility language and stratification 
levels for Phase II:
In Phase II, patients will be enrolled in a 
randomized manner to investigate efficacy and 
safety of BI 836858 at RP2D in patients either 
previously untreated or following 
progression/resistance after the treatment with 
ESAs and/or approved MDS drugs such as 


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HMAs5-aza. Treatment failure on 5-azaHMA is 
defined as 1) no response after at least four cycles 
of 5-azaHMA, 2) progression of disease on 5-
azaHMA or 3) Grade 3-4 non-hematologic 
toxicity. Patients also must have experienced 
treatment failure on ESAs, except for patients 
who do not qualify for ESA treatment. As defined 
above, treatment failure on ESAs is defined as 1) 
failure or ceasing to show hematologic response 
after at least 8 weeks of 40,000 to 60,000 
IU/week of erythropoietin (EPO) or equivalent or 
2) low chance/response to ESA with endogenous 
serum EPO>500.  Randomization will be 
stratified by number of previous lines of MDS 
therapy (0, 1, >=2), where previous MDS therapy 
also includes previous ESA therapy Patients are 
stratified by no previous MDS therapy vs. 
previous ESA and/or 5-aza therapy (refer to 
Section 7.5).  A total of 150 patients, 75 each arm, 
will be enrolled in Phase II.
Rationale for change
Revised Phase II eligibility and Stratification 
levels in response to FDA feedback on potential
patients eligible for trial.
Section to be changed
3.1.1.1 Phase I
Description of change
Added additional eligibility language: 
Adult patients with low to intermediate-1 risk 
MDS, according to International Working Group 
(IWG) criteria, who, at a minimum, experienced 
ESA treatment failure, except for patients that do 
not qualify for ESA treatment and are refractory 
to or are not amenable or eligible for approved 
MDS therapy, will be enrolled for the Phase I.  
Approximately three Phase I sites in the United 
States will participate in the Phase I.
Rationale for change
Revised entry criteria based on FDA feedback
Section to be changed
3.1.1.1 Phase I
Description of change
Clarified what data may and will be available for 
the DSB meetings:  The Phase I dose-escalation 
will be guided by a Bayesian logistic regression 
model (BLRM) with overdose control (refer to 
Section 7).  The DSB will consist of the Phase I 
investigators, Team Member Medicine (TMM), 
Trial Clinical Monitor (TCM), Project 
Statistician, Clinical Pharmacological Project 
Lead (CPPL) and TransMed Expert (TME).  The 


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1
information on the overdose risk will be presented 
by the trial statistician to the DSB. Additional 
information, such as lower grade adverse events, 
pharmacokinetics (PK), if available, progressive 
disease (PD), individual patient profiles and other 
relevant information will also be presented. Based 
on this information, the members of the DSB will 
reach a joint decision on the next dose level to be 
investigated. This dose level may be above, below 
or identical to the currently investigated dose 
level. The DSB will also recommend the size for 
the next cohort. However, the final decision on 
the next cohort size will be made by a mutual 
decision between the TMM and the Coordinating 
Investigator (CI).  Minutes of the DSB meetings 
and recommendations will be documented and 
archived by the TCM. 
Rationale for change
Clarification and Update
Section to be changed
3.1.1.2  Phase II
Description of change
Updated eligibility language:
Adult patients with low to intermediate-1 risk 
MDS, who received no prior treatment or 
progressed/become resistant after ESA and/or 
approved MDS drugs, such as HMAs 5-aza 
treatment will be included in the Phase II.  
Approximately 20 sites from United States and 
select European countries will participate in the 
Phase II.
Rationale for change
Revised entry criteria based on FDA feedback
Section to be changed
3.2 Discussion of Trial Design, Including the 
Choice of Control Group(s) 
Description of change
Revise language on intra-patient dose escalation.  
Intra-patient dose escalation will not be allowed. 
Single intra-patient dose escalation will be 
permitted.  See Section 4.1.4 for details.
Rationale for change
Clarification and Update
Section to be changed
3.3 Selection Of Trial Population
Description of change
Revised Phase II entry criteria based on FDA 
feedback: Phase II will enter approximately 150 
patients with lower risk MDS who were either 
previously untreated or progressed/became 
resistant following ESA and/or approved MDS 
drugs such as HMAs5-aza treatment.  
Approximately 20 sites from United States and 
European countries are expected to participate in 


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Phase II.
Rationale for change
Revised entry criterion based on FDA feedback
Section to be changed
3.3.2 Inclusion Criteria
Description of change

Revised Inclusion Criterion #1 to 
reflect FDA feedback:  Documented 
diagnosis of MDS according to World 
Health Organization (WHO) criteria 
that meets International Prognostic 
Scoring System (IPSS) classification 
of low or intermediate-1 risk disease as 
determined by microscopic and 
standard cytogenetic analyses of the 
bone marrow and peripheral complete 
blood count (CBC) and who are 
refractory to or are not amenable or 
eligible for approved MDS therapy.
Rationale for change
Revised entry criterion based on FDA feedback
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Revised Inclusion #3 to better clarify entry 
requirements based on previous ESA exposure 
and EPO levels. Replaced Patients must have 
serum erythropoietin level > 500 U/L, or, if ≤ 500 
U/L, patient is non-responsive to, refractory to, or 
intolerant of ESAs, or ESAs are contraindicated 
or unavailable. With Patient is non-responsive to, 
refractory to, or intolerant of ESAs, or ESAs are 
contraindicated or unavailable, or a documented 
serum erythropoietin level of > 500 U/L. 
Rationale for change
Clarification and Update
Section to be changed
3.3.3 Exclusion Criteria
Description of change
Removed Exclusion # 4 to be in line with FDA 
feedback on patients eligible for the trial:
Phase II only: any previous treatment for low or 
intermediate-1 risk MDS with lenalidomide or 
decitabine.
Rationale for change
Revised exclusion criteria based on FDA 
feedback
Section to be changed
4.1.1 Identity of BI investigational product and 
comparator product(s)
Description of change
Clarfied the infusion rates for all infusions on trial 
and added language on stability and maximum 
time allowed for infusions.
The first and second infusionAll infusions will be 
started at a rate of 10 mL/h.  The infusion rate 
should be increased every 30 (+/-10) minutes by 


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10 mL/h to a maximum of 80 mL/h as long as 
tolerated by the patient.  Infusion should not 
exceed 8 hours. If considered safe by the 
Investigator, the stepwise increase of infusion rate 
during the third and subsequent infusions may be 
faster or steps may be omitted, but the maximum 
infusion rate must not exceed 120 mL/h. If 
symptoms of an infusion-related reaction occur, 
the infusion should be temporarily stopped. Upon 
recovery, it should be infused at 50% of the rate 
at which the reaction occurred and should not be 
dose escalated from this dose for at least 30 
minutes. Lower rates may be selected if clinically 
indicated. Depending on the time of occurrence 
and the severity of the reaction, the investigator 
may consider administering additional supportive 
medication, e.g. corticosteroids. A stepwise re-
increase of the infusion rate to a maximum of 80 
mL/h is possible. For medical reasons, in case a 
patient experiences an adverse event during the 
infusion, the duration of the infusion may be 
expanded until the use-by date and use-by time 
indicated on the label is reached. The actual 
duration of the infusions and infusion steps need 
to be documented in the eCRF including actual 
start and end time, actual time points for 
interruption and restart of the infusion and the 
actual infusion rates.  Infusions should not exceed 
8 hours.  In cases where an infusion is ongoing at 
8 hours from the time of the start of infusion, the 
infusion must be stopped and documented.
Rationale for change
Clarification and Updated
Section to be changed
4.1.3 Selection of Doses in the Trial – Phase I  
and Table 4.1.3: 1  Entry of patients into trial, by 
cohort 
Description of change
Replaced enrollment with entry
Rationale for change
Updated based on Boehringer Ingelheim 
standards
Section to be changed
4.1.3 Selection of Doses in the Trial – Phase I
Description of change
Clarified the permitted timing of the start of a 
new patient within a cohort:  A one-week 
observation period must be followed between the 
first administration of BI 836858 and the start of 
treatment of the subsequent patient for all patients 
in the 20 mg cohort.


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Rationale for change
Clarification and Updated
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change
Added language on allowance of intra-patient 
dose escalation and required tests: 
Intra-patient dose escalation may be considered 
after agreement between investigator and sponsor 
for selected patients. It is restricted to patients 
who have completed and received a minimum of 
8 administrations of BI 836858 and tolerate the 
treatment well at the time of dose escalation. 
Intra-patient dose escalation can only be 
performed at a time when the next higher dose 
cohort has been reviewed and considered safe by 
the DSB. The dose escalation step is limited to the 
dose which has been administered to the next 
higher cohort.  Only one dose escalation will be 
permitted for a patient.  Dose escalations can only 
occur on Day 1, or Visit 1 of a cycle.  After the 
first dose at the higher dose level, patients have to 
be monitored for at least 24 hours after the end of 
the infusion, including a safety laboratory 24 
hours after the first administration of the escalated 
dose of BI 836858.  Patients who have escalated 
to a higher dose and who experience toxicities 
may be permitted to reduce back to a lower dose, 
following the criteria described above. Intra-
patient dose escalation of BI 836858 will not be 
allowed in this trial.
Rationale for change
Clarification and Updated
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change
A log of all patients pre-screened and enrolled 
into the study (i.e. having given informed 
consent) will be maintained in the Investigator 
Site File (ISF) at the investigational site 
irrespective of whether they have been treated 
with investigational drug or not.
Rationale for change
Updated based on Boehringer Ingelheim 
standards
Section to be changed
4.2.1 Rescue medication, emergency procedures, 
and additional treatment(s)
Description of change
Clarified use of Growth factors does not include 
ESAs while on trial.
“Rescue medication to reverse the action of BI 


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836858 is not available.  Potential side effects of 
BI 836858 have to be treated symptomatically.  
Patients should receive supportive care according 
to the local guidelines regarding treatment of 
infusion-related reactions, blood product support, 
antibiotics, antivirals, analgesics, skin and mouth 
care, etc.  The use of growth factors such as 
granulocyte colony stimulating factor (G-CSF) 
will be allowed (other than ESAs), but growth
factors should be avoided during the first four 
administrations (2 cycles) for better assessment of 
safety and response parameters.  G-CSF should 
not be given prophylactically.”
Rationale for change
Clarification and Updated
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Clarified use of Growth factors does not include 
ESAs while on trial.
“Patients must not be receiving any concurrent 
treatment for MDS while on study.  Exceptions 
will be made for supportive therapies such as 
transfusions or use of growth factors.   The use of 
colony stimulating factor (G-CSF) will be 
allowed (other than ESAs), but growth factors 
should be avoided during the first four 
administrations (2 cycles) of BI 836858 for better
assessment of safety and response parameters.  G-
CSF should not be given prophylactically.”
Rationale for change
Clarification and Updated
Section to be changed
Description of change
Rationale for change
Section to be changed
5.1.2.1 Bone marrow aspirate and peripheral 
blood
Description of change
Clarification that a “fresh” bone marrow sample 
is required.    Historical samples will not be 
permitted for submission for analysis.
“At baseline a BM aspirate is required. A BM 


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biopsy will be required if aspiration is 
inadequate. If these assessments were done prior 
to the patient’s participation in the trial, they will 
be acceptable as long as they were obtained 
within 4 weeks prior to start of treatment with 
the trial drugs, otherwise, new samples will need 
to be obtained for the purpose of the study.”
Rationale for change
Clarification and Updated
Section to be changed
Description of change
Rationale for change
Section to be changed
5.2.1 Endpoint(s) of safety
Description of change
Revised DLT definition based on FDA feedback 
to consider events that are non disease-related 
events as possible DLTs:
“The safety of BI 836858 in the Phase I and II 
will be assessed by a descriptive analysis of 
incidence and intensity of adverse events graded 
according to CTCAE (version 4.0), the incidence 
of non disease-related adverse events qualifying 
for dose limiting toxicity (DLT), laboratory data 
and results of physical examination.”
Rationale for change
Revised DLT definition  based on FDA feedback
Section to be changed
5.2.1.1 Dose Limiting Toxicity (DLT)
Description of change
Revised DLT definition based on FDA feedback 
to consider events that are non disease-related 
events as possible DLTs:
“The Dose Limiting Toxicity is defined as 
follows:

Grade ≥ 3, according to CTCAE version 
4.0, drug non disease-related, non-
hematologic toxicity adverse events, with 
the following exceptions:

Any laboratory abnormality, which is not 
considered clinically significant by the 
investigator or resolves spontaneously or 
can be recovered with appropriate 
treatment within 5 days


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
For patients with neutrophils <500 /µL 
(0.5 x 109/L) at start of treatment febrile 
neutropenia with neutrophils <500 /µL 
(0.5 x 109/L) or infection with neutrophils 
<500 /µL (0.5 x 109/L) will not constitute 
a DLT if they can be recovered with 
appropriate treatment within 14 days.”
Rationale for change
Revised DLT definition  based on FDA feedback
Section to be changed
5.2.2.2 Adverse Event and Serious Adverse Event 
Reporting
Description of change
Revised the timing of EOT visits from 28 days (+ 
7 days) to 30 days (+ 7 days) after last 
administration of BI 836858. 
“The Residual Effect Period (REP) for BI 836858 
is 2830 days.  Therefore all events reported within 
2830 days after the last trial medication will be 
considered on drug. All adverse events will be 
reported up until the last per protocol visit (EOT) 
which is 2830 days after the last dose of trial 
medication. The investigator does not need to 
actively monitor patients for adverse events once 
the clinical trial has ended. However, if the 
investigator becomes aware of an SAE(s) that 
occurred after the patient has completed the 
clinical trial (including any protocol required REP 
and / or follow-up), it should be reported by the 
investigator to the sponsor if considered relevant 
by the investigator.”
Rationale for change
Boehringer Ingelheim Standards
Section to be changed
Table 5.2.2.2:1 AE/SAE Reporting Requirements
Description of change
Clarfication on the reporting of death after the 
REP:
“Please note: The event(s) leading to death (other 
than progressive disease) should always be 
reported as SAE in this trial”
Rationale for change
Clarification and Updated
Section to be changed
5.2.2.2 Adverse Event and Serious Adverse Event 
Reporting and Table 5.2.2.2: 1 AE/SAE reporting 
requirements
Description of change
Clarified SAE reporting relative to deaths that 
occur after REP that are due to progressive 
disease:
“Exemption to SAE Reporting
Disease progression/relapse of the underlying 
condition is a study endpoint for analysis of 


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efficacy. Disease progression/relapse is exempted 
from reporting as a (S)AE. Progression/relapse of 
the subject's underlying condition will be 
recorded in the appropriate pages of the (e)CRF 
as part of efficacy data collection. Death due to 
disease progression/relapse is to be recorded on 
the appropriate (e)CRF page and not on a SAE 
form.
Examples of exempted events of disease 
progression/relapse are:

Progression/relapse of underlying 
condition (Progressive disease PD): if PD 
is clearly consistent with the suspected 
progression as defined by the respective 
response criteria.

