Clinical trial NCT01690624
Conditions: Leukemia, Myeloid, Acute
Sponsor: Boehringer Ingelheim
Start date: 2012-09-13; Completion date: 2018-05-21
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Patients with acute myeloid leukemia who experience a relapse after at least one prior regimen may be enrolled in this trial. In addition, acute myeloid leukemia patients who are in complete remission with high risk to relapse may be eligible for this trial. The trial will examine whether monotherapy with BI 836858 is safe and tolerable at escalating dose levels.

Detailed description:

Arms: arm 1: Patients with relapsed\\refractory AML were administered BI 836858 10 mg solution for infusion intravenously on day 1 and day 8 of the 14-day cycles (1 cycle with 2 administrations). arm 2: Patients with relapsed\\refractory AML were administered BI 836858 20 mg solution for infusion intravenously on day 1 and day 8 of the 14-day cycles (1 cycle with 2 administrations). arm 3: Patients with relapsed\\refractory AML were administered BI 836858 40 mg solution for infusion intravenously on day 1 and day 8 of the 14-day cycles (1 cycle with 2 administrations). arm 4: Patients with AML in complete remission (CR) with high risk to relapse were administered BI 836858 40 mg solution for infusion intravenously on Day 1 of Cycles 1, 2 and 3. From the 4th administration onwards, patients received monthly (every second cycle) infusions (i.e. 4th infusion on Cycle 5 Day 1, 5th infusion on Cycle 7 Day 1, etc.) for overall up to 12 months of treatment unless the patient relapsed or infusions were not tolerated.
Interventions: intervention 1: BI 836858
Intervention descriptions: intervention 1: Monotherapy with BI 836858 administered as intravenous infusion

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02543230-04
BI Trial No.:
1315.1
BI Investigational
Product:
BI 836858
Title:
A Phase I, open-label, cohort dose escalation trial with BI 836858 in patients 
with refractory or relapsed acute myeloid leukemia and patients with acute 
myeloid leukemia in complete remission with high risk to relapse
Clinical Phase:
I
Trial Clinical 
Monitor:
Phone: 
Fax: 
Co-ordinating 
Investigator:
Phone: 
Fax: 
Status:
Revised Protocol (based on Global Amendments 01, 02, and 03)
Version and Date:
Version: 4.0
Date: 28 APRIL 2016
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 836858
Protocol date:
Trial number:
Revision date:           
28 APRIL 2016
21 DEC 2011
1315.1
Title of trial:
A Phase I, open-label, cohort dose escalation trial with BI 836858 in patients with 
refractory or relapsed acute myeloid leukemia and patients with acute myeloid 
leukemia in complete remission with high risk to relapse
Co-ordinating 
Investigator:
Trial sites:
Multi-centre trial
Clinical phase:
I
Objectives:
To investigate the maximum tolerated dose (MTD), safety and tolerability, 
pharmacokinetics and efficacy of BI 836858 monotherapy in acute myeloid leukemia 
(AML) patients with refractory or relapsed AML and  patients with AML in complete 
remission (CR) with high risk to relapse
Methodology:
Open-label cohort dose escalation
No. of patients: 
Planned number: about 63
        total entered:
              each treatment:
About 36 (for refractory or relapsed AML) and 27 (for AML patients in CR)
About 3-6 (per dose cohort, for each patient population) 
Diagnosis :
Acute Myeloid Leukemia
Main criteria
for inclusion:
Adult patients with relapsed or refractory AML
AND
Patients with AML in CR with high risk to relapse defined as: 
a)
AML patients with non-favorable genetics (according to European 
LeukemiaNet (ELN) classification) that are in CR after having received 
induction and consolidation chemotherapy and are not candidates for 
allogeneic hematopoietic stem cell transplantation (SCT) (e.g., no donor 
available, not eligible/fit enough) 
or
b)
AML patients with non-favorable genetics (according to ELN classification) 
that are in CR after allogeneic hematopoietic stem cell transplantation


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 836858
Protocol date:
Trial number:
Revision date:           
28 APRIL 2016
21 DEC 2011
1315.1
Test product:
BI 836858
dose:
The starting dose for BI 836858 will be 
-
10 mg for refractory or relapsed AML patients and 
-
40 mg for AML patients in CR with high risk to relapse
mode of admin.:
Intravenous (i.v.) infusion
Comparator products:
Not applicable
Duration of treatment: Patients with refractory or relapsed AML
Patients are eligible for up to 8 repeated administrations as long as neither patient nor 
Investigator requests treatment discontinuation.
Patients with clinical benefit, defined by the International Working Group (IWG) as 
having objective response (partial remission (PR) or complete remission (CR) or 
complete remission with incomplete blood recovery (CRi)) or subjective response (in 
the absence of objective response) after 8 administrations and who are tolerating the 
infusions, may continue until progressive disease (PD)
AML patients in CR with high risk to relapse
The first three administrations will be given every second week, on day 1 of Cycles 1, 
2 and 3.  From the 4th administration onwards, patients will receive monthly (every 
second cycle) infusions of BI 836858 (i.e. 4th infusion on Cycle 5 Day 1, 5th infusion 
on Cycle 7 Day 1, etc.) for overall up to one year of treatment unless these patients 
relapse or infusions are not tolerated.
Patients are eligible for repeated administrations as long as neither patient nor 
Investigator requests treatment discontinuation.
Criteria for efficacy:
Progression-free survival, time to treatment failure
 
Best overall response
 
 applies only to refractory or relapsed 
AML patients.
 applies only to 
AML patients in CR.
Criteria for safety:
Maximum tolerated dose, incidence and intensity of adverse events graded according 
to the common terminology criteria for adverse events (CTCAE, version 4.0), 
incidence of dose-limiting toxicity, vital signs, ECG, physical examination and 
laboratory parameters.
Statistical methods:
Descriptive statistics.


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FLOW CHART - A (REFRACTORY OR RELAPSED PATIENTS)
Trial Periods
Screen
Treatment*
EOT
Further Treatment**
FU
Screen
Cycle 1 – Cycle 4 
(1 Cycle = 14 days)       
EOT
FTE
EOFT
FU
Visit
1
Cx
V1
Cx
V2
Cx
V3
Cx
V4
Cx
V1
Cx
V2
Days 
(in respective cycle)* 
-14 to -
1
1
4
±11
8
11
±11
1
8
Informed consent
x
Informed consent for 
pharmacogenetics
x
Demographics and baseline 
conditions
x
Medical history
x
Review of in-/exclusion 
criteria
x
x 2
Dose assignment
x 3
LABS/SAFETY ASSESSMENTS
Safety laboratory parameters 
incl. urinalysis4
x
x
x1
x
x1
x
x
x
x
x
Physical examination
ECOG performance status
x
x5
x
x5
x
x
Vital signs, height6, weight 6
x
x
x
x
x
x
x
x
x
x
Serum pregnancy test 7
x
x
x
x
x
12 lead-ECG
x
x
x
x8
Adverse events
x
x
x
x
x
x
x
x
x
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x9
DISEASE ASSESSMENTS
Bone marrow aspiration
x
x10
x10
x11
x8, 11
x 11
 
 
TRIAL MEDICATION
Drug Administration
x 
x
x
x
Eligibility for further 
administration
x16
x16
x16,17
x16, 17
x16, 17
End of active trial treatment
x
End of further treatment
x
Other therapy for AML
x
Vital Status
x


