Clinical trial NCT02632721
Conditions: Leukemia, Myeloid, Acute
Sponsor: Boehringer Ingelheim
Start date: 2016-06-16; Completion date: 2023-01-16
Enrollment: 49 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Phase I Dose Escalation:

Primary objective is to determine the Maximum Tolerated Dose (MTD) and the recommended dose for Phase I Extension.

Secondary objective is to investigate the safety, pharmacokinetics and efficacy of BI 836858 in combination with decitabine

Phase I Extension:

Primary objective is to collect additional data on safety, pharmacokinetics and efficacy and to define the Recommended Phase II Dose (RP2D) of BI 836858 in combination with decitabine.

Phase II: Primary objective is to investigate efficacy, safety and pharmacokinetics of BI 836858 in combination with decitabine compared to decitabine monotherapy.

Detailed description:

Arms: arm 1: Dose escalation. arm 2: Dose escalation. arm 3: Dose escalation. arm 4: Extension phase. arm 5: Extension phase.
Interventions: intervention 1: Decitabine intervention 2: BI 836858
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
n.a.
Name of active ingredient:
BI 836858
Protocol date:
19 Oct 2015
Trial number:
1315.2
Revision date:
21 Aug 2019
Title of trial:
An open-label, Phase I/II trial to determine the maximum tolerated 
dose and investigate safety, pharmacokinetics and efficacy of 
BI 836858 in combination with decitabine in patients with acute 
myeloid leukemia
Coordinating 
Investigator:
Phone: 
Fax:
E-mail:
Trial site(s):
Multi-centre trial
Clinical phase:
Phase I/II
Objective(s):
Phase I Dose Escalation: To determine the maximum tolerated 
dose (MTD) and the recommended dose for Phase I Extension 
(RExP1D) and to investigate the safety, pharmacokinetics and 
efficacy of BI 836858 in combination with decitabine in patients
≥65 years of age with previously untreated acute myeloid leukemia 
(AML) and considered ineligible for standard intensive therapy, or
patients ≥18 years of age with refractory or relapsed AML. 
Phase I Extension: To collect additional data on safety, 
pharmacokinetics and efficacy and to decide if the RExP1D will 
become the Recommended Phase II Dose (RP2D) of BI 836858 in 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
n.a.
Name of active ingredient:
BI 836858
Protocol date:
19 Oct 2015
Trial number:
1315.2
Revision date:
21 Aug 2019
combination with decitabine in patients ≥65 years of age with 
previously untreated AML and considered ineligible for standard 
intensive therapy, or if additional patients need to be enrolled in 
existing or additional dose escalation cohorts.
Phase II: To investigate efficacy, safety and pharmacokinetics of 
BI 836858 in combination with decitabine compared to decitabine 
monotherapy in patients ≥65 years of age with previously 
untreated AML and considered ineligible for standard intensive 
therapy.
Methodology:
Phase I Dose Escalation: Open-label, single-arm, dose escalation
(i.e. consecutive cohorts of escalating doses of BI 836858 plus 
intensive decitabine treatment schedule), Bayesian logistic 
regression model (BLRM) with overdose control.
Phase I Extension: Open-label, two consecutive groups (i.e. Cohort 
A treated with BI 836858 plus intensive decitabine treatment 
schedule, followed by Cohort B treated with BI 836858 plus
standard decitabine treatment schedule).
If deemed necessary by the Sponsor and the SMC (Safety 
Monitoring Committee): 
Option to open further Phase I Dose Escalation cohort(s) to 
determine the RP2D, based on additional biomarker, PK/PD and 
safety data with either the intensive or the standard decitabine 
schedule, as specified for each cohort separately prior to starting 
enrollment. 
Phase II: Open-label, two-arm randomized, BI 836858 plus 
decitabine versus decitabine monotherapy.
No. of patients: 
Approximately 160-170 patients


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Name of company:
Boehringer Ingelheim 
Name of finished product:
n.a.
Name of active ingredient:
BI 836858
Protocol date:
19 Oct 2015
Trial number:
1315.2
Revision date:
21 Aug 2019
total entered:
Phase I Dose Escalation: 16 patients
Phase I Extension: 33 patients
After completion of recruitment to Phase I Extension Cohort A 
and Cohort B, the recruitment to this trial is discontinued.
Phase I option for additional dose tiers: option to add further Dose 
Escalation cohort(s) with at least 3 patients each (based on SMC 
recommendation)
Phase II: approx. 100 (2 x 50) patients
each treatment:
All patients participating in any part of this trial will receive 
decitabine.
Phase I Dose Escalation, Extension, and potential additional dose 
tiers: All patients (approx. 60-70) will receive the combination 
treatment of BI 836858 and decitabine.
Phase II: 50% of patients (approx. 50 patients) will receive the 
combination treatment of BI 836858 and decitabine, and 50% of 
patients (approx. 50 patients) will receive decitabine 
monotherapy.
Diagnosis :
Phase I Dose Escalation: Patients ≥65 years of age with
previously untreated AML, who are considered ineligible for 
standard intensive therapy, or patients ≥18 years of age with
relapsed or refractory AML.
Phase I Extension, Phase II and potential additional dose tiers: 
Patients ≥65 years of age with previously untreated AML who 
are considered ineligible for standard intensive therapy


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Name of company:
Boehringer Ingelheim 
Name of finished product:
n.a.
Name of active ingredient:
BI 836858
Protocol date:
19 Oct 2015
Trial number:
1315.2
Revision date:
21 Aug 2019
Main criteria
for inclusion:
∀Phase I Dose Escalation only: 
Patients ≥65 years of age with previously untreated AML, or 
patients ≥18 years of age with relapsed or refractory AML
∀Phase I Extension and Phase II only: 
Patients ≥65 years of age with previously untreated AML 
∀Histologically or cytologically confirmed AML according to 
the WHO classification
∀Patients eligible for treatment with decitabine
Test product:
BI 836858
dose:
The Phase I starting dose of BI 836858 is 20 mg.
The Recommended Phase II Dose (RP2D) is based on the MTD 
determined in Phase I.
mode of 
administration:
Intravenous (i.v.) infusion 
Combination treatment:
Decitabine (standard of care)
dose:
20 mg/m² (daily)
mode of 
administration:
Intravenous (i.v.) infusion 
Duration of treatment:
Patients will be treated in repeated cycles until disease 
progression or relapse in the absence of other withdrawal criteria, 
and as long as neither patient nor investigator request treatment 
discontinuation.
Endpoints for efficacy 
and pharmacokinetics:
Primary endpoint (Phase II):
∀#umber of patients with objective response combining
-
Complete Remission (CR)
-
CR with incomplete blood count recovery (CRi)
Secondary endpoint (Phase I):


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Name of company:
Boehringer Ingelheim 
Name of finished product:
n.a.
Name of active ingredient:
BI 836858
Protocol date:
19 Oct 2015
Trial number:
1315.2
Revision date:
21 Aug 2019
∀#umber of patients with objective response (CR+CRi)
Secondary endpoints (Phase II):
∀Event-free survival (EFS)
∀Relapse-free survival (RFS)
∀Remission duration
∀Time to remission
Safety criteria:
Primary endpoints (Phase I):
∀Maximum tolerated dose (MTD) of BI 836858 in 
combination with decitabine.
∀Number of patients with Dose Limiting Toxicity (DLT)
for BI 836858 in combination with decitabine during 
Cycle 1.
Statistical methods:
Descriptive statistics and exploratory data analysis.
Dose escalation is guided by a Bayesian logistic regression model 
(BLRM) with overdose control that will be fitted to binary toxicity 
outcomes. The estimate of parameters will be updated as data are 
accumulated using the BLRM. At the end of Phase I Dose 
Escalation, the toxicity probability at each dose level will be 
calculated to determine an estimate of the MTD.






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*)
The planned duration of a treatment cycle is 28 days. Day 1 of each cycle is defined as the day when the first dose of decitabine in that cycle is administered. The start of the next cycle must not be earlier than 
Day 29 of the previous cycle.There will be a maximum of 4 administrations of BI 836858 in one treatment cycle (with the exception of treatment Cycle 1, where there is a maximum of 3 administrations of 
BI 836858). All assessments should be performed prior to dose administration on dosing days, unless otherwise specified.
**)
Days are calculated as calendar days. Please refer to Section 6.2 for details on time windows for visits and individual study procedures or assessments.
***)
In case treatment with BI 836858 cannot be started on Day 8 of Cycle 1 (due to documented medical or administrative reasons), the first dose of BI 836858 may be administered on Day 9 of Cycle 1 (at the 
latest). All procedures described in this Flow Chart for Day 8, Day 9 and Day 10 (especially blood sampling for PK and biomarkers as per Table 1 and Table 3) should be shifted accordingly.
****)
Day 29 (Visit 4) can be the same day as Day 1 (Visit 1) of the next treatment cycle if the patient is eligible to receive further treatment without delay. In that case Day 29 becomes Day 1 of next cycle, and all 
procedures and assessments as indicated for EOC and Day 1 of the next cycle have to be performed.
In case a patient does not continue immediately with the next cycle for any reason (and not moving to EoT), additional visits are recommended to be performed on a weekly basis, at investigator’s discretion, 
in the period until the next cycle starts. These additional (unscheduled) visits should be documented in eCRF.
*****) For patients treated in Phase I only two FU visits are scheduled; the first FU visit will be at approximately 3 months after the EOT visit and the second FU visit will be at approximately 6 months after the 
EOT visits. For patients treated in Phase II, FU visits are scheduled approximately every 3 months until death or lost to follow-up. In case patients do not visit the site, the FU visit can be conducted by phone.
1)
Due to intensive PK sampling schedule during Cycle 1 and Cycle 2 it is strongly recommended to follow the proposed visit days and sampling time points as outlined in Table 1 and Table 2. The permitted 
visit windows (as per Section 6.2) should only be used if medically indicated. For exact time points please refer to Table 1 and Table 2.
2)
For each patient entering this trial the investigator will document in detail in the source document and in the eCRF the medical reason(s) why the patient is considered ineligible for standard intensive therapy 
(see Section 5.6.1)
3)
Physical examination only every second cycle (i.e. before cycle 1, 3, 5, 7 etc.) Physical examination may be completed up to 2 days prior to Day 1 of next planned treatment cycle.
4)
Eastern Cooperative Oncology Group (ECOG) performance status only every second cycle (i.e. before cycle 1, 3, 5, 7 etc.). If the first administration of decitabine occurs within 3 days of the screening visit, 
this examination does not need to be repeated on Day 1 of Cycle 1.
5)
Vital signs at FU visits only when patient is visiting the site
6)
For details refer to Section 5.3.6.1. Safety lab assessments will be performed at the Investigator’s local lab. Time points for TLS monitoring (selected hematology and biochemistry parameters) sample 
collection as per Table 1. All other safety lab assessments may be completed up to 2 days prior to the next scheduled administration of BI 836858.
7)
An additional safety lab will be collected on Day 10 (i.e. 24 hours after start of the first administration of BI 836858). Other lab test to be included on that day (i.e. in addition to standard panel) are: 
haptoglobin and direct antiglobulin test. 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.
8)
Urinalysis (dipstick; reported as semiquantitative measurements) at screening, after completion of Cycle 4 and at EOT.
9)
For women of childbearing potential only. Serum pregnancy test completed at Screening, Visit 1 of each Cycle and EOT.
10)
Only needed in case safety lab values were outside normal range or ECG was abnormal at EOT with findings not present at baseline.
11)
Separate portion of BM aspirate required at screening and in Cycle 1 at Day 29 (±3 days) and at EOT for central lab assessment for biomarkers (refer to Table 3 and Table 4). In Cycle 1 at Day 16 (± 2 days) 
the BM aspirate is required for central lab assessment for biomarkers only, i.e. no mandatory local disease assessment on that day.
12)
BM aspirate (and biopsy if indicated) to assess efficacy at end of Cycle 1, at end of Cycle 2 and then every other cycle thereafter. The BM sample collection at the end of Cycle 2 is not a mandatory trial 
procedure in patients with ≥5% blasts in peripheral blood. From Cycle 2 onwards, BM samples can be taken up to 7 days before the scheduled visit 4 (EOC), i.e. between Day 22 and Day 29, unless the 
patient has achieved CR in which case further bone marrow aspiration/biopsies are not required unless clinically indicated; earlier response assessments can be performed based on count recovery. If 
progressive disease or relapse is diagnosed, perform EOT visit.
13)
BM aspirate (only in patients who did not end treatment due to PD or relapse and who did not have a BM aspirate within the past four weeks, or if PD is suspected but not cytologically confirmed)
14)
In Phase I no mandatory separate BM sampling and/or local testing for cytogenetics and molecular genetics is required; cytogenetic and molecular genetic data from initial diagnosis/clinical routine can be 
used for eCRF completion, if available (see Section 5.3.6.2).
In Phase II BM sampling and shipment to central lab for cytogenetics and molecular genetic testing is mandatory.
15)
Follow-up of AEs not recovered at EoR. Concomitant therapy at EoR visit collected only if indicated for treatment of adverse event.
16)
Individually customized decitabine treatment schedule for Cycles ≥ 2 depending on WBC at the end of previous cycle. For details refer to Table 4.1.3.1:1 for patients treated in Phase I Dose Escalation and 
Table 4.1.3.2:1 for patients treated in Phase I Extension and Phase II. No trial-specific visits need to be performed (irrespective of “x” in this Flow Chart) when treatment with decitabine was already stopped 
in that cycle.
17)
For time windows of drug administration days of BI 836858 refer to Section 4.1.4.
18)
The treatment schedule with BI 836858 will be individually customized for cycles ≥ 2 based on the response to the treatment. Depending on the time point when the response was observed and the type of 
response (CR or CRi), the weekly infusions with BI 836858 may be reduced to monthly infusions (maintenance treatment). For details refer to Table 4.1.3.1:2 for patients treated in Phase I Dose Escalation 
and to Table 4.1.3.2:1 for patients treated in Phase I Extension and Phase II






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*)
The planned duration of a treatment cycle is 28 days. Day 1 of each cycle is defined as the day when the first dose of decitabine in that cycle is administered. The start of the next cycle must not be earlier 
than Day 29 of the previous cycle.There will be a maximum of 4 administrations of BI 836858 in one treatment cycle (with the exception of treatment Cycle 1, where there is a maximum of 3 
administrations of BI 836858). All assessments should be performed prior to dose administration on dosing days, unless otherwise specified.
**)
Days are calculated as calendar days. Please refer to Section 6.2 for details on time windows for visits and individual study procedures or assessments.
***)
In case treatment with BI 836858 cannot be started on Day 8 of Cycle 1 (due to documented medical or administrative reasons), the first dose of BI 836858 may be administered on Day 9 of Cycle 1 (at the 
latest). All procedures described in this Flow Chart for Day 8, Day 9 and Day 10 (especially blood sampling for PK and biomarkers as per Table 1 and Table 3) should be shifted accordingly.
****)
Day 29 (Visit 4) can be the same day as Day 1 (Visit 1) of the next treatment cycle if the patient is eligible to receive further treatment without delay. In that case Day 29 becomes Day 1 of next cycle, and 
all procedures and assessments as indicated for EOC and Day 1 of the next cycle have to be performed.. In case a patient does not continue immediately with the next cycle for any reason (and not moving 
to EoT), additional visits are recommended to be performed on a weekly basis, at investigator’s discretion, in the period until the next cycle starts. These additional (unscheduled) visits should be 
documented in eCRF.
*****) For patients treated in Phase I only two FU visits are scheduled; the first FU visit will be at approximately 3 months after the EOT visit and the second FU visit will be at approximately 6 months after the 
EOT visits. For patients treated in Phase II, FU visits are scheduled approximately every 3 months until death or lost to follow-up. In case patients do not visit the site, the FU visit can be conducted by 
phone. After approval of Protocol version 7.0, no Follow-up visits.
1)
Due to intensive PK sampling schedule during Cycle 1 and Cycle 2 it is strongly recommended to follow the proposed visit days and sampling time points as outlined in Table 1 and Table 2. The permitted 
visit windows (as per Section 6.2) should only be used if medically indicated. For exact time points please refer to Table 1 and Table 2.
2)
For each patient entering this trial the investigator will document in detail in the source document and in the eCRF the medical reason(s) why the patient is considered ineligible for standard intensive 
therapy (see Section 5.6.1)
3)
Physical examination only every second cycle (i.e. before cycle 1, 3, 5, 7 etc.) Physical examination may be completed up to 2 days prior to Day 1 of next planned treatment cycle.
4)
Eastern Cooperative Oncology Group (ECOG) performance status only every second cycle (i.e. before cycle 1, 3, 5, 7 etc.). If the first administration of decitabine occurs within 3 days of the screening 
visit, this examination does not need to be repeated on Day 1 of Cycle 1.
5)
Vital signs at FU visits only when patient is visiting the site
6)
For details refer to Section 5.3.6.1. Safety lab assessments will be performed at the Investigator’s local laboratory. Time points for TLS monitoring (selected hematology and biochemistry parameters) 
sample collection as per Table 1. All other safety lab assessments may be completed up to 2 days prior to the next scheduled administration of BI 836858.
7)
An additional safety lab will be collected on Day 10 (i.e. 24 hours after start of the first administration of BI 836858). Other lab test to be included on that day (i.e. in addition to standard panel) are: 
haptoglobin and direct antiglobulin test. 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.
8)
Urinalysis (dipstick; reported as semiquantitative measurements) at screening, after completion of Cycle 4 and at EOT.
9)
For women of childbearing potential only. Serum pregnancy test completed at Screening, Visit 1 of each Cycle and EOT.
10)
Only needed in case safety lab values were outside normal range or ECG was abnormal at EOT with findings not present at baseline.
11)
Separate portion of BM aspirate required at screening and in Cycle 1 at Day 29 (±3 days) and at EOT for central lab assessment for biomarkers (refer to Table 3 and Table 4). In Cycle 1 at Day 16
(± 2 days) the BM aspirate is required for central lab assessment for biomarkers only, i.e. no mandatory local disease assessment on that day. After the approval of Protocol version 7.0, bone marrow 
sampling for response assessment is no longer mandatory at defined visits but is performed at the investigator’s discretion; BM samples are evaluated at the trial site only, and shipping 
samples to the biomarker lab is stopped.
12)
BM aspirate (and biopsy if indicated) to assess efficacy at end of Cycle 1, at end of Cycle 2 and then every other cycle thereafter. The BM sample collection at the end of Cycle 2 is not a mandatory trial 
procedure in patients with ≥ 5% blasts in peripheral blood. From Cycle 2 onwards, BM samples can be taken up to 7 days before the scheduled visit 4 (EOC), i.e. between Day 22 and Day 29, unless the 
patient has achieved CR in which case further bone marrow aspiration/biopsies are not required unless clinically indicated; earlier response assessments can be performed based on peripheral blood count 
recovery. If progressive disease or relapse is diagnosed, perform EOT visit. After the approval of Protocol version 7.0, bone marrow sampling for response assessment is no longer mandatory at 
defined visits but is performed at the investigator’s discretion and BM samples are evaluated at the trial site only (no shipment of samples to central biomarker lab).
13)
BM aspirate (only in patients who did not end treatment due to PD or relapse and who did not have a BM aspirate within the past four weeks, or if PD is suspected but not cytologically confirmed): After 
the approval of Protocol version 7.0, bone marrow sampling for response assessment is no longer mandatory at defined visits but is performed at the investigator’s discretion and BM samples 
are evaluated at the trial site only (no shipment of samples to central biomarker lab).
14)
In Phase I no mandatory separate BM sampling and/or local testing for cytogenetics and molecular genetics is required; cytogenetic and molecular genetic data from initial diagnosis/clinical routine can 
be used for eCRF completion, if available (see Section 5.3.6.2). In Phase II BM sampling and shipment to central lab for cytogenetics and molecular genetic testing is mandatory.
15)
Follow-up of AEs not recovered at EoR. Concomitant therapy at EoR visit collected only if indicated for treatment of adverse event.
16)
Individually customized decitabine treatment schedule for Cycles ≥ 2 depending on WBC at the end of previous cycle. For details refer to Table 4.1.3.1:1 for patients treated in Phase I Dose Escalation 
and Table 4.1.3.2:1 for patients treated in Phase I Extension and Phase II. No trial-specific visits need to be performed (irrespective of “x” in this Flow Chart) when treatment with decitabine was already 


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stopped in that cycle.
17)
For time windows of drug administration days of BI 836858 refer to Section 4.1.4.
18)
The treatment schedule with BI 836858 will be individually customized for cycles ≥ 2 based on the response to the treatment. Depending on the time point when the response was observed and the type 
of response (CR or CRi), the weekly infusions with BI 836858 may be reduced to monthly infusions (maintenance treatment). For details refer to Table 4.1.3.1:2 for patients treated in Phase I Dose 
Escalation and to Table 4.1.3.2:1 for patients treated in Phase I Extension and Phase II.
19)
Procedures/assessments not mandatory after approval of CTP version 7.0, but assessments (e.g. 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 (S)AE.
20)
Results on Vital signs during and after trial drug infusion to be documented in the eCRF only if qualifying for (S)AE.
21)
Documentation of Concomitant Therapy information in the eCRF only if the indication is treatment for (S)AE.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................7
TABLE OF CONTENTS ......................................................................................................20
ABBREVIATIONS................................................................................................................24
1.
INTRODUCTION...............................................................................................27
ACUTE MYELOID LEUKEMIA.....................................................................27
1.1
1.1.1
Acute myeloid leukemia in patients ≥65 years of age .....................................28
DRUG PROFILE................................................................................................29
1.2
1.2.1
BI 836858 .............................................................................................................29
1.2.2
Decitabine ............................................................................................................30
1.2.3
Combination Treatment of BI 836858 and Decitabine....................................32
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....34
RATIONALE FOR PERFORMING THE TRIAL.........................................34
2.1
TRIAL OBJECTIVES........................................................................................34
2.2
BENEFIT - RISK ASSESSMENT.....................................................................35
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................38
OVERALL TRIAL DESIGN AND PLAN .......................................................38
3.1
3.1.1
Administrative structure of the trial .................................................................42
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................44
SELECTION OF TRIAL POPULATION .......................................................45
3.3
3.3.1
Main diagnosis for trial entry ............................................................................46
3.3.2
Inclusion criteria .................................................................................................47
3.3.3
Exclusion criteria ................................................................................................47
3.3.4
Removal of patients from therapy or assessments...........................................49
Removal of individual patients .............................................................................49
3.3.4.1
Discontinuation of the trial by the Sponsor ..........................................................50
3.3.4.2
4.
TREATMENTS...................................................................................................51
TREATMENTS TO BE ADMINISTERED.....................................................51
4.1
4.1.1
Identity of Investigational Medicinal Product and combination treatment..51
4.1.2
Method of assigning patients to treatment groups...........................................52
4.1.3
Selection of doses in the trial..............................................................................53
Treatment in the Phase I Dose Escalation part of the trial....................................53
4.1.3.1
Phase I Extension..................................................................................................56
4.1.3.2
Phase II..................................................................................................................58
4.1.3.3
4.1.4
Drug assignment and administration of doses for each patient......................58
Premedication........................................................................................................60
4.1.4.1






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TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT .........................................................................................................105
DATA QUALITY ASSURANCE ....................................................................106
8.2
RECORDS.........................................................................................................106
8.3
8.3.1
Source documents .............................................................................................106
8.3.2
Direct access to source data and documents...................................................106
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS107
8.4
8.4.1
Listedness...........................................................................................................107
8.4.2
Expedited reporting to health authorities and IEC / IRB.............................107
STATEMENT OF CONFIDENTIALITY......................................................107
8.5
TRIAL MILESTONES.....................................................................................107
8.6
PROTOCOL VIOLATIONS ...........................................................................108
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY............................................................................108
9.
REFERENCES..................................................................................................109
PUBLISHED REFERENCES..........................................................................109
9.1
UNPUBLISHED REFERENCES....................................................................115
9.2
10.
APPENDICES...................................................................................................116
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
10.1
PERFORMANCE STATUS.............................................................................116
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
10.2
AND DATA SCENARIOS ...............................................................................116
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................122




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FDA
Food and Drug Administration
GCP
Good Clinical Practice
i.v.
intravenous
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRR
Infusion-related reaction
IRT
Interactive Response Technology
ISF
Investigator Site File
LDAC
Low-Dose Cytarabine
LPDD
Last Patient Drug Discontinuation
mAb
Monoclonal antibody
MDS
Myelodysplastic Syndrome
MedDRA
Medical Dictionary for Drug Regulatory Activities
MTD
Maximum Tolerated Dose
NC
Not calculated
NCCN
National Comprehensive Cancer Network
NOA
Not analyzed
NOR
No valid result
NOS
No sample
NYHA
New York Heart Association
OS
Overall Survival
p.o.
per os (oral)
PD
Disease Progression (Progressive Disease)
PK
Pharmacokinetics
PR
Partial Remission
RDC
Remote Data Capture (BI system that enables sites to enter data into eCRF)
REP
Residual Effect Period; after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RExP1D
Recommended Extension Phase I Dose (recommended dose of BI 836858 
for Phase I Extension)
RFS
Relapse-free survival
RP2D
Recommended Phase II Dose
SAE
Serious Adverse Event
SD
Stable Disease
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TDMAP
TLS
Trial Data Management and Analysis Plan
Tumor Lysis Syndrome
TMF
Trial Master File




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1.
INTRODUCTION
ACUTE MYELOID LEUKEMIA
1.1
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic 
progenitor cells and represents the most common malignant myeloid disorder in adults, with a 
prevalence of 3.8 cases per 100,000 rising to 17.9 cases per 100,000 adults aged 65 years and 
older (R07-2768). The median age at presentation is about 70 years, and three men are 
affected for every two women. Without therapeutic intervention the disease progresses and 
leads to death within months after initial diagnosis (R07-2768).
Genetic alterations in leukemic cells constitute the most important factor for the prognosis of 
AML (R07-2768, R07-2770, R07-2774). AML patients are classified in groups of favourable, 
intermediate, and unfavourable risk. Other factors with impact on prognosis are age, 
performance score, white blood cell count, blood chemistry disturbances and de novo versus
secondary AML.
Intensive treatment approaches for AML with curative intention include two phases. The first, 
induction treatment, most commonly cytarabine and an anthracycline, is aiming to reach a 
complete remission (CR). The second phase, post-remission treatment, is aiming to 
consolidate remission. AML patients under the age of 60 years achieve complete remission 
rates of up to 75 % following intensive treatment regimens, while AML patients over 
60 years of age (referred to as elderly patients) have a 40-60 % chance of CR when receiving 
intensive remission induction treatment (R07-2767).
While the majority of younger AML patients receive intensive treatment, a substantial 
number of elderly patients are considered ineligible for this treatment approach (R07-2773, 
R07-2854). Therefore, the CR rates up to 60 % reported in elderly previously untreated AML 
patients receiving intensive treatment are by no means representative of the entire group of 
elderly AML patients. For AML patients considered ineligible to receive intensive treatment 
investigational treatments are widely regarded as the preferred therapeutic option (R07-2769, 
R07-2772). With these non-approved drugs CR rates up to 20 % are observed in randomized 
Phase III trials. Although patients who are considered as ineligible for intensive treatment 
constitute a generally accepted subgroup of AML patients, no validated criteria are defined to 
judge a patient's eligibility for intensive treatment (R07-2771). 
The median overall survival (OS), for patients, not achieving a CR is < 1 year, even with best 
palliative treatment. The risk of leukemic relapse along with the poor prospects of long-term 
survival after a relapse calls for novel therapeutic strategies to maintain CR in AML. 
Beside treatment in clinical trials, re-induction followed by allogeneic stem cell 
transplantation (ASCT) is the most common regimen for refractory or relapsed AML patients. 
However, many are not eligible for such an intensive treatment. For those patients with 
refractory or relapsed AML ineligible for intensive treatment, or for those with refractory or 
relapsed disease after allogeneic stem cell transplantation, no approved or standard treatment 
is available.