Hospitalization/Procedures due solely to 
the progression/relapse of underlying 
condition Clinical symptoms and/or signs 
of progression/relapse (with or without 
confirmation by objective criteria), if the 
symptom can exclusively be determined to 
be due to the progression/relapse of the 
underlying condition  and meets the 
expected pattern of progression/relapse for 
the disease under study.
If the observed event is not unequivocally due to 
progression/relapse of the underlying
condition and there is a reasonable possibility for 
a causal relationship to administration of study 
medication, the event must be reported as (S)AE 
on both the SAE form and the (e)CRF.
Exempted events are collected and tracked 
following the protocol-specified monitoring plan.  
Exempted events are monitored at appropriate 
intervals preferably by an independent committee 
such as a Data Monitoring Committee.”
Rationale for change
Clarification and Updated
Section to be changed
5.2.3.1 General Safety Laboratory Parameters
Description of change
Updated Hematology panel to clarify type of tests 
and frequency.
“Hemoglobin, red blood cell count (RBC), white 
blood cell count (WBC) with differential 


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(neutrophils, basophils lymphocytes, monocytes, 
eosinophil),  platelets (PLT)
Reticulocytes have to be measured only at Visit 1 
of every second cycle, EOC4, EOT. Visit 1 of 
every second cycle after EOC4 and EOT.”
Rationale for change
Clarification and Updated
Section to be changed
5.2.3.1 General Safety Laboratory Parameters
Description of change
Updated Biochemistry  panel to clarify type of 
tests and frequency.
“Glucose, sodium, potassium, calcium, inorganic 
phosphate, creatinine, AST, ALT, alkaline 
phosphatase (AP), lactate dehydrogenase (LDH), 
bilirubin, urea (preferred) or BUN, total protein, 
albumin, uric acid
Serum immunoglobulin levels (IgG, IgM, IgA) 
and direct antiglobulin (direct Coombs) test have 
to be measured only every 8 weeks2 cycles, 
EOC4 and EOT.”
Rationale for change
Clarification and Updated
Section to be changed
5.2.3.1 General Safety Laboratory Parameters
Description of change
Added clarification and language that additional 
safety tests are required 24 hours after a patient 
dose escalates.   
“An additional Additional safety labs will be 
collected on day 2 of Cycle 1 (i.e., 24 hours after 
the first administration of BI 836858) and after 
the first infusion of a higher dose, following  
intra- patient dose escalation (i.e. 24 hours after 
the first administration of the higher dose). Other 
lab tests to be included for these visits: 
haptoglobin, direct antiglobulin/Coombs test, 
bilirubin (direct and indirect) and free 
hemoglobin. Non pre-existing abnormal 
laboratory values (CTCAE Grade 3 or higher) 
will be followed up every 48 hours until these 
laboratory values are back to at least CTCAE 
Grade 1 or baseline.”
Rationale for change
Clarification and Updated
Section to be changed
Description of change


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Rationale for change
Section to be changed
Description of change


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Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
6.2.1 Screening and Run-in Period(s)
Description of change
Clarified the collection of Molecular genetics and 
cytogenetics.  Phase I patients will only require 
historical and available data.  Phase II patients are 
required to have tests performed as part of 


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Screening.

“Molecular genetics and cytogenetics of MDS 
(Historical/available data for Phase I patients 
and required at screening for Phase II 
patients)”
Rationale for change
Clarification and Updated
Section to be changed
6.2.2 Treatment Period(s)
Description of change
Clarify the frequency and timing of Physical 
exams.
“Physical examination and ECOG performance 
score completed Day 1 of every second cycle 
beginning with cycle 1. Physical exam may be 
completed up to 2 days prior to administration 
and ECOG must be completed on the day of the 
administration. Height only at Day 1 of first 
cycle.  If the first administration of BI 836858, or 
BSC treatment on trial (Phase II) is completed 
within 3 days of the screening visit, these 
examinations do not need to be repeated”
Removal of erroneous text.

- Bone marrow aspiration (Required before 
the 9th administration of BI 836858 or by 
EOC4 and at the discretion of the 
Investigator)
Clarification on timing of  PGx sample 
Blood for pharmacogenomics (Day 1 of Cycle 1.  
If not obtained at C1D1, a sample may be 
collected anytime during Cycle 1)
Rationale for change
Clarification and Updated
Section to be changed
6.2.2.2 Visit 2 and Visit 4 (+ 1 day window 
allowed beginning in Cycle 3), following 
administration of BI 836858 (Phase II: these visits 
will also occur for BSC patients, 
 
Description of change
Correct text in header as visits 2 and 4 are not 
dosing days
Rationale for change
Clarification and Updated
Section to be changed
6.2.2.2 Visit 2 and Visit 4
Description of change
Updated language to remove erroneous text as 
Visit 2 and 4 and not dosing days:
In Cycles 1 and 2, visits will occur at Day 8 and 


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Day 22 after the administration.  Beginning in 
Cycle 3 and thereafter, patients will come to the 
clinic only for infusions and will not be required 
to complete the visits on Day 8 and Day 22 unless 
medically indicated.  On the Visit 2 and Visit 4 
days, the following parameters and investigations 
will be obtained and / or performed:
Rationale for change
Clarification and Updated
Section to be changed
6.2.2.3 End of Cycle 4 (EOC4)
Description of change
Clarify that testing is only required for patients 
enrolled in Phase II

“Molecular genetics and cytogenetics of MDS
(Phase II patients only)”
Rationale for change
Clarification and Updated
Section to be changed
6.2.2.5 Maintenance Cycles (Visit 1)
Description of change
Correct typographical error.  PEs starting with 
Cycle 1 of the maintenance phase and not Cycle 
5.

“Physical examination every other cycle 
starting with cycle 51 (may be completed up 
to 2 days prior) and ECOG performance score 
Rationale for change
Clarification and Updated
Section to be changed
6.2.3 End of trial Treatment and Follow-up Period
Description of change
Revised and clarified header of section refers to 
end of treatment and not trial
Rationale for change
Clarification and Updated
Section to be changed
6.2.3.1 End of Treatment (EOT)
Description of change
Revised timing of EOT visit to be in line with 
Boehringer-Ingelheim standards.
“The EOT visit is to occur 2830 days (+7 days) 
after the last administration of BI 836858. “   
Clarified that Molecular/cytogenetic testing only 
required for Phase II patients

“Molecular genetics and cytogenetics of MDS 
(Phase II patients only)”
Clarified text and fixed error.

End of trial treatment.  This will include the 
reason for conclusion of trial treatment if 
applicable, premature discontinuation of 
trialtreatment, and date of last administration 
of the trial drug  


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Rationale for change
Clarification and Updated
Section to be changed
6.2.3.2 Follow-up
Description of change
Clarify and revised follow-up period for Phase I 
and Phase II patients.
“Follow-up visits or telephone calls will be 
performed after the patient has completed or 
discontinued treatment according to protocol or is 
not eligible for further treatment cycles.  Follow-
up visits or telephone calls will begin 4 weeks 
after the EOT visit.  Follow-up will end in case 
the patient is lost to follow-up or in case the 
Investigator and Sponsor agree not to pursue 
further follow-up visits.  In phase I, Follow-up 
visits should be performed at 4 week intervals for 
6 months.  After the 6 month assessment, patients 
will be considered off trial.  In Phase II, Follow-
up visits should be performed at 4 week intervals 
for the first 12 months or earlier if appropriate as 
determined by the Investigator, and thereafter in 6 
month intervals.
Rationale for change
Clarification and Updated
Section to be changed
7.3 Planned Analyses 
Description of change
Clarified definition that the intent to treat 
population  as randomized set and not treated.
”For the Phase II the full analysis set (Phase II) is 
defined, in analogy to the intention to treat 
population as the treated randomized set with 
respect to Phase II; i.e. all patients randomized.”
Rationale for change
Clarification and Updated
Section to be changed
7.3.3 Safety Analysis
Description of change
Revised definitions.
“All treated patients of the full analysis set (both 
Phase I and Phase II) will be included in the 
safety analyses. Two analyses will be performed. 
The first analysis of safety will be performed for 
the first part of the trial (determination of the 
MTD, first cycle only, treatment regimen = initial 
dose at the start of the treatment, full 
analysistreated set (Phase I only)). This 
descriptive analysis will evaluate the MTD for the 
monotherapy of BI 836858 in MDS patients. The 
second analysis will be performed with respect to 
all cycles and will act as a support for the 


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determination of the MTD (full analysistreated set 
(both Phase I and Phase II)).”
Rationale for change
Clarification and Updated
Section to be changed
7.5 Randomization
Description of change
Randomization will be performed in the phase II 
part of this trial only. In Phase I, doses will be 
assigned based on the decision made by the DSB 
(see Section 7.3.4.).  In Phase II, the 
randomization ratio is 1:1 for the two treatment 
arms, i.e. BI 836858 plus BSC vs. BSC alone, per 
investigator’s choice.  Randomization will be 
stratified by number of previous lines of MDS 
therapy (0, 1, ≥ 2), where previous MDS therapy 
also includes previous ESA therapy.  
Randomization will be performed using 
IVRS/IWRS. Boehringer Ingelheim Pharma 
GmbH & Co. KG, Clinical Trial Support Group 
or a CRO appointed by the Sponsor will provide 
the randomization lists using a validated 
randomization number generating system. Access 
to the randomization codes will be controlled and 
documented.
Rationale for change
Revised Phase II Stratification levels in response 
to FDA feedback on potential patients eligible for 
trial.
Section to be changed
Description of change
Rationale for change


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11.2
GLOBAL AMENDMENT 2
Number of global amendment
2
Date of CTP revision
16 JUN 2017
EudraCT number
N/A
BI Trial number
1315.7
BI Investigational Product(s)
BI 836858
Title of protocol
A Phase I/II, Multicenter, Open-Label, Dose
Escalation and Randomized Trial of BI 836858 in 
Patients with Low or Intermediate-1 Risk 
Myelodysplastic Syndromes
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
1.2.1 BI 836858
Description of change
The following has been added: 
There are two combination studies for patients 
diagnosed with AML ongoing, one with azacytidine 
(ClinicalTrials.gov Identifier: NCT03013998) and 
another one with decitabine (ClinicalTrials.gov 
Identifier: NCT02632721). Only limited 
pharmacokinetic, pharmacodynamic and tumor 
response data are not available at this point.
Rationale for change
Update on  BI 836858 clinical program
Section to be changed
2.1 Rationale for Performing The Trial


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Description of change
The following text in bold below is added:
It has been described that previous treatments with 
HMAs or lenalidomide reduce the number and 
activity of NK cells. [R17-1502, R17-1503, R17-
1510].  BI 836858 mediated ADCC depends on 
functional NK cells. Therefore, it is hypothesized 
that Lower-Risk MDS patients it without previous 
HMA or lenalidomide treatments may respond better 
to BI 836858, providing the rationale for an MTD 
expansion cohort targeting this group of patients.
Low to intermediate-1 risk MDS patients comprise 
around 70% of the entire MDS populations. In 
clinical practice, lower-risk patients are those with 
expected median survival measured in years, and 
those who have a lower chance to progress to AML. 
The main clinical burden in this group of patients is 
symptomatic cytopenias and their associated 
complications, such as bleeding, risk of infection and 
iron overload. The goal of treatment is to alleviate 
symptomatic cytopenias and abrogate or reduce RBC 
transfusion requirements leading to better quality of 
life. 
This rationale is supported by FDA and EMA 
approval of lenalidomide in MDS patients with a del 
5q. 
Overall treatment options for patients with lower risk 
MDS, especially for those without a 5q deletion, are 
limited and benefit to available treatment is not 
satisfactory.  Rates of RBC TI for at least 8 weeks 
for patients with Low to Intermediate-1 risk MDS 
with treatment of HMAs or lenalidomide are 15 to 
30% without improvement in overall survival.
Furthermore the outcomes for those patients who 
failed treatment with HMAs or lenalidomide are 
poor with an estimated 3 year overall survival rate of 
27% [R11-1106, R17-1501, R17-1504, R17-1505, 
R17-1506, R17-1507, R17-1508, R17-1509, R17-
1521 ]. 
Rationale for change
Rationale and justification for enrolling treatment 
naïve patients in the expansion cohort 
Section to be changed
2.2 Trial Objectives