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EOT: 
End of treatment evaluation, including an evaluation for further treatment.  Those patients with clinical benefit, 
PR, CRi, or CR after 8 administrations and who are tolerating the infusions well may continue until PD or other 
criteria for withdrawal are met as noted in Section 3.3.4.1.  For those patients who will receive more than 8 
administrations, this visit is to be performed 7 days (±2 days) after the 8th administration of BI 836858.  For those 
patients who receive < 8 administrations, this visit is to be performed 14 days (±2 days) after the last 
administration of BI 836858.
FTE:
Further treatment evaluation.  Each patient who will receive more than 8 administrations will have a FTE visit for 
each infusion.  The visit numbers are 6, 7, 8, etc. until the patient discontinues.
EOFT:
End of further treatment.  For each patient who receives more than 8 administrations, there will be an end of 
further treatment evaluation.  This visit is to be performed 14 days (±2 days) after the last administration of 
BI 836858.
FU: 
Follow-up, starts after the last administration of BI 836858, visits at least every 4 weeks until 6 months after the 
last administration of BI 836858.
*   The planned duration of a treatment cycle is 14 days; there will be two administrations of BI 836858 per cycle.
** These visits are only for those patients with clinical benefit, PR, CRi or CR after 8 administrations and who are tolerating 
the infusions well who continue until PD or other criteria for withdrawal are met as noted in Section 3.3.4.1.  
1
Visit window of +1 day only allowed beginning in Cycle 3 and for all subsequent cycles.  In Cycles 1 and 2 visit 
window not allowed due to the PK schedule as outlined in Tables 1a and 2a.
2
Review of inclusion/exclusion criteria during screening and again on day of first administration. 
3
After informed consent and review of inclusion/exclusion criteria (timing described in footnote 2).
4
For details refer to Section 5.2.3.1. Urine has to be measured only at screening, EOT, EOFT and FU visits.  Safety 
laboratory assessments may be completed up to 2 days prior to administration. An additional safety lab will be 
collected on day 2 (i.e., 24 hours after the first administration of BI 836858). Other lab tests to be included: 
Haptoglobin, direct antiglobulin test, bilirubin (direct and indirect) and free hemoglobin.
5
Only every second cycle (i.e. before cycle 1, 3, 5, 7 etc.) Physical examination may be completed up to 2 days 
prior to administration.  Eastern Cooperative Oncology Group (ECOG) score must be completed on the day of the 
administration. If the first administration of BI 836858 occurs within 3 days of the screening visit, these 
examinations do not need to be repeated.
6
Height and weight only at day 1 of first administration of BI 836858; weight also at EOT and EOFT.
7
For women of childbearing potential only.  Serum pregnancy test is to be completed at odd numbered 
administrations only (e.g. administration 1, 3, 5, etc.). 
8
ECG, bone marrow aspiration, 
 tests will be performed at EOFT only if the patient has 
completed at least 2 cycles (e.g. received 4 administrations) since the EOT visit.
9
Concomitant therapy during FU is collected only if indicated for treatment of adverse event.
10
Bone marrow aspirate to assess efficacy before 5th and 9th administrations (i.e., BM performed on Day 1 (+/- 1) of 
cycles 3 and 5 and treatment started on day 1 (up to +3 days) of cycles 3 and 5) (see Section 5.1.2).  
 
11
Only one sample to be collected at the time of PD or the time of initiation of other anti-leukemia therapy, which 
may be at the EOT/EOFT, if PD or initiation of other anti-leukemia therapy occurs during treatment, or during 
follow-up. If the patient is non-progressing/not receiving other anti-leukemia therapy at the end of follow-up or the 
trial, the sample will be obtained at the last follow-up visit for this patient.
 
 
  
 
 
16
Can be performed up to 2 days prior to this visit.
17
After the 8th infusion, at the end of treatment visit, patients will be evaluated to determine if they have clinical 
benefit, as defined by IWG objective response (PR, CRi or CR) or subjective response (in the absence of objective 
response) and are tolerating the infusions well and who would like to continue to receive infusions until PD or 
other criteria for withdrawal are met as noted in Section 3.3.4.1.  For each infusion past the 8th administration, 
patients will continue to be assessed after each cycle for clinical benefit (objective or subjective response), and that 
they are tolerating the infusions well and would like to continue until PD or other criteria for withdrawal are met as 
noted in Section 3.3.4.1.


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FLOW CHART - B (AML PATIENTS IN CR) 
Trial Periods
Screen
Treatment*
       Further        
Treatment**
    End of               End of Residual                            
Treatment               Effect Period        Follow-up
                             and Follow-up 1
Cycle 1 – Cycle 3
 (1 Cycle = 14 days)
FTE                
(every 2nd cycle;  
Cycles   5, 7, 9…21)
       EoT
    EoR/FU1         FU2 to FU6
Visit
1
Cx          Cx       Cx
V1          V2       V3
Cx        Cx          Cx
V1        V2          V3
As soon as possible 
but not later than 
one week after 
permanent 
discontinuation of 
trial medication
Not earlier than 30 
days after permanent 
discontinuation of 
trial medication
Every 4 
weeks
Days (in respective 
cycle)*1
-14 to  
-1
   1           2          8
  1           2          8
Informed consent 
x
Informed consent for 
pharmacogenetics
x
Demographics and baseline 
conditions
x
Medical history
x
Review of incl-/excl criteria
x
   x2
Dose assignment
x3
LABS/SAFETY 
ASSESSMENTS
Safety laboratory 
parameters incl. urinalysis4
x
   x           x
  x
x
x
x
Physical examination and
ECOG performance status5
x
   x5
  x5
x
x
Vital signs, height6, weight6
x
  x         x
  x
x
x
x
Serum pregnancy test 7
x
   x
  x
x
12 lead-ECG
x
   x
  x
x
x8
Adverse events
x
   x          x          x
  x          x              x
x
x
x
Concomitant therapy
x
   x         x          x
  x          x              x
x
x
x9
DISEASE ASSESSMENT
Bone marrow (BM) 
aspiration10
x
  x 
x
x
 
 
Disease assessment w/ PB 
and clinical assessment
   x
  x
x
Disease assessment w/ BM 
or biopsy 12
   x
  x
x
 
   
 
                      
                          
 
   
  
                               
TRIAL MEDICATION
Drug Administration
     x
  x 
x
Eligibility for further 
administration
     x
  x16
End of active trial treatment
x
Other therapy for AML
x
x
x
Vital Status
x


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EOT: 
End of treatment evaluation. The EOT visit will be performed as soon as possible but no later than one week (7 
days) after permanent discontinuation of trial medication for any reason, or when the Investigator decides with the 
patient to permanently discontinue the trial medication.  
FTE:
Further treatment evaluation.  Each patient who will receive more than 3 administrations will have a FTE visit for 
each infusion.  The visits are completed on day 1 of every second cycle (i.e. 5, 7, 9, etc.) until the patient 
discontinues or completes up to 12 months of therapy. Infusions are every 2 weeks for the first 3 cycles then for 
FTE, these treatments are monthly.  
EoR:
The End of Residual End Period visit should not be performed earlier than 30 days after permanent discontinuation 
of the trial medication.
FU: 
Follow-up visits after the last administration of BI 836858 completed, at least every 4 weeks until 6 months after 
the last administration of BI 836858. In case patients do not visit the site, the FU visit can be conducted by phone.
*   The planned duration of a treatment cycle is 14 days; there will be one administration of BI 836858
** These visits are only for those patients after 3 administrations and who are tolerating the infusions well who continue 
until PD or other criteria for withdrawal are met as noted in Section 3.3.4.1. These visits occur every second cycle (i.e., 
Cycles 5, 7, 9…21) 
1
Visit window of +1 day only allowed beginning in Cycle 9.  In Cycles 1 through 7 visit window not allowed due to 
the PK schedule as outlined in Tables 1b and 2b.
2
Review of inclusion/exclusion criteria during screening and again on day of first administration. 
3
After informed consent and review of inclusion/exclusion criteria (timing described in footnote 2).
4 
For details refer to Section 5.2.3.1. Urine has to be measured only at screening, FTE, EOT and FU visits.  Safety 
laboratory assessments may be completed up to 2 days prior to administration. An additional safety lab will be 
collected on day 2 (i.e., 24 hours after the first administration of BI 836858). Other lab tests to be included: 
Haptoglobin, direct antiglobulin test, bilirubin (direct and indirect) and free hemoglobin.
5
At screening and every second cycle (i.e. before cycle 1, 3, 5, 7 etc.) Physical examination may be completed up to 
2 days prior to administration.  Eastern Cooperative Oncology Group (ECOG) score must be completed on the day 
of the administration. If the first administration of BI 836858 occurs within 3 days of the screening visit, these 
examinations do not need to be repeated.
6
Height and weight only at day 1 of first administration of BI 836858; weight also at EOT.
7
For women of childbearing potential only.  Serum pregnancy test to be completed at odd numbered administrations 
only (e.g., administration 1, 3, 5, etc.) 
8
ECG will be performed at visit 1 of each cycle and at EoR if abnormal at EOT.
9
Concomitant therapy during FU is collected only if indicated for treatment of adverse event.
10
Bone marrow aspirate to be performed, at investigator discretion, if there is suspicion of relapse. 
 