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Even for patients who have received induction and consolidation treatment the overall 
survival and cure rate are poor: over 60% will die due to their disease within 5 years. ASCT 
is only indicated for young patients and is an option for < 10% of all patients diagnosed with 
AML.
Currently, major efforts are focused on the improvement of the therapy in these subgroups of 
patients with unfavourable prognosis.
1.1.1
Acute myeloid leukemia in patients ≥ 65 years of age
Patients of ≥ 65 years of age with AML are biologically and clinically distinct from younger
patients. Although the prognosis of AML worsens with increasing age, older patients are
generally considered as age 60 years or older. They are more likely to die early and to exhibit 
therapeutic resistance (R07-2772, R10-2948). Increasing age is associated with factors 
predictive of early death, such as poor performance status or various comorbidities, and of 
treatment resistance (e.g. adverse cytogenetics, secondary AML or the multidrug resistant
phenotype (R10-5308). A recent analysis suggested that while intensive chemotherapy can be 
delivered to older patients (≥ 70 years) with AML, it may not be beneficial to most, and could 
be harmful to some. Indeed, this analysis showed that the prognosis of most patients (72%) 
aged ≥ 70 years with AML is poor with intensive chemotherapy, with an 8-week mortality of 
36% and a median survival < 6 months (R10-5306). Therefore, a substantial number of older 
AML patients are not considered eligible for intensive treatment; available data indicate that 
about 70% of patients aged 65 to 74 and less than 30% of patients aged ≥ 74 years receive 
intensive therapy at initial diagnosis of AML. Alternatives to standard dose intensive 
treatment are sought for these patients (R10-1398, R10-2947). Although substantial numbers 
of AML patients are considered as ineligible for intensive treatment, no validated criteria are 
defined to judge a patient's eligibility for intensive treatment (R07-2771). The assessment of 
eligibility for intensive treatment is regularly done for every single patient based on the 
specialized physician's clinical experience and the comprehensive review of factors like 
patient’s age, AML cytogenetics/molecular genetics, performance score, organ dysfunctions 
and co-morbidities, as well as the patient's informed decision. In current practice, the final 
decision to treat intensively or not is made by the treating haematologist on a case by case 
basis. This approach is reflected in current practice guidelines (e.g. European Leukemia Net
recommendations (R10-2947), NCCN (National Comprehensive Cancer Network) guideline 
(R15-5032)).
Based on data showing a significant benefit in survival for AML patients ≥ 65 years of age
treated with cytarabine compared with hydroxyurea, low-dose cytarabine (LDAC) is an
established treatment option although the outlook for patients who receive LDAC remains
unsatisfactory (R07-2771). In a Phase III trial in patients with previously untreated AML,
decitabine has shown a similar safety profile compared to LDAC and demonstrated higher 
response rates and a trend for overall survival advantage (R12-3309). According to guidelines 
for AML patients ≥ 65 years of age considered ineligible to receive intensive treatment, 
investigational treatment is widely regarded as the preferred therapeutic option beside LDAC 
and decitabine (R07-2768, R07-2772, R10-2947).




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For a more detailed description of the drug profile refer to the current Investigator’s Brochure 
(c02324887-03) which is included in the Investigator Site File (ISF).
1.2.2
Decitabine
Decitabine is a marketed product. In 2006, decitabine was approved by the Food and Drug 
Administration (FDA) for the treatment of MDS including previously treated and untreated, 
de novo and secondary MDS of all French-American-British (FAB) subtypes. In 2012, 
decitabine was approved in Europe for the treatment of adult patients (≥ 65 years) with newly 


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diagnosed de novo or secondary AML, who are not candidates for standard induction 
chemotherapy. 
Decitabine is a hypomethylating agent that hypomethylates DNA by inhibiting the DNA 
methyltransferase. Decitabine is believed to exert its antineoplastic effects after 
phosphorylation and direct incorporation into the DNA and inhibition of the DNA 
methyltransferase, which causes hypomethylation of DNA and cellular differentiation or 
apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations 
that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation 
in neoplastic cells may restore normal function to genes that are critical for the control of 
cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of 
decitabine may also be attributed to the formation of covalent adducts between DNA 
methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are 
relatively insensitive to decitabine (R11-1093).
Decitabine has been shown to induce hypomethylation both in vitro and in vivo. 
Pharmacokinetics of decitabine following i.v. infusion have been evaluated in patients with 
hematologic malignancies (R15-3858, R15-3859, R15-3860). Plasma concentration time 
profiles after discontinuation of infusion showed a bi-exponential decline. Decitabine 
disappears rapidly from plasma and its high volume of distribution suggests extensive tissue 
distribution. The terminal half-life (t1/2) was about 35 min. Upon repeated doses there was no 
systemic accumulation of decitabine or any changes in PK parameters.
Decitabine has been studied in the treatment of previously treated and untreated young adult 
and elderly patients (≥ 65 years) with AML (R11-1089, R11-1105, R11-1099, R11-2725,
R11-2726, R11-2727).
One of the recommended treatment regimens for decitabine is continuous i.v. infusion over 
1 h repeated daily for 5 days, but more intensive treatment regimen starting with repeated i.v. 
infusions daily for 10 days for the first few cycles, followed by individually customized 
therapy in subsequent cycles is also widely used. The intention of this more intensive, but 
individually customized treatment based on response and toxicity, is to improve tolerability 
and response. 
Repeated cycles of decitabine are given every 4 weeks, irrespective of the duration of the 
decitabine administration (i.e. consecutive Days 1-5 or Days 1-10 of each cycle), in order to 
allow efficient incorporation of drug into the newly synthesized DNA of myeloid blast. Most 
common adverse reactions of decitabine (> 50%) are neutropenia, thrombocytopenia, 
anaemia, and pyrexia. Other common adverse events include nausea, vomiting, diarrhoea, 
constipation, fever, oedema, hyperglycemia, hypomagnesemia, hypokalemia, arthralgias, 
back pain, cough, headache, insomnia, rash, petechiae, and pallor (R11-1101, R11-1104). For 
detailed efficacy, safety, and pharmacology profile information of decitabine, refer to the EU 
Summary of Product Characteristics (SPC) for decitabine (R15-4802). Detailed information 
on this medicinal product is available on the website of the European Medicines Agency 
(EMA) website.ema.europa.eu.
Also, in patients ≥ 65 years of age with previously untreated AML, who were ineligible for 
intensive therapy, decitabine has been investigated. Recently, the trial results from a Phase III 


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trial, the largest to date in patients ≥ 65 years of age with AML, have been released (R12-
3309). In this Phase III trial, patients ≥65 years of age with newly diagnosed de novo or 
secondary AML and poor- or intermediate-risk cytogenetics were randomized into two 
treatment groups: decitabine 20 mg/m2 once daily 1 h i.v. for 5 consecutive days, every 4 
weeks; or either treatment choice of supportive care or 20 mg/m2 low-dose cytarabine
(LDAC) subcutaneously once daily for 10 consecutive days, every 4 weeks. Of 485 enrolled 
patients, 242 were randomized to receive decitabine and 243 to treatment choice of 
supportive care (N=28) or LDAC (N=215). In the decitabine group, 25.6% achieved 
objective response rate (CR+CRi); the median duration of treatment was 4.4 months and the
median survival was 7.7 months. In the supportive care or LDAC group, 10.7% of patients 
achieved objective response (CR+CRi); the median duration of treatment was 2.4 months and 
the median survival was 5.0 months. Decitabine compared to LDAC has demonstrated a 
trend for overall survival advantage and higher objective response rates without major 
differences in safety.
Also widely used, especially at academic sites, is a decitabine treatment regimen with 
repeated i.v. infusions daily for 10 days. This intensified regimen of decitabine (20 mg/m2
daily for 10 days) was applied to 53 patients (median age 74 years) who were unsuitable for 
standard chemotherapy. Most of the patients received one or two cycles of 10 day decitabine 
followed by cycles with the standard regimen of 5 days decitabine. The CR rate was 47% and 
CRi was 17%, with 30- and 60-day mortality rates of 2% and 15%, respectively. Median OS 
and disease-free survival durations were 55 and 46 weeks, respectively. Responses were 
present in all subgroups regardless of age, cytogenetics, leukocyte count, and antecedent
myelodysplasia. The data from this small single-arm trial are encouraging (R12-3308).
In patients with relapsed or refractory AML, decitabine has been used for salvage 
chemotherapy. Medical records of 79 patients who received decitabine-based salvage therapy 
have been reviewed from September 2006 through July 2009 at Weill Cornell Medical 
College (R11-1105). Patients with relapsed or refractory AML were given salvage 
chemotherapy with decitabine 20 mg/m2 daily for 10 days or decitabine 20 mg/m2 x 5 days 
with gemtuzumab ozogamicin. Overall, 16% of patients achieved a CR and 5% CRi (platelets 
< 100,000). Patients receiving decitabine alone had a median OS of 209 days and those 
receiving decitabine/gemtuzumab ozogamicin had a median OS of 177 days but the 
difference was not statistically significant. These study results suggested that decitabine-
based treatment for relapsed and refractory AML is a low intensity alternative that has 
activity rivalling more intensive regimens. However, further investigation of decitabine-based 
salvage is warranted as a second retrospective trial of decitabine for the treatment of relapsed 
or refractory AML observed a lack of response in a heavily pre-treated population.
1.2.3
Combination Treatment of BI 836858 and Decitabine
This trial will investigate tolerability, safety, pharmacokinetics and efficacy of BI 836858 in 
combination with decitabine in patients with AML for the first time in the clinical setting. 
Therefore, no data on tolerability, safety, pharmacokinetics or efficacy on this combination in 
humans are available to date.




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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Treatment for relapsed or refractory adult patients with AML independent of age and 
previously untreated AML patients ≥ 65 years of age, who are considered ineligible for 
intensive treatment, remains a major challenge. While progress has been made in treating 
younger adults, challenges still remain in treating the elderly population. Patients who are 
aged ≥65 years, particularly those with non-favourable cytogenetics, aged ≥75 years, or 
those with significant co-morbidities are considered ineligible for standard intensive 
chemotherapy. Therefore, there is an urgent need for discovering innovative treatments. 
CD33 is a valid target to treat patients with AML, as CD33 is expressed on the majority of 
AML cells (R11-1472) and on leukemic stem cells, but not outside of the hematopoietic 
system (R11-1473). The clinical experience with lintuzumab supports the assumption that 
targeting CD33 with an IgG1-type antibody may translate into clinical response in patients 
with AML with an acceptable side effect profile. Preclinical data demonstrating an enhanced 
ADCC of BI 836858 over lintuzumab support the development of BI 836858 in patients with 
AML (see Section 1.2).
Recent studies have demonstrated clinical activity of decitabine in AML (R12-3309). The
result suggested that decitabine as monotherapy may have at least activity similar to LDAC. 
Therefore, besides LDAC, decitabine provides another established treatment option for 
patients with previously untreated AML that are considered ineligible to receive standard 
intensive therapy. 
Especially in a proliferative disease like AML, where number and functionality of effector 
cells may be limited, antibodies like BI 836858 need a combination partner to enhance their 
efficacy.
Preclinical data (see Section 1.2.3) showing that treatment with decitabine can enhance the 
ADCC activity of BI 836858 supports the clinical investigation of this drug combination.
The trial is aimed to investigate BI 836858 in combination with decitabine in patients with 
AML with regard to safety and efficacy.
TRIAL OBJECTIVES
2.2
The objective of the present trial is to investigate BI 836858 in combination with decitabine. 
If justified by safety and efficacy data of BI 836858 in combination with decitabine, late 
phase development of BI 836858 in combination with decitabine may be considered in the 
future.
The trial will be performed in two parts: a Phase I part consisting of a dose escalation and an
extension part, as well as a randomized Phase II part (see also Figures 3.1.1 and 3.1.2).


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The objectives of the Phase I Dose Escalation part of the trial are to determine the MTD and
to investigate safety, pharmacokinetics and efficacy of BI 836858 in combination with
decitabine in previously untreated patients ≥ 65 years of age and considered ineligible for 
standard intensive therapy, or patients ≥18 years of age with relapsed or refractory AML.
In case the MTD would not be reached because of preliminary signals of activity or due to 
tolerability issues in repeated treatment cycles at doses below the MTD, the dose to be used 
for further development of BI 836858 in combination with decitabine in adult patients with 
AML would be determined (also see Section 3.1). Within the context of this trial that dose 
will be referred to as the Recommended Extension Phase I Dose (RExP1D).
The objectives of the Phase I Extension cohorts are to collect additional data on safety, 
pharmacokinetics and efficacy and to decide if the RExP1D will become the Recommended 
Phase II Dose (RP2D) of BI 836858 in combination with decitabine in patients ≥ 65 years of 
age, or if additional patients need to be enrolled in existing or additional dose escalation 
cohorts. Furthermore, based on the totality of efficacy and safety data, the treatment duration 
of decitabine in the combination treatment with BI 836858 will be assessed for the 
subsequent use in the Phase II part.
In the randomized Phase II part, the primary objective is to investigate the efficacy, safety 
and pharmacokinetics of BI 836858 in combination with decitabine compared to decitabine 
monotherapy in previously untreated patients with AML, who are≥65 years of age and 
considered ineligible for standard intensive therapy.
BENEFIT - RISK ASSESSMENT
2.3
The treatment of patients with AML ≥65 years of age has become increasingly important as 
the age of population increases. Patients ≥65 years of age with previously untreated, relapsed 
or refractory AML have an overall poor prognosis with very limited treatment options. If
patients are unfit for standard intensive treatment, the participation in a clinical trial would be
the appropriate choice as recommended by clinical practice guidelines (R15-5032).
The most relevant side effect of decitabine administration is expected to be a transient 
inhibition of proliferation of normal dividing cells (e.g. in bone marrow). The effects on the 
hematopoietic system lead to a temporary decrease of blood cells (red cells, white blood cells 
and platelets). 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.
As the cardinal symptom of AML patients is cytopenia, the symptoms of AML and 
haematological side effects of treatment with BI 836858 and decitabine are expected to 
overlap. For most anti-leukemia therapy, a drug-related transient worsening of cytopenia is 
common and inevitable. Therefore, especially the CTCAE grade and duration of cytopenia (as 
well as complications of cytopenia) will be important safety criteria that will be closely 
monitored for clinical symptoms of infections throughout this trial in order to limit the risk of 
the treatment with the trial drugs used in combination in this trial. The use of anti-infective 
prophylaxis (refer to Section 4.2.1) is strongly recommended.


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The preclinical safety assessments for BI 836858 have revealed TNF-alpha and INF-gamma 
release, suggesting a potential for infusion-related reactions. So far only clinical data from 
20 patients with refractory/relapsed AML, treated with weekly 10 and 20 mg of BI 836858 in 
the ongoing first in human trial, are available. Infusion-related reaction (IRR) was the most 
frequent drug-related adverse event (AE), reported in 7 patients (35%). Considering these 
data and the experience with other monoclonal antibodies in hemato-oncology indications, 
infusion-related reactions are likely. Prophylactic measures will be recommended for primary 
prevention, and supportive treatments are available (see Section 4.1.4).
In order to minimize the risk associated with the potentially additive adverse effects of the 
combination therapy, in both parts of the trial, a group of experts will be responsible for 
continuous surveillance and assessment of the trial data to ensure overall safety of the 
patients treated (refer to Section 3.1).
Investigators participating in the Phase I part of the trial will participate in frequent and 
periodic Safety Monitoring Committee (SMC) teleconference meetings to review the status 
of ongoing patients. In addition, during these SMC teleconference meetings, safety data to 
date will be summarized and reviewed with all participating Investigators, and options for 
dose escalations and de-escalations will be discussed.
In Phase II, the ongoing monitoring of safety data will be conducted by the Data Monitoring 
Committee (DMC). 
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
Sponsors and regulators. Therefore, this trial ensures timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to protect patients’
safety, see also Section 5.3.8.1.
A case of tumor lysis syndrome (TLS) with fatal outcome was reported in trial 1315.2 in 
AML. The patient was diagnosed with AML with extramedullary disease (skin (confirmed), 
abdominal and mediastinal lymph nodes (suspected)), assigned to a dose of 80 mg BI 836858 
in combination with decitabine, and classified as low risk for TLS based on LDH and WBC
(R18-1901). The event triggered measures for this trial to ensure patients safety including a 
modification of the infusion schedule (see Section 4.1.3) to mitigate the risk for rapid onset of 
activity and additional mandatory laboratory monitoring for early detection of TLS (see 
Section 5.3.6 and Table 1).
The benefits of participating in this protocol may include disease response to the trial
treatment, better disease control, improvement of leukemia-related symptoms and/or
improvement in quality of life, as a result of receiving BI 836858 and decitabine as a 
combination treatment. In addition, all patients who are taking part in the trial may derive 
general medical benefit from careful and close monitoring by the treating Investigator and 
site personnel during the trial. Safety will be ensured by monitoring of the patients for AEs,
both clinically and by laboratory testing.


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Given the above considerations, the benefit-risk assessment in this highly compromised AML 
patient population is considered favourable for this trial and the potential benefit of therapy 
with BI 836858 in combination with decitabine is expected to outweigh the treatment-related
risks.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
The trial will be performed according to an open-label design for both, Phase I and Phase II
part. The data obtained from the Phase I part of the trial will be used to determine the MTD 
(or a Recommended Extension Phase I Dose (RExP1D), see Section 4.1.3 for details) of BI 
836858 in combination with decitabine based on a Bayesian logistic regression model
(BLRM) with overdose control. 
Based on data from the Phase I Extension it will be decided if the RExP1D will become the 
Recommended Phase II Dose (RP2D) of BI 836858, or if additional patients need to be 
enrolled in existing or additional dose escalation cohorts to determine the RP2D.
In Phase II, this trial will explore efficacy and safety of BI 836858 in combination with 
decitabine versus decitabine monotherapy in a randomized manner.
In both phases of the trial, a group of experts (in Phase I a trial-internal Safety Monitoring 
Committee (SMC) and in Phase II a Sponsor-internal DMC) will be responsible for 
continuous assessment of the trial data as described in this protocol and the DMC charter 
(filed in the Trial Master File) to ensure overall safety of the patients treated. In Phase I, the 
SMC’s responsibility will be the recommendation of the dose escalation and de-escalation 
steps and the monitoring of the quality of the data. In Phase II the DMC will provide advice 
about the conduct of the trial and the integrity of the data.
After having provided informed consent and after a screening period of up to 14 days, 
eligible patients will be allocated to treatment by Interactive Response Technology (IRT) to 
the respective dose cohort or treatment group. The patients will be asked to remain under the 
Investigator's or their staff’s supervision during the duration of administration of decitabine 
as well as BI 836858. The patients will visit the site at regular intervals for assessment of 
safety and efficacy and for collection of blood for analysis of the PK of BI 836858 and 
decitabine. Treatment will continue until progression or relapse of the underlying AML or if 
patients and/or Investigators decide to discontinue therapy according to the criteria as defined 
in Section 3.3.4. 
In Phase I patients will be followed up at regular intervals for approx. 6 months after end of 
treatment or until death, whichever occurs earlier. In Phase II, after the last administration of 
any of the two trial drugs the patients will be followed up at regular intervals for OS until 
death or until the end of the whole trial, whichever occurs earlier (refer to Section 6.2.3).
The results of the trial will aid in the decision-making on the further development program of 
BI 836858 in AML.
Phase I:
In the Phase I Dose Escalation, patients ≥65 years of age with previously untreated AML, 
who are considered ineligible for standard intensive therapy, or patients ≥18 years of age 


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with relapsed or refractory AML will be assigned to the respective dose cohort that is being 
investigated when the patient is entering the trial. The Phase I Dose Escalation will be guided 
by a Bayesian logistic regression model (BLRM) with overdose control (refer to Section 7). 
As new patient safety information becomes available, the BLRM estimates the MTD by 
updating estimates of the probability of observing a DLT in the first cycle for each dose level 
in the study. 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.
At least 3 patients will be required for every dose escalation cohort, (refer to Section 7). In 
the case that only 2 patients are evaluable and neither has experienced a dose-limiting toxicity 
within Cycle 1 (patient has received at least 3 administrations of BI 836858 and reached end 
of Cycle 1, i.e. patient is eligible to continue trial treatment on Day 1 of Cycle 2 at the latest 
on Day 57 after start of Cycle 1, refer to Section 5.3.1), 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 without experiencing a DLT, the Bayesian logistic regression model (BLRM) 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 fulfilling the EWOC criterion and the 
additional 100% escalation rule. Based on the model and on additional information (e.g. PK, 
pharmacodynamics, AE, patient profiles), the members of the SMC will determine the next 
dose level and cohort size.
If DLTs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort will be stopped. The BLRM will be re-run to confirm 
that the dose level still fulfils the EWOC criterion. Based on this information, the SMC will 
evaluate whether the next patients will be enrolled on the same dose level, or if they will be 
enrolled on a lower dose level. 
The SMC may recommend stopping the dose escalation phase after the criterion for MTD 
(refer to Sections 5.3.2 and 7.1) 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 SMC may recommend to include an additional number of patients at the same dose level 
and to declare this dose as the RExP1D. 
Based on the totality of data (PK, pharmacodynamics, biomarker and safety) the SMC may 
also recommend treating additional patients prior to the Phase I Extension part with the MTD 
(or RExP1D) or higher doses of BI 836858 in combination with the standard treatment 
schedule of decitabine. The number of patients to be treated and the dose of BI 836858 to be 
tested will be discussed and recommended by the SMC.
In the Phase I Extension part of the trial, up to 30 previously untreated patients with AML 
who are ≥65 years old and considered ineligible for standard intensive therapy, will be 
allocated subsequently into two cohorts. Up to 15 patients will be allocated to Cohort A, i.e. 
treatment with BI 836858 and decitabine 20 mg/m² for 10 consecutive days (decitabine 


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intensive treatment schedule) and up to 15 patients will be allocated to Cohort B, i.e.
treatment with BI 836858 and decitabine 20 mg/m² for 5 consecutive days (decitabine 
standard treatment schedule).
If deemed necessary by the Sponsor and the SMC, based on a comprehensive review of 
available clinical trial data, biomarker results (including CD33 receptor saturation) and PK-
results, additional patients may be enrolled after the extension cohorts into pre-existing or 
new dose escalation cohorts to further optimize the BI 836858 dose and determine the RP2D. 
Dose escalation steps for additional dose cohorts will be defined according to the rules as 
outlined for the phase I dose escalation part of this protocol.
The decitabine schedule to be used for each cohort will be determined by the Sponsor in 
agreement with the SMC and documented in the SMC meeting minutes.
A final recommendation on the RP2D dose of BI 836858 and on the duration of treatment 
with decitabine will be given after Phase I safety data of both, the dose escalation part as well 
as the extension part, will have been summarized and reviewed by the SMC. 
Prior to the initiation of Phase II, safety and preliminary PK results will be analyzed and 
documented in a safety analysis report or lean interim Clinical Trial Report (CTR). This 
Phase I safety analysis report or lean interim CTR will be sent to competent authorities/ethic 
committees. A summary of safety and efficacy endpoints and determination of the RP2D will 
be included in this report.
The RP2D of BI 836858 with either the standard 5 day treatment schedule or the intensive 10 
day treatment schedule of decitabine will be used in the combination treatment Arm 1 of the 
Phase II of the trial.
After completion of recruitment to Phase I Extension Cohort A and Cohort B, the 
recruitment to this trial is discontinued.
Phase II:
In Phase II, previously untreated patients with AML, who are ≥65 years old and considered 
ineligible for standard intensive therapy will be randomized in a 1:1 manner to investigate 
efficacy and safety of BI 836858 at RP2D in combination with decitabine versus decitabine 
monotherapy. The screening phase may be up to 14 days; therefore, the first dose of trial
treatment should occur no more than 15 days after the informed consent is signed. The type 
of AML (de novo, secondary AML) is an important prognostic factor (R07-2768); therefore,
patients will be stratified by type of AML to ensure a balanced distribution of this prognostic 
factor between treatment groups. A total of approx. 100 patients, 50 in each arm, will be 
enrolled in Phase II. 
Patients will be enrolled in the trial once they have signed the informed consent form and 
entered into the trial once they have been confirmed to meet the inclusion and exclusion 
criteria.