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Description of change
The following text in bold below is added: The Phase 
I primary objectives of the trial are to determine the 
maximum tolerated dose (MTD) and the 
Recommended Phase II Dose (RP2D) to be used in 
the Phase II. Secondary objectives include safety, 
pharmacokinetics, exploratory biomarkers and 
efficacy of BI 836858 monotherapy. The trial will 
enroll patients with low or intermediate-1 risk MDS 
with symptomatic anemia, who at a minimum, 
experienced ESA treatment failure or do not qualify 
(serum erythropoietin level > 500 U) for ESA 
treatment and are refractory to or are not amenable 
or eligible for approved MDS therapy in the dose 
escalation phase and for one of the MTD expansion 
cohorts.  The second MTD expansion cohort will 
enroll patients with low or intermediate-1 risk MDS 
with symptomatic anemia, experienced ESA 
treatment failure or do not qualify (serum 
erythropoietin level > 500 U) for ESA treatment and 
who have not received prior HMA and/or 
lenalidomide (this cohort is referred to as 
“untreated”). Patients with a deletion 5q cytogenetic 
abnormality will be allowed in Phase I who do not 
qualify for lenalidomide treatment (Absolute 
Neutrophil Count (ANC) < 500/µL or platelets 
<50,000/µl) or who experience primary lenalidomide 
failure (not for untreated expansion cohort).  
lenalidomide failure is defined as lack of 
hematological improvement after 4 months of 
therapy, or secondary failure defined as loss of prior 
lenalidomide response at any time point.
Rationale for change
Updated to reflect new expansion cohort
Section to be changed
Figure 3.1:1 Structure of the 1315.7 Phase I/II
Description of change
Figure updated
Rationale for change
Update to reflect additional expansion cohort
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
Added: The second expansion cohort will enroll 
patients with low or intermediate-1 risk MDS with 
symptomatic anemia, who at a minimum, 
experienced ESA treatment failure or do not qualify 
(serum erythropoietin level > 500 U) for ESA 
treatment and who have not received prior HMA 
and/or lenalidomide.
Rationale for change
New language for additional expansion cohort


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Section to be changed
3.1 Overall Trial Design and Plan
Description of change
The following text below in bold is added: In Phase I 
dose escalation part, patients with low to 
intermediate-1 risk MDS, who have experienced 
ESA treatment failure, except for patients who do 
not qualify for ESA treatment and are refractory to 
or are not amenable or eligible for approved MDS 
therapy will be assigned to a dose cohort under 
investigation. After determination of the MTD/RP2D 
the same group of patients as for the dose escalation 
will be enrolled in the first expansion cohort 
(referred to as “pre-treated” patients). The second 
expansion cohort will enroll patients with low or 
intermediate-1 risk MDS with symptomatic anemia, 
who at a minimum, experienced ESA treatment 
failure or do not qualify (serum erythropoietin 
level > 500 U) for ESA treatment and who have not 
received prior HMA and/or lenalidomide (referred to 
as “untreated” patients). Treatment failure on ESAs 
is defined as 1) failure or ceasing to show 
hematologic response after at least 8 weeks of 
40,000 to 60,000 IU/week of erythropoietin (EPO) 
or equivalent or 2) low
Rationale for change
New language for additional expansion cohort
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
The following text has been added: two expansion 
cohorts (untreated and pre-treated with HMA and/or 
lenalidomide) will recruit up to 12 patients per 
cohort.   Overall a minimum of 12 patients 
(including both expansion cohorts and the last 
escalation cohort) will
Rationale for change
New language for additional expansion cohort
Section to be changed
3.1.1.1 Administrative structure of the trial
Description of change
The text below in bold below has been added: Adult 
patients with low to intermediate-1 risk MDS, 
according to International Working Group (IWG) 
criteria, who, at a minimum, experienced ESA 
treatment failure, except for patients that do not 
qualify for ESA treatment and are refractory to or 
are not amenable or eligible for approved MDS 
therapy, will be enrolled for the Phase I dose 
escalation part. After determination of the 
MTD/RP2D, the same group of patients as for the 
dose escalation will be enrolled in the first expansion 
cohort (referred to as “pre-treated” patients)


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The second expansion cohort will enroll patients 
with low or intermediate-1 risk MDS with 
symptomatic anemia, who, experienced ESA 
treatment failure or do not qualify (serum 
erythropoietin level > 500 U) for ESA treatment and 
who have not received prior HMA and/or 
lenalidomide (referred to as “untreated” 
patients).Approximately three Phase I sites in the
United States will participate in the dose escalation 
portion of Phase I.  An additional 2-3 sites in the 
United States will participate during the cohort 
expansion portion of Phase I.
The Phase I dose-escalation will be guided by a 
Bayesian logistic regression model (BLRM) with 
overdose control (refer to Section 7).  The DSB will 
consist of the Phase I investigators, Team Member 
Medicine (TMM), Trial Clinical Monitor (TCM), 
Project Statistician, Clinical Pharmacological Project 
Lead (CPPL) and TransMed Expert (TME).  The 
information on the overdose risk will be presented 
by the trial statistician to the DSB. Additional 
information, such as lower grade adverse events, 
pharmacokinetics (PK), if available, progressive 
disease (PD), individual patient profiles and other 
relevant information will also be presented. Based on 
this information, the members of the DSB will reach 
a joint decision on the next dose level to be 
investigated. This dose level may be above, below or 
identical to the currently investigated dose level. The 
DSB will also recommend the size for the next 
cohort. However, the final decision on the next 
cohort size will be made by a mutual decision 
between the TMM and the Coordinating Investigator 
(CI).  Minutes of the DSB meetings and 
recommendations will be documented and archived 
by the TCM.  Two expansion cohorts (untreated or 
pre-treated with HMA and/or lenalidomide) will 
recruit up to 12 patients per cohort and receive 
treatment at the RP2D prior to start of Phase II. 
Prior to the initiation of Phase II, a Phase I safety 
analysis report will be prepared based on the Phase I 
data.  A summary of safety and efficacy from the 
dose escalation cohorts and from either one or both 


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of the expansion cohorts and RP2D will be included 
in the Phase I safety analysis report.  The Phase I 
safety analysis report will be made available for all 
investigators who participate in the Phase II.  
Rationale for change
New language for additional expansion cohort
Section to be changed
3.2 Discussion of Trial Design, Including The 
Choice of Control Group(s)
Description of change
The text in bold below has been added: The Phase I 
is designed to determine the dose of BI 836858 
monotherapy in patients with low to intermediate-1 
MDS with symptomatic anemia.  The study will be 
conducted in an open label, single arm dose 
escalation trial design. Dose escalation and cohort 
size will be determined based on the 
recommendation by the DSB, according to a 
Bayesian Model with overdose control.  An 
escalation with overdose control design will increase 
a chance of treating patients at efficacious doses 
while reducing the risk of overdosing.  This design is 
based on practical experience and is a preferable 
algorithmic method due to its superior ability to
identify the dose with the desired toxicity rate and its 
allocation of a greater proportion of patients to doses 
at, or close to, that dose (R13-4802, R13-4804, R13-
4805).  Expansion cohorts will enroll at the RP2D 
defined during the dose escalation portion of Phase I.
Rationale for change
New language for additional expansion cohort
Section to be changed
3.3 Selection of Trial Population
Description of change
The text in bold below has been added: Phase I will 
enter approximately 50 patients from approximately 
3-5 sites in the United States. In the Phase I dose 
escalation part, the trial will recruit patients with 
lower risk MDS who were either previously 
untreated or progressed/became resistant following 
ESA treatment. After determination of the 
MTD/RP2D, the same group of patients as for the 
dose escalation will be enrolled in the first expansion 
cohort.  The second expansion cohort will enroll 
patients with low or intermediate-1 risk MDS with 
symptomatic anemia, who experienced ESA 
treatment failure or do not qualify for ESA treatment 
and who have not received prior HMA and/or 
lenalidomide.
Rationale for change
New language for additional expansion cohort
Section to be changed
3.3.2 Inclusion criteria


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Description of change

The text in bold below has been added: 

1.Documented diagnosis of MDS 
according to World Health Organization 
(WHO) criteria that meets International 
Prognostic Scoring System (IPSS) 
classification of low or intermediate-1 
risk disease at screening as determined by 
microscopic and standard cytogenetic 
analyses of the bone marrow and 
peripheral complete blood count (CBC) 
and who are refractory to or are not 
amenable or eligible for approved MDS 
therapy. The second expansion cohort 
will enroll patients with low or 
intermediate-1 risk MDS with 
symptomatic anemia, experienced ESA 
treatment failure or do not qualify (serum 
erythropoietin level > 500 U) for ESA 
treatment and who have not received 
prior HMA and/or lenalidomide.


-Phase I (dose escalation and “pre-
treated” expansion cohort only): 
refractory to or not amendable or eligible 
for established MDS therapy (HMA, 
lenalidomide)

-Phase I (“untreated” expansion cohort 
only): no [prior HMA and/or 
lenalidomide treatment

2. Patient has the evidence of 
symptomatic anemia according to the 
following criteria: 

-Phase I only: Patients must have mean 
haemoglobin concentration <10.0 g/dL of 
2 measurements (not influenced by RBCs 
within 8 weeks prior to start of treatment 
OR,

-Phase I/II: Patients must have received ≥ 
2 units of RBCs for hemoglobin ≤ 9.0 
g/dL within 8 weeks prior to start of 
treatment.
Rationale for change

New language for additional expansion
cohort


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Section to be changed

3.3.3 Exclusion criteria
Description of change

The following text has been removed:

7. Prothrombin time (PT) > 1.5x ULN for 
patients not on therapeutic vitamin K 
antagonists (phenprocoumon, warfarin)


The following text has been modified:

Known human immunodeficiency virus 
(HIV) infection and / or active hepatitis B 
infection (defined as presence of Hep B 
DNA), active hepatitis C infection 
(defined as presence of Hep C RNA) 
active hepatitis B virus or hepatitis C 
virus infection. Patients with any 
serological evidence of current or past 
hepatitis B exposure are to be excluded 
unless the serological findings are clearly 
due to vaccination.
Rationale for change

Update and clarify exclusion criterion 
Section to be changed

3.3.3 Exclusion criteria
Description of change
14. Female patients of childbearing potential who are 
sexually active and unwilling to use a medically 
acceptable method of contraception during the 
trial and for 6 months after the last 
administration of BI 836858, i.e. combination of 
two forms of effective contraception (defined as 
hormonal contraception, intrauterine device, 
transdermal patch, implantable or injectable 
contraceptive, bilateral tubal ligation etc.).  

Women of childbearing potential are 
defined as females who:

a)Have experienced menarche  and

b)Are not postmenopausal (12 months 
with no menses without an alternative 
medical cause) and

c) Are not permanently  sterilized (e.g.        
hysterectomy, bilateral oophorectomy  or 
bilateral salpingectomy
Rationale for change

Update and Clarification
Section to be changed

3.3.4 Removal of patients from therapy or 
assessments


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Description of change
The text below has been added:

Delay in start of subsequent treatment cycle 
of more than 8 weeks due to a drug-related 
event (e.g. delay in recovery of blood 
counts). Refer to section 4.1.4.
Rationale for change
Update and Clarification
Section to be changed
4.1.3 Section of doses in the trial
Description of change
The text below has been added: If no DLT is 
observed at a dose that efficacy is considered 
sufficient, the DSB may decide to include additional 
number of patients at the same dose level and to 
declare this dose level as the RP2D.  Before the 
conclusion of Phase I and prior to initiating the 
Phase II, two expansion cohorts (untreated or pre-
treated with HMA and/or lenalidomide) will recruit 
up to 12 patients per cohort (overall a minimum of 
12 patients – inclusive of the lase dose escalation 
cohort) and receive treatment at RP2D.  In the 
expansion cohorts new patients may be enrolled at 
any time without observation period.
Rationale for change
New language for additional expansion cohort
Section to be changed
4.1.4 Drug assignment and administration of doses 
for each patient
Description of change
The text in bold below has been added:
Before the administration of BI 836858, adverse 
events and safety laboratory will be assessed.  To 
start or continue treatment with further 
administrations, all of the following criteria must be 
met
Rationale for change
Clarify start of treatment
Section to be changed
5.1.1 Endpoints of efficacy
Description of change
The text below has been added:

Mean hemoglobin increase ≥ 1.5 g/dL
Rationale for change
Additional endpoint
Section to be changed
5.1.2.3 Assessment and definition of response 
criteria
Description of change
The text below has been added:

Mean hemoglobin increase ≥ 1.5 g/dL  —
Time Frame: Up to approximately 48 weeks.  
Proportion of subjects achieving hemoglobin 
(Hgb) increase from baseline ≥ 1.5 g/dL over 
any consecutive 56-day period in absence of 


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2
Red blood cell (RBC) transfusions.
Rationale for change
Additional endpoint
Section to be changed
5.2.1.3 Recommended Phase 2 Dose (RP2D)
Description of change
The text in bold below has been added: 
Before the conclusion of Phase I and prior to 
initiating the Phase II, two expansion cohorts 
(untreated or pre-treated with HMA and/or 
lenalidomide) will recruit up to 12 patients per 
cohort  (overall minimum of 12 patients – inclusive 
of the last dose escalation cohort) and receive 
treatment at RP2D.
The following text has been removed from this 
section: Based on the overall Phase I data, the DSB 
will make a final determination of the RP2D, which 
must not exceed the MTD. The Phase I safety 
analysis report, including the rationale of RP2D 
determination will be made available to all 
investigators prior to the initiation of Phase II.
Rationale for change
New language for additional expansion cohort
Section to be changed
Description of change
Rationale for change 
Section to be changed
6.2.3.1 End of treatment (EOT)
Description of change
The following text has been removed from this 
section:

Physical examination including weight (may be 
completed up to 2 days prior) and ECOG 
performance score  
Rationale for change
Remove timing of Physical Assessment at EOT
Section to be changed
7.1 Statistical Design- Model
Description of change
The text below has been added:
The DSB may recommend stopping the dose finding 
phase after the criterion for MTD is fulfilled. Further 
patients may be included to confirm this MTD 
estimate. If no DLT is observed at a dose of which 
the efficacy is considered sufficient, the DSB may 
decide to include additional number of patients at 