12
Disease assessment with bone marrow (or biopsy) is to be performed if suspicion of relapse
    
 
 
   
 
 
16
Can be performed up to 2 days prior to this visit. 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART - A (REFRACTORY OR RELAPSED 
PATIENTS)..................................................................................................4
FLOW CHART - B (AML PATIENTS IN CR) ..............................................6
TABLE OF CONTENTS ................................................................................ 13
ABBREVIATIONS.......................................................................................... 18
1.
INTRODUCTION.................................................................................... 22
1.1
MEDICAL BACKGROUND............................................................................22
1.2
DRUG PROFILE...............................................................................................23
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 26
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................26
2.2
TRIAL OBJECTIVES.......................................................................................27
2.3
BENEFIT - RISK ASSESSMENT ...................................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 30
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................30
3.1.1
Administrative structure of the trial...................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................33
3.3.1
Main diagnosis for study entry............................................................33
3.3.2
Inclusion criteria...................................................................................34
3.3.3
Exclusion criteria ..................................................................................34
3.3.4
Removal of patients from therapy or assessments.............................36
3.3.4.1
Removal of individual patients................................................36
3.3.4.2
Discontinuation of the trial by the sponsor..............................36
4.
TREATMENTS........................................................................................ 38
4.1
TREATMENTS TO BE ADMINISTERED....................................................38
4.1.1
Identity of BI investigational product and comparator product......38
4.1.2
Method of assigning patients to treatment groups ............................39
4.1.3
Selection of doses in the trial................................................................39
4.1.4
Drug assignment and administration of doses for each patient .......40


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4.1.5
Blinding and procedures for unblinding ............................................43
4.1.5.1
Blinding....................................................................................43
4.1.5.2
Procedures for emergency unblinding .....................................43
4.1.6
Packaging, labelling, and re-supply ....................................................43
4.1.7
Storage conditions.................................................................................43
4.1.8
Drug accountability ..............................................................................44
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................44
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................44
4.2.2
Restrictions............................................................................................45
4.2.2.1
Restrictions regarding concomitant treatment .........................45
4.2.2.2
Restrictions on diet and life style.............................................45
4.3
TREATMENT COMPLIANCE.......................................................................46
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 47
5.1
EFFICACY – PHARMACODYNAMICS.......................................................47
5.1.1
Endpoints of efficacy.............................................................................47
5.1.2
Assessment of efficacy...........................................................................47
5.1.2.3
Assessment and definition of best overall response ................48
5.1.2.4
Progression free survival (PFS) ...............................................49
5.1.2.5
Time to treatment failure (TTF)...............................................50
5.2
SAFETY..............................................................................................................51
5.2.1
Endpoints of safety................................................................................51
5.2.1.1
Dose limiting toxicity (DLT) for refractory or relapsed AML 
patients.....................................................................................51
5.2.1.2
Dose limiting toxicity (DLT) for AML patients in CR............52
5.2.2
Assessment of adverse events...............................................................53
5.2.2.1
Definitions of AEs ...................................................................53
5.2.2.2
Adverse event collection and reporting ...................................56
5.2.3
Assessment of safety laboratory parameters......................................58
5.2.3.1
General safety laboratory parameters ......................................58
5.2.4
Electrocardiogram................................................................................59
5.2.5
Assessment of other safety parameters...............................................60


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5.2.5.1
Vital signs ................................................................................60
5.2.5.2
Physical examination ...............................................................60
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................60
 
6.
INVESTIGATIONAL PLAN.................................................................. 66
6.1
VISIT SCHEDULE............................................................................................66
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................66
6.2.1
Screening and run-in period ................................................................66
6.2.2
Treatment periods for refractory or relapsed AML patients...........67
6.2.2.1
Visit 1 and Visit 3 – day of BI 836858 administration 
(administrations 1-8)................................................................67
6.2.2.2
Visit 2 and Visit 4 (+ 1 day window allowed beginning in 
Cycle 3), following administration of BI 836858....................68
6.2.3
End of treatment and follow-up period for refractory or 
relapsed AML patients .........................................................................68
6.2.3.1
EOT visit..................................................................................68
6.2.3.2
Further treatment (Visit 1 and Visit 2).....................................69
6.2.3.3
End of further treatment...........................................................70
6.2.4
Treatment period for AML patients in CR ........................................70
6.2.4.1
Visit 1– Day 1 of BI 836858 administration (administrations 1-
3) ..............................................................................................70
6.2.4.2
Further treatment......................................................................71
6.2.4.3
End of Treatment (EOT) visit..................................................72


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6.2.4.4 End of Residual Effect Period visit (EoR)...............................72
6.2.5
Follow up................................................................................................73
6.2.6
End of the whole trial ...........................................................................73
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 75
7.1
STATISTICAL DESIGN - MODEL................................................................75
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................75
7.3
PLANNED ANALYSES....................................................................................75
7.3.1
Primary analyses...................................................................................75
7.3.2
Secondary analyses ...............................................................................76
7.3.2.3
Best overall response ...............................................................76
7.3.2.4
Progression free survival, time to treatment failure, 
7.3.3
Safety analyses.......................................................................................77
7.3.4
Interim analyses ....................................................................................77
7.4
HANDLING OF MISSING DATA ..................................................................79
7.5
RANDOMISATION ..........................................................................................80
7.6
DETERMINATION OF SAMPLE SIZE ........................................................80
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 81
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................81
8.2
DATA QUALITY ASSURANCE .....................................................................81
8.3
RECORDS..........................................................................................................82
8.3.1
Source documents .................................................................................82
8.3.2
Direct access to source data and documents.......................................82
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................83
8.4.1
Listedness...............................................................................................83
8.4.2
Expedited reporting to health authorities and IECs/IRBs................83


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8.5
STATEMENT OF CONFIDENTIALITY.......................................................83
9.
REFERENCES......................................................................................... 84
9.1
PUBLISHED REFERENCES...........................................................................84
9.2
UNPUBLISHED REFERENCES.....................................................................87
10. APPENDICES .......................................................................................... 88
10.1
PUBLICATION POLICIES .............................................................................88
10.2       EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS ............................................................................88
10.3
CLINICAL EVALUATION OF LIVER DISEASE .......................................89
10.3.1 Introduction...........................................................................................89
10.3.2 Procedures .............................................................................................89
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 91


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ABBREVIATIONS
AE
AESI
ALT
AML
AMP
ANC
anti-HB
anti-HCV
AP
APL
aPTT
AST
ASCT
BI
BLQ
BM
CA
◦C
CL
Cmax
CML
CNS
CR
Adverse Event
Adverse event of special interest
Alanine amino transferase
Acute myeloid leukemia
Auxiliary medicinal product
Absolute neutrophil count
Hepatitis B surface antibody
Hepatitis C antibody
Alkaline phosphatase
Acute promyelocytic leukemia
Activated partial thromboplastin time
Aspartate amino transferase
Allogeneic stem cell transplantation
 