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Patients will be treated within the assigned cohort or treatment arm until progression/relapse
or until patients and/or Investigators decide to discontinue therapy (refer to Section 3.3.4.). 
No patients will be allowed to continue trial treatment and switch or be entered into another 
part of this trial. 
The overall structure of the trial is described in Figures 3.1: 1. (Phase I) and 3.1: 2 (Phase II)
Figure 3.1: 1
Overall structure of the trial Phase I


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Figure 3.1: 2
Overall structure of the trial Phase II
3.1.1
Administrative structure of the trial
Boehringer Ingelheim (BI) is the Sponsor of this trial. 
The Coordinating Investigator will be appointed by BI and shall be experienced in treatment 
of patients with AML and also experienced in performance of Phase I and other clinical trials 
in this patient population. The Coordinating Investigator will be responsible for the 
coordination of Investigators at different centres participating in this multicentre trial. The
tasks and responsibilities of the Coordinating Investigator will be defined in a contract. 
Participating Investigators will be physicians experienced and specialized in the treatment of 
AML and in the conduct of Phase I/II trials. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in the ISF.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI Standard Operating Procedures (SOPs). A list of responsible persons 
and relevant local information can be found in the ISF. On-site monitoring will be performed 
by BI or a Clinical Research Organizations (CRO) appointed by BI.
Boehringer Ingelheim will appoint CROs for special services such as IRT for patient 
enrolment, entry and trial medication logistics.
All trial relevant documentation will be stored in the trial master file (TMF) at BI. In addition 
each site will have an Investigator Site File (ISF) containing all trial documents
relevant for the site.


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The safety laboratory investigations (hematological, biochemical, coagulation, and urine; for 
details see Section 5.3.6) will be performed at local laboratories associated with the sites, i.e.
no central laboratory will be used for this purpose.
Local and/or central laboratories will be used for assessment of biomarkers, 
pharmacokinetics, cytogenetics, molecular genetics and pharmacogenomics analyses. For 
details on analyses of BI 836858 and decitabine concentrations in plasma please refer to 
Section 5.4.
Both parts of the trial will be overseen by a group of experts (in Phase I by SMC, in Phase II 
by DMC) to ensure patient safety.
For Phase I, the SMC will consist of the Phase I Investigators and experts of the Sponsor, 
namely the following functions will be represented: Team Member Medicine (TMM), Trial 
Clinical Monitor (TCM), Project Statistician (PSTAT), Clinical Pharmacological Project 
Lead (CPPL) and TransMed Expert (TME). Additional experts may be invited as needed. 
The information on the overdose risk will be presented by the trial statistician to the SMC. 
Additional information, such as lower grade adverse events, PK, pharmacodynamics, 
individual patient profiles or data listings and other relevant information may also be 
presented. Based on this information, the members of the SMC will reach a 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 SMC will also recommend the size of the next cohort. 
Minutes of the SMC meetings and recommendations will be documented and archived by the 
TCM.
In Phase II, the DMC shall be responsible for safeguarding the interests of trial participants, 
assessing the safety and efficacy of the interventions during the trial, and for monitoring the 
overall conduct of the trial. The DMC shall provide recommendations to BI on whether the 
study should continue, be modified or stopped for efficacy or safety concerns. Further details 
of the DMC members and how the DMC will operate will be described in a separate DMC 
Charter that will be filed in the ISF.
Boehringer Ingelheim has appointed a TCM, responsible for coordinating all required
activities, in order to 
∀
manage the trial in accordance with applicable regulations and internal SOPs,
∀
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
∀
order the materials as needed for the trial, 
∀
ensure appropriate training and information of local clinical monitors (CMLs), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI or a CRO appointed by BI 
according to BI SOPs.


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Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information
can be found in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP
Decitabine is an established treatment option for patients with previously untreated AML 
who are considered ineligible to receive standard intensive therapy, and is a recommended 
treatment according to NCCN clinical practice guidelines (R15-5032). All patients 
participating in this clinical trial will be treated with decitabine. The dose and duration of 
treatment with decitabine in the Phase II part of the trial will be the dose and duration of the 
therapy regimen which has been investigated in the Phase I Extension part of this trial and 
was considered safe and potentially effective.
In Europe, the approved posology of decitabine is 20 mg/m² body surface area (BSA) by i.v. 
infusion over 1 h (as per decitabine SPC) repeated daily for 5 consecutive days in 28-day 
cycles. This treatment schedule will be referred to as the “decitabine standard treatment 
schedule”. However, in clinical practice and in completed and ongoing clinical trials (e.g. 
EORTC (European Organisation for Research and Treatment of Cancer) 1301-LG trial, 
EudraCT Number 2014-001486-27, ClinicalTrials.gov Identifier NCT02172872) a dosing 
schedule of decitabine 20 mg/m² BSA i.v. over one hour (as per decitabine SPC) repeated 
daily for 10 consecutive days is also widely used. This treatment schedule will be referred to 
as the “decitabine intensive treatment schedule”. The overall goal is to optimize the therapy 
of the patients with AML. A SMC will continuously supervise the safety of the patients, 
assess the risk-benefit profile and recommend any changes in the design in case a change of 
the risk-benefit profile would require a variation to the protocol.
In Phase I Dose Escalation of the trial, the investigational drug BI 836858 will be combined 
with decitabine to determine the MTD/RExP1D (Section 4.1.3) for the decitabine intensive 
treatment schedule. Dose escalation for BI 836858 will be conducted following a Bayesian
logistic regression model (BLRM) with overdose control. An escalation with overdose 
control design will increase the chance of treating patients at efficacious doses while reducing 
the risk of overdosing. This design is based on practical experience and is an efficient method 
due to its ability to identify the dose with a desired toxicity rate and its allocation of a greater 
proportion of patients to doses at, or close to that dose (R13-4802, R13-4804, R13-4805). The 
use of Bayesian models for Phase I studies has also been advocated by the EMA guideline on 
small populations (R07-4856) and by the FDA (R13-4881).
Once a RExP1D has been defined, patients will be treated at the RExP1D in two consecutive 
extension cohorts (Section 4.1.3) using the two different decitabine treatment schedules as 
described above (also refer to Figure 3.1: 1). Based on efficacy and safety data, the treatment 
duration of decitabine in the combination treatment with BI 836858, which will be used in 
Phase II part, will be determined.
If deemed necessary by the Sponsor and the SMC, based on a comprehensive review of 
available clinical trial data, biomarker results (including CD33 receptor saturation) and PK-


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results, additional patients may be enrolled after the extension cohorts into pre-existing or 
new dose escalation cohorts to further optimize the BI 836858 dose and determine the RP2D. 
In Phase II of the trial, patients ≥65 years of age with previously untreated AML considered 
ineligible to receive standard intensive therapy will be randomized to either receive 
decitabine in combination with BI 836858 at RP2D or decitabine alone. To avoid potential 
bias at inclusion, in the Phase II part the patients will be randomly allocated to the treatment 
arms (stratified by type of AML; refer to Section 3.1). In both treatment arms decitabine will
be administered according to the same treatment schedule as determined at the end of Phase I.
Due to the fact that the study drug is administered intravenously and additional placebo 
infusions should be avoided, this part of the trial is also performed open-label (Section 
4.1.5).The conduct of this part of the trial, including patient safety and integrity of the trial 
data as per the DMC charter, will be overseen by the DMC.
BI 836858 will be investigated in combination with the established compound decitabine 
throughout this trial, with the exception of the control arm in Phase II, where patients will be 
treated with decitabine monotherapy. This control arm is needed to allow a clear comparison
of the combination treatment effect versus the monotherapy treatment.
SELECTION OF TRIAL POPULATION
3.3
In order to enter approximately 150 evaluable patients to the trial, it is anticipated that about 
200 patients will need to be screened (i.e. screening of approximately 30 patients for the 
Phase I Dose Escalation part of the trial, 40 patients for the Phase I Extension part and 130
patients for the Phase II part of the trial). During the Phase I Dose Escalation part of the trial, 
approximately 2 patients are expected to be entered every month; approximately 5-10 patients 
are expected to be entered every month in the Phase I Extension and the Phase II part of the 
trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
The Phase I Dose Escalation of the trial will be conducted at approximately 6-8 sites 
preferably in Germany and the USA; possibly further countries will also participate. The 
Phase I Extension and the Phase II part of the trial will be performed at approximately 15-25
sites in the USA, Germany and approx. 5 other countries. 
Screening of patients for this trial is competitive; screening for the trial will be terminated
once the number of screened patients is considered sufficient to achieve the required number
of entered and randomized patients, respectively. Investigators will be notified about the end 
of screening (for both Phase I and Phase II) and will not be allowed to recruit additional 
patients for this trial beyond the definite date. Patients who have signed the informed consent 
for the Phase I Extension cohort or Phase II prior to notification of the termination of 
recruitment will be allowed to continue in the trial, if they meet all entry criteria.
The Investigators are trained to assess a patient's eligibility for standard intensive AML 
therapy based on their special medical experience. The criteria impacting the decision to 


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assess a patient's eligibility will be documented to allow continuous monitoring and to enable 
reporting of the rationale to enter patients into the trial.
3.3.1
Main diagnosis for trial entry
Phase I Dose Escalation: Patients ≥18 years of age with relapsed or refractory AML
(defined as persisting AML after at least two induction cycles) or patients ≥65 years of age
with previously untreated AML, who are considered ineligible for standard intensive therapy.
Phase I Extension and Phase II: Patients ≥65 years of age with previously untreated AML 
who are considered ineligible for standard intensive therapy.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria. The investigator’s decision to consider a patient as 
ineligible for standard intensive therapy must be based on documented medical reasons (e.g. 
disease characteristics like AML genetics, type of AML (de novo or secondary), and patient 
characteristics like performance score, concomitant diagnoses, organ dysfunctions). 


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3.3.2
Inclusion criteria
1)
Phase I Dose Escalation: 
a. Male or female patients ≥18 years of age with relapsed or refractory AML (defined 
as persisting AML after at least two induction cycles) and no anti-leukemia therapy 
within 2 weeks before first treatment with decitabine.
b. Male or female patients ≥65 years of age with previously untreated AML ineligible 
for receiving standard intensive therapy based on documented medical reasons as 
defined in Section 5.6.1. 
Phase I Extension and Phase II: 
Male or female patients ≥65 years of age with previously untreated AML ineligible for 
receiving standard intensive therapy based on documented medical reasons as defined 
in Section 5.6.1. 
2)
Histologically or cytologically confirmed AML according to the WHO classification
(R09-2581).
3)
Patients must be eligible for treatment with decitabine.
4)
Eastern co-operative oncology group (ECOG) performance score < 2 at screening 
5)
Signed and dated written informed consent (including consent for biomarker and 
genetic testing; refer to Section 8.1) by the start date of the Screening Visit in 
accordance with GCP and local legislation.
Please note that prior therapy for MDS is allowed for all patients participating in Phase I and 
Phase II of this trial (with the exception of hypomethylating agents such as decitabine and 
azazitidine). 
Prior treatment with hydroxyurea in order to reduce high WBC and treatment with 
hydroxyurea to control the WBC count during the first treatment cycle is allowed (refer to 
Section 4.2.2.1).
3.3.3
Exclusion criteria
1)
Acute promyelocytic leukemia (FAB subtype M3), according to WHO classification
(R09-2581).
2)
Patients who are candidates for allogeneic stem cell transplantation.
3)
Active chronic graft versus host disease requiring immunosuppressive treatment. 
4)
Prior treatment with a hypomethylating agent (this also includes prior MDS treatment 
with decitabine or azazitidine).
5)
Prior treatment with CD33 antibody.
6)
Second malignancy currently requiring active therapy (except for hormonal/anti-
hormonal treatment, e.g. in prostate or breast cancer).


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7)
Current clinical central nervous system symptoms deemed by the Investigator to be 
related to leukemic CNS involvement (no lumbar puncture required, clinical assessment 
per Investigator’s judgment is sufficient).
8)
Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater than 
2.5 x the upper limit of normal (ULN) or AST or ALT greater than 5 times the ULN for 
those with Gilbert syndrome.
9)
Prothrombin time > 1.5 x ULN.
10)
Total bilirubin ≥ 1.5 mg/dL (>26 μmol/L) unless elevation is thought to be due to 
hepatic infiltration by AML, Gilbert syndrome, or hemolysis.
11)
Serum creatinine ≥ 2.0 mg/dL.
12)
Presence of concomitant intercurrent illness, or any condition which in the opinion of 
the Investigator, would compromise safe participation in the trial, e.g. active severe 
infection, unstable angina pectoris, new onset of exacerbation of a cardiac arrhythmia.
13)
Psychiatric illness or social situation which in the opinion of the Investigator would 
limit compliance with trial requirements.
14)
Known human immunodeficiency virus (HIV) infection or 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.
15)
Pregnant or breast feeding patients.
16)
Female patients of childbearing potential who are sexually active and unwilling to use a 
medically acceptable method of contraception during the trial and for a minimum of 
6 months after completion of trial treatment [i.e. combination of two forms of effective 
contraception (hormonal contraception, intrauterine device, transdermal patch,
implantable or injectable contraceptive, bilateral tubal occlusion, 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 sterilised (e.g. hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy)
17)
Male patients with partners of childbearing potential who are unwilling to use condoms 
in combination with a second medically acceptable method of contraception during the 
trial and for a minimum of 6 months after completion of trial treatment.
18)
Treatment with another investigational agent under the following conditions:
a) Within 2 weeks (for biologics 4 weeks or 5 half-lives, whichever is longer) of first 
administration of BI 836858; or
b) Patient has persistent toxicities from prior anti-leukemic therapies which are
determined to be relevant by the Investigator.


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c) Concomitant treatment with another investigational agent while participating in this 
trial.
19)
Known hypersensitivity to the trial drugs.
20)
Patients unable or unwilling to comply with the protocol.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment, i.e. treatment with any trial 
medication, if:
∀
The patient withdraws consent. Patients are free to withdraw consent for trial treatment 
only or both, trial treatment and trial participation, without the need to justify the 
decision.
∀
Patients who are assigned to the combination treatment (any of the Phase I parts, or Arm 
1 in the Phase II part) and who decide to withdraw consent for further administration of 
only one of the trial drugs, i.e. BI 836858 or decitabine, may not continue with 
monotherapy treatment of the other drug, but have to end the treatment phase. In that case 
the patient will be asked to have the EOT and EoR visits performed and will be followed 
up as per protocol.
∀
The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication (please refer to Section 4.2.2)
∀
Start of subsequent treatment cycle needs to be delayed by longer than 8 weeks due to a 
drug-related event (e.g. delay in recovery of blood counts or awaiting resolution of
toxicity; please refer to Section 4.1.4.2).
∀
The patient can no longer be treated with trial medication for other medical reasons (e.g. 
adverse events unrelated to therapy or disease progression, concomitant diagnoses, 
pregnancy, surgery or administrative reasons). The Investigator may also stop a patient’s 
participation if the patient is no longer able to attend trial visits.
∀
For patients in Phase I only: The patient is not eligible for treatment with BI 836858 on 
Day 8 (or Day 9 at the latest) of Cycle 1. The patient will be asked to have the EOT and 
EoR visit performed and will be followed up as per protocol (i.e. the patient will be 
withdrawn from the trial treatment and may be treated with decitabine monotherapy 
according to local standard of care).
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. As soon as a 
patient is withdrawn from the trial treatment, the End of Treatment (EOT) visit and the End 
of Residual Effect Period (REP) visit (EoR visit) have to be performed if feasible. 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 documented 
full consent withdrawal (i.e. withdrawal from both, trial treatment and trial participation), no 
further visits will be completed and no further trial data will be collected. However, if


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information about survival status is publicly available, then the Investigator is requested to 
report this information in the eCRF.
A patient has to discontinue trial drug administration, i.e. both BI 836858 and decitabine, in 
case:
∀
a DLT occurs which does not recover to a degree that allows treatment continuation (see 
Section 4.1.4).
∀
development of progressive disease (PD) or any other concomitant diagnosis including 
deterioration of general condition develops resulting in an indication to start any other 
therapy for AML.
Patients who have not completed at least 3 administrations of BI 836858 during cycle 1 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 3 administrations (1 cycle) of BI 836858 for reasons 
other than BI 836858-related toxicity will be replaced.
Patients who experienced DLT but have subsequently recovered and are able to resume trial
treatment will be allowed to continue on trial treatment, as long as criteria for further 
treatment are met (Section 4.1.4.1).
Discontinuation of the trial by the Sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1)
Failure to meet expected enrolment goals overall or at a particular trial site.
2)
Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3)
Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the 
trial.
4)
Recommendation by the SMC/DMC to discontinue the trial.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
After completion of recruitment to Phase I Extension Cohort A and Cohort B, the 
recruitment to this trial is discontinued. 


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
The investigational product BI 836858 will be administered in the defined treatment regimen
in Phase 1 and Phase 2 (refer to Sections 4.1.3.1, 4.1.3.2 and 4.1.3.3). All patients 
participating in this trial will receive decitabine as standard of care treatment, which is 
backbone chemotherapy (R15-5032).
BI 836858 will be administered as rate-controlled intravenous infusion for up to 8 h. The 
actual duration of the infusion needs to be documented in the eCRF including actual start and 
end time, actual time points for interruption and restart of the infusion, as well as reason for 
interruption and the actual infusion rates.
Adverse events during the infusion will be thoroughly documented and characterized 
(documentation of individual symptoms) to allow differentiation of infusion-related reactions 
(R10-4428, R10-4517).
4.1.1
Identity of Investigational Medicinal Product and combination treatment
Table 4.1.1: 1
BI 836858 (Investigational Medicinal Product):
Substance:
BI 836858
Pharmaceutical formulation:
Concentrate for solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/mL (vials with 10 mL)
Posology
Rate controlled infusion (volume: 250 mL)
Route of administration:
Intravenous


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Table 4.1.1: 2
Decitabine (standard of care/backbone chemotherapy treatment):
Substance:
Decitabine 
Pharmaceutical formulation:
Powder for concentrate for solution for infusion
Source:
Commercially available decitabine may be locally 
supplied to sites according to local regulations in 
participating countries. Complete guidelines for 
preparation, storage and administration of decitabine 
can be found in the country package insert.
Details about the options for reimbursement by the 
Sponsor will be stated in the Investigator or 
pharmacy contract, respectively.
Unit strength:
50 mg/vial
Posology
Infusion according to manufacturer’s instruction
Route of administration:
Intravenous
4.1.2
Method of assigning patients to treatment groups
All patients will be treated with decitabine for treatment of AML.
In the Phase I Dose Escalation part of the trial, patients will be assigned in an open fashion 
into escalating dose cohorts of BI 836858 using IRT. 
After determination of the MTD (or RExP1D) approximately 30 additional patients (2 x 15 
patients per cohort) will be assigned via IRT into the Phase I Extension part. The patients will 
be allocated to treatment with either BI 836858 and decitabine in the intensive treatment 
schedule (Extension Cohort A, starting with 10 consecutive days of decitabine per treatment 
cycle) or with BI 836858 plus decitabine using the standard treatment schedule (Extension 
Cohort B, starting with 5 consecutive days of decitabine per treatment cycle). The two 
cohorts will be filled consecutively starting with Cohort A, followed by Cohort B.
In case there will be further Dose Escalation cohort(s) after the Phase I Extension part of the 
trial, this will be consecutive cohorts of escalating doses of BI 836858 plus decitabine, using 
the BLRM with overdose control. The number of patients and the decitabine schedule to be 
used for each cohort will be determined by the Sponsor in agreement with the SMC.
In Phase II of the trial, patients will be randomly allocated via IRT to treatment with 
BI 836858 in combination with decitabine or decitabine monotherapy. Randomization will be 
stratified for de novo vs secondary AML to ensure a balance of this prognostic factor between 
treatment groups.
To facilitate the use of the IRT, the Investigator will receive an IRT manual including all 
necessary instructions. A copy of the manual will be available in the ISF.




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Table 4.1.3.1: 1
Decitabine intensive treatment schedule 
Cycle
Blasts in % at end of precedent cycle
Decitabine i.v. treatment duration 
Cycle 1
n.a.
20 mg/m² for 10 consecutive days 
(Days 1-10 of 28-day cycle)
Cycle 2-3
No blasts in peripheral blood 
and
BM blasts < 5%
20 mg/m² for 5 consecutive days 
(Days 1-5 of 28-day cycle)
Blasts in peripheral blood ≥5% (no BM 
assessment required)
or
No blasts in peripheral blood and
BM blasts ≥ 5%
20 mg/m² for 10 consecutive days 
(Days 1-10 of 28-day cycle)
Cycles 4 and 
further, until 
'progression or 
toxicity'
non-PD patients*
20 mg/m² for 5 consecutive days 
(Days 1-5 of 28-day cycle)
*) 
Only non-PD patients (i.e. patients without disease progression or relapse) will continue treatment within the trial.
In case the initially planned treatment duration (as assigned prior to Day 1 of any new cycle) 
is not considered to be safe by the Investigator (e.g. due to myelotoxicity in precedent cycle), 
Day 4 and/or Day 5 may be omitted in the current and all subsequent cycles.
The Phase I Dose Escalation for BI 836858 will be guided by a Bayesian logistic regression 
model (BLRM) with overdose control.
The dose is planned to be escalated in cohorts at pre-specified provisional dose levels based 
on a maximum escalation of 100%. The provisional dose levels to be assigned to separate 
cohorts of patients are listed in Table 4.1.3.1: 2. Dose levels above 40 mg will only be 
explored after safety data from monotherapy studies with BI 836858 have become available 
and if data from PK and pharmacodynamics analysis support further dose escalation.
Intermediate or lower dose levels, depending on the number of DLTs observed in the study, 
and dose levels higher than 320 mg, as long as they fulfil the safety criteria, may be 
investigated if recommended by SMC and agreed upon between Investigator and Sponsor.


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Table 4.1.3.1: 2
BI 836858 dose escalation scheme
Cohort
BI 836858 i.v. weekly a), b)
in 28-day cycles
Decitabine i.v. 
in 28-day cycles
Cohort 1
20 mg/m²
Cohort 2
20 mg/m²
Cohort 3
c)
20 mg/m²
Cohort 4
c)
20 mg/m²
Cohort 5d)
c)
20 mg/m²
a)
BI 836858 will be administered in weekly intervals, e.g. on Days 1, 8, 15 and 22 of 28-day treatment cycles with the 
exception of Cycle 1, where BI 836858 will be administered for the first time on Day 8 (or Day 9 at the latest), 
followed by further weekly administrations, e.g. on Days 16 and 23 of the first cycle. In case WBC on Day 8 (or 
Day 9) of Cycle 1 is ≥10 x 10³/μL, treatment with BI 836858 will not be initiated and the patient will be withdrawn 
from the trial treatment and replaced within the corresponding cohort (i.e. patients may be treated with decitabine 
monotherapy according to local standard of care and followed up as per protocol).
b)
For patients who achieve CR during any of Cycles 1 through 4, the weekly administration of BI 836858 should 
continue for one additional cycle and should then be reduced to monthly administration (maintenance treatment, 
starting on Day 1 of the next cycle).
After completion of Cycle 6 and only for patients with CR or CRi the weekly administration of BI 836858 will be 
reduced to monthly administration, starting on Day 1 of Cycle 7 (maintenance treatment).
c)
Dose levels above 40 mg will only be explored after safety data from monotherapy studies with BI 836858 have 
become available and if data from PK and pharmacodynamics analysis support further dose escalation.
d)
Further cohorts with intermediate or lower dose levels may be explored, depending on the number of DLTs observed 
in the trial, and dose levels higher than 320 mg of BI 836858 may be investigated if recommended by SMC and agreed 
upon between Investigators and Sponsor. Additional Phase I Dose Escalation cohorts may also be opened if deemed 
necessary by the Sponsor and the SMC following the Phase I Extension cohorts of the trial.
A time interval of at least 7 days must have elapsed between the 1st administration of 
BI 836858 and initiation of treatment with decitabine to the next patient in treatment 
Cohort 1. 
A time interval of at least 3 days must have elapsed between the 1st administration of 
BI 836858 and initiation of treatment with decitabine to the next patient in treatment Cohort 2 
or higher (see Table 4.1.3.1: 2).
For the optional Dose Escalation Cohorts following Extension Cohorts A and B, a time 
interval of at least 3 days must have elapsed between the 1st administration of BI 836858 for 
each new patient treated. This means that start of trial treatment with decitabine 
(Cycle 1_Day 1) for the next subsequent patient may occur at the earliest on Cycle 1_Day 4 
of the previous patient.
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 DLT
within the Cycle 1 (i.e. patient has received at least 3 administrations of BI 836858 and 
reached end of Cycle 1; please refer to Section 5.3.2) then dose escalation can occur based on 
these 2 patients. 