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2
this dose level and to declare this dose as the 
recommended dose for phase 2 (RP2D).
Rationale for change
Update DSB Dose finding definition
Section to be changed
7.3.3 Safety analyses
Description of change
The text in bold below has been added: 
All treated patients (both Phase I and Phase II) will 
be included in the safety analyses. Two analyses will 
be performed. The first analysis of safety will be 
performed for the first part of the trial (determination 
of the MTD, first cycle only, treatment regimen = 
initial dose at the start of the treatment, treated set 
(Phase I only)). This descriptive analysis will 
evaluate the MTD for the monotherapy of BI 836858 
in MDS patients. The second analysis will be 
performed with respect to all cycles and will act as a 
support for the determination of the MTD (treated
set (both Phase I and Phase II)). In addition a 
sensitivity analysis for the second expansion cohort 
will be conducted. Further details will be described 
in the TSAP.
Rationale for change
Update for additional expansion cohort


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11.3
GLOBAL AMENDMENT 3
Number of global amendment
3
Date of CTP revision
12 DEC 2018
EudraCT number
2018-002177-21
BI Trial number
1315.7
BI Investigational Product(s)
BI 836858
Title of protocol
A Phase I/II, Multicenter, Open-Label, Dose 
Escalation and Randomized Trial of BI 836858 
in Patients with Low or Intermediate-1 Risk 
Myelodysplastic Syndromes
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
Title Page
Description of change
Add EudraCT No. 2018-002177-21
Rationale for change
Added European Country to Trial 
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Objectives: Deleted text:
Phase II: To investigate safety and efficacy of BI 
836858 plus Best Supportive Care (BSC) 
compared to Best Supportive Care alone in low or 
intermediate-1 risk MDS patients with 
symptomatic anemia. without a deletion 5q 
cytogenetic abnormality.
Rationale for change
Definition of Phase II patient population was
further clarified 
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Diagnosis section:  Phase I patient population 
updated with bold text and Phase II patient 


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population deleted:
Phase I: Patients with MDS with symptomatic 
anemia due to low or intermediate-1 risk (i.e., 
International Prognostic Scoring System
(IPSS) score 0-1) who at a minimum have 
experienced Erythropoiesis-Stimulating Agent 
(ESA) treatment failure or low chance of response 
to ESAs and are refractory to or are not 
amenable or eligible for approved MDS 
therapy.   
Phase II: Patients with MDS with symptomatic 
anemia due to low or intermediate-1 risk (i.e., 
International Prognostic Scoring System (IPSS) 
score 0-1) without a deletion 5q cytogenetic 
abnormality who at a minimum have experienced 
ESA treatment failure or low chance of response 
to ESAs and are refractory to or are not amenable
or eligible for approved MDS therapy.
Rationale for change
Definition of Phase I patient populations was
further clarified and Phase II patient population 
was removed 
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Main criteria for Inclusion section was updated
for Phase I (added bold text) and revised for 
Phase II (deleted text): 
Phase I: Adult patients with low or intermediate-1 
risk MDS who, experienced ESA treatment 
failure, except for those who have a low chance to 
respond to ESA treatment and are refractory to 
or are not amenable or eligible for approved 
MDS therapy.
Phase II: Adult patients with low or intermediate-
1 risk MDS either previously untreated or 
following progression/resistance after ESA and 
are refractory to or are not amenable or eligible 
for approved MDS therapy.
Rationale for change
Definitions of Phase I and Phase II patient 
populations inclusion criteria further clarified as 
requested by German Health Authority
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Duration of treatment section was further 
clarified with added bold text:
Patients with clinical benefit, PR or CR after 
the 4th (or 6th) Cycle will receive repeated cycles 


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until relapse after Complete Response (CR), 
Partial Response (PR), erythroid response (HI-E), 
Red Blood Cell transfusion independency or 
Marrow Complete Response (mCR), Progressive 
Disease (PD), or unacceptable adverse event(s), in 
the absence of other withdrawal criteria.
Rationale for change
Clarify point at which patients can transition to 
Maintenance phase
Section to be changed
Section 1.2.1 BI 836858
Description of change
Reference for unpublished data was updated:
Reference P17-02032 was added.  References 
section 9.1 updated with citation
Rationale for change
Supporting Data was published, reference updated
Section to be changed
Section 2.1 Rationale for Performing the Trial
Description of change
Reference for unpublished data was updated:
Reference P17-02032 was added.  References 
section 9.1 updated with citation
Rationale for change
Supporting Data was published, reference updated
Section to be changed
2.2 Trial Objectives
Description of change
Deleted text:
In the randomized Phase II, primary objectives 
are to investigate the efficacy of BI 836858 plus 
Best Supportive Care (BSC) vs. Best Supportive 
Care alone, in low or intermediate-1 risk MDS 
patients with symptomatic anemia without a 
deletion 5q cytogenetic abnormality who are 
previously untreated or who progressed/became 
resistant following ESA, and are refractory to or 
are not amenable or eligible for approved MDS 
therapy. Secondary objectives include the 
investigation of safety and tolerability of BI 
836858 in this patient population
Rationale for change
Definition of Phase II patient population further 
clarified as requested by German Health 
Authority
Section to be changed
2.3 Benefit – Risk Assessment
Description of change
Added bold text:
Considering these data and the experience with 
other monoclonal antibodies in hemato-oncology 
indications, infusion-related reactions are likely. 
Prophylactic measures will be stipulated for 
primary prevention, and supportive treatments are 
available (Section 4.1.4).  Although rare, a 
potential for drug-induced liver injury is under 
constant surveillance by sponsors and regulators. 


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Therefore, this study requires timely detection, 
evaluation, and follow-up of laboratory alterations 
of selected liver laboratory parameters to ensure 
patients´ safety.  A Phase I safety analysis report 
will be prepared based on the Phase I data and 
made available to regulatory authorities, ethics 
committees/IRBs and all investigators, and the 
protocol will be amended prior to initiating 
Phase II as defined in detail in Section 3.1.1.1.   
In addition, this study will utilize a Data Safety 
Board to oversee safety, review dose limiting 
toxicities and determine dose escalations.
Rationale for change
German Health Authority required Phase I safety 
report and Phase II protocol amendment to be 
finalized and distributed before start of Phase II 
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
The following text was deleted/added (in bold): 
Phase I:
In Phase I dose escalation part, patients with low 
to intermediate-1 risk MDS, who have 
experienced ESA treatment failure, except for 
patients who do not qualify for ESA treatment 
and are refractory to or are not amenable or 
eligible for approved MDS therapy will be 
assigned to a dose cohort under investigation. 
After determination of the MTD/RP2D the same 
group of patients as for the dose escalation will be 
enrolled in the first expansion cohort (referred to 
as “pre-treated” patients). The second expansion 
cohort will enroll patients with low or 
intermediate-1 risk MDS with symptomatic 
anemia, who at a minimum experienced ESA 
treatment failure or do not qualify (serum 
erythropoietin level > 500 U) for ESA treatment 
and who have not received prior HMA and/or 
lenalidomide (referred to as “untreated” patients). 
Treatment failure on ESAs is defined as 1) failure 
or ceasing to show hematologic response after at 
least 8 weeks of 40,000 to 60,000 IU/week of 
erythropoietin (EPO) or equivalent or 2) low 
chance/response to ESA with endogenous serum 
EPO>500.   It is expected that approximately 50 
patients will be enrolled. 
Phase II


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In Phase II, patients will be enrolled in a 
randomized manner to investigate efficacy and 
safety of BI 836858 at RP2D in patients either 
previously untreated or following 
progression/resistance after the treatment with 
ESAs and/or approved MDS drugs such as 
HMAs. Treatment failure on HMA is defined as 
1) no response after at least four cycles of HMA, 
2) progression of disease on HMA or 3) Grade 3-
4 non-hematologic toxicity. Patients also must 
who have experienced treatment failure on ESAs, 
except for patients who do not qualify for ESA 
treatment. As defined above, treatment failure on 
ESAs is defined as 1) failure or ceasing to show 
hematologic response after at least 8 weeks of 
40,000 to 60,000 IU/week of erythropoietin 
(EPO) or equivalent or 2) low chance/response to 
ESA with endogenous serum EPO>500.  For 
further details regarding inclusion of patients 
in Phase II please see inclusion criteria (section 
3.3.2). Randomization will be stratified by 
number of previous lines of MDS therapy (0, 1, 
>=2), where previous MDS therapy also includes 
previous ESA therapy (refer to Section 7.5).  A 
total of 150 patients, 75 each arm, will be enrolled 
in Phase II.
Rationale for change
Definition of Phase I  and Phase II patients 
updated to align with updated inclusion criteria
Section to be changed
3.1.1.1 Phase I
Description of change
The bolded text was added:
Adult patients with low to intermediate-1 risk 
MDS, according to International Working Group 
(IWG) criteria, who experienced ESA treatment 
failure, except for patients that do not qualify for 
ESA treatment and are refractory to or are not 
amenable or eligible for approved MDS therapy,
will be enrolled for the Phase I dose escalation 
part. After determination of the MTD/RP2D, the 
same group of patients as for the dose escalation 
will be enrolled in the first expansion cohort 
(referred to as “pre-treated” patients) The second 
expansion cohort will enroll patients with low or 
intermediate-1 risk MDS with symptomatic 
anemia, who experienced ESA treatment failure 


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or do not qualify (serum erythropoietin level > 
500 U) for ESA treatment and who have not 
received prior HMA and/or lenalidomide 
(referred to as “untreated” patients). 
Approximately three Phase I sites in the United 
States will participate in the dose escalation 
portion of Phase I.  An additional 2-3 sites in the 
United States and/or European country(ies) 
are expected to participate during the cohort 
expansion portion of Phase I.
Rationale for change
Per German Ethics Committee, paragraph was 
revised to include language stating other 
countries, in addition to the United States will be 
participating in Phase Ib
Section to be changed
3.1.1.1 Phase I
Description of change
Paragraph updated and includes additional 
information in bold text.
Prior to the initiation of Phase II, a Phase I safety 
analysis report will be prepared based on the 
Phase I data.  A summary of safety and efficacy 
from the dose escalation cohorts and from either 
one or both of the expansion cohorts and RP2D 
will be included in the Phase I safety analysis 
report.  The Phase I safety analysis report will be 
made available for all investigators who 
participate in the Phase II.
Revised:
Prior to the initiation of Phase II, a Phase I safety 
analysis report will be prepared and the protocol 
will be amended based on Phase I results to 
update the benefit-risk assessment, stipulate 
the BI 836858 dose to be used in the Phase II 
part and define details of the patient 
population to be enrolled in phase II.  A 
summary of safety and efficacy from the dose 
escalation cohorts and from the expansion cohorts 
and RP2D will be included in the Phase I safety 
analysis report.  The Phase I safety analysis report 
and amended protocol will be made available 
for Health Authority and Ethics 
Committee/IRB review and approval (where 
applicable) and to all investigators who 
participate in Phase II. Phase II is not allowed by 
regulatory authority yet, and Phase II will not 


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Number of global amendment
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be started prior to regulatory approval as 
required in attending countries. Patients must 
not be recruited to Phase II until local Health 
Authority and ethics committee/IRB approvals 
(where applicable) are granted.
Rationale for change
German Health Authority required Phase I safety 
report and Phase II protocol amendment to be 
finalized and distributed before start of Phase II
Section to be changed
3.3  Selection of Trial Population
Description of change
New text added in bold. And text deleted
Phase I will enter approximately 50 patients from 
approximately 3-7 sites in the United States 
and/or European country(ies).  In the Phase I 
dose escalation part, the trial will recruit patients 
with lower risk MDS who were either previously 
untreated or progressed/became resistant 
following ESA treatment. After determination of 
the MTD/RP2D, the same group of patients as for 
the dose escalation will be enrolled in the first 
expansion cohort. The second expansion cohort 
will enroll patients with low or intermediate-1 
risk MDS with symptomatic anemia, who 
experienced ESA treatment failure or do not 
qualify for ESA treatment and who have not 
received prior HMA and/or lenalidomide
Rationale for change
Per German Ethics Committee, paragraph was 
revised to include language stating other 
countries, in addition to the United States will be 
participating in Phase Ib
Section to be changed
3.3  Selection of Trial Population
Description of change
Text deleted:  
Phase II will enter approximately 150 patients 
with lower risk MDS who were either previously 
untreated or progressed/became resistant 
following ESA and/or approved MDS drugs such 
as HMAs.  Approximately 20 sites from United 
States and European countries are expected to 
participate in Phase II. 
Rationale for change
Definition of Phase II patients updated to align 
with updated inclusion criteria
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Inclusion 1 updated with bold text:

Documented diagnosis of MDS 
according to World Health 
Organization (WHO) criteria that 


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meets International Prognostic Scoring 
System (IPSS) classification of low or 
intermediate-1 risk disease at 
screening as determined by 
microscopic and standard cytogenetic 
analyses of the bone marrow and 
peripheral complete blood count 
(CBC).
- Phase I dose escalation: patients who 
experienced ESA treatment failure or 
do not qualify (serum erythropoietin 
level > 500 U) for ESA treatment, and 
are refractory to or not amenable or 
eligible for established MDS therapy 
(HMA, lenalidomide)
- Phase I expansion: 

- Expansion cohort 1 (“pre-treated”): 
patients who experienced ESA 
treatment failure or do not qualify 
(serum erythropoietin level > 500 U)
for ESA treatment and are refractory to 
established MDS therapy (HMA and 
/or lenalidomide)

- Expansion cohort 2 (“untreated”): 
patients who experienced ESA 
treatment failure or do not qualify 
(serum erythropoietin level > 500 U)
for ESA treatment and who have not 
received prior HMA and/or 
lenalidomide (because not amenable or 
eligible for these treatments).
Phase II: patients who experienced 
ESA treatment failure or do not qualify 
(serum erythropoietin level > 500 U)
for ESA treatment. For definition of 
further details of the phase II patients 
to be included the protocol will be 
amended based on Phase I results 
Rationale for change
To further clarify the inclusion criteria between 
Phase I dose escalation, expansion and Phase II
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
Added Criterion #6:

Neutrophils <1000 /μL (1.0 x 109/L).
Rationale for change
Per German Health Authorities neutrophil 


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Number of global amendment
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criterion was added 
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
Corrected formatting of exclusion criterion #14. 
Move bold text under #14 criterion

Female patients of childbearing 
potential who are sexually active and 
unwilling to use a medically 
acceptable method of contraception 
during the trial and for 6 months after 
the last administration of BI 836858, 
i.e. combination of two forms of 
effective contraception (defined as 
hormonal contraception, intrauterine 
device, transdermal patch, implantable 
or injectable contraceptive, bilateral 
tubal ligation etc.).  