 
 
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Below the lower limit of quantification
Bone marrow
Competent Authority
Degree Celcius
Total plasma clearance
Maximum measured plasma concentration
Local Clinical Monitor
Central nervous system
Complete Remission


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CRi
CRA
CRF
CRO
CTCAE
CTMF
CTP
CTR
DEDP
DILI
DLT
DNA
eCRF
ECG
ECOG
EDTA
ELN
EOFT
EoR
EOT
FDA
FTE
FU
GCP
G-CSF
GvHD
HBsAg
HIV
Complete Remission with incomplete blood recovery
Clinical Research Associate
Case Report Form
Clinical Research Organization
Common Terminology Criteria for Adverse Events
Clinical Trial Master File
Clinical Trial Protocol
Clinical Trial Report
Drug exposure during pregnancy
Drug Induced Liver Injury
Dose Limiting Toxicity
Deoxyribonucleic-acid
Electronic Case Report Form
Electrocardiogram
Eastern Cooperative Oncology Group
Ethylen-diamine-tetraacetic acid
European LeukemiaNet
End of further treatment
End of Residual Effect Period
End of active treatment
Food and Drug Administration
Further treatment evaluation
Follow-up
Good Clinical Practice
Granulocyte colony stimulating factor
Graft versus Host Disease
Hepatitis B surface antigen
Human immunodeficiency virus


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IB
ICH
IEC
INR
IRB
IRR
ISF
i.v.
IWG
LDH
LFT
mAB
mg
MTD
MedDRA
MRT
NBE
NC
NIMP
NK
NOA
NOP
NOR
NOS
OPU
ORR
Investigator’s Brochure
International Conference on Harmonization
Independent Ethics Committee
International normalized ratio
Institutional Review Board
Infusion-related reaction
Investigator Site File
Intravenous
International Working Group
Lactate dehydrogenase
Liver function test
Monoclonal antibody
milligram
Maximum Tolerated Dose
Medical Dictionary for Drug Regulatory Activities
Mean residence time
New biological entity
Not calculated
 
Non-investigational medicinal product
Natural killer (cells)
Not analyzed
No peak detectable
No valid result
No sample available
Operative Unit
Objective Response Rate


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PD
PFS
PK
PLT
PR
PT
REP
RNA
RTPCR
SAE
sCD33
SCT
SD
SDV
SOP
SUSAR
TCM
TDMAP
TF
TNF
TTF
ULN
WBC
WHO
Progressive disease
Progression free survival
Pharmacokinetics
Platelets
Partial Remission
Prothrombin time
Residual Effect Period; after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
Ribonucleic-acid
Reverse transcription polymerase chain reaction
Serious Adverse Event
Soluble CD33
Stem cell transplantation
Stable disease
Source data verification
Standard Operating Procedure
Suspected unexpected serious adverse reaction
Trial Clinical Monitor
Trial Data Management and Analysis Plan
Treatment Failure
Tissue necrosis factor
Time to treatment failure
Upper limit of normal
White blood cell count
World Health Organization


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
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 favorable, 
intermediate, and unfavorable 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 consists of cytarabine and an anthracycline, is 
aiming to reach a 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 
to75 % 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 is 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 assessment of eligibility for intensive treatment is performed regularly for 
every single patient based on the specialised physician's clinical experience and the 
comprehensive review of factors such as patient age, performance score, organ dysfunctions 
and co-morbidities, as well as the patient's informed decision.
The median overall survival (OS), for patients not achieving a CR is <1 year, even with best 
palliative treatment. Even for patients who have received induction and consolidation 
treatment the OS and cure rate are poor: Over 60 % will die due to their disease within 
5 years. 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.


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AML patients in CR who have been initially diagnosed with non-favorable genetics and 
either have received induction and consolidation treatment and are not candidates for 
allogeneic hematopoietic stem cell transplantation (e.g. no donor available, not eligible/fit 
enough) or have received an allogeneic hematopoietic stem cell transplantation have a very 
high risk to relapse. For those patients no standard therapy to maintain the CR is currently 
available. 
For refractory or relapsed AML patients, outside of treatment in clinical trials, re-induction 
followed by allogeneic stem cell transplantation is the most common regimen. 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 relapses 
disease after allogeneic stem cell transplantation, no approved or standard treatment is 
available. 
Evidence that targeting of CD33 can result in clinical benefit for patients suffering from 
AML is provided by the unconjugated, humanized IgG1 monoclonal antibody lintuzumab 
(SGN-33, HuM195) which showed signs of clinical efficacy as monotherapy in a Phase I 
clinical trial in relapsed / refractory AML patients with an objective response rate (ORR) 
of 17 % (R11-1481). Objective response was defined as either CR, CRi or PR.
Lintuzumab was also explored in a Phase I study in patients with acute promyelocytic 
leukemia (APL) after remission induction. Multiple doses of lintuzumab could be 
administered safely and appeared to eliminate minimal residual disease detectable by RTPCR 
in some patients. (R11-4695)
Currently, major efforts are focused on the improvement of the therapy in these subgroups of 
patients with unfavourable prognosis.
1.2
DRUG PROFILE
BI 836858 is a fully human IgG1 antibody specific for human CD33 which is Fc-engineered 
for increased binding to FcRIIIa. Please see full details in latest version of Investigator’s 
Brochure (c02324887-03).
CD33 is a myeloid differentiation antigen which is expressed on the cell surface of non-
malignant leukocytes of the myeloid lineage and with high frequency on malignant cells in 
AML, chronic myeloid leukemia and myelodysplastic syndrome (R11-1467, R11-1468, 
R11-1470, R11-2960). In addition to expression on malignant myeloid blast cells, CD33 
expression was reported for leukemic stem cells (R11-1469). For normal leukocytes, CD33 
expression was reported for monocytes, macrophages, dendritic cells, and to a lower extent, 
granulocytes (R11-1467), but not for CD34+CD38- hematopoietic stem cells in the bone 
marrow (R11-1469). Based on the expression profile of CD33, transient pharmacodynamic 
effects of CD33 antibody treatment on CD33 positive normal cell types may be expected.
 
 


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BI 836858 is Fc-engineered for increased binding to FcRIIIa, which results in increased 
antibody dependent cellular cytotoxicity (ADCC) activity of BI 836858 as compared to a 
non-Fc-engineered IgG1-type of antibody. The ADCC activity of BI 836858 was assessed on 
a panel of AML-derived cell lines and primary AML cells and compared to the ADCC 
activity of lintuzumab, a humanized CD33-specific antibody which has been in clinical 
development for AML (R11-1471). 
 
 
 
The CD33 antigen is known to internalize upon antibody binding (R11-4256).
 