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After all patients in a cohort have either experienced a DLT or have been observed 
throughout Cycle 1 (refer to Section 5.3.2) 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. Based on the model and on additional information 
(e.g. PK, pharmacodynamics, AE, patient profiles), the members of the Safety Monitoring 
Committee (SMC) will recommend the next dose level and cohort size.
If DLTs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort will be stopped. The Bayesian logistic regression model 
(BLRM) will be re-run to confirm that the dose level still fulfils the EWOC criterion. Based 
on this information, the SMC 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 MTD may be considered reached if the following criteria are fulfilled:
1) The posterior probability of the true DLT rate in the target interval [0.16, 0.33) of the 
MTD is above 0.50, OR
2) At least 15 patients have been treated in the study, of which at least 6 were treated at the 
MTD.
If no DLT is observed at a dose of which the efficacy is considered sufficient, the SMC may 
decide to include additional patients at this dose level and to declare this dose as the 
RExP1D.
Phase I Extension
4.1.3.2
Patients enrolled into the Phase I Extension part of the trial will be assigned via IRT in an 
open fashion into one of two treatment groups, Cohort A and Cohort B:
∀
In the first opened Cohort A patients will be treated with BI 836858 at the dose 
determined during the dose escalation part of the trial in combination with decitabine in 
the intensive treatment schedule (see Table 4.1.3.2: 1)
∀
After completion of enrolment into Cohort A, patients will be enrolled into Cohort B and
treated with BI 836858 at the determined dose in combination with decitabine in the 
standard treatment schedule (see Table 4.1.3.2: 1). 
During treatment in the extension cohorts, new patients may be enrolled at any time.
If deemed necessary by the Sponsor and the SMC, there will be an option to open further 
Dose Escalation cohort(s) following the extension cohorts to optimize or confirm the RP2D, 
based on additional biomarker, PK/PD and safety data. For further details on dose escalation 
procedures refer to Section 4.1.3.1.


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Table 4.1.3.2: 1
Phase I Extension treatment Cohorts A and B
Extension Cohort A
“decitabine intensive treatment
schedule” plus BI 836858 i.v. weekly a), b)
in 28-day cycles
Extension Cohort B
“decitabine standard treatment 
schedule” plus BI 836858 i.v. weekly a), b)
in 28-day cycles
Cycle
Blasts in % at end 
of precedent cycle
Decitabine 
i.v. treatment 
duration**)
Clinical 
disease status
Decitabine 
i.v. treatment 
duration**)
Cycle 1
n.a.
20 mg/m² for
10 consecutive days
n.a.
20 mg/m² for 
5 consecutive days
Cycle 2-3
No blasts in 
peripheral blood 
and
BM blasts < 5%
20 mg/m² for 
5 consecutive days
non-PD patients
20 mg/m² for 
5 consecutive days 
Blasts in peripheral 
blood ≥ 5% (no BM 
assessment 
required)
or
No blasts in 
peripheral blood 
and
BM blasts ≥ 5%
20 mg/m² for 
10 consecutive days
Cycles 4 and 
further, until 
'progression 
or toxicity'
non-PD patients*
20 mg/m² for 
5 consecutive days
non-PD patients
20 mg/m² for 
5 consecutive days
*)
Only non-PD patients (i.e. patients without disease progression or relapse) will continue treatment within the trial.
**)
In case the initially planned treatment duration (as assigned prior to Day 1 of any new cycle) is not considered to be 
safe by the Investigator (e.g. due to myelotoxicity in precedent cycle), Day 4 and/or Day 5 may be omitted in the 
current and all subsequent cycles.
a)
BI 836858 will be administered in weekly intervals, e.g. on Days 1, 8, 15 and 22 of 28-day treatment cycles with the
exception of Cycle 1, where BI 836858 will be administered for the first time on Day 8 (or Day 9 at the latest), 
followed by further weekly administrations, e.g. on Days 16 and 23 of the first cycle. In case WBC on Day 8 (or 
Day 9) of Cycle 1 is ≥ 10 x 10³/μL, treatment with BI 836858 will not be initiated and the patient will be withdrawn 
from the trial treatment and replaced within the corresponding cohort (i.e. patients may be treated with decitabine 
monotherapy according to local standard of care and followed up as per protocol).
b)
For patients who achieve CR during any of Cycles 1 through 4, the weekly administration of BI 836858 should 
continue for one additional cycle and should then be reduced to monthly administration (maintenance treatment, 
starting on Day 1of the next cycle).
After completion of Cycle 6 and only for patients with CR or CRi the weekly administration of BI 836858 will be 
reduced to monthly administration, starting on Day 1 of Cycle 7 (maintenance treatment).
The RP2D dose of BI 836858 will be defined after all patients have been treated in the 
Phase I Extension part and optional additional dose escalation cohorts of the trial and 
received more than 1 administration of BI 836858 and have completed Cycle 1. The RP2D 


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dose will be either BI 836858 in combination with decitabine intensive treatment or BI 
836858 in combination with decitabine standard treatment.
Phase II 
4.1.3.3
In the Phase II part of this trial, patients will receive the RP2D of BI 836858 in combination 
with decitabine (standard or intensive decitabine treatment schedule) as defined after the
Phase I Extension part.
Patients will be randomized 1:1 via IRT in an open fashion into one of two treatments, Arm 1 
or Arm 2:
∀
In Arm 1 patients will be treated with BI 836858 in combination with decitabine 
∀
BI 836858 will be administered in weekly intervals, e.g. on Days 1, 8, 15 and 22 of 28-
day treatment cycles with the exception of Cycle 1, where BI 836858 will be 
administered for the first time on Day 8 (or Day 9 at the latest), followed by further 
weekly administrations, e.g. on Days 16 and 23. In case WBC on Day 8 (or Day 9) of 
Cycle 1 is ≥10 x 10³/μL, treatment with BI 836858 will not be initiated at a later time 
point. Instead, the patient will continue treatment within this trial with decitabine 
monotherapy.
∀
In Arm 2 patients will receive decitabine monotherapy.
In both treatment arms the decitabine treatment schedule will follow Table 4.1.3.2: 1 for the 
defined RP2D of BI 836858.
4.1.4
Drug assignment and administration of doses for each patient
BI 836858 and decitabine will be prepared according to the instructions provided in the ISF 
and administered as an intravenous infusion under the supervision of the Investigator or 
designated personnel.
Decitabine will be administered according to Sections 4.1.3.1 and 4.1.3.2 depending on the 
phase and part of the trial in which the patient is being treated. 
BI 836858 will be administered as weekly i.v. infusions in 28-day cycles in combination with 
daily infusion of decitabine 20 mg/m2 as per the defined decitabine treatment schedule (with 
the exception of treatment Arm 2 in Phase II where patients will be treated with decitabine 
monotherapy). BI 836858 will be administered on Days 1, 8, 15 and 22 from Cycle 2 
onwards. In Cycle 1 BI 836858 will be administered on Day 8 and Day 9, Day 16 and Day 23 
if WBC is < 10 x 10³/μL on Day 8. In case WBC is ≥10 x 10³/μL on Day 8 (or Day 9 at the 
latest) of Cycle 1, the patient will not be treated with BI 836858. WBC from blood sample 
collected one day prior to the planned start of treatment with BI 836858 is acceptable in order 
to allow sufficient time for treatment decision, IRT and pharmacy logistics, as well as for 
preparation and delivery of the infusion. In case the platelet count prior to the 1st planned 
infusion with BI 836858 on Day 8 (or Day 9 at the latest) is not ≥ 25,000/μL, the patient must 
be transfused to at least 25,000 platelets/μL.


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Whenever possible, BI 836858 should be administered in weekly intervals, i.e. two 
consecutive infusions should be 7 days apart. Should any unanticipated circumstances arise 
that might require more flexibility in the treatment schedule in order to ensure patient safety 
and allow patients to continue treatment within the trial, the following exceptions are 
acceptable and won’t be classified as protocol violations: The minimum duration between 
two administrations of BI 836858 is 5 days and the maximum duration is 10 days. Should the 
need arise to deviate from the weekly administration schedule, every attempt should be made 
to bring the patient back to the initial schedule in order to align with the 28-day decitabine 
administration cycles. It is not acceptable to have more than 4 administrations of BI 836858 
within any treatment cycle.
After treatment with BI 836858 was administered on Day 1 of any specific cycle, in case any 
one of the further weekly administrations of BI 836858 of that specific cycle cannot be 
administered within the acceptable time period as defined above (due to medical or 
administrative reasons), that week’s dose will be considered as “missed” and the visit 
registered as “visit with no BI 836858 assigned” into the IRT system.
For patients who achieve complete remission (CR) during Cycles 1 through 4, the 
weekly administration of BI 836858 should continue for one additional cycle and will 
then be reduced to monthly administration as maintenance treatment. The treatment 
schedule of decitabine will remain unchanged in that case.
After completion of Cycle 6 and only for patients with CR or CRi, the weekly administration 
of BI 836858 will be reduced to monthly administration as maintenance treatment, starting on 
Day 1 of Cycle 7.
The first (Cycle 1 Day 8 and 9) and second (Cycle 1 Day 16) infusion of BI 836858 will be 
started at a rate of 10 mL/h. The infusion rate should be increased every 30 (+/-10) min by 10 
mL/h to a maximum of 80 mL/h as long as tolerated by the patient. The duration of the 
infusion should not exceed a total of 8 h. 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 the infusion rate should not be escalated from this rate for at least 30 min. 
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, but never longer than a 
maximum total of 8 h.
BI 836858 may be administered at any time during the day, but never prior to the 
administration of decitabine. However, to facilitate blood sampling for PK and 
pharmacodynamic analyses, it is recommended to start the infusion during the morning 
hours.


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Premedication
4.1.4.1
Premedication to prevent infusion-related reactions is obligatory 30 min (up to 120 min 
before start of administration of BI 836858 is permissible) prior to the first administrations of 
BI 836858 (Cycle 1, Day 8 and 9), unless a contraindication for premedication exists, and 
should include all of the following:
∀
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 no IRR is associated with BI 836858 in the first administration (Day 8 and 9), 
glucocorticoid premedication should be reduced to a dose equivalent of 50 mg prednisolone 
for the 2nd (Day 16) administration. In case no IRRs grade 2 or higher are observed with the 
2nd administration of BI 836858, omit the glucocorticoid for subsequent infusions. However, 
in case an administration of BI 836858 is associated with an IRR grade 2 or higher, 
premedication should be re-escalated to 100 mg prednisolone equivalent.
Re-treatment criteria
4.1.4.2
Patients will be treated in repeat cycles in the absence of permanent treatment discontinuation 
criteria according to Section 3.3.4.1.
Before the start of a subsequent cycle, adverse events and safety laboratory will be 
assessed. To continue treatment with further administrations of any of the two trial drugs, 
all of the following criteria must be met (depending on the disease status only criterion 1 
or 2 is applicable):
1)
For patients with circulating blasts or persistent marrow disease (≥ 5% BM 
blasts; evidence of active leukemia): Treatment shall proceed as per the initially 
allocated treatment group regardless of pre-treatment neutrophils. 
a.
Patients with active leukemia with grade 4 thrombocytopenia (platelets 
< 25,000/μL) may continue on trial treatment as allocated provided that there 
is no evidence of bleeding and post-transfusion platelet count is at least 
25,000/μL.
b. Patients with pre-existing (prior to study entry) grade 3 or 4 neutropenia or 
grade 3 or 4 thrombocytopenia will continue with therapy in the absence of 
fever (≥38.5°C) and/or uncontrolled infection as prescribed. However, 
patients allocated to the intensive decitabine treatment schedule (10 
consecutive days) with pre-existing grade 2 (or better) neutropenia or 
thrombocytopenia who have grade 4 neutropenia or thrombocytopenia shall 
be cut to the standard decitabine treatment schedule (5 consecutive days) for 
future cycles (EXCEPT for patients with absolute blasts count > 5000/μL 
who may be eligible to continue with the intensive decitabine treatment (10 
consecutive days) and should be discussed with the TCM and/or the 
Coordinating Investigator). 


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2)
For patients with no evidence of disease in blood or marrow (< 5% BM blasts):
After completion of the first on-trial treatment cycle, the initially allocated treatment 
shall proceed regardless of neutropenia or thrombocytopenia. However, patients must 
be transfused to ≥25,000/μL platelets prior to administration of next treatment 
(including weekly administrations of BI 836858 therapy, if applicable). 
a.
For subsequent cycles, patients with pre-existing grade 4 neutropenia shall 
proceed with treatment in the absence of ongoing fever or uncontrolled 
infection. However, patients with pre-existing grade 2 (or better) neutropenia 
who have grade 4 neutropenia (neutrophils < 500/μL) should have all 
treatment(s) held for 2 weeks and then discussed with the TCM and/or the 
Coordinating Investigator if grade 4 neutropenia persists. Patients without 
evidence of fever or uncontrolled infection may be eligible to continue with 
treatment as allocated. 
b. Patients with grade 4 thrombocytopenia may continue on allocated trial 
treatment provided that post-transfusion platelet count is at least 25,000/μL, 
but patients with pre-existing grade 2 (or better) thrombocytopenia should 
have treatment held for 2 weeks and then discussed with the TCM and/or the 
Coordinating Investigator if grade 4 thrombocytopenia persists. Patients 
without evidence of bleeding may be eligible to continue therapy provided 
the patient can be transfused to ≥25,000/μL.
3)
Acceptable tolerability (in case of a drug related 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). Patients who do 
not meet these criteria for further therapy should be discussed with the TCM and/or the 
Coordinating Investigator and may be eligible to continue if the toxicity is not 
clinically significant.
In case criterion 1 and 3 (or criterion 2 and 3) are not fulfilled, blood counts and/or the 
adverse events should be re-evaluated at least weekly.
Subsequent cycles can be delayed up to 2 weeks to meet the above criteria. Longer delays 
should be discussed with the Coordinating Investigator. Patients with delays longer than 8 
weeks due to a drug-related event (e.g. delay in recovery of blood counts or awaiting 
resolution of toxicity) will be withdrawn from study.
All of the above re-treatment criteria apply when a subsequent cycle is started, i.e. this is 
applicable for combination treatment in both parts of Phase I, for combination treatment in 
Arm 1 of the Phase II part, and also for the start of a new cycle with decitabine 
monotherapy in Arm 2 of Phase II.
Furthermore, the re-treatment criteria absence of fever (≥ 38.5°C) and/or uncontrolled 
infection and platelets ≥25,000/μL apply for the weekly administrations of BI 836858 
after Day 1 of any given cycle, (i.e. Day 16 and Day 23 of Cycle 1 and Day 8, Day 15 and 
Day 22 of any further cycle).


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BI 836858 dose reduction and dose escalation criteria
4.1.4.3
Administration of the trial drugs (i.e. both, decitabine and BI 836858 for patients receiving 
the combination treatment) has to be stopped temporarily in case of a DLT (see Section 
5.3.1). 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. No dose levels for the new dose of BI 836858 have been pre-defined; any new 
dose outside of the currently tested dose level/cohort 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 with BI 836858 has to be permanently 
discontinued. Likewise, treatment with BI 836858 has to be discontinued in case the DLT is 
not reversible. In Phase I such patients will need to be withdrawn from study treatment, 
perform EOT and EoR visits and followed-up as per protocol. Patients in Arm 1 of Phase II 
however may continue on decitabine monotherapy at the discretion of the investigator.
Intra-patient dose escalation
Intra-patient dose escalation may be considered in agreement between the Investigator and 
Sponsor for selected patients. It is restricted to patients who have received at least 4 
administrations of BI 836858 and tolerated the treatment well up to 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 SMC. The dose escalation step is 
limited to the dose which has been administered to the next higher cohort. In addition, after 
the first dose at the higher dose level, patients have to be monitored for at least 24 h after the 
end of the infusion, including safety laboratory 24 h after the first administration of the 
escalated dose of BI 836858.
Patients eligible for a subsequent treatment cycle will not start treatment before 28 days after
the start of the previous cycle. If the criteria above (Section 4.1.4.2) are not met on Day 29, 
the subsequent cycle must be delayed. The period of delay is limited to a maximum of 8 
weeks. Re-treatment should be initiated as soon as the criteria are met, unless other criteria 
for discontinuation or withdrawal apply, according to Sections 3.3.4 and 4.1.4.2. Any delay 
of more than three weeks between the end of the previous and the start of the next treatment 
cycle should be communicated to the clinical monitor of BI prior to re-treatment.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
This is an open-label study (see Section 3.2 for justification). Blinding is not applicable on 
individual patient level. However, to reduce bias, the BI study team will be blinded for the 
aggregated Phase II part data at the treatment level until the trial database lock.
Unblinding and breaking the code
4.1.5.2
Not applicable.


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4.1.6
Packaging, labelling, and re-supply of BI 836858
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
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.
Re-supply of BI 836858 will be managed by IRT.
4.1.7
Storage conditions
Trial drug supplies will be kept in their original packaging and in a secure limited access 
storage area according to the recommended storage conditions on the medication label. 
A temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts in the ISF) must be contacted immediately and the 
corresponding procedures described in the ISF need to be followed.
4.1.8
Drug accountability
The Investigator and/or Pharmacist will receive the trial drug(s) delivered by the Sponsor or a 
CRO appointed by the Sponsor when the following requirements are fulfilled:
∀
Approval of the trial protocol by the IRB / ethics committee, 
∀
Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site,
∀
Approval/notification of the regulatory authority, e.g. competent authority,
∀
Availability of the curriculum vitae of the principal Investigator,
∀
Availability of a signed and dated clinical trial protocol
∀
Availability of the proof of a medical license for the principal Investigator
∀
Availability of Form 1572 or equivalent
The Investigator and/or Pharmacist must maintain records of the product’s delivery to the 
trial site, the inventory at the site, the use by each patient, and the return to the Sponsor or 
alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / Pharmacist will maintain records that document adequately that the patients 
were provided the doses specified by the CTP and reconcile all investigational products 
received from the Sponsor. At the time of return to the Sponsor and/or appointed CRO and/or 


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prior to local destruction of any unused trial medication, the Investigator / Pharmacist must 
verify that all unused or partially used drug supplies have been fully accounted for on 
appropriate drug accountability/ drug inventory logs and that no remaining supplies are in the 
Investigator’s possession.
The only exception to the above will be commercial decitabine that will be sourced locally by 
participating trial sites/pharmacies from local suppliers (if allowed by local regulations). In 
that case drug accountability (including details as described above) will be done on patient 
and site level only, without detailed records of the product’s delivery to the trial site.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
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 will be allowed, but growth 
factors should be avoided during the first four administrations of BI 836858 for better 
assessment of safety and response parameters.
Anti-infective prophylaxis
Based on the known myelosuppressive effect of decitabine, patients should receive 
anti-infective prophylaxis as follows:
∀
Antibiotic prophylaxis: it is mandatory that patients receive prophylaxis with antibiotics 
when absolute neutrophil count (ANC) counts are < 500/μL. This prophylaxis should be 
continued at least until the ANC counts have reached ≥ 500 cells/μL and can be 
prolonged if clinically appropriate. Antibiotics used for infection prophylaxis should be 
selected based on institutional and published guidelines (R15-3877, R15-4167) as well as 
on patient-specific medical considerations.
∀
Antimycotic prophylaxis: surveillance for mycotic infections should be maintained during 
therapy, mainly in patients with persistent and long-lasting neutropenia. Antimycotic 
prophylaxis is recommended and should be implemented at discretion of Investigator 
when deemed medically necessary. 
Prevention and treatment of Tumor Lysis Syndrome (TLS)
Risk for TLS should be assessed as per published guidelines prior to starting treatment with 
BI836858 (R18-1901). All patients should receive adequate hydration prior to start of each 
administration of BI 836858 in Cycle 1. Prophylactic administration of anti-hyperuricaemic 
agents (e.g. allopurinol, rasburicase) should be considered according to individual patient 
risk. Laboratory monitoring for TLS is mandatory as outlined in Table 1 and Section 5.3.6.1. 
In patients developing laboratory or clinical signs of a tumor lysis syndrome (e.g. 
hyperkalemia, hyperphosphatemia, hyperuricemia and hyperuricosuria, hypocalcemia, and 
acute renal failure), accepted treatments standards as per published recommendations must be 
applied (R18-1901, R10-4517).


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All concomitant non-anti-leukemia 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.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
In patients with relapsed or refractory AML, prior anti-leukemia therapy must have been 
discontinued at least two weeks before first treatment with decitabine and the patient must 
have recovered from all clinically relevant reversible toxicities as determined by the 
Investigator. A time interval of at least two weeks (four weeks for biologicals) must have 
elapsed from the last administration of any other investigational treatment for AML to the 
first administration of BI 836858.
For WBC control (e.g. to keep WBC < 10,000/μL), treatment with hydroxyurea will be 
allowed during Cycle 1 only. 
No other concomitant anti-neoplastic therapy is allowed during the treatment phase of this 
trial.
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.
Intrathecal treatment to control symptoms associated with central nervous system
involvement is allowed but must be discussed and agreed upon between Investigator and 
Sponsor. All concomitant therapy will be recorded in the eCRF.
No formal clinical drug-drug interaction studies with BI 836858 have been conducted for 
decitabine. For restrictions regarding concomitant treatment with decitabine, refer to 
manufacturer’s SPC (R15-4802).
Restrictions on diet and life style
4.2.2.2
No restrictions apply with regard to diet or life style. However, patients are required to be 
hospitalized for approximately 48 h after start of the first administration of BI 836858 to
allow close monitoring for infusion-related reactions or other AEs. Subsequent infusions of 
BI 836858 may be administered in the out-patient setting depending on the Investigator’s 
decision.


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TREATMENT COMPLIANCE
4.3
BI 836858 will be administered as a single i.v. infusion under supervision of the Investigator 
or dedicated clinic personnel. Compliance may also be verified by PK assessment. Any 
discrepancies will be explained in the eCRF by the Investigators or their designee.
Decitabine will be administered as an i.v. infusion under the supervision of the Investigator or
designated personnel at the investigative site according to the manufacturer’s product
information (available in the ISF). Administration of decitabine will also be documented in 
the eCRF.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoints
In the Phase I part of this trial, the primary endpoints to assess safety are the MTD of BI 
836858 in combination with decitabine and the number of patients with DLTs during the first 
treatment cycle. For details on determination of MTD, please refer to Section 5.3.2 and 7.1.
In the Phase II part of the trial, the primary objective is to assess the preliminary efficacy of 
BI 836858 in combination with decitabine in comparison to standard therapy with decitabine 
alone. The primary endpoint in Phase II is objective response (CR+CRi) defined as best 
overall response of CR or CRi, analyzed by the number of patients with CR or CRi.
None of the endpoints listed below are assessing known safety issues.
Phase I:
∀
MTD of BI 836858 in combination with decitabine
∀
Number of patients with DLTs during the first treatment cycle (see Section 5.3.2)
∀
Time frame: From start of treatment until end of cycle 1 (end of REP; approximately up 
to 12 months). 
Phase II:
∀
Number of patients with objective response combining
-
Complete remission (CR)
-
CR with incomplete blood count recovery (CRi)
∀
Time frame: From randomization until the earliest of progression, death or end of trial 
(approximately up to 30 months).
5.1.2
Secondary Endpoints
The secondary endpoint of the Phase I part of this trial is objective response (CR/CRi) as 
defined in Section 5.2.1. Secondary endpoints of the Phase II part of this trial are event-free 
survival (EFS), relapse-free survival (RFS), remission duration and time to remission.
None of the endpoints listed below are assessing known safety issues.
Phase I:
∀
Number of patients with objective response combining
-
Complete remission (CR)
-
CR with incomplete blood count recovery (CRi)
∀
Time frame: From start of treatment until the earliest of progression, death or end of trial 
(approximately up to 30 months).


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Phase II:
∀
Event-free survival (EFS)
∀
Relapse-free survival (RFS)
∀
Remission duration
∀
Time to remission
Event-free survival (EFS):
∀
EFS is measured from the date of randomization to the date of progression, relapse, or 
death from any cause, whichever occurs first. 
∀
The date of progression/relapse will be the earliest of the dates of the disease assessment 
(blood sample, bone marrow sample, or clinical assessment) in which the 
progression/relapse was observed. For patients who did not progress, relapse, or die, EFS 
will be censored at the date of last disease assessment. Patients who stopped active 
treatment will be followed up as described in Section 6.2.3.
∀
Time frame: From randomization until the earliest of progression, relapse, death or end of 
trial (approximately up to 30 months).
Relapse-free survival (RFS):
∀
RFS is defined only for patients who achieve a best overall response of CR or CRi and is 
measured from the date of first occurrence of CR or CRi until the date of relapse or death 
from any cause, whichever occurs first. 
∀
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.
Patients not known to have relapsed or died at last follow-up are censored on the date 
they were last examined. Patients who stopped active treatment will be followed up as 
described in Section 6.2.3.
∀
Time frame: From first documented response of CR or CRi until the earliest of relapse, 
death or end of trial (approximately up to 30 months). 
Remission duration:
∀
Remission duration is defined analogously to RFS only for patients with a best overall 
response of CR or CRi, with the exception of censoring patients who die before 
recurrence; i.e. remission duration is measured from the date of first occurrence of CR or 
CRi 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, remission 
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.
∀
Time frame: From first documented response of CR or CRi until the earliest of relapse or 
end of trial (approximately up to 30 months).