Women of childbearing potential are 
defined as females who:
a) Have experienced menarche  and
b) Are not postmenopausal (12 months 
with no menses without an alternative 
medical cause) and
c) Are not permanently  sterilized (e.g. 
hysterectomy, bilateral oophorectomy  
or bilateral salpingectomy 
Rationale for change
Corrected formatting error to include definition of 
women of childbearing potential under exclusion 
criterion #14. 
Section to be changed
4.1.2 Method of Assigning Patients to 
Treatment Groups
Description of change
Added bold text: 
In Phase I of the trial, patients will be assigned 
into escalating dose cohorts and Phase I 
Expansion cohorts using IRT. After 
determination of the MTD/RP2D, and Phase I 
safety analysis report and protocol amendment 
(see section 3.1.1.1), Phase II enrollment will be 
initiated.
Rationale for change
Clarification made to note end of Phase I report 
and protocol amendment to be made available and 
submitted before start pf Phase II
Section to be changed
4.1.3 Selection of Doses in the Trial


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Description of change
Deleted text: 
The dose is planned to be escalated in cohorts at 
pre-defined dose levels based on a maximum 
escalation of 100%. The provisional dose levels 
are 20mg, 40mg, 80mg, 160mg, and 320mg. 
Intermediate or lower dose levels, depending on 
the number of DLTs observed in the study, and 
dose levels higher than 320 mg may be 
investigated if agreed upon between Investigator 
and Sponsor
Rationale for change
Paragraph was updated indicating that doses 
above 320 mg of BI 836858 will not be tested in 
this trial 
Section to be changed
4.1.4 Drug Assignment and Administration of 
Doses for Each Patient
Description of change
Text was re-bulleted (split to create 3 bullets from 
2) and text deleted:  
Before the administration of BI 836858, adverse 
events and safety laboratory will be assessed.  To 
start or continue treatment with further 
administrations, all of the following criteria must 
be met:
1) Neutrophils ≥1000 /μL (1.0 x 109/L) and
2) Platelets ≥50,000 /μL (50 x 109/L), unless 
CTCAE Grade 3 or 4 neutropenia or
thrombocytopenia was preexistent prior to 
trial entry.  Patients who go from Grade 3 
neutropenia to Grade 4 neutropenia after 
treatment may continue on study provided 
there is no evidence of infection or febrile 
neutropenia. Patients who go from Grade 
3 to Grade 4 thrombocytopenia after 
treatment may continue on study provided 
that post-transfusion platelet count is at 
least 20,000/uL before therapy is given.
3) Acceptable tolerability (in case of an AE 
at the planned start of a further 
administration, patients may continue 
therapy only after recovery to a level 
which would allow further therapy, i.e. 
CTCAE grade 1 or baseline value.)
Rationale for change
In response to German Health Authority, the on 
study dosing requirements were updated and 
clarified
Section to be changed
4.1.8 Drug Accountability


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Description of change
Bold text added.
Each Investigator and/or pharmacist will receive 
the investigational drugs delivered by the Sponsor 
when the following requirements are fulfilled:

approval of the study protocol by the 
Institutional Review Board (IRB) / 
Independent Ethics Committee (IEC), 

availability of a signed and dated clinical 
trial contract between the sponsor and the 
Head of Trial Center,

approval/notification of the regulatory 
authority, e.g. competent authority,

availability of the curriculum vitae of the 
principal Investigator,

availability of a signed and dated CTP or 
immediately imminent signing of the CTP,

availability of the proof of a medical 
licence for the principal investigator,

availability of the FDA Form 1572, if 
applicable.
Rationale for change
Updated to reflect global requirements 
Section to be changed
5.2.1.3 Recommended Phase 2 Dose (RP2D)
Description of change
Deleted text and updated with bold text:
Based on the Phase I data, the DSB will make a 
final determination of the RP2D, which must not 
exceed the MTD. The Phase I safety analysis 
report, including the rationale of RP2D 
determination will be made available to all 
investigators prepared prior to the initiation of 
Phase II.
Rationale for change
Added clarification on the preparation of the end 
of Phase I report
Section to be changed
6.2.3.3 End of the Whole Trial
Description of change
Added bold text: 
In the case that the trial is ended by the Sponsor 
when patients are still being treated and the final 
report of the trial is being prepared, the patients 
will either be included in a follow-up trial or
alternatively kept on treatment in this trial 
provided that treatment continuation is in the 
best interest of the patient, based on clinical 
trial results and the investigator´s benefit risk 
assessment for an individual patient. Those 
patients will then be reported in a revised report 


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and it will be noted in the original report that such 
a revised report will be written. At least one 
Follow-up visit is requested whenever feasible for 
all patients who discontinue study treatment due 
to the trial termination by the sponsor.
Rationale for change
Further clarification made to section on ongoing 
participation of patients who are receiving benefit 
at trial closure
Section to be changed
7.3.4.1 Phase I
Description of change
Updated paragraph with additional bold text:
A Phase I safety analysis report will be prepared 
prior to the initiation of Phase II. A summary of 
safety and efficacy from the dose escalation 
cohorts and from the expansion cohorts will be 
included in the Phase I safety analysis report. 
Results of this evaluation will be documented, 
archived and made available for Health Authority 
and Ethics Committee/IRB review and approval 
(where applicable) and to all investigators who 
participate in the Phase II. Such an analysis will 
be defined in more detail in the TSAP.
Rationale for change
Statistical section was updated to align with 
protocol changes on availability of end of Phase I 
report prior to starting Phase II
Section to be changed
9.1 Published References
Description of change
Added:
P17-02032 Eksioglu, E A, Chen, X, Heider, K-H, 
Rueter, B, McGraw, K L, Basiorka, A A, et al. 
Novel therapeutic approach to improve 
hematopoiesis in low risk MDS by targeting 
MDSCs with the Fc-engineered CD33 antibody 
BI 836858.  Leukemia 2017; 31(10), 2172-2180.
Rationale for change
Updated references list with new publication


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11.4
GLOBAL AMENDMENT 4
Number of global amendment
4
Date of CTP revision
11 Sep 2019
EudraCT number
2018-002177-21
BI Trial number
1315.7
BI Investigational Product(s)
BI 836858
Title of protocol
A Phase I/II, Multicenter, Open-Label, Dose 
Escalation and Randomized Trial of BI 836858 
in Patients with Low or Intermediate-1 Risk 
Myelodysplastic Syndromes
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
Title Page
Description of change
Change of Trial Clinical Monitor from 
 
to 
Rationale for change
New Trial Clinical Monitor assignment
Section to be changed
After the Sponsor’s decision to discontinue 
development of BI 836858 and to stop further 
recruitment of patients into study 1315.7, trial 
participants still on treatment and with clinical 
benefit from BI 836858 are kept on treatment in 
this trial (as per protocol section 6.2.3.3). 
With the aim to minimize the burden for trial 
participants, the mandatory protocol procedures 
and assessments are reduced for all patients in 
treatment cycles ≥5. 


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4
Changes made in the following sections will be 
effective after approval of CTP version 5.0:
Synopsis – section “Number of patients”
Actual number of patients entered/treated in 
Phase I Dose Escalation (21 patients) and in 
Phase I Expansion (6 patients) was added.
One new sentence added: 
Recruitment in this trial was discontinued 
prematurely during the Phase I expansion 
cohort 
Flow Chart and Footnotes:
Section amended to clarify visits, assessments 
and procedures that are mandatory/not 
mandatory at visits ≥5.
Flow Chart – Maintenance and Footnotes:
Sections amended to clarify visits, assessments 
and procedures that are mandatory/not 
mandatory at visits ≥5. 
Table 1 and Footnotes:
Section amended to clarify visits, assessments 
and procedures that are mandatory/not 
mandatory at visits ≥5. 
Table 3 and Footnotes:
Section amended to clarify assessments and 
procedures that are mandatory/not mandatory 
at visits ≥5. 
3.1 Overall Trial Design and Plan
Clarification added about premature 
discontinuation of recruitment to this trial.
3.3.4.2 Discontinuation of the trial by the 
Sponsor
Clarification added about premature 
discontinuation of recruitment to this trial.
4.2.1 Rescue medication, emergency 
procedures, and additional treatment(s)


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4
New Text:
After implementation of CTP version 5.0 
collection of Concomitant Therapy information 
only if the indication is treatment of an (S)AE.
5.2 Safety
New text:
Recruitment in this trial was discontinued 
prematurely during the Phase I expansion 
cohort.
With the aim to minimize the burden for trial 
participants, after implementation of CTP 
version 5.0, the mandatory protocol procedures 
described below in section 5.2.2, Assessment 
of adverse events, 5.2.3, Assessment of safety 
laboratory parameters, 5.2.4, 
Electrocardiogram, 5.2.5, Assessment of other 
safety parameters, and 5.3.1 Physical 
Examinations are reduced for all patients who 
continue to receive trial medication in 
treatment cycles ≥5. Instead, safety 
assessments should be performed at the 
investigator’s discretion, based on standard 
medical care. For details refer to Flow Chart.
Findings are documented in the eCRF only if 
qualifying for an adverse event (see sections 
5.2.2, which remains unchanged).
5.2.2.2 Definition of adverse events 
(Pregnancy)
New Text
After implementation of CTP version 5.0, 
pregnancy test results will not be documented 
by default in the eCRF. Only positive 
pregnancy tests will be documented via the 
Pregnancy Monitoring Form (and reported as 
an AE if applicable).
5.2.5.1 Vital Signs
New text:
After implementation of CTP version 5.0, vital 
signs are mandatory only at the day of 
administration of BI 836858. Results will be


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Number of global amendment
4
documented in the eCRF only if qualifying for 
an adverse event.
6.2 Details of trial procedures at selected 
visits
Clarifications added about reduced mandatory 
protocol procedures for treatment cycles ≥5 
with reference to updated Flow chart.
New text:
With the aim to minimize the burden for trial 
participants, after implementation of CTP 
version 5.0, the mandatory protocol procedures 
are reduced for all patients who continue to 
receive trial medication in treatment cycles ≥5. 
Instead, safety assessments should be 
performed at the investigator’s discretion, 
based on standard medical care. Refer to 
updated Flow Chart for specific requirements 
during treatment period.
Findings during safety assessments are 
documented in the eCRF only if qualifying for 
an adverse event (see sections 5.2.2, which 
remain unchanged).
6.2.3.2 Follow-up
New text:
After implementation of CTP version 5.0, no 
further follow-up visits after EoR, unless 
follow-up is for S(AE) that occurred before 
EoR period.
6.2.3.3 End of the whole trial
Clarification added about the definition of the 
end of the whole trial. 
7.1 Statistical Design - Model
New text:
Recruitment in this trial was discontinued 
prematurely during the dose expansion cohort
Description of change
Recruitment in this trial was discontinued 
prematurely during the Phase I expansion 
cohort.
Rationale for change
To minimize the burden for trial participants, 


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Number of global amendment
4
the mandatory protocol procedures and 
assessments are reduced for all patients in 
treatment cycles ≥5.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02304070
7.0
clinical-trial-protocol-version-5
A Phase I/II, Multicenter, Open-label, Dose Escalation and Randomized Trial of BI
836858 in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes
Approval-Clinical Trial Leader
12 Sep 2019 20:34 CEST
Approval-Therapeutic Area
12 Sep 2019 22:41 CEST
Approval-Biostatistics
13 Sep 2019 17:50 CEST
Approval-Team Member Medicine
17 Sep 2019 10:12 CEST
Author-Trial Clinical
Pharmacokineticist
20 Sep 2019 17:36 CEST
Approval-Clinical Trial Leader
20 Sep 2019 18:09 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02304070
7.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c02189546-02
BI Trial No.:
1315.7
Title:
A Phase I/II, Multicenter, Open-label, Dose Escalation and 
Randomized Trial of BI 836858 in Patients with Low or 
Intermediate-1 Risk Myelodysplastic Syndromes
Including Protocol Amendments 1, 2 3 and 4 [c02304070-06]
Investigational
Product(s):
BI 836858
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
07 JAN 2020 SIGNED
Version:
Final
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Boehringer Ingelheim
TSAP for BI Trial No.: 1315.7
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1. TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
LIST OF FIGURES ............................................................................................5
2.
LIST OF ABBREVIATIONS ...............................................................6
3.
INTRODUCTION..................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......9
4.1
CLARIFICATIONS .................................................................................................9
4.2
CHANGES.................................................................................................................9
5.
ENDPOINTS ........................................................................................10
5.1
PRIMARY ENDPOINTS.......................................................................................10
5.2
SECONDARY ENDPOINTS.................................................................................11
5.2.1
Key secondary endpoints........................................................................................11
5.2.2
Secondary endpoints...............................................................................................11
6.
GENERAL ANALYSIS DEFINITIONS...........................................19
6.1
TREATMENTS.......................................................................................................19
6.2
IMPORTANT PROTOCOL DEVIATIONS .......................................................20
6.3
PATIENT SETS ANALYSED...............................................................................21
6.5
POOLING OF CENTERS .....................................................................................22
6.6
HANDLING OF MISSING DATA AND OUTLIERS........................................22
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS ......................22
7.
PLANNED ANALYSES......................................................................23
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.............23
7.2
CONCOMITANT DISEASES AND MEDICATION .........................................23
7.3
TREATMENT COMPLIANCE............................................................................24
7.4
PRIMARY ENDPOINTS.......................................................................................24
7.5
SECONDARY ENDPOINTS.................................................................................24
7.5.1
Key secondary endpoint .........................................................................................24
7.5.2
Other secondary endpoints ....................................................................................25
7.7
EXTENT OF EXPOSURE.....................................................................................25
7.8
SAFETY ANALYSIS..............................................................................................25