 
 
 
 
 
 
 
Preliminary data from this first-in-human dose escalation study with BI 836858 (trial number 
1315.1) in patients with relapsed or refractory acute myeloid leukemia investigating a weekly 
dose (q1w) is available.  As of the data cut-off date 12 April 2016, 26 patients were treated 
with BI 836858, all with doses of 10, 20 and 40 mg, respectively. The most frequent drug-
related AE Preferred Term (PT) was infusion-related reaction (IRR) in eleven out of 26 
patients (42 %). Adverse events considered a sign or symptom of an IRR by the investigator 
included back pain, chest pain, chills, dyspnea, fever and hypotension. All patients recovered 
from their IRRs with adequate symptom-oriented therapy. Drug-related transient increase of 
liver function tests was reported in four patients: one patient with grade 1 aspartate amino 


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transferase (AST) and alanine amino transferase (ALT), one patient with grade 1 ALT, grade 
3 AST and grade 3 bilirubin, one patient with grade 3 AST, grade 3 ALT and no increase of 
bilirubin and another one (not yet entered in the database) with grade 3 AST, grade 1 ALT 
and no increase of bilirubin. 
 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
New therapeutic strategies are needed to significantly improve the prognosis of AML patients 
with relapsed/refractory disease, but also for AML patients in CR with a high risk to relapse. 
Recent successful developments of signal transduction inhibitors or antibodies targeting
specific molecules that are deemed important for the malignant cell biology have spurred the 
search for other targets and respective antibodies.
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). 
CD 33 targeting approaches have been evaluated in clinical trials in AML patients. 
Gemtuzumab Ozogamicin (Mylotarg®), an immunoconjugate of a CD 33 mAb and 
calicheamicin, was approved by the Food and Drug Administration (FDA) in 2000 for 
patients over the age of 60 with relapsed AML, or those who are not considered candidates 
for standard chemotherapy. In June 2010 Mylotarg® was withdrawn by FDA request, due to a 
negative benefit risk assessment in a Phase III trial. As Mylotarg is an immunconjugate of a 
CD 33 mAb and a toxin, the MoA and also the safety profile are different to BI 836858. 
Clinical data of relapsed/refractory AML patients who were treated with the humanized 
CD33 IgG1 monoclonal antibody (mAb) lintuzumab are published (R11-1474, R01-1267, 
R11-1481). In these trials, administration of lintuzumab was safe and has shown signs of 
clinical efficacy (ORR) of 17 % in a Phase I trial in relapsed / refractory AML (R11-1481).  
Lintuzumab was also explored in a Phase I study in patients with APL after remission 
induction. Multiple doses of lintuzumab could be administered safely and appeared to 
eliminate minimal residual disease detectable by RTPCR in some patients. (R11-4695)
The clinical experience with lintuzumab supports the assumption that targeting CD33 with an 
IgG1-type antibody may translate into clinical benefit in patients with AML with an 
acceptable side effect profile. 
 
BI 836858 is a monoclonal antibody which mechanistically relies on effector-cell mediated
immune mechanisms, in particular ADCC (antibody dependent cellular cytotoxicity) and
ADCP (antibody dependent cellular phagocytosis). ADCC predominantly depends on the
presence of natural killer (NK) cells and ADCP on the presence of myeloid derived effector
cells (i.e. monocytes and macrophages). In a recent publication, where NK cell phenotype 
and function was assessed in 32 consecutive AML patients including 12 achieving complete 
remission, it was reported that NK cells in relapsed and refractory AML patients have 
impaired functionality. It was also shown that phenotypic and functional abnormalities of NK 
cells are partially restored in AML patients achieving a CR. (R15-6192).


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It is likely that BI 836858 requires the presence of functional NK cells and monocytes to 
achieve clinical benefit in AML patients. AML patients who have achieved a CR have an 
improved effector cell profile (NK cells and monocytes) and may have a higher likelihood to 
benefit from the pharmacological activity of BI 836858.
 
 
 
 
 
 
This trial was the first administration of BI 836858 in humans.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to determine the maximum tolerated doses (MTDs) of 
BI 836858.  BI 836858 is a new biological entity (NBE) and the MTD may not be reached. 
To learn more about the safety and preliminary efficacy there will be an expansion cohort 
either at the MTD or the highest tested dose (e.g. 320 mg). Secondary objectives are to 
document the safety and tolerability of BI 836858, 
 
and to evaluate efficacy (see Section 5).
2.3
BENEFIT - RISK ASSESSMENT
Although considerable progress has been achieved in understanding the etiology and biologic 
behavior of AML and the development of more effective treatment regimens are ongoing,


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most patients with refractory or relapsed AML have a very poor prognosis. Re-induction 
followed by allogeneic stem cell transplantation 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. 
AML patients in CR who have been initially diagnosed with non-favorable genetics and 
either have received induction and consolidation treatment and are not candidates for 
allogeneic hematopoietic stem cell transplantation (e.g. no donor available, not eligible/fit 
enough) or have received an allogeneic hematopoietic stem cell transplantation have a very 
high risk to relapse. For those patients no standard therapy to maintain the CR is currently 
available. 
BI 836858 is a monoclonal antibody, which specifically targets CD33. Targeting CD33 in 
patients with AML may potentially offer a benefit to those patients since CD33 is expressed 
on AML blasts in the majority of AML patients (see Section 1.2). In vitro, BI 836858 is a 
potent inducer of ADCC, which results in cytolysis of AML-derived cell lines and primary 
AML blasts from peripheral blood and bone marrow. In the clinical setting, these effects may 
potentially result in anti-leukemic activity as a monotherapy, but also offer potential for 
combination with other drugs in patients with AML.
CD33 is not known to be expressed outside of the hematopoietic system. The anticipated side 
effect profile of BI 836858 based on the CD33 expression profile comprises predominantly 
hematologic adverse events such as neutropenia. These hematological adverse events are 
frequently reported in patients with hematological diseases and may be due to the underlying 
disease, the treatment or both. The preclinical safety assessments for BI 836858 have 
revealed TNF-alpha and INF-gamma release, suggesting a potential for infusion reactions. 
Clinical data from 26 patients are available from this first in human study 1315.1. 
 
 
Infusion reactions were the most frequently observed drug related adverse event in this first 
in human study and is newly classified as a listed (expected) adverse event. Infusion-related 
reactions are frequently observed with monoclonal antibodies in hematological indications, 
and signs/symptoms of IRRs reported for BI 836858 are in line with AEs reported for other 
antibodies approved in hematology indications. To mitigate the risk for IRRs, protocol 
specified precautions must be adhered to, i.e. premedication, rate-controlled infusion 
schedule and symptom monitoring. If an IRR occurs the infusion of BI 836858 should be 
paused and additional supportive measures are recommended based on standard of care, e.g. 
additional corticosteroid or non-steroidal analgesics and/or opioids.in. So far no case of life-
threatening IRR was reported; however in case a patient is developing a life-threatening IRR 
despite appropriate premedication the patient should discontinue the treatment with BI 
836858 permanently. Drug-related transient increase of LFT was reported in 4 patients. In 
none of these cases Hy´s law criteria were met. Frequent testing of LFTs is mandated during 
treatment with BI 836858 (frequency defined in the clinical trial protocols). In case of 