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Time to remission:
∀
Time to remission is defined only for patients who achieve a best overall response of CR 
or CRi; it is measured from the date of randomization until the date of first achieving CR
or CRi.
∀
Time frame: From randomization until the first documented response of CR or CRi 
(approximately up to 30 months).


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ASSESSMENT OF EFFICACY
5.2
5.2.1
Overall response assessment
Response to treatment will be evaluated based on bone marrow samples (aspirations and 
biopsies will be collected as described in the Flow Chart) according to the following criteria 
(based on diagnosis and management of AML in adults: recommendations from an 
international expert panel, on behalf of the European Leukemia Net (R10-2947)
∀
Complete remission (CR)
Bone marrow (BM) blasts < 5%; absence of blasts with Auer rods; absence of 
extramedullary disease; absolute neutrophil count > 1.0 x 109/L [1,000/μL]; platelet count 
> 100 x 109/L [100,000/μL]; independence of red blood cells transfusions (no transfusion 
for 1 week prior to the assessment). No minimum duration of response is required.
∀
Complete remission with incomplete neutrophil or platelet recovery (CRi)
All CR criteria except for residual neutropenia (< 1.0 x 109/L [1,000/μL]) or 
thrombocytopenia (< 100 x 109/L [100,000/μL]).
∀
Partial remission (PR)
All haematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; 
and decrease of pre-treatment bone marrow (baseline) blast percentage by at least 50%.
Bone marrow samples with <5% blasts and with presence of Auer rods also represent PR.
∀
Stable disease (SD)
Patient alive with no CR, CRi, PR or PD.
∀
Progressive disease (PD)
Progressive disease is defined as at least one of the criteria below:
o 50% increase in BM blast count over baseline (AML diagnosis);
o 50% increase in peripheral blast count over baseline that is considered clinically
relevant by the Investigator;
o evidence of new extramedullary disease;


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o clinically progressive disease based on the judgement of the Investigator (any attempt
should be made to verify clinically diagnosed PD by a BM assessment).
∀
Relapse (recurrence)
In patients with previous CR or CRi: Bone marrow leukemic blasts ≥5% or 
reappearance of blasts in the blood not attributable to any other cause (e.g. bone marrow 
regeneration), or development of extramedullary disease.
∀
Death in aplasia
Deaths occurring ≥7 days following completion of treatment cycle while cytopenic; with 
an aplastic or hypoplastic bone marrow obtained within 7 days of death, without evidence 
of persistent leukemia. Completion of treatment cycle is defined as reaching of Day 28 of 
the cycle.
∀
Death from indeterminate cause
Deaths occurring before completion of a treatment cycle, or < 7 days following its 
completion; or deaths occurring ≥7 days following completion of treatment course with 
no blasts in the blood, but no bone marrow examination available. Completion of 
treatment cycle is defined as reaching Day 28 of the cycle.
ASSESSMENT OF SAFETY
5.3
After completion of recruitment to Phase I Extension Cohort A and Cohort B, the 
recruitment to this trial is discontinued. 
With the aim to minimize the burden for trial participants, after approval of Protocol
version 7.0, the mandatory protocol procedures described below in sections 5.3.4 
(Physical Examination), 5.3.6 (Safety laboratory parameters), 5.3.7 
(Electrocardiogram), are reduced for all patients who continue to receive trial 
medication in treatment cycles >7. 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 5.3.8 and 5.3.9, unchanged).
5.3.1
Dose limiting toxicity (DLT)
DLT is defined as any non-disease-related non-hematological AE of CTCAE grade 3 or 
higher.
Expected non-hematological disease-related AEs will not be regarded as a DLT. These 
include complications resulting from hematological AEs such as:
∀
Bleeding and complications from bleeding due to thrombocytopenia as defined by the
Investigator
∀
Infection and complications from infections due to neutropenia as defined by the
Investigator
∀
Constitutional symptoms due to anaemia as defined by the Investigator


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Infusion-related reactions (IRR) associated with the administration of BI 836858 should be 
reported as Adverse Event of Special Interest (AESI, refer to Section 5.3.8.1), but will not be
regarded as a DLT. The exception is anaphylaxis which occurs despite premedication with
glucocorticoid or which does not resolve with glucocorticoid (i.e. such cases of anaphylaxis
will be regarded as a DLT).
Patients who do not receive at least 3 administrations of BI 836858 due to BI 836858-related 
toxicity are considered to have developed a DLT. If Cycle 2 is not started until 57th day from 
Day 1 of Cycle 1 as a result of drug-related AE, this AE is considered as DLT (i.e. treatment 
delay of ≥4 weeks of the start of Cycle 2 due to drug-related AE). Patients who do not 
experience a DLT but do not receive all 3 planned administrations of BI 836858 during 
Cycle 1 for reasons other than toxicity or tolerability will not be evaluable for DLT and 
cannot be used to establish the MTD. 
Infection will not constitute a DLT unless it is felt that the infection resulted from 
unexpectedly complicated myelosuppression; degree of severity and/or duration as assessed 
by the Investigator. 
Since patients with refractory leukemia have infections and bleeding complications from 
myelosuppression, these events will not be considered as DLT unless they occur in the setting 
of prolonged myelosuppression from the combination treatment. Prolonged 
myelosuppression is defined as ANC < 1000/μL and PLT < 100,000/μL by day 56 of Cycle 1 
in the setting of bone marrow showing < 5% blasts, without evidence of persistent 
cytogenetic abnormalities or minimal residual disease by flow cytometry. In case persistent 
cytogenetic abnormalities or immunophenotypic evidence of leukemia is present, 
myelosuppression would be considered secondary to leukemia even if morphology shows 
< 5% blasts.
All DLTs, occurring during the first or repeated treatment cycle will be reported as Adverse 
Event of Special Interest (AESI, see Sections 5.3.8.1 for definitions and 5.3.9 for reporting 
requirements).
5.3.2
Maximum Tolerated Dose (MTD)
The MTD estimate after the dose escalation part of the trial will be obtained on the basis of 
DLTs observed during the first treatment cycle. However, for those patients who receive 
more than one cycle of the combination treatment, all AEs that constitute a DLT will be 
considered for re-estimation of the MTD based on the BLRM. To obtain this, the model will 
be re-run including the DLT information from all cycles. Based on both MTD estimates, the 
recommended dose for the extension cohort, the Phase II part and/or further development will 
be selected. In regular intervals, all available safety data including adverse events qualifying 
for DLT will be submitted to the SMC. The SMC will assess this information and provide 
recommendations for trial conduct and dose escalation.
The SMC may recommend stopping the dose finding part of the trial after the criterion for 
MTD is fulfilled (refer to Section 7.1). 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 SMC may 


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decide to include additional number of patients at this dose level and to declare this dose as 
the RExP1D (Recommended Extension Phase I Dose), that will be used for the Phase I 
Extension part of the trial.
5.3.3
Recommended Phase II Dose (RP2D)
Before the conclusion of Phase I and prior to initiating the Phase II, up to 30 patients will 
receive the combination treatment of BI 836858 at MTD (or RExP1D if applicable) and 
decitabine in one of the two extension cohorts.
If deemed necessary by the Sponsor and the SMC, there will be an option to open further 
Dose Escalation cohort(s) following the extension cohorts to determine the RP2D, based on 
additional biomarker, PK/PD and safety data.
Based on the overall Phase I data, the SMC will make a final determination of the RP2D,
which must not exceed the MTD. The Phase I safety analysis report or lean interim CTR, 
including the rationale of RP2D determination will be sent to competent authorities/ethic 
committees and made available to all participating Investigators prior to the initiation of
Phase II.
5.3.4
Physical examination
A physical examination including height (only measured once at screening visit), 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 and/or baseline conditions (at screening). The physical examination should preferably be 
performed by the same member of the trial team at the sites.
5.3.5
Vital Signs
Vital signs (blood pressure and heart rate) will be recorded at screening, during the treatment 
phase (including the EOT visit and EoR visit) and follow-up as specified in the FlowChart. 
Additional time points for blood pressure and heart rate at the day of the first administration 
of BI 836858 are: prior to the start of premedication, prior to the start of BI 836858 infusion, 
and in 30 (±10) min intervals throughout the course of the infusion of BI 836858 and 60 
(±10) min after the end of the infusion, thereafter every 4-8 h until at least 24 h 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 the 2nd infusion of BI 836858, blood pressure and heart rate will be assessed 
at the same time points as during the 1st infusion and until 60 (±10) min after end of infusion.
After implementation of Protocol version 7.0 the vital sign results will be documented in 
the eCRF only if qualifying for an adverse event (see sections 5.3.8 and 5.3.9, 
unchanged).


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5.3.6
Safety laboratory parameters
General safety laboratory parameters
5.3.6.1
Blood samples and urine have to be collected at the time points specified in the Flow Chart. 
All safety laboratory examinations will be performed at the Investigator’s local laboratory 
and include hematology, biochemistry, coagulation and qualitative urine analysis:
Hematology
Hemoglobin, white blood cell count (WBC) with differential
count, platelets
Reticulocytes have to be measured only at Visit 1 of every
second cycle, EOT and EoR visit
Biochemistry
Glucose, sodium, potassium, calcium, inorganic phosphate, 
creatinine, aspartate amino transferase (AST), alanine amino 
transferase (ALT), alkaline phosphatase (AP), lactate 
dehydrogenase, total bilirubin, urea (preferred) or BUN, total 
protein, albumin, uric acid, C-reactive protein (CRP).
Serum immunoglobulin levels (IgG, IgM, IgA) and direct 
antiglobulin test have to be measured only every other cycle
(starting on Day 1 of Cycle 1) and at the EOT visit.
Coagulation
Activated partial thromboplastin time, prothrombin time, 
international normalized ratio where indicated (e.g. treatment 
with vitamin K antagonists)
Urine
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be 
analyzed by dipstick and reported as semiquantitative 
measurements at screening, completion of Cycle 4 and at EOT 
visit . 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.
Monitoring for laboratory evidence of tumor lysis syndrome
Tumor lysis syndrome (TLS) is characterized by a group of metabolic derangements caused 
by the massive and abrupt release of cellular components into the blood after rapid lysis of 
malignant cells, potentially leading to hyperuricemia, hyperkalemia, hyperphosphatemia, 
hypocalcemia, and uremia (R10-4517). To allow for early treatment in case TLS develops, 
vigilant monitoring is mandatory. 
Parameters for TLS screening are included in the routine safety labs. Additional blood 
samples for TLS monitoring have to be obtained at the time points in Cycle 1 indicated in 
Table 1, further samples may be obtained as clinically indicated. Sampling for TLS in course 




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Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:
∀
results in death,
∀
is life-threatening,
∀
requires inpatient hospitalisation or 
∀
prolongation of existing hospitalisation,
∀
results in persistent or significant disability or incapacity, or
∀
is a congenital anomaly/birth defect,
or
∀
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Every new occurrence of cancer of new histology must be reported as a serious event (for 
the reporting periods please refer to Section 5.3.9). 
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.


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The latest list of “Always Serious AEs” can be found in the RDC portal. A copy of the latest 
list of “Always Serious AEs” will be provided to the Investigators/sites upon request. These 
events should always be reported as SAEs as described in Section 5.3.9.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.9.
The following are considered as protocol-specified AESIs:
∀
Infusion-related reactions (CTCAE grade 3 or higher)
∀
Tumor Lysis Syndrome (any CTCAE grade)
∀
Any event that qualifies for DLT
∀
Drug Induced Liver Injury (DILI) 
A hepatic injury (DILI) is defined by the following alterations of hepatic laboratory 
parameters: 
o 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
o marked peak aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These laboratory findings constitute a hepatic injury alert and the patients showing these 
laboratory abnormalities need to be followed up according to the “DILI checklist” 
provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without laboratory
results (ALT, AST, total bilirubin) available, the Investigator should make sure these 
parameters are analyzed, if necessary in an unscheduled blood test. Should the results 
meet the criteria of hepatic injury alert, the procedures described in the DILI checklist 
should be followed.
Severity of AEs
The severity of adverse events should be classified and recorded in the eCRF according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (R09-2850).
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 


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confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Indicators of a reasonable causal relationship are:
∀
The event is consistent with the known pharmacology of the drug 
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-existing 
or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
∀
Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.3.9
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate eCRF by the 
Investigator:
∀
From signing the informed consent onwards until the end of treatment (including the 
Residual Effect Period (REP)): 
All AEs (non-serious and serious) and all AESIs.
∀
After the end of treatment (including the REP) until the individual patient’s end of trial 
(i.e. during extended Follow-up; for details refer to Section 6.2.3):
All related SAEs and all related AESIs.


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∀
After the individual patient’s end of the trial: 
The Investigator does not need to actively monitor the patient for AEs but 
should only report relevant SAEs and relevant AESIs of which the Investigator 
may become aware of. 
The rules for Adverse Event Reporting exemptions (see below in paragraph 
“Exemptions to (S)AE Reporting”) still apply, but only for Phase II part.
The Residual Effect Period (REP) is defined as 30 days after the last trial medication 
application (BI 836858 or decitabine, whichever is last). All AEs which occurred through the 
treatment phase and throughout the REP will be considered as “on treatment”, refer to
Section 7.3.4. Events which occurred after the REP will be considered as “post treatment”
events.
AE reporting to Sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI on the BI SAE form via fax immediately (within 24 h) to the 
Sponsor’s unique entry point (country-specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, e.g. onset, end date, severity, treatment required, outcome, 
seriousness, and action taken with the investigational drug(s). The Investigator should 
determine the causal relationship to the trial medication.


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The following should also be recorded as an (S)AE in the eCRF and SAE form (if 
applicable):
∀
Worsening of the underlying disease or of other pre-existing conditions (for exemptions 
see below in paragraph “Exemptions to (S)AE Reporting”)
∀
Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into 
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 h) a potential drug exposure during pregnancy (DEDP) in a female patient or in a 
partner to a male patient to the sponsor’s unique entry point (country-specific contact details 
will be provided in the ISF). The Pregnancy Monitoring Form for Clinical Trials (Part A) 
should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
Exemptions to (S)AE Reporting
Disease Progression has to be reported as SAE in the Phase I part. However, disease 
progression is an endpoint for analysis of efficacy in the Phase II part of the trial and as such
is exempted from reporting as an (S)AE. Progression of the patient's underlying malignancy
will be recorded on the appropriate pages of the eCRF as part of efficacy data collection only 
and will not be reported on the SAE Form. It will therefore not be entered in the safety
database (Adverse Reactions Information System global, ARISg) and hence not get 
expeditiously reported. Death due to disease progression is also to be recorded on the 
appropriate eCRF page and not on the SAE Form.


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Examples of exempted events of PD may be:
∀
Progression of underlying malignancy (Progressive disease [PD]): if PD is clearly 
consistent with the suspected progression of AML as defined by the respective response 
criteria.
∀
Hospitalization/Procedures due solely to the progression of underlying malignancy (PD)
∀
Clinical symptoms and/or signs of progression (without confirmation by objective criteria 
e.g. imaging, clinical measurement): If the symptom can exclusively be determined to be 
due to the progression of the underlying malignancy and does meet the expected pattern 
of progression for the disease under study.
However, when there is evidence suggesting a causal relationship between the trial drug(s)
and the progression of the underlying malignancy, the event must be reported as an (S)AE 
on the SAE Form and on the eCRF.
Exempted events are monitored at appropriate intervals by the applicable independent 
committees (i.e. SMC or DMC).
Reporting of related Adverse Events associated with any other BI drug
The Investigator is encouraged to report all adverse events related to any marketed BI product 
according to the local regulatory requirements for spontaneous AE reporting at the 
Investigator’s discretion by using the locally established routes and AE report forms. The 
term AE includes drug exposure during pregnancy, and, regardless of whether an AE 
occurred or not, any abuse, off-label use, misuse, medication error, occupational exposure,
lack of effect, and unexpected benefit.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
Patients must satisfy all inclusion and exclusion criteria prior to treatment administration (see
Section 3.3). Details of any patient who is screened for the trial but is found ineligible must
be entered in an enrolment log (see ISF) and documented in the eCRF.
All patients are to adhere to the visit schedule and the allowed visit windows as specified in 
the Flow Chart.
Patients are required to be hospitalized under close surveillance with access to intensive care 
for at least 24 h after start of 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 AML-related symptoms, and as a result, the patient
may receive subsequent infusions in the out-patient setting.
In case a patient misses a visit and the patient reports to the Investigator between the missed 
and the next scheduled visit, the delayed visit should be done and the actual date and the 
reason should be given for the delayed visit. Subsequent visits should follow the original visit
schedule.
Additional unscheduled clinic visit(s) might be arranged at the discretion of the Investigator.
For unscheduled visit, it is sufficient to record only the visit date, clinically relevant 
laboratory data and safety findings on the applicable eCRF.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
The investigations as outlined in the Flow Chart will be performed at the respective visits as 
described in detail in the following sections.
6.2.1
Screening and run-in period
The screening period begins when the informed consent form is signed and ends just prior to 
the start of trial treatment on Day 1 of Cycle 1. The maximum duration of the screening 
period is 14 days and includes the randomization/treatment allocation. 
Randomization/treatment allocation should be done as close as possible to the planned start 
of trial medication.
The following parameters and investigations will be obtained and/or performed:
∀
Informed consent (including mandatory biomarker assessments and mandatory 
pharmacogenetic testing)
∀
Informed consent for optional DNA-biobanking
∀
Demographics (sex, year of birth, race and ethnicity, smoking and alcohol status) 


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∀
Medical history (oncological and relevant non-oncological) including detailed history of 
AML, previous malignant disease and previous therapies of malignant disease/other 
therapies
∀
WHO classification of the disease, date of first cytological diagnosis (month and year) 
and cytogenetics of AML
∀
Baseline conditions
∀
Review of inclusion and exclusion criteria (patient eligibility)
∀
Safety laboratory (hematology, biochemistry, coagulation, urine; for details please refer 
to Section 5.3.6)
∀
Physical examination, height, weight, vital signs and ECOG performance score
∀
Serum pregnancy test in women of childbearing potential
∀
12-lead ECG
∀
Bone marrow aspiration for disease assessment and biomarker. In case of punctia sicca
disease assessment should be done via bone marrow biopsy.
∀
Molecular genetics and cytogenetics of AML (please refer to Sections 5.5.1.1 and 5.5.1.2; 
available data from local analysis should be entered in eCRF; analysis at central 
laboratory will only be performed for patients in Phase II) 
∀
Peripheral blood for disease assessment and biomarkers as per Table 3
∀
Documentation of adverse events (AEs) since signing the Informed Consent Form. 
∀
Documentation of concomitant medications (including transfusions and anti-infectives) at 
trial entry and / or during screening
∀
Documentation of planned hospitalisations (only in source documents, not recorded in 
eCRF)
∀
Phase I Dose Escalation and Extension: Dose assignment via IRT (before the first 
administration of the trial drug and after informed consent and review of in- and 
exclusion criteria)
∀
Phase II: Randomization via IRT
Re-Screening
Sites will be allowed to re-screen patients after 1 week from when they initially screen failed. 
Re-screened patients will keep their initial patient number. Any re-screening does require 
renewed signature of informed consent. 
6.2.2
Treatment period
The first trial drug administration should occur as soon as possible after the randomization /
treatment allocation. A treatment cycle is defined as 28 days. If initiation of a subsequent 
cycle is delayed due to medical reasons, visits beyond Day 28 may be necessary. Additional 
unscheduled visits may be performed at the Investigator’s discretion if medically indicated, 
but at least weekly; these unscheduled visits should also be reported in the eCRF.
An End of Cycle (EOC) visit will be performed at the end of each treatment cycle, i.e. on 
Day 29 (±3 days). A subsequent treatment cycle should not start earlier than on the 29th day
of the precedent cycle (if e.g. the previous cycle started on a Tuesday the next cycle will start 
earliest on a Tuesday 4 weeks later). 






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∀
Date and type of contact
∀
Vital Signs
∀
Safety laboratory parameters only if not within normal range at EOT 
∀
12-lead ECG only if abnormal at EOT and pathological findings were not present at 
baseline
∀
Follow-up of adverse events in case they were not yet recovered at EoT visit
∀
Documentation of concomitant medications only if indicated for treatment of adverse 
events
∀
In case the patient receives further anti-cancer treatment: regimen, drug name and start 
and stop dates
With the aim to minimize the burden for trial participants, after approval of Protocol
version 7.0, the mandatory protocol procedures at EoR visit are reduced for all patients 
who continue to receive trial medication in treatment cycles >7. Instead, 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.
6.2.3
Follow-up Period and Trial Completion
Extended follow-up period
6.2.3.1
6.2.3.1.1
Follow-up of Phase I Patients
Patients in the Phase I part will be followed-up for approximately 6 months after the EOT 
visit, irrespective whether a patient progressed on treatment or not. The first follow-up visit 
will be performed approximately 3 months and the second follow-up visit approximately 6 
months after the EOT visit. Completion of the second follow-up visit will define the 
individual patient’s end of trial participation (also refer to Section 6.2.3.2).
The following information will be collected during the follow-up visits and documented in 
the eCRF:
∀
Date and type of contact
∀
Vital Status: Collect information on progression or relapse, death, lost to follow-up
∀
Follow-up of adverse events in case they were not yet recovered at EoR visit
∀
In case the patient receives further anti-cancer treatment: regimen, drug name and start 
and stop dates
After approval of Protocol version 7.0, no further follow-up visits will be carried out. 
The last visits of an individual patient after withdrawal from trial treatment will be the 
EoR visit.
6.2.3.1.2
Follow-up of Phase II Patients
Patients in the Phase II part will be followed-up for overall survival at 3 monthly intervals 
until death, lost to follow-up or completion of the whole trial (as specified in Section 6.2.3.3) 


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whatever occurs earlier. For all patients, irrespective whether a patient progressed on 
treatment or not, the follow-up period for overall survival starts 3 months after the EOT visit.
These visits may also be performed by e.g. telephone interview or via written correspondence 
in case the patient is unable to visit the Investigator.
The following information will be collected during the follow-up for survival period and 
documented in the eCRF:
∀
Date and type of contact
∀
Vital Status : Collect information on progression or relapse, death, lost to follow-up
∀
Follow-up of adverse events in case they were not yet recovered at EoR visit
∀
In case the patient receives further anti-cancer treatment: regimen, drug name and start 
and stop dates
Trial completion for an individual patient
6.2.3.2
A patient is considered to have completed the trial in case any of the following applies:
∀
Completion of planned follow-up period including extended follow up (for patients in the
Phase I part approximately 6 months after EOT; patients in the Phase II part will be 
followed-up for vital status until death)
∀
Lost to follow-up
∀
Refusal to be followed-up
∀
Death
∀
Decision of the Sponsor to end the trial (refer to Section 6.2.3.3)
End of the whole trial
6.2.3.3
The end of the trial will be defined as when both of the following have occurred:
1)
All entered and treated patients have discontinued trial 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. 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
STATISTICAL DESIGN - MODEL
7.1
7.1.1
Phase I Dose Escalation
The primary objective of the Phase I Dose Escalation part is to determine the MTD of 
BI 836858 in combination with an intensive 10 day treatment schedule of decitabine. To 
determine the MTD, patients are entered sequentially into escalating dose cohorts. The dose-
finding will be guided by a Bayesian 5-parameter logistic regression model with overdose 
control [R13-4806], [R13-4803], [R15-4233].
In the following, DLT denotes a dose-limiting toxicity occurring during the first treatment 
cycle.
The 5-parameter logistic regression model is defined as follows. Let π1,d1 be the probability of 
having a DLT when giving dose d1 of BI 836858, and π2,d2 the probability of having a DLT 
when giving dose d2 of decitabine, respectively. A logistic regression is used to model the 
dose-toxicity relationship for each of these drugs individually:
BI 836858:
logit(π1,d1) =log(α1) + β1log(d1/d1*)
Decitabine:
logit(π2,d2) =log(α2) + β2log(d2/d2*)
Here, the doses d1* = 160 mg and d2* = 20 mg/m² represent the reference doses for BI 
836858 and decitabine, respectively. 
Under independence, the probability of a DLT when giving the combination dose d1, d2 is 
obtained as 
π0
12,d1,d2 = π1,d1 + π2,d2 - π1,d1π2,d2
with corresponding odds 
odds(π0
12,d1,d2)= π0
12,d1,d2 /(1- π0
12,d1,d2).
In order to account for a potential positive (higher toxicity than expected under 
independence) or negative (lower toxicity than expected under independence) interaction 
between BI 836858 and decitabine, a dose-dependent interaction term -∞<η<∞ is introduced 
in the model:
odds(π12,d1,d2) = odds(π0
12,d1,d2) exp(η d1/d1* d2/d2*)
and π12,d1,d2 is used in the likelihood
rd1,d2 ~ Binomial(nd1,d2,π12,d1,d2)
where rd1,d2 denotes the number of DLTs observed in nd1,d2 patients at dose combination 
d1, d2.
Since a Bayesian approach is applied, prior distributions f for each of the parameter vectors 
θ1=(log(α1),log(β1)), θ2=(log(α2),log(β2)) and for the interaction term η need to be specified. 