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7.8.1
Adverse events.........................................................................................................25
7.8.1.1
Maximum tolerated dose and dose limiting toxicity.................................................25
7.8.1.2
Adverse events..........................................................................................................26
7.8.2
Laboratory data ......................................................................................................32
7.8.3
Vital signs.................................................................................................................35
7.8.4
ECG..........................................................................................................................35
7.8.5
Others.......................................................................................................................35
8.
REFERENCES.....................................................................................36
10.
HISTORY TABLE...............................................................................37


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LIST OF TABLES
Table 5.2.2:1 Derivation rules for Duration of Response........................................................12
Table 6.1:1 Definition of analysing treatment periods ............................................................19
Table 6.2:1 Important protocol deviations...............................................................................20
Table 7.8.1.2:1 Definition of user defined AE categories .......................................................28
Table 7.8.1.2:2 User defined (sub-) search category of “Cardiac Failure”..............................30
Table 7.8.1.2:3 Laboratory Signs of Cell Destruction.............................................................31
Table 7.8.1.2:4 Clinical Signs of Cell Destruction..................................................................31
Table 7.8.2:1 Conversion of urine measurements based on dipsticks.....................................33
Table 10:1 History table...........................................................................................................37


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LIST OF FIGURES
Figure 7.8.2:1 Assessment of patients fulfilling the criteria for potential Hy’s law cases. Top:
patient fulfils criteria. Bottom: patient does not fulfil criteria.........................................35


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2. LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse events of special interest
ALQ
Above limit of quantification
ALT
Alanine Amino Transferase
AML
Acute Myelogenous Leukemia
AST
Aspartate Amino Transferase
ATC classification
Anatomical, Therapeutic, Chemical classification
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BLRM
Bayesian logistic regression model
BMI
Body Mass Index
BSA
Body Surface Area
CR
Complete Response
CT
Concomitant therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Data base lock
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
eCRF
Electronic case report form
EFS
Event free survival
HI
Hematologic improvement
HI-E
Hematologic improvement erythroid
HI-N
Hematologic improvement neutrophils
HI-P
Hematologic improvement platelets
ICH
International Conference on Harmonisation


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Term
Definition / description
iPD
Important Protocol Deviation
IRR
Infusion related reaction
LLOQ
Lower limit of quantification
mCR
Marrow Complete Response
MedDRA
Medical Dictionary for Regulatory Activities
mL
Millilitre
MQRM
Medical and Quality Review Meeting
MTD
Maximum tolerated dose
OR
Objective response
PD
Progressive disease
PR
Partial response
PT
Preferred term
RBC TI
Red Blood Cell Transfusion Independence
REP
Residual effect period
RP2D
Recommended phase 2 dose
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard deviation
SMQ
Standardized MedDRA Queries
SOC
System organ class
SS
Screened set
TLS
Tumor Lysis Syndrome
TS
Treated set
ULN
Upper Limit of Normal
ULOQ
Upper limit of quantification
WHO DD
World Health Organization 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, definition of measurements and variables, planning of sample size, 
randomization. This TSAP follows the Boehringer Ingelheim (BI) internal reference (2).
This TSAP is based on the Project Statistical Analysis Plan wherever possible. Wordings like 
"randomization (first administration of study treatment in non-randomized trials)" should 
therefore be interpreted as applicable. 
 
 SAS version 9.4 (or later) will be used for all other 
analyses.


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4. CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
4.1
CLARIFICATIONS
As stated in the CTP, one of the Phase I primary endpoints is “occurrence of dose limiting 
toxicity (DLT)”. To clarify, this is defined as the number of patients with DLTs during the 
maximum tolerated dose (MTD) evaluation period. 
4.2
CHANGES
This study was terminated prematurely during the Phase I expansion cohort stage. No patients 
were recruited for the Phase II part of the study. Therefore none of the Phase II analyses 
stated in the CTP will be performed. The rest of this TSAP specifies analyses pertaining to 
Phase I part of the study only.


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5. ENDPOINTS
This study is an open label Phase I/II trial of BI 836858 in patients with low or intermediate-1 
risk myelodysplastic syndromes. Only the Phase I part is conducted; the study is terminated 
with recruitment discontinued before the commencement of the Phase II part.
Phase I consists of a single arm, dose escalation stage followed by an expansion cohort stage.
Dose-escalation is guided by a Bayesian logistic regression model with overdose control. The 
primary objectives are determination of the MTD and the recommended phase II dose 
(RP2D). After determination of the MTD/RP2D, two expansion cohorts—untreated or pre-
treated with HMA and/or lenalidomide—are enrolled at the selected dose.
5.1
PRIMARY ENDPOINTS
The primary endpoints in the Phase I part of the trial are the MTD and the number of patients 
with dose limiting toxicities (DLTs) during the MTD evaluation period.  
Maximum tolerated dose (MTD) and number of patients with DLTs during the MTD 
evaluation period:
The MTD is defined as the highest dose of BI 836858 with less than 25% risk of the true 
DLT rate being above 33% during the MTD evaluation period. The other primary endpoint, 
the number of patients with DLTs during the MTD evaluation period will be used to 
determine the MTD.
MTD evaluation period:
The MTD evaluation period is defined as the time from the first administration of trial 
medication to start of the third administration of BI 836858, excluding the day of the third 
administration of BI 836858. In case the third infusion of BI 836858 is not administered, the 
evaluation period ends 30 days after the last administration. 
In case a patient has not completed the required number of administrations due to BI 836858 
related toxicity, he/she will not be replaced and this will be considered as DLT. However, 
patients who have not completed the required number of administrations of BI 836858 for 
reasons other than BI 836858 related toxicity will be replaced.  Patients who were replaced 
during the MTD evaluation period will not be considered for MTD evaluation. That is, a 
patient will be considered evaluable for MTD assessment if he/she received at least 2 
administrations of BI 836858 or if he/she received less than 2 administrations due to DLT. 
The MTD estimate after the dose escalation part of the trial will be obtained on the basis of 
DLTs observed during the MTD evaluation period. However, for those patients who receive 
more than one cycle of the treatment, all AEs that constitute a DLT will be considered in the 
final determination of the dose recommended for the Phase II part.
As part of this additional analysis the probabilities of the Bayesian 2-parameter logistic 
regression model with overdose control will be also computed including all considered DLTs.


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5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
No key secondary endpoints are defined in this study.
5.2.2
Secondary endpoints
The secondary endpoints in Phase I are

RBC Transfusion Independence (RBC TI)

Hematologic improvement neutrophils (HI-N)

Hematologic improvement platelets (HI-P)

Hematologic improvement erythroid (HI-E)

Time to HI-E response

Mean hemoglobin increase ≥ 1.5 g/dL

Duration of Response (RBC Transfusion Independency, HI-N, HI-P, HI-E or 
Objective Response)

Overall Objective Response (OR) [Complete Response (CR), Partial Response (PR), 
and Hematologic Improvement (HI)]
RBC Transfusion Independence (RBC-TI):
The definition of RBC TI is given in section 5.1.2.3 of the CTP. RBC-TI is evaluated in 
patients who are transfusion dependent at baseline. Percentages will be calculated using all 
treated patients, who are transfusion dependent at baseline, as the denominator. 
The investigator's assessment as reported on the "Disease Assessment eCRF" will be used for 
the analysis of this endpoint. No derivation from the "Concomitant Blood Product Therapies 
eCRF" is planned. Consistency between these two eCRF pages will be reviewed during the 
trial's Medical Quality Review Meetings (MQRMs).
HI-N, HI-P and HI-E:
HI-N, HI-P and HI-E are defined in section 5.1.2.3 of the CTP. The investigator's assessment 
as reported on the "Disease Assessment eCRF" will be used for the analysis of these 
endpoints. No derivation from the "Laboratory eCRF" (or the "Concomitant Blood Product 
Therapies eCRF") is planned. Consistency between these eCRF pages will be reviewed 
during the trial's Medical Quality Review Meetings (MQRMs).
Time to HI-E response:
Time to HI-E response is defined only for patients who achieve a HI-E response as follows:
Time to HI-E response [days] = date of first assessment indicating HI-E response –
date of first administration of trial medication + 1.


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Mean hemoglobin increase ≥ 1.5 g/dL:
The definition of “Mean hemoglobin increase ≥ 1.5 g/dL” is given in CTP section 5.1.2.3.
Duration of Response:
Duration of objective response is defined only for patients who achieve an overall response of 
CR or mCR or RBC TI.
Duration of response is defined as:
Duration of Response [days] = date of outcome – date of first assessment indicating 
CR or mCR or RBC TI after first administration of trial medication + 1.
The censoring rules and dates of outcome (i.e. event or censoring) for Duration of Response 
under different scenarios are specified in Table 5.2.2:1. The evaluation period for duration of 
response is until treatment discontinuation (see also section 5.1.2.3 of the CTP).
Table 5.2.2:1 Derivation rules for Duration of Response
Situation
Outcome (event 
or censored)
Date of outcome
No relapse, no death
censored
Date of last disease assessment
Relapse (no subsequent anti-
cancer therapy before relapse)
event
Date of disease assessment of 
relapse
Death without relapse, no 
subsequent anti-cancer therapy
censored
Date of death
Death without relapse, but 
subsequent anti-cancer therapy 
prior death
censored
Date of last disease assessment 
before initiation of subsequent 
anti-cancer therapy
Subsequent anti-cancer therapy before relapse (check interval between start of new 
medication and relapse)
Interval <= 7 days
Event
Date of disease assessment of 
relapse
Interval > 7 days
Censored
Date of last disease assessment 
before initiation of subsequent 
anti-cancer therapy
Overall Objective Response:
Overall Objective Response is defined as Complete Response (CR), Partial Response (PR), 
HI-N, HI-P, or HI-E. A patient's " Overall Objective Response " = "Yes" if one of these 
responses was reported at least once throughout the trial.


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6. GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
In the Phase I part, treatments are not randomized (open-label, dose escalation). Different 
dose levels (planned and intermediate) of the investigational medicinal product will be 
evaluated. The data will be presented for all dose cohorts separately, in particular, patients 
will be analysed by the treatment group initially assigned in the first treatment course. In 
addition, totals over all dose cohorts will be given.
“Analysing treatment periods” will be used for reporting of treatment emergent adverse 
events (AE) and to differentiate between screening, on-treatment, post-treatment and post-
study safety data. The inequalities start date ≤ onset date of AE < stop date will determine 
whether the AE will be assigned to the “analysing treatment period” or not. Table 6.1:1
defines the “analysing treatment periods” which will be used for reporting of treatment 
emergent AEs and safety laboratory parameters. 
Table 6.1:1 Definition of analysing treatment periods
Analysing 
treatment period
Start date (including)
Stop date (excluding)
Screening
Date of informed consent
Date of first administration 
of trial medication
MTD evaluation 
period
Date of first administration of trial 
medication
Date of third infusion or (if 
the third infusion was not 
administered) Date of first 
administration of trial 
medication + 28 days 
On-treatment
Date of first administration of trial 
medication
Start date of ‘Follow-up’
Follow-up
Date of end of REP +1 day, i.e. Date of 
last administration of trial medication + 
30 days of REP + 1 day
Start date of ‘Post-study’
Post-study
Last date patient status obtained / last 
date patient known to be alive + 1 (if 
patient is lost to follow-up) / date of 
refusal + 1 day / the date patient died + 
1
DBL + 1 day
Data recorded between the first administration of trial medication until up to 30 days 
(Residual effect period; REP) after the last administration of trial medication will be 
considered as on-treatment.
In addition, to justify the MTD determination, AEs occurring during the MTD evaluation 
period will be presented separately from those occurring during the complete on-treatment 
period.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Even though no per protocol population is defined, patients with potentially important 
protocol deviations (iPD) will be identified and documented.
Potentially important protocol deviations are defined in Table 6.2:1. The final list of iPDs 
will be confirmed at the last report planning meeting (RPM) before the database lock at the 
time of the CTR.
If any manual iPDs are identified, they are to be summarized into categories and will be 
captured in the MQRM/RPM minutes via an accompanying Excel spreadsheet (3).
Table 6.2:1 Important protocol deviations
Category/
Code
Description
Comment/Example
Excluded 
from
A
Inclusion/Exclusion Criteria
A1
Criteria related to safety
A1.11
Patient has condition that may cause 
additional risk from study medication
EX 11, IN 4
None
A1.21
Patient has laboratory assessments that may 
cause additional risk.
EX 6-9
None
A1.31
Patient is unable to comply with the protocol
EX 12, EX 21
None
A1.41
Patient has condition that may interfere with 
evaluation of safety (and/or efficacy)
EX 3-5, EX 10, EX 13, EX 17-20
None
A2
Criteria related to efficacy
A2.11
Patient does not have trial diagnosis or is not 
part of the target population
IN 1-3, EX 1, EX 2 (Phase II only)
None
B
Legal criteria
B11
Informed consent not available/not done
IN 6
All
B21
Informed consent too late
Informed consent date after 
screening visit date.
None
B31
Men or women who are sexually active and 
not using adequate contraception.
EX 14, EX 15
None
B41
Pregnant or nursing female patient
EX 16, positive pregnancy test
None
B51
Patient’s age < 18
IN 5
None
C
Trial medication and randomization
C12
Administration of trial medication not in 
accordance with the protocol
As marked in the eCRF, after 
discussion and decision in MQRM
None
C22
Continuation of treatment although criteria for 
re-treatment are not met
Create listing, decision at MQRM / 
report planning meetings (RPM), 
see CTP section 4.1.4 
None