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alterations of liver laboratory parameters the clinical evaluation of liver disease and follow up 
on liver laboratory parameters should be done as outlined in the clinical trial protocol.
Patients with refractory or relapsed AML with limited or no standard treatment options may 
benefit from blast cell reduction and disease stabilization following treatment with 
BI 836858. AML patients in CR who have been initially diagnosed with non-favorable 
genetics with a very high risk to relapse with limited or no standard treatment options may 
benefit from targeting CD33 positive leukemic stem cells and maintenance of achieved 
complete remission to initial standard therapy.
The potential benefit of therapy with BI 836858 is expected to outweigh the treatment-related 
risks.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial will be performed in two separate patient populations: 1) Patients diagnosed with 
relapsed or refractory AML who have failed at least one prior line of therapy and 2) patients 
with AML who are in complete remission (CR) with a high risk to relapse. It will be 
performed in an open, non-randomized, 3+3 design followed by an expansion cohort. A cycle 
will comprise of 14 days. 
For patients with refractory or relapsed AML, one cycle is 14 days with two administrations 
of BI 836858 (i.e. administrations on Days 1 and 8).  Patients with clinical benefit, defined by 
the International Working Group (IWG) as having objective response (partial remission (PR) 
or complete remission (CR) or complete remission with incomplete blood recovery (CRi)) or 
subjective response (in the absence of objective response) after 8 administrations and who are 
tolerating the infusions, may continue until progressive disease (PD) and as long as neither 
patient nor Investigator requests treatment discontinuation.
For AML patients in CR, one cycle is 14 days with one administration of BI 836858 (i.e. 
administrations on Days 1) in Cycles 1, 2 and 3.  From the 4th cycle onwards, patients will 
receive monthly (every second cycle) infusions of BI 836858 (i.e. 4th infusion on Cycle 5 Day 
1, 5th infusion on Cycle 7 Day 1) for overall up to one year of treatment unless these patients 
relapse or infusions are not tolerated.  
To determine separate MTDs for each patient population, cohort dose escalation will be 
conducted following the 3+3 design for the refractory or relapsed AML patients and the 
patients with AML in CR with high risk to relapse, respectively.  The dose level will be 
escalated with each new cohort until at least one out of three patients of a cohort experiences 
a dose limiting toxicity (DLT; for definition see Section 5.2.1.1) during the first two cycles
(DLT evaluation period).  If exactly one out of the three patients of the cohort experiences a 
DLT, three additional patients will be treated at the same dose level.  If none of the three 
additional patients experiences a DLT, then the cohort dose escalation will be continued by 
treating the next three patients at the next higher dose level.  If at least two out of up to six 
patients at a dose level experience a DLT, the MTD has been exceeded and the dose will be 
deescalated until a dose level is reached in which at most one DLT out of six patients is 
observed (R01-0028).  The MTD is defined as the dose of BI 836858 that is one dose cohort 
below the dose at which two or more out of six patients experienced DLT.  At the maximum 
tolerated dose, no more than one patient out of six patients may experience DLT, i.e., the 
MTD is defined as the highest dose studied for which the incidence of dose-limiting toxicity 
is no more than 17% (i.e. 1/6 patients) during the first two cycles.
Patients are considered to have completed the first two cycles if they have reached end of 
cycle 2 and have received all planned administrations of BI 836858 (i.e. 4 administrations for 
patients with relapsed or refractory AML and 2 administrations for patients in CR).


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However, for those patients who receive more than two cycles of BI 836858, all DLT 
occurring after end of cycle 2 will be taken into consideration for further development of BI 
836858.
Table 3.1: 1
Table of action taken in response to DLTs
Patients 
experiencing a 
DLT
Number of patients in 
cohort
Action taken by Sponsor
0
3
Open the next cohort
1
3
Add 3 additional patients (see below) 
at same dose level
1
6
If there are no new DLTs in additional 
3 patients,  open next cohort
2
6
If there is at least one new DLT in 
additional 3 patients, MTD is 
exceeded, expansion cohort opened at 
next lower dose level.
During the dose escalation phase, each patient will receive up to 2 repeated treatment cycles
before DLT assessment. 
For both patient populations the dose is planned to be escalated in cohorts at pre-defined dose 
levels based on a multiplication factor of 2. The dose levels are 10 mg, 20 mg, 40 mg, 80 mg, 
160 mg, and 320 mg as outlined in Section 4.1.3. However, for AML patients in CR, the dose 
escalation will start with the 40 mg dose cohort and follow the same dose escalation levels.
Intermediate dose levels and dose levels higher than 320 mg may be investigated if agreed 
upon between Investigator and Sponsor.  
After definition of the MTD, it is planned to enroll an expansion cohort of 12 patients to 
better characterize the safety of BI 836858. In case no MTD is reached up to the highest 
planned dose (e.g., 320 mg), 12 additional patients will be treated with each respective 
schedule at the highest test dose (i.e., 320 mg) of BI 836858. 
The primary analysis will take place when all patients from the cohort dose escalation and 
dose expansion cohorts have had a minimum of 4 cycles or have discontinued from the trial 
prior to reaching end of cycle 4 due to meeting the criteria for withdrawal as outlined in 
Section 3.3.4.1.
3.1.1
Administrative structure of the trial
Boehringer Ingelheim is the Sponsor of this trial. The Coordinating Investigator will be 
 participating Investigators will be physicians experienced and specialized 
in the treatment of AML and in the conduct of Phase I trials.


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In regular telephone conferences between the participating Investigators and the Sponsor, 
there will be discussions of safety assessments, recommendations for cohort dose escalation, 
to reach a consensus on DLT, and whether to continue or modify the trial.  
All safety laboratory analyses will be performed locally at each clinic site in the schedule 
outlined in the Flow Charts. All of the biomarker analyses will be performed at 
 
 with the exception of cytokine analyses which will be performed in locations 
noted in Section 5.6.3.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The primary objective of this trial is to determine the MTD for both patient populations 
separately. The most important secondary objective is to assess the safety of BI 836858.  This 
can be achieved by an open label, single arm design without a control group.
Adult patients with refractory/relapsed AML are considered eligible for this trial.  
Relapsed AML is defined as recurrent disease after prior remission of any duration. 
Refractory disease is defined as failure to achieve remission to most recently administered 
therapy. Patients with primary refractory disease, defined as failure to achieve remission to 
initial therapy, are eligible. Typically patients with primary refractory disease are defined as 
refractory after failure of two cycles of intensive induction. Patients with failure of a single 
cycle of induction are eligible for this trial if they refuse to receive a second induction cycle 
or if they are not candidates for a second intensive induction cycle. Patients receiving 
hypomethylating agents as initial induction should receive at least two cycles of induction 
before designation as refractory.
AML patients in CR who have been initially diagnosed with non-favorable genetics have a 
very high risk to relapse. Eligible patients for this trial should either have received induction 
and consolidation treatment and are not candidates for allogeneic hematopoietic stem cell 
transplantation (e.g. no donor available, not eligible/fit enough) or have received allogeneic
hematopoietic stem cell transplantation. For those patients no standard therapy to maintain 
the CR is currently available.
These AML patient groups were selected for inclusion in this trial, because these patients 
constitute groups with unfavourable prognosis for whom currently no satisfactory standard 
treatment exists.
The trial design will follow a 3+3 design with cohort dose escalation and de-escalation for 
both patient groups. Once the MTD has been defined, an expansion cohort of 12 patients is 
planned to be enrolled to better characterize the safety profile and tolerability of the MTD. In 
case no MTD is reached up to the highest planned dose (e.g., 320 mg), 12 additional patients 
will be treated with the respective schedule of the highest tested dose (e.g., 320 mg) of         
BI 836858.  This trial design is accepted for hematology Phase I studies. 


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For patients with refractory or relapsed AML, the first efficacy assessment via bone marrow 
aspirate will be performed after 2 cycles (4 administrations).  Subsequent disease assessment 
will be performed after 4 cycles (8 administrations) and at the discretion of the Investigator.  
For AML patients in CR, disease status will be followed up on a regular basis with peripheral 
blood count and a bone marrow assessment will be performed if suspicion of relapse. Patients 
with a MRD marker will be followed up on this marker as well, however this is explorative.  
Intra-patient dose escalation will be allowed for selected patients in case the next higher dose 
cohort is free of DLT and considered safe. This is not considered a safety risk because it will 
be restricted to patients who have tolerated at least three cycles of BI 836858 at the time of 
dose escalation and may offer a potential benefit to patients enrolled at a lower dose.
Each patient will be closely monitored for infusion-related reactions, as this is a potential 
side-effect for mAbs.
Safety assessments will be performed at all visits during the treatment phase.
The trial shall allow the investigation of BI 836858 in AML with regard to safety and the 
definition of the optimal dose for the future clinical development program in this disease.
3.3
SELECTION OF TRIAL POPULATION
Approximately 50 patients with relapsed or refractory AML and about 35 AML patients in 
CR with high risk to relapse will be screened. Of these patients, approximately 36 with 
refractory or relapsed AML and approximately 27 patients with AML in CR with high risk to 
relapse will be included in this trial from a target of 5 sites. Each site will screen a target of 
about 10 patients.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the investigator site file (ISF) at the investigational site irrespective of whether 
they have been treated with investigational drug or not.
3.3.1
Main diagnosis for study entry
Patients with relapsed or refractory AML as defined according to the World Health 
Organization (WHO) criteria will be eligible for this trial (see Section 3.2),
AND
Patients with AML in CR with high risk to relapse will be eligible for this trial (see also 
Section 3.2). AML in CR with high risk to relapse is defined as follows:
a) AML patients with non-favorable genetics (according to European LeukemiaNet 
(ELN) classification) that are in CR after having received induction and consolidation 
chemotherapy and are not candidates for allogeneic hematopoietic stem cell 
transplantation (SCT) (e.g., no donor available, not eligible/fit enough) 