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


	 ,	 ,


	
,


Mixture prior distributions have the advantage that they allow for specification of different
logistic dose-toxicity curves, therefore making the prior more robust. 
A weakly-informative normal prior distribution will be used for η.
The estimated probability of DLT at each dose level from the model will be summarized 
using the following intervals: 
Under dosing: [0.00, 0.16)
Targeted dosing: [0.16, 0.33)
Over dosing: [0.33, 1.00]
The BLRM-recommended dose for the next cohort is the level at which the probability for 
the target dosing interval is maximal out of the dose candidates satisfying the overdose 
control criterion: P(over dosing) < 25%.
However, the maximum allowable dose increment for the subsequent cohort will be no more 
than 100% of previous dose levels.
The MTD may be considered reached if the following criteria are fulfilled:
1. The posterior probability of the true DLT rate in the target interval [0.16, 0.33) of the 
MTD is above 0.50, OR
2. At least 15 patients have been treated in the study, of which at least 6 were treated at the 
MTD.
The SMC 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 SMC may decide to include additional 
patients at this dose level and to declare this dose as the RExP1D.
Prior derivation
To determine the prior distributions for (log(α1), log(β1)) and (log(α2), log(β2)), a meta-
analytic predictive (MAP) approach will be used. For BI 836858 toxicity information from 
the ongoing 1315.1 Phase I study will be used. For decitabine toxicity information from three 


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published studies will be incorporated. The historical data used for BI 836858 and decitabine 
can be found in Table 7.1.1: 1 and Table 7.1.1: 2 respectively.
Table 7.1.1: 1
Historical data for BI 836858
Study
Dose [mg]
N of patients with DLT
during Cycle 1 / N of 
patients
1315.1(1)
10
0/3
20
0/3
(1)
Using data after the clinical hold. Trial 1315.1 is still ongoing.
Table 7.1.1: 2
Historical data for decitabine
Study
Dose 
N of patients with DLT
during Cycle 1 / N of 
patients
Issa et al 2004 [R11-1101](1)
n.a. (1)
7/50
Blum et al 2007 [R15-4796](2)
n.a. (2)
3/25
Blum et al 2010 [R12-3308](3)
20 mg/m2 (10 day schedule)
7/53
(1)
Phase I study of low-dose prolonged exposure schedules of decitabine in hematopoietic malignancies: No DLTs were 
reported for this study. The number of DLTs was therefore approximated by the number of non-haematological AEs of 
CTCAE grade 3 and 4 that would also constitute a DLT in the present trial; data from all investigated decitabine doses 
and dosing schedules was used: 5x10, 10x10, 15x10, 20x10, 15x15, 15x20, 15x10 [mg/m² x days]
(2)
Phase I study of decitabine alone or in combination with valproic acid in AML: No DLTs were reported for this study. 
The number of DLTs was therefore approximated using the number of non-haematological AEs (possibly attributable to 
decitabine or valproic acid) of CTCAE grade ≥3 overall cycles that would also constitute a DLT in the present trial. 
Furthermore, the reported average number of treatment cycles was used to approximate the number of DLTs during the 
first treatment cycle. Data from all investigated decitabine doses was used: 15 mg/m² x 10 days; 20 mg/m² x 10 days
(3)
No DLTs were reported for this study. The number of DLTs was therefore approximated using the number of non-
haematological AEs of CTCAE grade ≥3 experienced during the first two cycles of treatment that would also constitute 
a DLT in the present trial.


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The following steps were used to derive the prior distributions for all parameters:
1. log(α1), log(β1): 
a.
The meta-analytic-predictive prior was derived using the information in 
Table 7.1.1: 1, allowing for moderate between-trial heterogeneity. This 
mixture component was assigned 90% mixture weight.
b. A second, weakly-informative component was added with 10% mixture 
weight.
2. log(α2), log(β2): 
a.
The meta-analytic-predictive prior was derived using the information in 
Table 7.1.1: 2, allowing for substantial between-trial heterogeneity. This 
mixture component was assigned 90% mixture weight.
b. A second, weakly-informative component was added with 10% mixture 
weight.
3. η: based on the a priori assumption of no interaction between the two compounds (but 
with considerable uncertainty for interaction), a normal distribution with mean 0 and 
standard deviation 0.993 was chosen. 
A standard deviation of 0.993 allows for a 7-fold increase/decrease in the odds(%12, d1*, 
d2*) of a DLT at the dose combination d1*, d2*compared to the odds(%0
12, d1*, d2*) of a 
DLT at (d1*, d2*) with no interaction between the two compounds. For example, if the 
true DLT rate under no interaction, i.e. %0
12, d1*, d2, was 0.2 (odds = 1/4), the upper 
97.5% quantile for the DLT rate (allowing for interaction) would be 0.63636 
(odds=7/4). This corresponds to considerable uncertainty for interaction.
The prior distributions are given in Table 7.1.1: 3. The corresponding prior probabilities of a 
DLT at different doses and the corresponding probability of under-dosing, targeted dosing 
and overdosing are shown in Table 7.1.1: 4. As can be seen from Table 7.1.1: 4, the 
combination of 20 mg BI 836858 with 20 mg/m² decitabine has a prior probability of 
overdosing < 25%. It fulfils the overdose criterion and is therefore a suitable starting dose 
combination. 


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Table 7.1.1: 3
Summary of prior distributions 
Prior
Component
Mixture 
Weight
Mean 
SD 
Correlation
BI 836858
MAP
0.9
(-1.395, 0.337) 
(1.826, 0.959)
0.306
Weakly inf.
0.1
(-1.395, 0.337) 
(2.000, 1.000)
0.000
Decitabine
MAP
0.9
(-1.883, -0.0004) 
(0.633, 1.042) 
-0.003 
Weakly inf.
0.1
(-1.883, -0.0004) 
(2.000, 1.000)
0.000
η
n.a.
n.a.
0
0.993
n.a.
Table 7.1.1: 4
Prior probabilities of DLT at selected doses
Dose 
BI 
836858
[mg]
Dose 
decitabi
ne
[mg/m²]
Probability of true 
DLT rate in
Quantiles
[0, 
0.16)
[0.16, 
0.33)
[0.3
3, 1]
Mean
SD
2.5%
50%
97.5%
20*
20
0.483 
0.384
0.133 0.202
0.146
0.040
0.164
0.640
40*
20
0.420
0.394
0.186 0.228
0.165
0.042
0.183
0.714
80
20
0.335 
0.353
0.312 0.283
0.202
0.043
0.226
0.820
160
20
0.230
0.232
0.537 0.413
0.277
0.034
0.364
0.954
320
20
0.209 
0.126
0.665 0.564
0.355
0.011
0.618
>.999
* Doses with asterisk meet the overdose criterion (P(over-dosing) < 0.25)).
The prior distribution may be updated once the trial has started if new relevant data become 
available. The prior distribution that is used in the BLRM for the purpose of the SMC’s 
determination of the next dose level will be documented in the SMC meeting minutes. 
Details on the prior distribution for the final analysis will be given in the trial statistical 
analysis plan (TSAP).


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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 
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 10.2.
7.1.2
Phase I Extension
In the Phase I Extension part of the trial, a minimum of two times 15 patients will receive 
treatment with BI 836858 at MTD (or RExP1D if applicable) in combination with either 
decitabine intensive treatment schedule or decitabine standard treatment schedule.
Based on the overall Phase I data, the SMC will make a final determination of the RP2D. The 
BLRM will be re-run to confirm that the RP2D satisfies the overdose control criterion.
After completion of recruitment to Phase I Extension Cohort A and Cohort B, the 
recruitment to this trial is discontinued.
7.1.3
Phase II efficacy comparison
In the phase II part the efficacy of the two arms (BI 836858 in combination with decitabine vs
decitabine monotherapy) will be compared in an exploratory manner.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The analyses in this trial are descriptive and exploratory. No formal statistical tests will be 
performed.
PLANNED ANALYSES
7.3
During the Phase I Dose Escalation part, cohorts of patients treated with BI 836858 in 
combination with decitabine will be evaluated continuously based on the totality of the safety 
data available in order to determine the MTD (or RExP1D if applicable).
After determination of the RP2D in the Phase I Extension part and optional additional Dose 
Escalation cohort(s), a safety analysis report or lean interim CTR will be written to justify the 
RP2D prior to the initiation of Phase II. 
The primary analysis of all primary, secondary and further efficacy endpoints will be 
conducted at the end of the whole trial (Section 6.2.3.3).


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Efficacy analysis in Phase II will be based on the randomised set. This patient set includes all 
randomised patients, regardless of whether or not they have received treatment. For Phase I, 
efficacy endpoints will be summarized descriptively based on the treated set. No comparison 
will be done between cohorts.
The treated set includes all patients who have received at least one dose of study medication 
(BI 836858 and/or decitabine).
Safety analysis will be based on the treated set and will be summarized separately for patients 
treated in the Phase I and Phase II part of the trial. 
7.3.1
Primary endpoint analyses
Phase I: 
In order to estimate the MTD, the occurrence of a DLT in the first treatment cycle will be 
assessed on an individual patient level. However, for those patients who receive more than 
one cycle of the combination treatment, all AEs that constitute a DLT will be considered for 
re-estimation of the MTD based on the BLRM. To obtain this, the model will be re-run 
including the DLT information from all cycles. Based on both MTD estimates, the 
recommended dose for the extension cohort (and the Phase II part) will be determined. The 
MTD will be determined using the BLRM as described in Section 7.1.1. The number of 
DLTs at each dose level will be presented (all cycles and first cycle separately).
Phase II:
Objective response (CR+CRi) will be analyzed descriptively in terms of objective response 
rate (ORR), defined as the proportion of patients with complete response (CR) or complete 
response with incomplete blood count recovery (CRi).
7.3.2
Secondary endpoint analyses
Phase I: The secondary endpoint Objective response (CR+CRi) will be listed only. If 
considered useful, aggregated tables will be provided where different doses might be 
grouped.
Phase II: Event-free survival (EFS), relapse-free survival (RFS), remission duration and time 
to remission will be analyzed descriptively using Kaplan-Meier curves and Cox proportional 
hazard models. Details of censoring rules will be provided in the trial statistical analysis plan 
(TSAP).


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 30 days after the last dose of trial medication, will be assigned to the 
treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The residual effect 
period is defined as period of 30 days after the last dose of trial medication. Adverse events 
that start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
Adverse events will be graded according to CTCAE Version 4.03 and reported according to 
BI standards.
Serious adverse events, drug-related adverse events and adverse events of special interest will 
be tabulated. In addition, events leading to dose reduction or treatment discontinuation will 
be examined.
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).
Descriptive statistics will be used to describe changes in laboratory tests over time. In 
addition, all abnormalities of potential clinical significance will be reported. In general, 
potential clinical significance is defined as at least CTCAE grade 2 and an increase from 
baseline value by at least one CTCAE grade.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with
regard to possible changes compared to findings before start of treatment.


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INTERIM ANALYSES
7.4
In Phase I, interim safety evaluations will be performed as considered necessary. In particular 
safety evaluations will be performed after each dose cohort by the SMC consisting of the 
Investigators and representatives of the Sponsor (refer to Section 3.1.1). Based on this, the 
SMC will recommend the next dose level as well as the corresponding cohort size. SMC
meeting minutes and outputs provided for these SMC meetings will be documented and 
archived in the clinical trial master file (TMF). In addition, after determination of the RP2D 
in the Phase I Extension part of this trial and optional additional Dose Escalation cohort(s), a 
safety analysis report or lean interim CTR will be written to justify the RP2D.
During the Phase II part of the trial regular monitoring by the internal DMC will be 
performed to ensure a positive benefit-risk assessment. See Section 3.1.1.


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The BI study team will be blinded for the aggregated phase II part data at the treatment level 
until the trial database lock. See Section 4.1.5.1.
HANDLING OF MISSING DATA
7.5
No imputation will be performed on missing efficacy data.
Missing baseline laboratory values will be imputed by the respective values from the 
screening visit. No other imputations will be performed on missing data although every effort 
will be made to obtain complete information on all adverse events and to follow-up the 
patients for efficacy data.
For partial or missing AE onset and/or end dates, BI internal rules will be applied for 
imputation.


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RANDOMIZATION
7.6
Randomization will be performed in the Phase II part of this trial only. In the Phase I Dose 
Escalation part of the trial, doses will be assigned based on the decision made by the SMC.
In the Phase I Extension part, first approximately 15 patients will be allocated into to the 
Cohort A with treatment of BI 836858 in combination with decitabine intensive treatment
and then subsequently a further set of approximately 15 patients into Cohort B with treatment 
of BI 836858 in combination with decitabine standard treatment. 
In Phase II, patients will be randomized in a 1:1 ratio to treatment of either BI 836858 in 
combination with decitabine or decitabine monotherapy. As the type of AML is an important 
prognostic factor [R07-2768], randomization will be stratified by type of leukemia (de novo 
vs secondary AML). Within each stratum, a central randomization will be performed across 
all study centres. The method of permuted blocks will be used for the randomization. 
An Interactive Response Technology (IRT) will be used to perform the randomization 
centrally. BI will arrange for the randomization. A randomization list will be generated using 
a validated pseudo-random number generator, yielding reproducible and non-predictable 
results. Access to the randomization codes will be controlled and documented.
DETERMINATION OF SAMPLE SIZE
7.7
Phase I:
A maximum of 50 patients are expected for the Phase I part of this trial (including Phase I 
Dose Escalation and Phase I Extension). Fewer patients might be needed based on the 
recommendation of the SMC and the criteria specified (see Section 7.1). 
Phase II:
For the sample size estimation in Phase II we assume an objective response rate in the 
BI 836858 + decitabine arm of 70% compared to an objective response rate in the decitabine 
monotherapy arm of 40%. Based on these assumptions and a sample size of 2x50=100 
patients overall the probability of observing an unadjusted difference in objective response 
rates of more than 20% is approximately 83%.
On the other hand, if the true objective response rates are assumed to be 40% both in the 
BI 836858 + decitabine arm and the decitabine monotherapy arm, the probability for 
observing a difference in objective response rate between the two arms of more than 20% is 
smaller than 2%. 
Different scenarios and resulting probabilities for observing a difference in objective 
response rates of more than 20% are given in Table 7.7: 1.
In summary, a sample size of 2x50=100 patients is considered to be sufficient to clearly 
differentiate between the two treatment arms in case that a pronounced treatment benefit of 
BI 836858 + decitabine exists. On the other hand, if there is no or only a small benefit for 
BI 836858 + decitabine compared to decitabine monotherapy, the sample size is large enough 


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such that the probability for falsely observing a beneficial outcome for the combination arm 
is sufficiently small. 
Table 7.7: 1
Evaluation of the probabilities of observing a treatment difference 
objective response rate depending on assumed response rate and 
sample size.
Assumed true 
objective 
response rate 
decitabine 
monotherapy 
Assumed true 
objective response 
rate BI 836858 + 
decitabine
Sample size 
(randomization ratio)
Probability 
observing difference 
in Objective 
response rate bigger 
than 20%
40%
65%
100 (1:1)
0.67
40%
70%
100 (1:1)
0.83
40%
75%
100 (1:1)
0.94
40%
40%
100 (1:1)
0.02
40%
65%
80 (1:1)
0.64
40%
70%
80 (1:1)
0.79
40%
75%
80 (1:1)
0.91
40%
40%
80 (1:1)
0.03
40%
65%
120 (1:1)
0.68
40%
70%
120 (1:1)
0.85
40%
75%
120 (1:1)
0.95
40%
40%
120 (1:1)
0.01
Probabilities based on simulations (n= 1000000 iterations) using R 2.14.2.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), and 
relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, and also of any serious breaches of the 
protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. 
Insurance Cover: The terms and conditions of the insurance cover will be made available to 
the Investigator and the patients, and stored in the ISF (Investigator Site File).
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
This trial will require genetic testing of samples from all participating patients, i.e. there is no 
option for patients to participate in this trial without agreement to have samples taken for 
biomarkers and pharmacogenetic testing. However, patients will have the option to agree or 
reject to have DNA samples stored for future testing (DNA-biobanking, refer to Section 
5.5.2).


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DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
Case Report Forms (eCRF) for individual patients will be provided by the Sponsor. For drug 
accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported in the eCRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For eCRFs all data must be derived from source documents.
∀
Patient identification (gender, year of birth)
∀
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed and date when consent was obtained)
∀
Dates of Patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results (in validated electronic format, if available)
∀
Bone marrow assessments
∀
Completion of Patient’s Participation in the trial
∀
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 


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Associate (CRA) / on site monitor and auditor may review all eCRF, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known adverse reaction of the drug or 
not. Therefore, a unique reference document for the evaluation of listedness needs to be 
provided. For BI 836858 this is the current version of the Investigator’s Brochure 
(c02324887-03). 
For decitabine this is the EU SPC (R15-4802), or another regulatory label document.
The current versions of these reference documents are provided in the ISF. No AEs are 
classified as listed for matching placebo, trial design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
TRIAL MILESTONES
8.6
The start of the trial is defined as the initiation of the first site.
The “Last Patient Out” date, defined as the last patient in the whole trial completing the last 
visit, defines end of the trial (i.e. the end of the whole trial). The “Last Patient Drug 
Discontinuation“ (LPDD) date is defined as the date on which the last patient at an 
individual trial site ends trial treatment (as scheduled per protocol or prematurely). Individual 
Investigators will be notified of suspected unexpected serious adverse reactions (SUSARs)
occurring with the trial medication until 30 days after LPDD at their site. Early termination 
of the trial is defined as the premature termination of the trial due to any reason before the 
end of the trials as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
Sponsor with the intention to resume it.


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Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The Sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
When the trial is completed, the Investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
Sponsor of the completion in writing.
PROTOCOL VIOLATIONS
8.7
The Investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
patients or for other medically compelling reason, the Principal Investigator should prepare 
and submit the records explaining the reasons thereof to the Sponsor, and retain a copy of the 
records.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the Sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
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10.
APPENDICES
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
10.1
PERFORMANCE STATUS
ECOG PERFORMANCE STATUS (R01-0787)
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 self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair
5
Dead
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE AND 
10.2
DATA SCENARIOS
The model was assessed by two different metrics: hypothetical on-study scenarios and long-
run operational characteristics.
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.2: 1. These scenarios reflect the potential 
on-study data constellations and related escalation as allowed by the model and the 100% 
escalation limit. For each scenario, the probability of overdose for the current dose, as well as 
the next potential dose and related probabilities of under-dosing, target dosing and over-
dosing are shown.
For example, scenario 1.1 represents the case that no DLT is observed in 3 patients at the 
starting dose of 20 mg BI 836858 and 20 mg/m² decitabine. In this case, the next dose 
permitted by the model and by the 100% escalation rule is 40 mg of BI 836858 and 20 mg/m² 
decitabine. Similarly, scenario 1.2 represents the case that no DLT is observed in 3 patients at 
the alternative starting dose of 40 mg BI 836858 and 20 mg/m² decitabine (refer to Section 


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4.1.3). In this case, the next dose combination permitted by the model and by the 100% 
escalation rule is 80 mg of BI 836858 and 20 mg/m² decitabine.
Scenario 6 represents the case that no DLT is observed in the first cohort of 3 patients at 
20 mg of BI 836858 and 20 mg/m² decitabine, and 2 DLTs are observed in the cohort of 3 
patients at 40 mg of BI 836858 and 20 mg/m² decitabine. In this case, the model allows de-
escalation to 20 mg of BI 836858 and 20 mg/m² decitabine. 
Scenario 13 illustrates a case where no DLTs are observed in the first three cohorts, and then 
two DLTs occur in the fourth cohort of 3 patients at 160 mg of BI 836858 and 20 mg/m² 
decitabine. In this case the model allows de-escalation to 80 mg of BI 836858 and 20 mg/m² 
decitabine. Finally, scenario 14 represents a case where no DLTs are observed in the first 
four cohorts and then two DLTs occur in the cohort of 3 patients at the intermediate dose 
level of 240 mg of BI 836858 and 20 mg/m² decitabine. 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 the combination of 240 mg BI 836858 plus 20 mg/m² decitabine and 
requires a de-escalation of BI 836858 to 160 mg. Scenarios 13 and 14 illustrate the adaptive 
behaviour of the model even in extreme situations. 


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Table 10.2: 1
Hypothetical data scenarios
con’t
Scenario
Dose 
Combination
BI [mg]/ 
DAC[mg/m²]
# 
DLT
# 
Pat
Current Dose 
Combination: 
P(OD)
Next possible 
Dose 
Combination
BI [mg]/ 
DAC[mg/m²]
Next Dose Combination
P(UD)
P(TD)
P(OD)
1.1
20/20
0
3
0.040
40/20
0.559 
0.365 
0.076 
2.1
20/20
1
3
0.153
40/20
0.309 
0.468 
0.222 
3.1
20/20
2
3
0.417
NA
NA
NA
NA
1.2
40/20
0
3
0.056
80/20
0.475 
0.376 
0.150 
2.2
40/20
1
3
0.204
40/20
0.314 
0.482 
0.204 
3.2
40/20
2
3
0.509
NA
NA
NA
NA
4
20/20
40/20
0
0
3
3
0.027
80/20
0.545 
0.344 
0.111 
5
20/20
40/20
0
1
3
3
0.103
80/20
0.326 
0.430 
0.244 
6
20/20
40/20
0
2
3
3
0.291
20/20
0.282 
0.557 
0.161 
7
20/20
40/20
20/20
0
2
0
3
3
3
0.070
40/20
0.284 
0.548 
0.168 
8
20/20
40/20
20/20
0
2
1
3
3
3
0.177
20/20
0.210 
0.613
0.177 
9
20/20
40/20
1
0
3
3
0.086
80/20
0.372 
0.427 
0.201 
10
20/20
40/20
1
1
3
3
0.239
40/20
0.228 
0.533 
0.239 
11
20/20
40/20
1
2
3
3
0.516
NA
NA
NA
NA


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Table 10.2: 1
Hypothetical data scenarios (con’t)
Operational 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 simulations. Table 10.2: 2
describes 4 assumed true dose-toxicity scenarios which were used to assess the operating 
characteristics of the model. These scenarios reflect a wide range of possible cases as 
follows:
∀
Scenario 1: aligned with prior means
∀
Scenario 2: high-toxicity scenario
∀
Scenario 3: low-toxicity scenario
∀
Scenario 4: low-toxicity followed by high-toxicity
Scenario
Dose 
Combination
BI [mg]/ 
DAC[mg/m²]
# 
DLT
# 
Pat
Current Dose 
Combination: 
P(OD)
Next possible Dose 
Combination
BI [mg]/ 
DAC[mg/m²]
Next Dose Combination
P(UD)
P(TD)
P(OD)
12
20/20
40/20
80/20
160/20
0
0
0
0
3
3
3
3
0.066
240/20
0.587 
0.203 
0.210 
13
20/20
40/20
80/20
160/20
0
0
0
2
3
3
3
3
0.669
80/20
0.427 
0.475 
0.098 
14
20/20
40/20
80/20
160/20
240/20
0
0
0
0
2
3
3
3
3
3
0.665
160/20
0.263 
0.514 
0.223 


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Table 10.2: 2
Assumed true dose-toxicity scenarios
Scenario
BI 836858 dose (mg)
P(DLT)
20
40
80
160
320
1 (Prior)
0.202 
0.228 
0.283 
0.413 
0.564 
2 (High Tox)
0.250
0.270
0.340
0.400
0.600
3 (Low Tox)
0.060
0.100
0.120
0.180
0.250
4 (Low-High)
0.060
0.100
0.211
0.340
0.400
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-dosing 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 10.2: 3.
Table 10.2: 3
Simulated operating characteristics
Scenario
% of trials declaring the MTD with true DLT 
rate in
# Patients
# DLTs
Underdose
Target 
dose
Overdose
Stopped
Mean
(Min-Max)
Mean
(Min-
Max)
1: Prior
0.0
79.8
1.3
18.9
12.40
(3 - 27)
2.96
(1 - 8)
2: HighTox
0.0
45.3
22.1
32.6
11.12
(3 - 30)
3.14
(1 - 8)
3: Low Tox
68.8
29.8
0.0
1.4
17.21
(3 - 36)
2.07
(1 - 7)
4: Low-High
24.6
68.5
5.5
1.4
15.42
(3 - 39)
2.44
(1 - 7)
In Scenarios 1 and 4, more than 60% of the simulated trials correctly declared the MTD as a 
dose with true DLT rate in the target interval [0.16, 0.33).
Namely, in scenario 1, which reflects the case that the true dose-toxicity is aligned with prior 
means, 79.8% of the simulated trials declared the MTD as a dose with true DLT rate in the 
target interval [0.16, 0.33). In scenario 4 (Low-high scenario), the percentage of simulated 
trials with correctly identified MTD was 68.5%.