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Table 6.2:1 Important protocol deviations (cont.)
Category/
Code
Description
Comment/Example
Excluded 
from
C32
(Unjustified) intra-patient dose-escalation
Create listing, decision at MQRM / 
RPM, see CTP section 4.1.4 
None
C42
Withdrawal of patient not performed 
according to CTP
Create listing, decision at MQRM / 
RPM, see CTP section 3.3.4 
None
C52
Discontinuation of trial drug not performed 
according to CTP
Create listing, decision at MQRM / 
RPM, see CTP section 3.3.4
None
C62
Phase II: Wrong stratification factor input 
during randomization
Create listing comparing IVRS and 
eCRF information
None
D
Restrictions
D12
Additional experimental anti-cancer, chemo-, 
immuno-, hormone - or radiotherapy during 
the treatment period.
Create listing, decision at MQRM / 
RPM, see CTP section 4.2.2.1 and 
EX 3, EX 5
None
E
Missing data
E12
Baseline bone marrow assessment not within 
the required time-window
Create listing for patients whose 
bone marrow assessment was not 
within 14 days prior to first 
treatment, decision at MQRM / 
RPM
None
[1] iPD will be derived automatically
[2] iPD will be identified via individual review at MQRM/RPM/DBL
6.3
PATIENT SETS ANALYSED
The following patient sets are defined for the Phase I part:

Screened set (SS): This patient set includes all patients who have signed the informed 
consent. The SS will be used for patient disposition tables.

Treated set (TS): This patient set includes all patients who were documented to have 
received at least one dose of trial medication.

MTD evaluation set: The MTD evaluation set includes all patients from the TS who 
have not been replaced for the MTD evaluation. Rules for replacement of patients are 
defined in Section 5.1 and CTP section 3.3.4.1.
The MTD evaluation set will be used for the primary endpoint analyses whereas the TS will 
be used for all other efficacy and safety analyses in the Phase I part. The list of replaced 
patients will be provided by the clinical trial monitor no later than at the last RPM and will be 
attached to the RPM minutes.


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No per protocol population will be used for analyses. 
6.5
POOLING OF CENTERS
Not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
If not stated otherwise, missing data will not be imputed and will remain missing. Potential 
outliers will be reported and analysed as observed. Missing or incomplete AE dates will be
imputed according to BI standards (4).
 
 For missing laboratory data at Visit 1 (before the very first 
administration of study medication) data from preceding visits will be used if available.
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS
Study days and visits will be labelled according to the CTP's flow chart.
Unless otherwise specified, baseline is defined as the time-point closest to but prior to the
first administration of trial medication in course 1. Note that for some trial procedures (for 
example body weight, vital signs, laboratory tests) this may be the value measured on the 
same day the trial medication was started. In these cases it will be assumed that the 
measurements were taken according to protocol, i.e. prior to first intake of any trial 
medication. 
For laboratory values, baseline is defined as the latest time-point before the very first 
administration of any trial medication in course 1. When not only the examination date but 
also time are recorded, the examination time has to be taken into account when defining 
baseline. That is, a laboratory value on the same date as the first trial 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 trial drug administration.


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7. PLANNED ANALYSES
The labelling and display format of statistical parameters will follow the guideline “Standards 
for Reporting of Clinical Trials and Project Summaries” (5).
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / Standard deviation 
(SD) / Min / Median / Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles will be preferred to mean, standard deviation, minimum and maximum.
In general, means, SDs, medians, and percentiles will be presented to one more decimal place 
than the raw data. Minima and maxima will be presented to the same number of decimal 
places as the raw data.
Duration and time-to-event data will be listed only. If not specified otherwise, durations and
time-to-events will be displayed in months and a final decision will be made at the last RPM.
Tabulations of frequencies for categorical data will include all possible categories, even when 
the count is zero. The display will include the number of observations in a category as well as 
the percentage (%) relative to the number of patients in the respective treatment group. The 
percentages will be calculated out of all patients in the corresponding patient sets regardless 
of whether they have non-missing values or not, unless otherwise specified. Percentages will 
be rounded to one decimal place. The category “missing” will be displayed if and only if 
there are actually missing values.
If a table presents only categorical data, “N (%)” will be displayed in the column header only.
Abbreviations (e.g., Wors.) or acronyms (e.g., PD) will not be displayed in tables and Subject 
Data Listings (SDLs) without any explanation. They will be either spelled out or explained in 
footnotes.
If applicable, conversion from days to weeks, months and years will be as follows:

Weeks = days ÷ 7

Months = 12 × days ÷ 365.25

Years = days ÷ 365.25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Standard descriptive analyses and summary tables are planned for this section of the report. 
Data will be summarized by treatment group. A “total” column will also be included in the 
summary tables.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. 
Concomitant diseases will be coded similarly as for adverse events based on the most current 
version of Medical Dictionary for Regulatory Activities (MedDRA). Concomitant therapies
(CTs) will be coded according to World Health Organization Drug Dictionary (WHO DD).
CTs will be categorized by therapy type according to the third level of the Anatomical, 


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Therapeutic, Chemical (ATC) classification system. 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 CTs with more than one possible 
ATC level 3 category will be counted more than once; footnotes will clarify this possible 
double counting in tables.
7.3
TREATMENT COMPLIANCE
A listing of medication compliance will be provided in the corresponding section of the 
report.
7.4
PRIMARY ENDPOINTS
The primary endpoints are the MTD and the number of patients with dose limiting toxicities 
(DLTs) during the MTD evaluation period. The MTD is determined from the number of non-
replaced patients with DLT during the MTD evaluation period (for the definition of MTD 
evaluation period refer to Section 5.1). 
An overall summary of patients with DLT(s) which occurred during the MTD evaluation 
period and the on-treatment period will be provided for each dose cohort. 
Patients who were treated but replaced will be not considered for the MTD determination.  
However, all information, including adverse events qualifying for a DLT from later times, 
will be considered in the final determination of the recommended Phase II dose (RP2D).
The analysis of the MTD is based on a Bayesian logistic regression model (BLRM). The 
MTD is defined as the highest dose for a given schedule that is expected to cause less than 
25% risk of the true DLT rate being above or equal to 33% during the MTD evaluation 
period. Estimation of the MTD during the dose escalation phase of the study will be based 
upon the estimation of the posterior probability of the incidence of DLT in toxicity categories 
during the MTD evaluation period for all evaluable patients. The model to be used is 
specified in CTP section 7.
Tables and bar charts will be produced to display, for each dose level, the posterior 
probabilities that the true DLT rate being in the underdosing [0, 0.16), target-dosing [0.16, 
0.33) and overdosing [0.33, 1] intervals.
In order to describe the occurred dose escalation steps, a listing of all treated patients will be 
provided. This will include the initial dose of BI 836858, patient number, treatment start date, 
DLT in MTD evaluation period [y/n], evaluable for MTD [y/n]. The listing will be sorted by 
treatment start date.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.


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7.5.2
Other secondary endpoints
The analysis of secondary endpoints in Phase I will be performed in a descriptive manner. No 
inferential analysis will be conducted.  The secondary endpoints RBC-TI, HI-N,HI-P, HI-E, 
mean hemoglobin increase ≥ 1.5 g/dL and overall objective response will be summarized in a 
frequency table. Hereby the data will be presented for all dose cohorts separately as well as in 
total. Time-to-HI-E responses and durations of response will be listed only. 
7.7
EXTENT OF EXPOSURE
Standard descriptive analyses over all treatment courses will be performed. This will include 
a summary of the variables defined in Section 5.4.2 and will comprise a mixture of frequency 
and percentages, as well as summary statistics.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set, except for analyses pertaining to 
MTD determination described in Section 7.4 which will then be performed on the MTD 
evaluation set. Patients who were replaced within the MTD evaluation period will be 
excluded from the determination of the MTD but will be considered for all other safety 
evaluations. A listing of replaced patients will be provided.
7.8.1
Adverse events
7.8.1.1
Maximum tolerated dose and dose limiting toxicity
Analysis of MTD will be reported as described in Section 7.4.
In addition, tables displaying DLTs by primary system organ class and preferred term will be 
provided by initial treatment for the MTD evaluation period for the MTD evaluation set as 
well as for the treated set over the on-treatment period.
The purpose of these tables is to summarize and document the data that led to the selection of 
MTD. A summary of the number of patients with DLT within the MTD evaluation period 
(treatment course 1) and for all treatment courses of the on-treatment period will be given by 
initial treatment for the treated set.


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7.8.1.2
Adverse events
Unless otherwise specified, the analyses of adverse events (AEs) will be descriptive in nature. 
All analyses of AEs will be based on the number of patients with AEs and NOT the number 
of AEs. The analyses will be based on BI standards. Adverse events will be coded with the 
most recent version of MedDRA. The severity of AEs will be scaled according to CTCAE 
version 4.0.
For analysis of AE attributes such as duration, severity, etc. multiple AE occurrence data on
the CRF, will be collapsed into AE episodes provided that all of the following applies:

The same MedDRA lowest level term was reported for the occurrences.

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence.
For each patient, all episodes with the same preferred term (PT) (system organ class, SOC) 
will be condensed to one AE record using a worst case approach for all AE attributes 
including CTCAE grading. 
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events, where a treatment emergent AE has an onset in the analyzing treatment period. All 
adverse events occurring before first intake of trial medication will be assigned to ‘screening’ 
and all adverse events occurring after last intake of trial medication + 30 days will be 
assigned to ‘post-treatment’ (in randomized trials for listings only). For details on the 
treatment definition, see Section 6.1. In addition, a listing will be provided, detailing the 
actual treatment on the day when the adverse event started. For screening and post-study 
period, AEs will be listed.
An overall summary of adverse events will be presented. This will include the number of 
patients with AEs by the highest CTCAE grade. The frequency of patients with adverse 
events will be summarized by treatment, highest CTCAE grade, primary system organ class 
and preferred term (PT). Separate tables will be provided for the followings:

serious adverse events (SAEs), 

drug-related SAEs, 

drug-related AEs,

AEs leading to permanent discontinuation of trial medication, 

AEs leading to death, 

DLTs, and 

adverse events of special interest (AESIs) including infusion related reactions 
(IRRs).  
In addition, tables will be provided for patients with AEs of incidence ≥10% and with drug-
related AEs of incidence ≥10%.


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Tabulations of AEs using user-defined AE categories will also be provided.
Adverse events of special interest (AESIs):
Adverse events of special interest (AESIs) are defined in CTP section 5.2.2.1 as infusion 
related reactions (IRRs) of CTCAE grade >= 3, DLTs (occurring during the MTD evaluation 
period or repeated treatment courses) and drug induced liver injury (DILI).
Other significant AEs:
Other significant AEs are defined as serious and non-serious AEs that lead to dose reduction 
or permanent discontinuation of study medication. Their incidence will be reported by 
severity according to CTCAE grades.
Infusion related reactions (IRRs):
IRRs will be the object of special attention. 
Patients with any IRR will be tabulated by treatment and worst CTCAE grade. In addition, 
the number of infusions and the number of IRRs will be displayed by treatment.
The duration of IRR [h] and the time since start of the respective infusion [min] together with 
IRR related symptoms will be tabulated by infusion number and overall.

Duration of IRR [h] = (End time of IRR - Start time of IRR) [seconds] / 3600

Time since start of the respective infusion [min] = (Start time of IRR - Start time of 
infusion) [seconds] / 60
The relationship between the occurrence of IRRs and infusion rate as well as the 
administration of premedication will be examined.
Duration of IRR, time since start of infusion, and related symptoms will be summarized 
descriptively by infusion timepoints.
Fatal AEs:
AEs leading to death during the on-treatment period will be tabulated. Reported fatal AEs 
that occurred in the post-treatment phase will be listed.
Additionally, a table summarizing the information on deaths collected on the AE eCRF and 
the Patient Status eCRF will be provided.
User defined AE categories (UDAEC):
User defined AE categories (UDAEC) are defined in Table 7.8.1.2:1. For UDAECs which 
contain sub-searches and/or two sensitivity levels (broad and narrow) all possibilities will be 
displayed on the UDAEC level in tables. For example for UDAEC “Bleeding”, it will include
“Bleeding - SMQ Haemorrhage”, “Bleeding - SMQ Haemorrhage laboratory terms broad”, 
“Bleeding - SMQ Haemorrhage laboratory terms narrow” and “Bleeding - SMQ 
Haemorrhage terms (excl. laboratory terms) narrow”.