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or
b) AML patients with non-favorable genetics (according to ELN classification) that are 
in CR after allogeneic hematopoietic stem cell transplantation.
CR is defined as following: Morphologically leukemia free state (i.e. bone marrow 
with <5% blasts by morphologic criteria and no blasts with Auer rods, no evidence of 
extramedullary leukemia) and absolute neutrophil count ≥1000 /μL and platelets 
≥100,000 /μL. However, for being eligible for this trial, patients in CR must not be 
independent of red blood cell transfusions.
3.3.2
Inclusion criteria
1. Two patient populations: Patients with diagnosis of relapsed or refractory AML 
with at least one prior treatment for AML and patients with diagnosis of AML in 
CR with high risk to relapse.
2. For patients with refractory or relapsed AML: Expression of CD33 on more than 
30% of bone marrow blasts per central laboratory assessment at the Ohio State 
University.
For AML patients in CR with high risk to relapse: Patients should have had a 
CD33 positive expression of bone marrow blasts at the time of initial AML 
diagnosis. No CD33 expression confirmation at screening is required.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2. See 
Section 10.2
4. Age ≥18 years.
5. Written informed consent which is consistent with International Conference on 
Harmonization – Good Clinical Practice (ICH-GCP) guidelines and local 
legislation.
3.3.3
Exclusion criteria
1.   Patients with acute promyelocytic leukemia according to WHO definition
2.   Patients with refractory or relapsed AML, >5,000 blasts in the peripheral blood.
3.   Anti-leukemia therapy within two weeks before first treatment with BI 836858; 
however, parallel treatment with Hydroxyurea is allowed for patients with 
relapsed/refractory AML. (See Section 4.2.2.1)
4.   Allogeneic stem cell transplantation within the last 28 days before first treatment 
with graft versus host disease requiring more than 20 mg of steroids per day.
Steroid dosage must be stable within two weeks prior to start of treatment.
5.   Patients who are candidates for allogeneic stem cell transplantation (for patients 
with refractory or relapsed AML).
6.   Second malignancy currently requiring active therapy.  However, patients with 
organ-confined prostate cancer with no evidence of recurrent or progressive 


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disease based on prostate-specific antigen values are also eligible for this study if 
hormonal therapy has been initiated, or a radical prostatectomy or definitive 
radiotherapy has been performed.
7.  Symptomatic central nervous system involvement (see Section 4.2.2)
8.  Aspartate amino transferase (AST) or alanine amino transferase (ALT) greater 
than 2.5 times the upper limit of normal (ULN), or AST or ALT greater than 
5 times the ULN for those with Gilbert syndrome.
9.   Prothrombin time (PT) >1.5 x ULN for subjects not on therapeutic vitamin K 
antagonists (phenprocoumon, warfarin)
10. Bilirubin greater than 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 greater than 2.0 mg/dl
12. 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
13. Concomitant intercurrent illness, or any condition which in the opinion of the 
Investigator, would compromise safe participation in the study, e.g. active severe 
infection, unstable angina pectoris, new onset of exacerbation of a cardiac 
arrhythmia
14. Psychiatric illness or social situation that would limit compliance with trial 
requirements
15. Concomitant therapy, which is considered relevant for the evaluation of the 
efficacy or safety of the trial drug (see Section 4.2.2)
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 
6 months after the last administration of BI 836858, i.e. combination of two forms 
of effective contraception (defined as hormonal contraception, intrauterine device, 
condom with spermicide, etc.).  Subjects will be considered to be of childbearing 
potential unless surgically sterilized by hysterectomy, or bilateral tubal 
ligation/salpingectomy or post-menopausal for at least two years
17. Male patients with partners of childbearing potential who are unwilling to use 
condoms in combination with a second effective method of contraception (defined 
as hormonal contraception, intrauterine device, condom with spermicide, etc.)
during the trial and for 6 months after the last administration of BI 836858
18. Pregnant or nursing female patients
19. Treatment with another investigational agent under the following conditions:
a) Within two 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.
c) Concomitant treatment with another investigational agent while participating 
in this trial.
20. Prior treatment with a CD33 antibody
21. Patient unable or unwilling to comply with the protocol.


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3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient is to be withdrawn from the trial if:

The patient withdraws consent. Patients are free to discontinue their participation in 
this trial at any time without the need to justify the decision.

The patient needs to take concomitant drugs which may interfere with the 
investigational product (please refer to Section 4.2.2).

The patient is no longer able to participate for other medical reasons (e.g. adverse 
events unrelated to therapy or disease progression, concomitant diagnoses, pregnancy, 
surgery or administrative reasons). The Investigator may also stop a patient's 
participation if the patient is no longer able to attend trial visits.
A patient can be withdrawn from the trial after discussion between the Investigator and the 
Sponsor if eligibility criteria are violated and/or the patient fails to comply with the protocol.
All withdrawals will be documented and the reason for withdrawal recorded and discussed, as 
necessary, in the final report of the trial. As soon as a refractory or relapsed AML patient is 
withdrawn from the trial treatment, the end of active treatment (EOT) visit has to be 
performed if feasible. For patients with AML in CR, as soon as a patient is withdrawn from 
the trial treatment, the end of active treatment (EOT) visit and the End of Residual Effect 
Period (REP) visit (EoR visit) must 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 consent withdrawal, no further 
visits will be completed and no further trial data will be collected. However, if information 
about survival status is available in the public domain, then the Investigator is requested to 
report this information in the eCRF.
A patient has to discontinue trial drug administration in case:

A DLT occurs which does not recover to a degree that allows treatment continuation 
(see Section 4.1.4).

Progressive disease (PD) or any other concomitant diagnosis/symptom develops 
resulting in an indication to start any other therapy for AML, including deterioration 
of general condition.
Patients not completing the first two cycles (with all planned BI 836858 administrations) for 
reasons other than DLT will be replaced.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:


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1. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract by a trial site or 
Investigator, disturbing the appropriate conduct of the trial,
2. Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial,
3. Failure to meet expected enrolment goals overall or at a particular trial site.
4. Any other administrative reasons, including discontinuation of the clinical 
development program with BI 836858.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the first reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
BI 836858 will be administered as rate-controlled intravenous infusion. In case a patient 
experiences an adverse event during the infusion, the duration of the infusion may be 
expanded until the use-by date and use-by time indicated on the label is reached.  The actual 
duration of the infusion needs to be documented in the electronic case report form (eCRF)
including actual start and end time, actual time points for interruption and restart of the 
infusion and the actual infusion rates.
Adverse events during the infusion will be thoroughly documented and characterized to allow 
differentiation between infusion-related reactions (R10-4428, R10-4517).
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are below.