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In Scenario 2 (high-toxicity scenario), 45.3% of the simulated trials declared a dose as MTD 
which has its true DLT rate in the targeted toxicity range. However, since in this scenario 80 
mg has a DLT probability of 0.34 which is relatively close to the upper bound of the target 
interval [0.16, 0.33), the BI 836858 dose of 80 mg was quite often determined as MTD, 
namely in 21.6% of the simulated trials. When considering this as MTD as well, the rate of 
simulated trials with correctly identified MTDs would add up to 66.9%. Furthermore, in 
scenario 2, the starting dose has already 0.25 probability of observing a DLT in the first 
cohort. This contributes to the high percentage (32.6%) 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. 
In scenario 3 (low-toxicity scenario) 29.8% of the simulated trials declared the MTD with 
true toxicity rate in the target interval and 68.8% declared a MTD with true DLT rate in the 
underdose interval. This is an expected situation for a low-toxicity scenario.
The mean patient numbers range from 11.12 (high-toxicity scenario) to 17.21 patients (low-
toxicity scenario) and the maximum number of patients was 39. Therefore, the patient 
numbers are as expected and increase when moving away from the high-toxicity scenario.
In summary, the considered data scenarios show a reasonable behaviour of the model and the 
operating characteristics demonstrate a good precision of MTD determination.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
01 Mar 2016
EudraCT number
2015-002892-30
BI Trial number
1315.2
BI Investigational Product(s)
BI 836858
Title of protocol
An open-label, Phase I/II trial to determine the 
maximum tolerated dose and investigate safety, 
pharmacokinetics and efficacy of BI 836858 in 
combination with decitabine in patients with acute 
myeloid leukemia
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flow Chart (page 7)
Description of change
Two additional biochemistry time points have been 
added (Cycle 1: Day 9 and Day 16)
Rationale for change
Correction of typo (missing “x” in original protocol 
version)
Section to be changed
Flow Chart (page 10 and 11)
Description of change
All columns with details for “Cycle ≥ 7” deleted
and corresponding items included in modified 
columns “Cycle ≥ 4”. 
Rationale for change
Treatment with decitabine for 3 days per cycle is 
not a recommended dosing in the current Dacogen 
SmPC. Amended as proposed by the German 
Regulatory Authority
Section to be changed
Table 2 (page 15)
Description of change
Sample number “C2S9” added for time point Cycle 




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criteria: 
“Please note that prior therapy for MDS is allowed 
for all patients participating in Phase I and Phase II 
of this trial. 
Prior treatment with hydroxyurea in order to reduce 
high WBC and treatment with hydroxyurea to 
control the WBC count during the first treatment 
cycle is allowed (refer to Section 4.2.2.1).”
Rationale for change
The two paragraphs were moved within the 
inclusion criteria for more clarity as they are 
applicable for patients in both phases of the trial.
Section to be changed
3.3.2. / 3.3.3.
Description of change
Inclusion criterion #1 and exclusion criterion #4, 
both dealing with prior treatment for MDS, were 
re-worded.
Rationale for change
Wording was modified to increase clarity as 
recommended by the German Regulatory 
Authority.
Section to be changed
3.3.3
Description of change
Exclusion criterion #16: “condom with spermicide” 
was deleted from list of examples.
Rationale for change
Example removed as requested by the German 
Regulatory Authority.
Section to be changed
3.3.3 
Description of change
Exclusion criterion #18 was changed to include 
details about biologics. Added text: “for biologics 4 
weeks or 5 half-lives, whichever is longer”.
Rationale for change
Amended as proposed by the German Regulatory 
Authority.
Section to be changed
4.1.3.
Description of change
New text added:
“If medically indicated, individual administrations 
of decitabine may be skipped. Any skipped dose 
must not be administered at a later time during that 
cycle. The decitabine treatment duration in the 
following cycle should occur as prescribed, 
provided the re-treatment criteria (see Section 
4.1.4.2) are fulfilled.”
Rationale for change
Added to allow more flexibility for Investigators to 
individually customize decitabine treatment if 
medically indicated.


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Section to be changed
4.1.3.1 and 4.1.3.2
Description of change
Table 4.1.3.1: 1 and Table 4.1.3.2: 1 modified: 
separate description of decitabine dosing for 
“Cycle 7 and further, until 'progression or toxicity'” 
was deleted and is now included in section “Cycle 
4 and further, until 'progression or toxicity'”. 
Accordingly, the mandatory reduction of decitabine 
dosing to 3 consecutive days in Cycle 7 and further 
was deleted. 
Rationale for change
Treatment with decitabine for 3 days per cycle is 
not a recommended dosing in the current Dacogen 
SmPC. Amended as proposed by the German 
Regulatory Authority.
Section to be changed
4.1.3.1 and 4.1.3.2
Description of change
New text added below Table 4.1.3.1: 1 and Table 
4.1.3.2: 1: 
“In case the initially planned treatment duration (as 
assigned prior to Day 1 of any new cycle) is not 
considered to be safe by the Investigator (e.g. due 
to myelotoxicity in precedent cycle), Day 4 and/or 
Day 5 may be omitted in the current and all 
subsequent cycles.”
Rationale for change
Added to allow more flexibility for Investigators to 
individually customize decitabine treatment in case 
of myelotoxicity or other adverse events in 
previous cycles.
Section to be changed
4.1.4
Description of change
Deleted text: 
The treatment schedule of decitabine will be also 
reduced to administration on 3 consecutive days of 
each cycle (i.e. Day 1 to Day 3 of each subsequent 
cycle).
Rationale for change
Treatment with decitabine for 3 days per cycle is 
not a recommended dosing in the current Dacogen 
SmPC. Amended as proposed by the German 
Regulatory Authority.
Section to be changed
4.1.4.2
Description of change
Several modifications in the paragraph detailing the 
“re-treatment criteria” (e.g. changes in cut-off for 
platelet counts; added text) 
Rationale for change
Modified to increase alignment of trial-specific re-
treatment criteria with the current Dacogen SmPC, 






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Number of global amendment
2
Date of CTP revision
09 June 2016
EudraCT number
2015-002892-30
BI Trial number
1315.2
BI Investigational Product(s)
BI 836858
Title of protocol
An open-label, Phase I/II trial to determine the 
maximum tolerated dose and investigate safety, 
pharmacokinetics and efficacy of BI 836858 in 
combination with decitabine in patients with acute 
myeloid leukemia
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
X
Section to be changed
Flow Chart (pages 9 and 12, foot note # 12)
Description of change
The time point for bone marrow aspirate (and 
biopsy if indicated) to assess efficacy changed 
from “at end of cycle 3 and then every other cycle 
thereafter” to “at end of cycle 2 and then every 
other cycle thereafter”.
Rationale for change
Correction of typo. 
Disease assessment with bone marrow aspirate 
(and biopsy if indicated) is required at the end of 
cycle 2 rather than the end of Cycle 3 in order to 
allow a treatment decision at the end of Cycle 2. 
The overall number of BM assessments remains 
unchanged, only the timing is shifted within the 
treatment phase.
Section to be changed
6.2.2
Description of change
The time point for bone marrow aspirate (and 
biopsy if indicated) for local response assessment 
changed from “at end of cycle 3 and then every 
other cycle thereafter” to “at end of cycle 2 and 
then every other cycle thereafter”.


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Rationale for change
Correction of typo. 
Disease assessment with bone marrow aspirate 
(and biopsy if indicated) is required at the end of 
cycle 2 rather than the end of Cycle 3 in order to 
allow a treatment decision at the end of Cycle 2. 
The overall number of BM assessments remains 
unchanged, only the timing is shifted within the 
treatment phase.


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Number of global amendment
3
Date of CTP revision
16 Dec 2016
EudraCT number
2015-002892-30
BI Trial number
1315.2
BI Investigational Product(s)
BI 836858
Title of protocol
An open-label, Phase I/II trial to determine the 
maximum tolerated dose and investigate safety, 
pharmacokinetics and efficacy of BI 836858 in 
combination with decitabine in patients with acute 
myeloid leukemia
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flow Chart (pages 9 and 12, foot note # 7)
Description of change
The term “total bilirubin” was deleted from the list 
of “other lab test to be included” on Day 10. 
Rationale for change
As total bilirubin is already included in the 
standard panel of biochemistry safety lab test, the 
term “total bilirubin” was deleted from the 
description of “other lab test to be included” on 
Day 10.
Section to be changed
Flow Chart (pages 8, 9 and 12, foot note # 11)
Description of change
On Day 16 the “X” indicating local “Disease 
assessment with peripheral blood and clinical 
assessment” was removed and the following 
sentence added to foot note 11: “In Cycle 1 at Day 
16 (± 2 days) the BM aspirate is required for 
central lab assessment for biomarkers only, i.e. no 
mandatory local disease assessment on that day”.
Rationale for change
Text added for more clarity to indicate that on 
Day 16 the BM sample is not a “separate portion” 
of the BM sample collected for local disease 
assessment, but that the BM sample on that day is 




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randomized to treatment “Arm 2” with decitabine 
monotherapy).
Rationale for change
Patients in Phase II in treatment “Arm 2” with 
decitabine monotherapy don’t receive any 
infusions with BI 836858, so the blood collections
on Day 9 and Day 10 are not required for those 
patients.
Section to be changed
Table 3
Description of change
Foot note f) added to the “X” indicating bone 
marrow aspiration for biomarker analysis at EOT.
Rationale for change
The bone marrow aspirate at EOT is mandatory 
only in patients who did not end treatment due to 
PD or relapse, and patients who did not have a BM 
aspirate within the past four weeks.
Section to be changed
3.1
Description of change
The minimum requirement for the number of 
administrations with BI 836858 was updated from 
“at least 2” to “at least 3” in the section describing 
the minimum requirements for patients in order to 
be evaluable within the dose escalation cohort.
Rationale for change
Patients should have received all 3 scheduled
administrations of BI 836858 in Cycle 1 to be 
evaluable for DLT assessment.
Section to be changed
3.3
Description of change
The number of expected patients to be entered 
during the Phase I Dose Escalation part of the trial 
was amended from 4 to 2 patients per month. 
Rationale for change
The recruitment rate was amended to reflect the 
expected enrolment rate, consideringe the 
mandated waiting period of at least 7 (or 3) days 
between the 1st administration of BI 836858 and 
initiation of treatment with decitabine to the next 
patient in treatment Cohort 1 (or Cohort 2 or 
higher).
Section to be changed
3.3.3. 
Description of change
Exclusion criterion #10 was re-worded by adding 
“total” to the bilirubin.
Rationale for change
Re-worded for more clarity, as the original text 
also meant “total bilirubin”. 
Section to be changed
3.3.3. 
Description of change
Exclusion criterion #16 was amended and “bilateral 


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tubal occlusion” was added to the list of examples 
for effective contraception, while the term “tubal 
occlusion” was removed from the list of examples 
for permanent sterilization.
Rationale for change
Amended to reflect the most recent version of the 
“CTFG (Clinical Trial Facilitation Group) 
recommendations on contraception and pregnancy 
testing in clinical trials” and corresponding BI 
“Guidance on Contraception in Clinical Trials”
Section to be changed
3.3.4.1
Description of change
The following sentence was added to the list of 
criteria that require removal of individual patients 
from trial treatment: “Start of subsequent treatment 
cycle needs to be delayed by longer than 8 weeks 
due to a drug-related event (e.g. delay in recovery 
of blood counts or awaiting resolution of toxicity; 
please refer to Section 4.1.4.2).”
Rationale for change
Text added for more clarity and to specify a time 
frame for the maximum permissible delay for the 
start of a subsequent treatment cycle in case of a 
drug-related event.
Section to be changed
3.3.4.1
Description of change
The minimum requirement for the number of 
administrations with BI 836858 was updated from 
“at least 2” to “at least 3” in the following two 
sentences: “Patients who have not completed at 
least 3 administrations of BI 836858 during cycle 1 
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 
3 administrations (1 cycle) of BI 836858 for 
reasons other than BI 836858-related toxicity will 
be replaced.”
Rationale for change
The minimum requirement for the number of 
administrations with BI 836858 was changed to at 
least 3, as this is the scheduled number of 
administrations of BI 836858 for Cycle 1.
Section to be changed
4.1.3.1 and foot note c) in Table 4.1.3.1: 2 
(BI 836858 dose escalation scheme)
Description of change
Text and foot note c) added in the description of 
planned BI 835858 dose escalation scheme: “Dose 
levels above 40 mg will only be explored after 
safety data from monotherapy studies with 


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BI 836858 have become available and if data from 
PK and pharmacodynamics analysis support further 
dose escalation.”
Rationale for change
Explanatory text added to clarify that dose levels of 
BI 836858 above 40 mg will only be explored after 
specific criteria are fulfilled and if recommended 
by SMC.
Section to be changed
4.1.3.1
Description of change
The minimum requirement for the number of 
administrations with BI 836858 was updated from 
“at least 2” to “at least 3” in the following 
sentence: “However, in the case that only 2 patients 
are evaluable and neither has experienced a DLT
within the Cycle 1 (i.e. patient has received at least 
3 administrations of BI 836858 and reached end of 
Cycle 1; please refer to Section 5.3.2) then dose 
escalation can occur based on these 2 patients.
Rationale for change
The minimum requirement for the number of 
administrations with BI 836858 was changed to at 
least 3, as this is the scheduled number of 
administrations of BI 836858 for Cycle 1.
Section to be changed
4.1.4
Description of change
The following sentence was added in the paragraph 
describing how to proceed with the very 1st
infusion of BI 836858 on the planned Day 9 of 
Cycle 1: “In case the platelet count prior to the 1st
planned infusion with BI 836858 on Day 9 (or Day 
10 at the latest) is not ≥ 25,000/μL, the patient must 
be transfused to at least 25,000 platelets/μL.”
Rationale for change
The requirement that patients must have platelet 
counts ≥25.000/μL prior to infusion with 
BI 836858 was only written in Section 4.1.4.2 (Re-
treatment criteria). As this general safety criterion 
applies to all infusions with BI 836858, that 
criterion must also be respected for the very 1st
infusion of BI 836858 in Cycle 1.
Section to be changed
4.1.4.2
Description of change
At two instances the symbol “ > ” was replaced by 
“ ≥ ” when the meaning was “at least 25,000 
platelets/μL” (“greater or equal to 25,000
platelets/μL”)
Rationale for change
Correction of a typo. 


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Section to be changed
4.1.4.2
Description of change
The clause “for up to three weeks” was deleted 
from the sentence describing the need for weekly 
re-evaluation of blood counts and/or adverse events 
in case the applicable re-treatment criteria are not 
fulfilled. 
Rationale for change
The maximum delay to start a subsequent cycle is 
changed to 8 weeks; accordingly, the weekly re-
evaluation of blood counts and/or adverse events 
should continue beyond 3 weeks.
Section to be changed
4.1.4.2
Description of change
The following 3 sentences were added in section 
describing re-treatment criteria: “Subsequent cycles 
can be delayed up to 2 weeks to meet the above 
criteria. Longer delays should be discussed with the 
Coordinating Investigator. Patients with delays 
longer than 8 weeks due to a drug-related event 
(e.g. delay in recovery of blood counts or awaiting 
resolution of toxicity) will be withdrawn from 
study.” 
Rationale for change
Text added to specify a time frame for maximum 
permissible delay for start of subsequent treatment 
cycle.
Section to be changed
4.1.4.2
Description of change
The term “same” was deleted and further 
information on specific re-treatment criteria was 
added in the following sentence: “Furthermore, the 
re-treatment criteria absence of fever (≥ 38.5°C) 
and/or uncontrolled infection and platelets 
≥25,000/μL apply for the weekly administrations 
of BI 836858 after Day 1 of any given cycle,….”
Rationale for change
Explanatory text added to further specify what was 
meant by the term “same” within the context of re-
treatment criteria.
Section to be changed
4.1.4.3
Description of change
Text changed from: “The period of delay is not 
limited in time.” to “The period of delay is limited 
to a maximum of 8 weeks”.
Rationale for change
Text amended to align with updated information in 
Section 4.1.4.2 about maximum permissible delay 
for start of subsequent treatment cycle.
Section to be changed
5.3.1




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Section to be changed
5.5.1
Description of change
The following text was added: “All biomarker 
samples, bone marrow and peripheral blood, are to 
be collected prior to administration of trial 
medication unless otherwise specified.”
Rationale for change
Text added for more clarity on timing of biomarker 
sample collection in relation to dosing.
Section to be changed
6.2.1
Description of change
The bullet point describing safety laboratory 
assessments at screening was changed from
∀
Safety laboratory (hematology, biochemistry 
including serum immunoglobulin levels and 
direct antiglobulin test, coagulation, urine; for 
details please refer to Section 5.3.6)
to
∀
Safety laboratory (hematology, biochemistry, 
coagulation, urine; for details please refer to 
Section 5.3.6)
Rationale for change
“Serum immunoglobulin levels and direct 
antiglobulin test” was removed from the list of 
laboratory tests at screening, as this was 
inconsistent with Section 5.3.6 of the protocol. 
Sample collection for “serum immunoglobulin 
levels and direct antiglobulin test” only starts on 
Day 1 of Cycle 1.
Section to be changed
6.2.2
Description of change
The term “WBC” was replaced by “the blast count” 
in the sentence “During Phase I and Phase II the 
decitabine treatment schedule for Cycles ≥ 2 will 
be individually customized depending on the blast 
count at the end of previous cycle.”
Rationale for change
Correction of terminology.
Section to be changed
6.2.2
Description of change
Text describing the planned procedures on the bone 
marrow sample collected on Day 16 of Cycle 1 
modified (deleted text: “and biopsies for local 
response assessment”) to indicate that only 
biomarker assessments at central laboratory will be 
performed. 
Rationale for change
Local response assessment is not mandatory at 
Day 16 of Cycle 1.


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Section to be changed
6.2.2
Description of change
The following sentences were added: “The BM 
sample collection at the end of Cycle 2 is not a 
mandatory trial procedure in patients with ≥5% 
blasts in peripheral blood. From Cycle 2 onwards, 
BM samples can be taken up to 7 days before the 
scheduled visit 4 (EOC)”.
Section to be changed
Explanatory text added to indicate that BM sample 
collection is a mandatory test at the end of Cycle 2 
only in case there are no blasts or < 5% blasts in 
peripheral blood. This is to align with BM 
collection recommendations in tables 4.1.3.1: 1 and 
4.1.3.2: 1.
Section to be changed
Table 7.1.1: 3 (Summary of prior distributions) and 
Table 7.1.1: 4 (Prior probabilities of DLT at 
selected doses)
Description of change
Prior distributions and probabilities have been 
updated.
Rationale for change
The BI reference dose in the program used to 
derive the prior has been incorrectly specified as 
20 mg instead of 160 mg as written in the protocol. 
This has been corrected.
Section to be changed
9.1 
Description of change
For references R15-3877 and R15-5032 (NCCN 
Guidelines) the link to the website was corrected 
by replacing “https://www” with term “website”.
Rationale for change
Correction of website link for formal reasons.
Section to be changed
10.2 and Table 10.2: 1 (Hypothetical data 
scenarios) and Table 10.2: 2 (Assumed true dose-
toxicity scenarios) and Table 10.2: 3 (Simulated 
operating characteristics)
Description of change
Hypothetical data scenarios and operational 
characteristics have been updated.
Rationale for change
The BI reference dose in the program used to 
derive the prior has been incorrectly specified as 
20 mg instead of 160 mg as written in the protocol. 
This has been corrected.












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Section to be changed
CTP Synopsis
Description of change
Update in section ‘each treatment’ for
Phase I Dose Escalation and Extension from 
(approx. 50)” to now “(approx. 60-70)”
Rationale for change
Updated to reflect patients entered into the 
additional optional Phase I Dose Escalation 
cohort(s) to be recruited prior to starting the Phase 
II part of the trial.
Section to be changed
CTP Synopsis
Description of change
Update in section ‘diagnosis’ to specify the patient 
population to be entered in potential additional 
dose tiers. 
Rationale for change
Same patient population to be entered in potential 
additional dose tiers as for Phase I Extension and 
Phase II.
Section to be changed
CTP Synopsis
Description of change
Information about the test product dose updated to: 
The Recommended Phase II Dose (RP2D) is based 
on the MTD determined in Phase I.
Text in brackets “(or RExP1D)”deleted. 
Rationale for change
Updated to reflect patients entered into the 
additional optional Phase I Dose Escalation 
cohort(s) to be recruited prior to starting the Phase 
II part of the trial.
Section to be changed
Flow Chart
Description of change
Cycle 1 Visit 1 was updated with an additional 
column for newly added treatment Day 8 with 
individual “x” for visit-specific procedures 
(identical to Day 9 procedures).
Rationale for change
Day 8 added as a separate treatment day for 
application of the initial BI 836858 infusion as split 
dose (20 mg BI 836858 at the very first 
administration on Day 8). 
Section to be changed
Flow Chart 
Description of change
Foot note #6 was updated with the additional 
information on the Day 8 procedures and the timely 
relation to following days in visits.
Rationale for change
Day 8 added as a separate treatment day for 
application the initial BI 836858 infusion as split 
dose (20 mg BI 836858 at the very first 
administration on Day 8). Same flexibility (+ 1 


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day) allowed as before, i.e. subsequent visits to be 
shifted accordingly.
Section to be changed
Flow Chart 
Description of change
Foot note #6 was updated to reflect the additional 
lab sample collection for TLS monitoring and the 
specific requirements for collection time points. 
Reference to updated Table 1 added. 
Rationale for change
Newly introduced TLS monitoring requires a 
stricter adherence to the collection time points. 
Section to be changed
List of Abbreviations
Description of change
Added: TLS – Tumor Lysis Syndrome
Rationale for change
Abbreviation newly introduced as the term is 
referenced in several paragraphs in the amended 
CTP.
Section to be changed
Table 1
Description of change
One additional column added to indicate the time 
points for newly introduced TLS monitoring. One 
additional line added to indicate which parameters 
are for central laboratory assessment and which is 
for local lab assessment.
Two new footnotes # and ## added with further 
information on use of local laboratory for TLS 
monitoring and how to avoid duplicate sampling.
Rationale for change
Additional TSL monitoring introduced to allow for 
early detection of signs for potential TLS.
Footnotes updated/ added for more clarity.
Section to be changed
Table 1
Description of change
additional rows added to indicate the sampling 
time points for 
 and TLS monitoring on 
newly introduced BI 836858 infusion Day 8. 
Footnote *** updated with information on Day 8 
and subsequent treatment days.
Rationale for change
Day 8 added as a separate treatment day for 
administration of the initial BI 836858 infusion as 
split dose (20 mg BI 836858 at the very first 
administration on day 8). 
 TLS 
monitoring added to match with Day 9 lab 
sampling.
Footnotes updated for more clarity.
Section to be changed
Table 3
Description of change
Two additional columns added for samples to be 








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across two consecutive days: a fixed dose of 20 mg 
will be administered on Day 8 (or Day 9 at the 
latest) and the rest of the full planned dose for that 
week will be administered the following day. For 
example a planned dose of 80 mg will be 
administered as 20 mg i.v. infusion on Day 8 and 
60 mg i.v. infusion on Day 9 (or 20 mg i.v. 
infusion on Day 9 and 60 mg i.v. infusion on 
Day 10 at the latest).
Rationale for change
Due to a new safety finding (fatal case of TLS) it 
was decided to introduce an additional safety 
measure by splitting the very first dose of 
BI 836858 (Day 8 and Day 9, or Day 9 and Day 10 
at the latest). 
Section to be changed
Table 4.1.3.1: 2
Description of change
Footnote a) in Table 4.1.3.1: 2 was updated to 
reflect that the first administration of BI 836858 
will take place on Day 8 instead of Day 9 (or on 
Day 9 at the latest).
Footnote d) in Table 4.1.3.1: 2 was updated by 
adding the following text:
“Additional Phase I Dose Escalation cohorts may 
also be opened if deemed necessary by the Sponsor 
and the SMC following the Phase I Extension 
cohorts of the trial.”
Rationale for change
See above - same as for Sections 3.1(for 
footnote d) and 4.1.3 (for foot note a)
Section to be changed
4.1.3.1
Description of change
Text added in section describing ‘Treatment in 
the Phase I Dose Escalation part of the trial’:
“For the optional Dose Escalation Cohorts 
following Extension Cohorts A and B, a time 
interval of at least 3 days must have elapsed 
between the 1st administration of BI 836858 for 
each new patient treated. This means that start of 
trial treatment with decitabine (Cycle 1_Day 1) for 
the next subsequent patient may occur at the 
earliest on Cycle 1 Day 4 of the previous patient.”
Rationale for change
In other trials with BI 836858 a higher dose of 
160 mg has already been tested and was found to 
be safe. A time interval of at least 3 days between 
start of trial treatment in subsequent patients within 
one cohort is considered adequate in this setting. 