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Table 7.8.1.2:1 Definition of user defined AE categories
Special Search 
Category
Definition
Sensitivity
Infusion related 
reactions
(hypersensitivity)
SMQ 20000021 + infusion related reaction 
PT 10051792
Narrow (Algorithm)
Bleeding
SMQ Haemorrhage  20000038
SMQ Haemorrhage terms (excl. laboratory 
terms) 20000039
Narrow & broad
Narrow 
SMQ Haemorrhage laboratory terms 
20000040
Narrow & broad
Nausea 
BIcMQ Nausea  30000078
Narrow & broad
Vomiting 
BIcMQ  Vomiting  
30000091
Narrow & broad
Drug related hepatic 
disorders
SMQ Drug related hepatic disorders 
20000006
Narrow & broad
SMQ Cholestasis and jaundice of hepatic 
origin 
20000009
Narrow & broad
SMQ Drug related hepatic disorders - severe 
events only 20000007
Narrow & broad
SMQ Liver related investigations, signs and 
symptoms 20000008
Narrow & broad
SMQ Liver-related coagulation and bleeding 
disturbances 20000015
Narrow & broad
ALT
BIcMQ Elevated Specific Liver Function 
Parameters sub-search1    30000022
Narrow & broad
AST
BIcMQ Elevated Specific Liver Function 
Parameters sub-search2    30000023
Narrow & broad
ALKP
BIcMQ Elevated Specific Liver Function 
Parameters sub-search3    30000024
Narrow & broad
gGT
BIcMQ Elevated Specific Liver Function 
Parameters sub-search4   30000025
Narrow & broad
Bilirubin
BIcMQ Elevated Specific Liver Function 
Parameters sub-search5    30000026
Narrow & broad
Neutropenia
BIcMQ Neutropenia 30000031
Narrow & broad
Cardiac disorders1
SMQ Ischaemic heart disease 20000043
Narrow & broad
SMQ Cardiac failure 20000004
Narrow & broad
SMQ Cardiac arrhythmias 20000049
Narrow & broad


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Table 7.8.1.2:1 Definition of user defined AE categories (cont.)
Special Search 
Category
Definition
Sensitivity
Tumour Lysis
Syndrome
SMQ Tumour Lysis Syndrome 20000219
All broad
SMQ Torsade de point/QT prolongation
Broad (20000001)
SMQ Cardiac arrhythmia terms broad
(incl bradyarrhythmias and
tachyarrhythmias) (20000050)
SMQ Convulsions broad (20000079)
Fluid accumulation
HLT Total fluid volume increased 10044085
HLT Oedema NEC 10030113
HLT Pulmonary oedemas 10037424
HLT Pneumothorax and pleural effusions 
NEC 10035761
PT Ascites 10003445
PT Abnormal weight gain 10000188
Infections
Infections (incl. respiratory infections and 
sepsis) - SOC 10021881 use label 
"Infections and infestations"
Infections (incl. respiratory infections and 
sepsis) - HLGT 10024970 use label 
"Respiratory tract infections"
Infections (incl. respiratory infections and 
sepsis) - HLT 10040054 use label "Sepsis, 
bacteraemia, viraemia and fungaemia NEC"
Inflamed gut
PT Enterocolitis 10014893
PT Enterocolitis bacterial 10065206
PT Enterocolitis fungal 10065205
PT Enterocolitis helminthic 10065204
PT Enterocolitis infectious 10058838
PT Enterocolitis viral 10061841
PT Colitis 10009887
PT Enteritis 10014866
Acute febrile 
neutrophilic 
dermatosis
PT Acute febrile neutrophilic dermatosis 
10000748
1 A BIcMQ has been requested, however, as long as this is not available the terns as defined in Table 
7.8.1.2:2 will be used.


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Table 7.8.1.2:2 User defined (sub-) search category of “Cardiac Failure”
Selected PTs for Cardiac Failure
Cardiac asthma
Cardiac failure
Cardiac failure acute
Cardiac failure chronic
Cardiac failure congestive
Cardiac failure high output
Cardiac index decreased
Cardiac output decreased
Cardiogenic shock
Cardiomegaly
Cardiothoracic ratio increased
Dilatation ventricular
Left ventricular failure
Low cardiac output syndrome
Right ventricular failure
Oedema due to cardiac disease
Left ventricular dysfunction
Ejection fraction decreased
Cardiopulmonary failure
Diastolic dysfunction
Cardiac ventriculogram right abnormal
Cardiac ventriculogram abnormal
Cardiac ventriculogram left abnormal
Cardiac cirrhosis
Right ventricular dysfunction
Ventricular dysfunction
Cardiac resynchronisation therapy
Ventricular failure
Acute left ventricular failure
Acute right ventricular failure
Chronic left ventricular failure
Chronic right ventricular failure
Myocardial depression
Ventricular dyssynchrony
Systolic dysfunction
Neonatal cardiac failure
UDAEC will be summarized by dose cohort, search category, preferred term and CTCAE 
grade. Some events contribute to more than one UDAEC. Patients with such AEs are counted 
in each of the UDAEC but are counted only once in the overall number of patients with an 
AE in any UDAEC.


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Tumor Lysis Syndrome
In patients with a high tumor burden who are exposed to a highly effective therapy, there is a 
risk of rapid tumor destruction resulting in Tumor Lysis Syndrome (TLS). Patients will be 
identified as having potential TLS if they meet both of the following criteria:
(1) Two or more of the laboratory parameters meet the criteria in Table 7.8.1.2:3.
a.
Time window
i. on the day of BI 836858 infusion or the following 6 days,
ii. at least two of the qualifying lab values must have occurred within the 
same 24 hour period
(2) Have an adverse event identified by any of the SMQ in table 7.8.1.2:4 or have a 
qualifying creatinine value.
a.
Time window
i. AE onset or creatinine observation at any time during the treatment or 
residual effect period
Laboratory tests relevant to TLS and patients with potential TLS will be displayed in listings.
Table 7.8.1.2:3 Laboratory Signs of Cell Destruction
Laboratory parameter
Abnormal value
Uric acid
≥476 μmol/L AND increase from relative baseline1 by ≥25%
Potassium
value ≥ 6.0 mmol/L AND relative baseline < 6.0 mmol/L
Inorganic phosphate
≥1.45 mmol/L AND increase from relative baseline by ≥25%
Calcium
<7 mg/dL2 AND decrease from relative baseline by ≥25%
1Relative baseline is derived separately for each BI 836858 infusion as the last value prior to that BI 836858 
infusion. Relative baseline will be derived independently for the four parameters, ie. four baseline values do not 
necessarily have to be derived from the same laboratory assessment. 2For calcium, 0.25* mg/dL= mmol/L  
Table 7.8.1.2:4 Clinical Signs of Cell Destruction
Criterion 
TLS broad SMQ [20000219]
Torsade de point/QT prolongation broad SMQ [20000001]
Cardiac arrhythmia terms broad SMQ (incl bradyarrhythmias and tachyarrhythmias) 
[20000050]
Convulsions broad SMQ [20000079]
Creatinine 
Absolute increase from relative baseline by 26.5 μmol/L AND increase from relative 
baseline by ≥50%


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (8). The same on-treatment period as considered for the analysis of AEs will be 
applied for laboratory values. Patients having at least one post-baseline laboratory value will 
be displayed in the descriptive analyses.
Safety laboratory examinations include hematology, biochemistry, coagulation and 
qualitative urine analysis:
Hematology
Hemoglobin, red blood cell count (RBC), white blood cell count 
(WBC) with differential (neutrophils, basophils lymphocytes, 
monocytes, eosinophil, reticulocytes), platelets (PLT)
Biochemistry 
Glucose (plasma), sodium, potassium, calcium, inorganic phosphate,
creatinine, AST, ALT, alkaline phosphatase (AP), lactate
dehydrogenase (LDH), bilirubin (total and direct), urea (preferred) or 
BUN, total protein, albumin, uric acid, IgG, IgM, IgA and direct
antiglobulin (direct Coombs), Free haemoglobin(serum), Haptoglobin
Coagulation
Activated partial thromboplastin time (aPTT), prothrombin time (PT), 
international normalised ratio (INR) where indicated (e.g. treatment 
with vitamin K antagonists)
Urine 
pH, glucose, erythrocytes, leukocytes, protein, nitrite 
Neutrophil and platelet counts of each patients will be plotted in log scale graphs.
Descriptive statistics, including change from baseline and frequency of patients with 
transitions relative to the reference range, will be provided. CTCAE grades for applicable 
laboratory parameters will be calculated according to CTCAE version 4.0. The following 
outputs will be presented:

Worst CTCAE grade experienced during the on-treatment phase.

Transitions of CTCAE grade from baseline to worst laboratory value, from worst to 
last laboratory value during the on-treatment phase, and from baseline to last 
laboratory value.
Worse laboratory value and its CTCAE grade (highest CTCAE grade) over all courses will be 
calculated for each laboratory parameter. 
The last laboratory value on treatment is the laboratory value of the last visit during the on 
treatment period of each patient.
Patients with missing CTCAE grade at baseline or no baseline value but with post-baseline 
values will be displayed in the category “Missing CTCAE grade at baseline” for those 
laboratory parameters where CTCAE grading is applicable.
Possible clinically significant abnormal laboratory values:
Possible clinically significant abnormal laboratory values are defined as those laboratory 
values that are of CTCAE Grade ≥ 2 and show an increase from baseline value by at least one 
CTCAE grade. For those parameters for which no CTCAE has been defined, BI standard 
definition will be used to determine possible clinical significance. Frequency of patients with 


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possible clinically significant abnormal laboratory values will be provided whenever 
applicable. If no baseline value is available but the patient has a post-baseline laboratory 
value of CTCAE Grade ≥ 2 an increase from baseline will be assumed, i.e. the laboratory 
value considered as possible clinically significant.
Handling of laboratory parameters with CTCAE grade -1 and -9:
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 will be displayed as -9.
For Uric Acid, Glomerular filtration rate (GFR) and Hypokalemia, the CTCAE grade cannot 
always be assigned by the laboratory parameter itself as two different CTCAE grades have 
the same laboratory constellation, but are distinguished by additional clinical parameter. In 
this case a CTCAE grade of "-1" will be assigned initially. For all analyses, patients with a 
CTCAE grade of "-1" will be treated as

Grade 1 for Uric Acid,

Grade 3 for GFR, and

Grade 1 for Hypokalemia.
In laboratory data listings, the CTCAE grade will be displayed as -1. 
Handling of Urine protein (UPROZ)
For urine measurement based on dipsticks the indicated results will be converted as follows 
for the analysis:
Table 7.8.2:1 Conversion of urine measurements based on dipsticks
Original dipstick measurement
Converted dipstick measurement
“-” ; “NEG” ; “NEGATIVE” ; “NORMAL”
0.0
“0.5” ; “TRACES” ;  “TRACE” ;  “+/-” ;  “+-” ;  “-/+”
0.5
“+” ; “1+”      
1.0
“++” ;  “2+”   
2.0
“+++” ; “3+”     
3.0
“++++” ; “4+”    
4.0
In CTCAE Version 4.0 a 24 hours urine sample should be performed if the dipstick 
measurement is at least “2+” and the CTCAE grade should then be determined based on the 
24 hours urine sample. Urine protein 1.0 – 3.4 g/24hrs is graded as CTCAE grade 2 and urine 
protein ≥ 3.5 g/24hrs is graded as CTCAE grade 3. As this definition aggregates different 
urine analysis measurements, this will not be considered for laboratory analyses, but should 
be considered by the investigator when grading adverse events. 
To ensure medically rational and consistent (within BI) handling of urine protein assessed by 
dipstick only, no analyses based on CTCAE grades will be done. Instead urine protein will be 


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converted as for other urine measurements based on dipsticks (outlined in Table 7.8.2:1) and 
displayed in the urine analysis tables.
Hepatic injury:
As defined in the CTP a hepatic injury (DILI) is defined by 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 draw sample, and/or

marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
Potential Hepatic enzyme elevations (potential Hy’s law cases):
In addition, the following definition of potential Hy’s law cases was discussed with the FDA 
at the pre-NDA meeting of the NSCLC submissions of the nintedanib trials 1199.13 and 
1199.14 and was agreed by the authorities. Please also refer to the FDA guideline Guidance 
for Industry Drug- Induced Liver Injury: Premarketing Clinical Evaluation, version of July 
2009.
These are defined as those cases where a combination of all of the following events occurred: 
any on-treatment value of ALT or AST (or both) > 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, etc. 
Figure 7.8.2:1 gives 2 examples, first where the criterion is satisfied and second where it is 
not satisfied.
All of the above combinations of elevated liver enzymes will be analysed, i.e. DILI cases as 
defined in the CTP and additionally the definition of potential Hy's law cases which was 
discussed with the FDA by the nintedanib project. A listing with detail hepatic enzymes 
values will be created for the subjects who satisfied the condition. eDISH plot for ALT and 
total bilirubin will be displayed.


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Figure 7.8.2:1 Assessment of patients fulfilling the criteria for potential Hy’s law cases. Top:
patient fulfils criteria. Bottom: patient does not fulfil criteria.
7.8.3
Vital signs
Only descriptive statistics are planned for the analysis of vital signs. Observed values and 
changes from baseline will be summarized.
7.8.4
ECG
12-lead resting ECGs are done throughout the trial and are assessed for clinically relevant 
results which are to be recorded as either concomitant disease or AE by the investigator. No 
further ECG analysis is planned.
7.8.5
Others
Pregnancy tests:
A listing showing the results of pregnancy tests will be provided.


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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
001-MCS-50-415_RD-01: “TSAP annotations”, current version, IDEA for CON.
3
001-MCS-40-413: “Identify and Manage Important Protocol Deviations (iPD)”, 
current version, IDEA for CON.
4
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, 
current version; IDEA for CON.
5
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project 
Summaries”, current version; IDEA for CON.
6
001-MCS-36-472: “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics”, current version; IDEA for CON.
7
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; IDEA for CON.
8
BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; IDEA for CON.


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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
20-Dec-16
None
This is a draft TSAP.
Final
07-JAN-2020
All
This is the final TSAP. This study has 
been terminated prematurely and no 
patient has been recruited for the Phase 
II part. Section 4 clarifies that no 
planned analysis for Phase 2 in the CTP 
will be conduct. Sections 5 to 7 are 
updated with Phase II related content 
removed and minor edits. Section 8 is 
updated to the latest BI internal 
reference document.