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Section to be changed
4.1.3.2
Description of change
Text added in section describing the treatment in 
the “Phase I Extension” part of the trial:
“If deemed necessary by the Sponsor and the SMC, 
there will be an option to open further Dose 
Escalation cohort(s) following the extension 
cohorts to optimize or confirm the RP2D, based on 
additional biomarker, PK/PD and safety data. For 
further details on dose escalation procedures refer 
to Section 4.1.3.1.”
Rationale for change
See above - same as for Section 3.1
Section to be changed
4.1.3.3
Description of change
The text in this section was updated to reflect that 
the first administration of BI 836858 will take 
place on Day 8 instead of Day 9 (or on Day 9 at the 
latest).
Rationale for change
See above - same as for Section 4.1.3
Section to be changed
4.1.4
Description of change
The text in this section was updated to reflect that 
the first administration of BI 836858 will take 
place on Day 8 instead of Day 9 (or on Day 9 at the 
latest).
Rationale for change
See above - same as for Section 4.1.3
Section to be changed
4.1.4.1
Description of change
Text describing the premedication was updated to 
reduce the obligatory premedication from the first 
four to only the first two administration of 
BI 836858. During subsequent administrations 
allow for flexibility of glucocorticoid dose 
depending on occurrence of IRR grade 2 or higher.
Rationale for change
Treatment with glucocorticoids may interfere with 
activity of effector-cells; in patients without IRRs 
during the first infusion (Day 8+9) mandatory 
premedication with glucocorticoid should be 
reduced to 50 mg for the 2nd infusion (Day 16), and 
in case of good tolerability even be omitted in 
subsequent infusions. As this option is limited to 
patients with IRRs grade 1 or without IRRs, this 
approach is considered to offer the best possible 
activity to patients with the lowest risk for severe 
IRRs based on previous tolerability. 
Section to be changed
4.2.1


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Description of change
Additional information entered as a new paragraph 
“Prevention and treatment of Tumor Lysis 
Syndrome (TLS):
Risk for TLS should be assessed as per published 
guidelines prior to starting treatment with 
BI836858 (R18-1901). All patients should receive 
adequate hydration prior to start of each 
administration of BI 836858 in Cycle 1. 
Prophylactic administration of anti-hyperuricaemic 
agents (e.g. allopurinol, rasburicase) should be 
considered according to individual patient risk. 
Laboratory monitoring for TLS is mandatory as 
outlined in Table 1 and Section 5.3.6.1. In patients 
developing laboratory or clinical signs of a tumor 
lysis syndrome (e.g. hyperkalemia, 
hyperphosphatemia, hyperuricemia and 
hyperuricosuria, hypocalcemia, and acute renal 
failure), accepted treatments standards as per 
published recommendations must be applied (R18-
1901, R10-4517).”
Rationale for change
Implemented as an urgent safety measure, as 
careful monitoring and early medical intervention 
can minimize the risk for severe TLS.
Section to be changed
4.2.2.2
Description of change
Text updated from “at least 24 h” to now 
“approximately 48 hours” to reflect the prolonged 
requirement for hospitalization in treatment Cycle 
1 on Day 8 and Day 9. 
Rationale for change
Due to the newly introduced treatment Day 8 in 
Cycle 1 and the intensive blood sampling for PK, 
ADA and TLS lab parameters on Day 8 and Day 9, 
it is required to keep trial participants as in-patients 
for two days (approximately 48 hours).
Section to be changed
5.3.1
Description of change
Text corrected in DL T section from “at least 2 
administrations of BI 836858” to “at least 3 
administrations of BI 83685” to align with 
corresponding text in CTP Section 3.3.4.1.
Rationale for change
Correction of typo. 
Section to be changed
5.3.3
Description of change
Text added in section describing “Recommended 
Phase II Dose (RP2D)”: If deemed necessary by 
the Sponsor and the SMC, there will be an option 


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to open further Dose Escalation cohort(s) following 
the extension cohorts to determine the RP2D, based 
on additional biomarker, PK/PD and safety data.
Rationale for change
Updated to reflect patients entered into the 
additional optional Phase I Dose Escalation 
cohort(s) to be recruited prior to starting the Phase 
II part of the trial.
Section to be changed
5.3.6.1
Description of change
Text added in section describing “General safety 
laboratory parameters” to describe the new 
screening for laboratory evidence of tumor lysis 
syndrome.
Rationale for change
Implemented as an urgent safety measure, as 
careful monitoring and early medical intervention 
can minimize the risk for severe TLS.
Section to be changed
5.3.8.1
Description of change
Tumor Lysis Syndrome (TLS) added to the AESI 
list.
Rationale for change
TLS added to list of AESIs to minimize risk of 
delayed reporting.
Section to be changed
5.5
Description of change
The text in this section was updated to reflect that 
the first administration of BI 836858 will take 
place on Day 8 instead of Day 9 (or day 9 at the 
latest).
The reference to “[days]…of decitabine treatment” 
was deleted, as not all patients will receive 
treatment with decitabine on Day 8 and day 9.
Rationale for change
See above - same as for section 4.1.3 and 
correction of unclear reference.
Section to be changed
6.2.2
Description of change
The text in this section was updated to reflect that 
the first administration of BI 836858 will take 
place on Day 8 instead of Day 9 (or on Day 9 at the 
latest).
Rationale for change
See above - same as for Section 4.1.3
Section to be changed
7.4
Description of change
Text added in section describing “Planned 
Analysis” to describe the optional additional Dose 
Escalation cohort(s).
Rationale for change
Updated to reflect patients entered into the 


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additional optional Phase I Dose Escalation 
cohort(s) to be recruited prior to starting the 
Phase II part of the trial.
Section to be changed
7.4
Description of change
Text added in section describing “Interim 
Analysis” to describe the optional additional Dose 
Escalation cohort(s).
Rationale for change
Updated to reflect patients entered into the 
additional optional Phase I Dose Escalation 
cohort(s) to be recruited prior to starting the 
Phase II part of the trial.


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Number of global amendment
6
Date of CTP revision
21 Aug 2019
EudraCT number
2015-002892-30
BI Trial number
1315.2
BI Investigational Product(s)
BI 836858
Title of protocol
An open-label, Phase I/II trial to determine the 
maximum tolerated dose and investigate safety, 
pharmacokinetics and efficacy of BI 836858 in 
combination with decitabine in patients with acute 
myeloid leukemia
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
After the Sponsor’s decision to discontinue 
development of BI 836858 and to stop further 
recruitment of patients into study 1315.2, trial 
participants still on treatment and with clinical 
benefit from BI 836858 and decitabine 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 are reduced for all patients in 
treatment cycles >7. 
Changes have been made in the following 
sections:
Synopsis – section “Number of patients”
Actual number of patients entered/treated in 
Phase I Dose Escalation (16 patients) and in 
Phase I Extension (33 patients) was added.
One new sentence added:




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parameters), 5.3.7 (Electrocardiogram), are 
reduced for all patients who continue to receive 
trial medication in treatment cycles >7. Instead, 
routine 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 
5.3.8 and 5.3.9, unchanged).
∀5.3.5 Vital Signs
New text:
After implementation of Protocol version 7.0 the 
vital sign results will be documented in the 
eCRF only if qualifying for an adverse event 
(see sections 5.3.8 and 5.3.9, unchanged).
∀6.2.2 Treatment period
(also 6.2.2.1 and 6.2.2.2)
Clarifications added about reduced mandatory 
protocol procedures for treatment cycles >7 with 
reference to updated Flow chart.
New text:
“With the aim to minimize the burden for trial 
participants, after approval of Protocol version 
7.0, the mandatory protocol procedures are 
reduced for all patients who continue to receive 
trial medication in treatment cycles >7. Refer to
updated Flow Chart for specific requirements 
during treatment period.
[…] (after approval of Protocol version 7.0 BM 
assessments will be done at the investigator’s 
discretion)”.
∀6.2.3.1.1 Follow-up of Phase I Patients
Clarification added about discontinuation of
recruitment to this trial and no follow-up visits 
after completion of EoR visit. 
∀6.2.3.2 Trial completion for an individual 
patient
Clarification added about discontinuation of
recruitment to this trial.


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∀6.2.3.3 End of the whole trial
Clarification added about the definition of the 
end of the whole trial. No follow-up visit after 
the last patient has had the EoR visit.
∀7.1.2 Phase I Extension
Clarification added about discontinuation of 
recruitment to this trial.


 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Boehringer Ingelheim 
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Document Number: 
Technical Version Number:
(Continued) Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F


SAP_001.pdf: 
 
TRIAL STATISTICAL ANALYSIS PLAN
c10164918-03
BI Trial No.:
1315.2
Title:
An open-label, Phase I/II trial to determine the maximum tolerated 
dose and investigate safety, pharmacokinetics and efficacy of BI 
836858 in combination with decitabine in patients with acute 
myeloid leukemia 
Including:
Protocol Amendment 1 [c03377067-02]
Protocol Amendment 2 [c03377067-03]
Protocol Amendment 3 [c03377067-04]
Protocol Amendment 4 [c03377067-05]
Protocol Amendment 5 [c03377067-06]
Protocol Amendment 6 [c03377067-07]
Investigational
Product(s):
BI 836858
Responsible trial 
statistician(s):
Phone:
Fax:    
Date of statistical 
analysis plan:
19NOV 2019 SIGNED
Version:
Final
Page 1 of  33
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! 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.




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8.
REFERENCES....................................................................................................31
10.
HISTORY TABLE..............................................................................................33


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LIST OF TABLES
Table 6.1:1 
Definition of analysing treatment periods...................................................................13
Table 6.2:1
Important protocol deviations .....................................................................................14
Table 7.8.1:1
Definition of user-defined AE categories....................................................................22
Table 7.8.1:2
User-defined (sub-) search category of “Cardiac Failure”..........................................24
Table 7.8.1:3
Laboratory Signs of Cell Destruction..........................................................................26
Table 7.8.1:4
Clinical Signs of Cell Destruction...............................................................................26
Table 10: 1
History table................................................................................................................33


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
ALKP
ALT
AST
Adverse events of special interest
Alkaline phosphatase
Alkaline aminotransferase
Aspartate aminotransferase
ATC classification
Anatomical, Therapeutic, Chemical classification
AUC
Area Under Curve
BI
Boehringer Ingelheim
BLRM
Bayesian logistic regression model
BSA
Body Surface Area
RPM
Report planning meeting
Cmax
Maximum measured plasma concentration of the analyte
CL
Total plasma clearance 
CR
Complete Remission
CRi
Complete Remission with incomplete marrow recovery
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
DMS
Data Management and Statistics
DOR
Duration of Remission
ECG
Electrocardiogram
ECOG
eDISH
Eastern Cooperative Oncology Group
Evaluation of Drug Induced Serious Hepatotoxicity
EFS
Event free survival
eCRF
Electronic case report form
ICH
International Conference on Harmonisation


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Term
Definition / description
iPD
Important Protocol Deviation
IRR
Infusion Related  Reaction
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical and Quality Review Meeting
MTD
Maximum tolerated dose
NE
Not evaluable
OR
Objective response
OS
Overall survival
PD
Progressive disease
PFS
Progression free survival
PK
Pharmacokinetics
PKS
Pharmacokinetic set
PR
Partial remission
PT
Preferred term
PV
Protocol deviation
REP
Residual effect period
REPd
Duration of residual effect period in days
RFS
Relapse free survival
RP2D
Recommended phase 2 dose
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard deviation
SOC
System organ class
SOP
Standard Operating Procedure
SS
Screened set
TCM
Trial Clinical Monitor
TF
Treatment failure
tmax
Time from dosing to the maximum plasma concentration of the 
analyte
TOC
Table of contents
TS
Treated set


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Term
Definition / description
TTF
Time to treatment failure


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3.
INTRODUCTION
As per 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 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, randomisation. This TSAP follows the Boehringer 
Ingelheim (BI) internal reference (2).
This TSAP is based on the Project SAP wherever possible. Wordings like "randomisation 
(first administration of study treatment in non-randomised trials)" should therefore be 
interpreted as applicable. 
Furthermore, in this combination trial the term investigational medicinal product is used for 
BI 836858 while combination drug denotes the backbone chemotherapy decitabine. The term 
trial medication is used for any of the two trial drugs.
SAS Version 9.4 or later version will be used for all analyses. 
Due to company decision to stop this project, there is no Phase II subject enrollment so that
Phase II analyses stated in CTP will be omitted. 


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Due to the decision to discontinue  the development of  BI865868, the enrollment was stopped  after 
Phase I extension and Phase II  part of the trial was cancelled as stated in CTP amendment 7.0. Thus 
there will be no data collection nor analyses for Phase II part .
5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
Phase I 
The primary endpoints in the Phase I part of the trial are the maximum tolerated dose (MTD) and the 
number of subjects with of dose limiting toxicity (DLT) during the MTD evaluation period.
Maximum tolerated dose (MTD):
The MTD is defined as the highest dose of BI 836858 (in combination with decitabine) with 
less than 25% risk of the true DLT rate being above 33% during the MTD evaluation period.
MTD evaluation period:
The MTD evaluation period is defined as the time from the first administration of study drug 
to the start of the second treatment cycle or the end of 30-day residual effect period after last 
administration of study drug, whichever comes first. Subjects who were replaced during the 
MTD evaluation period will not be considered for MTD determination.  The subjects who are 
completed the MTD evaluation period without being replaced are considered MTD evaluable.
In case a subject 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, subjects who have 
not completed the required number of administrations of BI 836858 for reasons other than BI 836858 
related toxicity will be replaced. Subjects who were replaced during the MTD evaluation period will 
not be considered for MTD
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
No key secondary endpoints are defined in this study. 
5.2.2
Secondary endpoint(s)
Phase I
∀
Number of subjects with objective response combining
-
Complete remission (CR)
-
CR with incomplete blood count recovery (CRi)


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∀
Time frame: From start of treatment until the earliest of progression, death or end of trial 
(approximately up to 30 months).


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
Phase I


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In the Phase I Part, treatments are not randomized (open-label, dose escalation). Different 
dose levels of the investigational medicinal product (BI 836858) can arise while combined 
with fixed dose of decitabine at 20 mg/m² per day. The data will be presented for all dose 
cohorts separately, in particular, subjects will be analysed by the dose cohort initially 
assigned in the first treatment course.
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
First of  start of the second 
treatment cycle or the end of the 
30-day residual effect period
On-treatment
Date of first 
administration of trial 
medication
Start date of ‘Follow-up’
Follow-up
Date of end of REP +1
Start date of ‘Post-study’
Post-study
Last date subject status 
obtained / last date subject 
known to be alive + 1 (if 
subject is lost to follow-
up) / date of refusal + 1 
day / the date subject died 
+ 1
During the trial: open / empty; 
after database lock (DBL): 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.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Even though no per protocol population is defined, subjects 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).


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Table 6.2:1
Important protocol deviations
Category/
Code
Description
Comment/Example
Excluded
from
A
Inclusion/Exclusion Criteria
A1
Criteria related to safety
A1.1
Patient has condition that may 
cause additional risk from 
study medication
EX 7, EX 12, EX 19
None
A1.2
Patient has laboratory 
assessments that may cause 
additional risk.
EX 8-11
None
A1.3 
Patient is unable to comply 
with the protocol
EX 13, EX 20
None
A2
Criteria related to efficacy
A2.1
Patient does not have trial 
diagnosis or is not part of the 
target population
IN 1-4, EX 1, EX 2
None
B
Legal criteria
B1
Informed consent not 
available/not done
IN 5
All
B2
Informed consent after visit 1
IN 5
None
B3
Men or women who are 
sexually active and not using 
adequate contraception.
EX 16, EX 17
None
B4
Pregnant or nursing female 
patient
EX 15
None
B5
Patient’s age < 18
IN 1
None
C
Administration of trial 
medication not in accordance 
with the protocol
C1
Administration of trial 
medication not in accordance 
with the protocol
As marked in the eCRF, 
review and decision at 
medical and quality review 
meetings (MQRM) / report 
planning meetings (RPM)
None


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Table 6.2:1
Important protocol deviations (cont.)
Category/
Code
Description
Comment/Example
Excluded 
from
C2
Continuation of treatment 
although criteria for re-
treatment are not met
Create listing, decision at 
medical and quality review 
meetings (MQRM) / report 
planning meetings (RPM) 
None
C3
Unjustified intra-patient dose-
escalation
Create listing, decision at 
MQRM / RPM
None
C4
Withdrawal of patient not 
performed according to CTP
Create listing, decision at 
MQRM / RPM
None
C5
Discontinuation of decitabine 
not  
performed according to CTP
Create listing, decision at 
MQRM / RPM
None
C6
Discontinuation of BI 836858 
not  
performed according to CTP
Create listing, decision at 
MQRM / RPM
None
D
Restrictions
D1
Additional experimental anti-
cancer, chemo-, immuno-, 
hormone - or radiotherapy 
during the study or too shortly 
before the study.
Create listing, decision at 
MQRM / RPM (and EX 6) 
None
E
Missing data
E1
Baseline bone marrow 
assessment not within 14 days 
prior to first treatment
Create listing, decision at 
MQRM / RPM
None
E2
Missing disease assessment at 
a time point where disease 
assessment was required
Create listing, decision at 
MQRM / RPM  
None
6.3
SUBJECT SETS ANALYSED
Where applicable, the following subject sets will be defined for the Phase I and Phase II part 
separately.




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measurements were taken according to protocol, i.e. prior to first intake of any trial 
medication. 
Laboratory values: Baseline is defined as the latest time-point before the very first 
administration of any trial medication in course 1. For laboratories where not only the 
examination date but also time are recorded, examination time has to be taken into account 
when defining baseline. That is, a laboratory value on the same date as the first 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 ANALYSIS
The labelling and display format of statistical parameters will follow the guideline “Reporting 
of Clinical Trials and Project Summaries” (7).
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, medians, SD 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.
Tabulations of frequencies for categorical data will include all possible categories (even if 
with no count and also the missing category if there is missing data) and will display the 
number of observations in a category as well as the percentage (%) relative to the number of 
subjects in the respective treatment group (unless otherwise specified, all subjects in the 
respective subject set whether they have non-missing values or not). Percentages will be 
rounded to one decimal place. The category missing will be displayed only if there are 
actually missing values.
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 and a “total” column will be included in the 
summary tables.
Body Surface Area (BSA):
BSA[m2] = 0.007184×height[cm]0.725×weight[kg]0.425


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Time from first diagnosis [months] = (date of informed consent - date of first diagnosis 
+1)[days]×12/365.25 
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. 
Concomitant diseases will be coded similarly as adverse events based on the most current 
Medical Dictionary for Regulatory Activities (MedDRA®) version. Concomitant therapies 
(CTs) will be coded according to WHO DD. CTs will be classified according to the 
Anatomical, Therapeutic, Chemical (ATC) classification system. The third ATC level will be 
used to categorize CTs by therapy type. In situations where a medical product may be used 
for more than one equally important indication, there are often several classification 
alternatives. As appropriate, subjects receiving CTs with more than one possible ATC level-
three category will be counted more than once; footnotes will clarify this possible double 
counting in tables.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. 
7.4
PRIMARY ENDPOINT(S)
Phase I
The primary endpoints are the MTD and the occurrence of DLT. The MTD is determined 
from the number of non-replaced subjects with DLT during the MTD evaluation period.
The MTD evaluation period is defined as the time from the first administration of study 
treatment to the start of the second treatment cycle or the end of the 30-day residual effect 
period after the last drug administration, whichever comes first. Subjects who were replaced 
during the MTD evaluation period are not considered for MTD determination. Those subjects 
who have completed the MTD evaluation period without having been replaced are referred to 
as subjects evaluable for MTD.
An overall summary of subjects with DLT(s) which occurred during the MTD evaluation 
period and the on-treatment period will be provided for each dose cohort.
Subjects who were treated but replaced are 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).
In order to describe the occurred dose escalation steps, a listing of all treated subjects will be 
provided. This will include the initial dose of the investigational medicinal product, subject 
number, treatment start date, DLT in MTD evaluation period [y/n], Evaluable for MTD [y/n] 
and will be sorted by treatment start date.


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7.5
SECONDARY ENDPOINT(S)
Phase I
The secondary endpoint overall response will be listed only. If considered useful, aggregated 
tables will be provided where different doses might be grouped.
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 5.4.1 and will comprise a mixture of frequency 
and percentages, as well as summary statistics.
The time to treatment discontinuation is defined as (date of last administration of trial 
medication– date of randomisation + 1). Subjects who have not discontinued treatment will 
be censored at the earliest of the following: date of last administration of trial medication, or 
date of data cut-off. Subjects who are randomised, but did never receive study medication 
will be censored on the day of randomisation
A Kaplan-Meier plot of time to treatment discontinuation by treatment group will be 
presented.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse Events
The analyses of adverse events (AEs) will be descriptive in nature. All analyses of AEs will 
be based on the number of subjects 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 
4.03.
Reporting will be done according to version 6 of the AE guideline (8).


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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 subject, all episodes with the same preferred term (PT) (system organ class, SOC) 
will be  counted only once 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 analysing 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.
Adverse events of special interest (AESIs):
Adverse events of special interest (AESIs) are defined in CTP Section 5.3.8.1 as infusion 
related reactions (IRRs) of CTCAE grade >= 3, DLTs (occurring during the MTD evaluation 
period or repeated treatment courses), tumor lysis syndrome 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.
An overall summary of adverse events will be presented. This will include the number of 
subjects with AEs by worst CTCAE grade. The frequency of subjects with adverse events 
will be summarized by treatment, primary system organ class and preferred term. The system 
organ classes will be sorted by default alphabetically; preferred terms will be sorted by 
frequency (within system organ class).
AEs leading to dose reduction, AEs leading to overall permanent discontinuation, DLTs and 
Adverse events of special interest (AESIs) including Infusion Related Reactions (IRRs) will 
be tabulated.  
Infusion related reactions (IRRs):


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IRRs will be the object of special attention. 
Subjects 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.
For IRR summary, time since administration of treatment, duration of IRR, and related 
symptoms will be summarized descriptively by infusion timepoints. 
User-defined AE categories (UDAEC)
User-defined AE categories (UDAEC) are defined in in Table 7.8.1:1. 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 “Infusion related 
infections” the tables will include the UDAEC “Infusion related reactions broad” and 
“Infusion related reactions narrow”. Similarly for UDAEC “Bleeding”, it will include 
“Bleeding - SMQ Haemorrhage”, “Bleeding - SMQ Haemorrhage laboratory terms broad”, 
“Bleeding - SMQ Haemorrhage laboratory terms narrow”, “Bleeding - SMQ Haemorrhage 
terms (excl. laboratory terms) narrow”.
Table 7.8.1:1 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


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Table 7.8.1:1 Definition of user-defined AE categories (cont.)
Special Search 
Category
Definition
Sensitivity
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
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


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Table 7.8.1:1 Definition of user-defined AE categories (cont.)
Special Search 
Category
Definition
Sensitivity
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 terms as defined 
in Table 7.8.1:2 will be used.
Table 7.8.1:2 User-defined (sub-) search category of “Cardiac Failure”
Selected PTs for Cardiac Failure
Cardiac asthma
Cardiac failure


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Table 7.8.1:2 User-defined (sub-) search category of “Cardiac Failure” (cont.)
Selected PTs for 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 by summarized by dose cohort, search categories and preferred terms, 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.
Tumor Lysis Syndrome  


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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 Tumor Lysis Syndrome if they met both of the 
following two criteria:
(1)
Two or more of the laboratory parameters meet the criteria in Table 7.8.1:3, 
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 
with the same 24 hour period
(2)
Have an adverse event identified by the any of the SMQ in Table 7.8.1:4 or 
have a qualifying creatinine value 
a.
Time windows: AE onset or creatinine observation at any time during 
the treatment or residual effect periods 
Table 7.8.1:3 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 7.8.1:4 Clinical Signs of Cell Destruction
Criterion 
TLS broad SMQ [20000219]


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Table 7.8.1:4 Clinical Signs of Cell Destruction (cont.)
Criterion
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%
For AEs during the post-treatment period, only subjects with drug related serious adverse 
event and protocol-specified AEs of special interest by treatment will be presented in listing.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (9). It will include a graphical summary highlighting potential cases of Hy’s Law.
The analysis of laboratory data will use the same 'analysing treatments' as described for the 
AEs, except for that the baseline laboratory value will be included in the 'on-treatment period'.
Subjects having at least one post-baseline laboratory value will be displayed in the 
descriptive analyses. The following parameters are of particular interest: 
∀
haematology: haemoglobin, white blood cell count, Absolute Neutrophil Counts, 
platelets
∀
Biochemistry: aspartate transferase, alanine transferase, bilirubin, serum creatinine, 
urea, sodium, potassium, magnesium
∀
Coagulation: international normalised ratio, partial thromboplastin time
Laboratory values: Baseline is defined as the latest time-point before the very first 
administration of study medication. A laboratory value on the same date as the first study 
drug administration is considered as according to protocol, i.e. as prior to first study drug 
administration and will therefore be used as baseline value. 
The following outputs will be presented:


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∀
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 on treatment and from baseline to last laboratory value during 
the on-treatment phase.
Worst laboratory value and its CTCAE grade (highest CTCAE grade) over all courses will be 
calculated for each laboratory parameter specified above. 
The last laboratory value on treatment is the laboratory value of the last visit of the last 
course of each subject. 
Furthermore, a summary table of possible clinically significant abnormalities will be given.
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. Frequency of subjects with possible clinically significant abnormal laboratory 
values will be provided whenever applicable. If no baseline value is available but the subject 
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.
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): These are defined as those 
cases where a combination of all of the following events occurred: any on-treatment value of 
ALT and/or AST > 3ULN with total bilirubin ≥ 2ULN and ALKP < 2ULN. 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. Subjects with missing laboratory values for liver enzymes will be 
excluded from these analyses.
In addition, eDISH plot will be by plotted to display the maximum on-treatment AST/ALT 
and maximum bilirubin in terms of ULN. 
Neutrophil and platelet counts of each patients will be plotted in log scale graphs. 
7.8.3
Vital signs
Only descriptive statistics are planned for vital sign report. Observed value and change from 
baseline values will be summarized. 


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7.8.4
ECG
12-lead resting ECGs are done throughout the study and are assessed for pathological results 
which are to be recorded as either concomitant disease or AE by the Investigator. ECG    
results will be listed.


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8.
REFERENCES
1
CPMP/ICH/363/96 : “Statistical Principal for Clinical Trials”, ICH Guideline 
Topic E9 Step 5; Note For Guidance on Statistical Principal for Clinical Trials, 
current version, EMA webpage.
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;  KMED.
5
001-MCS-36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
6
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; IDEA for CON.
7
001-MCS-50-415: “Clinical Trial Data Analysis”, current version; IDEA for CON.
8
BI-KMED-BDS-HTG-410: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials ”, KMED.
9
BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED .


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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
14-Jul-16
None
This is the initial TSAP with 
necessary information for trial 
conduct.
Final
19-Nov-19
None
This is the final TSAP.