Substance (INN):
BI 836858

Pharmaceutical form:  
Solution for infusion after dilution

Source:
Boehringer Ingelheim Pharma GmbH & Co. KG

Unit strength: 
10 mg/mL (vials with 10mL)

Daily dose:
See Section 4.1.3

Duration of use:
Single administration every 7, 15, or 29 days
(depending on patient population)

Route of administration:
Intravenous

Posology:
Rate controlled infusion
(Volume:  250 mL)
The first and second infusion will be started at a rate of 10 mL/h. The infusion rate should be 
increased every 30 (+/-10) minutes by 10 mL/h to a maximum of 80 mL/h as long as 
tolerated by the patient. Infusion should not exceed 8 hours. If considered safe by the 
Investigator, the stepwise increase of infusion rate during the third and subsequent infusions 
may be faster or steps may be omitted, but the maximum infusion rate must not exceed 120 
mL/h. If symptoms of an infusion-related reaction occur, the infusion should be temporarily 
stopped. Upon recovery, it should be infused at 50% of the rate at which the reaction 
occurred and should not be dose escalated from this dose for at least 30 minutes. Lower rates 
may be selected if clinically indicated. Depending on the time of occurrence and the severity 
of the reaction, the investigator may consider administering additional supportive medication, 
e.g. corticosteroids. A stepwise re-increase of the infusion rate to a maximum of 80 mL/h is 
possible. For medical reasons, in case a patient experiences an adverse event during the 
infusion, the duration of the infusion may be expanded until the use-by date and use-by time 
indicated on the label is reached. The actual duration of the infusions and infusion steps need 
to be documented in the eCRF including actual start and end time, actual time points for 
interruption and restart of the infusion and the actual infusion rates.


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4.1.2
Method of assigning patients to treatment groups
Not applicable.  This is a single-arm, open-label, cohort dose escalation trial.
4.1.3
Selection of doses in the trial
BI 836858 will be administered as a rate-controlled intravenous infusion every 7 days to
refractory or relapsed AML patients.  
For AML patients in CR, the first three administrations will be given every second week, on 
day 1 of Cycles 1, 2 and 3.  From the 4th administration onwards, patients will receive 
monthly (every second cycle) infusions of BI 836858 (i.e. 4th infusion on Cycle 5 Day 1, 5th
infusion on Cycle 7 Day 1…) for overall up to 12 months of treatment unless these patients 
relapse or infusions are not tolerated.
Patients with refractory or relapsed AML have a high medical need and a bad prognosis. To 
treat this patient population with a sub saturating dose is not warranted and therefore a 
starting dose close to the full saturation of all CD33 sites is chosen. The starting fixed dose of 
10 mg which is a dose level expected to provide near to the full saturation of all CD33 sites at 
maximum measured plasma concentration (Cmax) based on estimated receptor occupancy (i.e. 
94.3% estimated CD33 occupancy). For lintuzumab, a CD33 monoclonal antibody, in a 
Phase I trial no MTD was reached up to 8mg/kg/week (R11-1481). A fixed dose regimen was 
chosen instead of a dose per m2 based a recent publication by Wang et al. The individual and 
population performance of body size-based and fixed dosing in adults were compared for 12 
oncology approved mAbs (R10-6267).  Although both dose regimens demonstrated similar 
performance, the fixed dose was recommended since it offered advantages in the ease of dose 
preparation and a lower chance of dosing errors.
For details please refer to the Investigator’s Brochure, Section 5.3.6 (c02324887-03).
The dose is planned to be escalated in cohorts at pre-defined dose levels based on a 
multiplication factor of 2. The dose levels are 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, and 320 
mg. Intermediate dose levels and dose levels higher than 320 mg may be investigated if 
agreed upon between Investigator and Sponsor.  In an ongoing Phase I study BI 836858 is 
administered to lower risk MDS patients every 14 days. In the 20 and 40 mg cohort no DLT 
occurred and the 80mg cohort is currently ongoing. The dose escalation in AML patients in 
CR will begin with infusions at the dose level of 40 mg.  The dose will be escalated to the 
next pre-defined or intermediate dose levels as needed. 
When a cohort dose escalation is to be performed, the data of all previous dose cohorts will 
be reviewed and discussed between the participating Investigators and the Sponsor. This 
assessment will determine if each patient population is able to continue treatment with         
BI 836858.
During the cohort dose escalation phase, enrolment into the first dose cohort (10 mg) will be 
allowed at the earliest 7 days after the first administration of  BI 836858 between patient 1 


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and 2 and subsequently between patient 2 and 3.  In case the 10 mg cohort has to be expanded 
to 6 patients, a one week observation period must be followed between the first 
administration of BI 836858 and the start of the subsequent patient. For subsequent cohorts 
(i.e., 20 mg, 40 mg, 80 mg, 160 mg, and 320 mg), consecutive screening is allowed; however, 
there has to be an interval of at least 3 days between the 1st administration of BI 836858 for
each patient. 
Enrolment into the next higher dose cohort is allowed after the previous dose cohort was 
found to be safe for the initial administration for all patients in this cohort (e.g. at least 28 
days after the first administration of drug in the last patient entered into the cohort).
Once the MTD for one of the patient populations is defined, a dose for treatment of the 
expansion cohort in this patient population will be determined, which will not exceed the 
MTD.  In case no MTD is reached up to the highest tested dose (e.g. 320 mg), 12 additional 
patients will be treated with the respective schedule of the highest tested dose (e.g. 320 mg)
of BI 836858 in the expansion cohort. During treatment of the expansion cohort, new patients 
may be enrolled at any time.
Table 4.1.3: 1
Entry of patients into trial, by cohort
Cohort
Day first patient 
in cohort 
receives infusion
Earliest day 
next patient can 
be enrolled
10 mg*
Day 1
Day 8
All other dose 
levels in cohort**
dose escalation
Day 1
Day 4
Dose Expansion
Day 1
Any time
* a one week observation period must be followed between the first administration of BI 836858 and the start of 
the subsequent patient - for all patients with refractory or relapsed AML in the 10 mg cohort
**This entry schedule also applies to AML patients in CR, starting at 40 mg cohort.
4.1.4
Drug assignment and administration of doses for each patient
Prior to inclusion of a new patient during the cohort dose escalation phase, the Investigator
has to confirm the actual dose tier of BI 836858 for the patient with the Sponsor who 
oversees the cohort dose escalation steps and the safety data of patients from all trial sites.  
BI 836858 will be administered as an intravenous infusion under the supervision of the 
Investigator or designated personnel.
BI 836858 may be administered at any time during the day.  However, to 
 
 it is recommended to 
start the infusion during the morning hours.  


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For refractory or relapsed AML patients:  BI 836858 will be administered as weekly i.v. 
infusions in 14-day cycles (i.e., Days 1 and 8; 2 infusions per cycle).
For AML patients in CR: the first three administrations will be given once every second week 
on day one of 14-day Cycles 1, 2 and 3 (i.e., Days 1, 15 and 29).  From the 4th administration 
onwards, patients will receive monthly (every second cycle) infusions of BI 836858 (i.e. 4th
administration on Cycle 5 Day 1, 5th administration on Cycle 7 Day 1 …) for overall up to 12 
months of treatment.
Premedication
Premedication to prevent infusion-related reactions is obligatory 30 minutes (up to 120 min 
before start of administration of BI 836858 is permissible) prior to the first three
administrations of BI 836858, unless a contraindication for premedication exists, and should 
include:

Acetaminophen/Paracetamol 650 mg - 1000 mg p.o., or equivalent

Antihistamine p.o. or i.v., equivalent to Diphenhydramine 50 mg i.v.

Glucocorticoid i.v., equivalent to prednisolone 100 mg
For patients with refractory or relapsed AML: 
If BI 836858 has been well tolerated without signs of infusion-related reactions in the first 
administration, glucocorticoid premedication may be reduced to a dose equivalent to 50 mg 
prednisolone for the second through fourth administrations, and in case this is well tolerated 
reduce the steroids with the 5th infusion (25 mg with the 5th and 0 mg with the 6th infusion.)
For AML patients in CR:
If BI 836858 has been well tolerated without signs of infusion-related reactions in the first 
administration, glucocorticoid premedication may be reduced to a dose equivalent to 50 mg 
prednisolone for the second administration, and in case this is well tolerated steroids can be 
omitted with the 3rd infusion. 
For both patient populations, however, in case an administration of BI 836858 was not well 
tolerated, the premedication with prednisolone can be re-escalated up to 100 mg.
Retreatment                                                                                                                         
Before the next administration of BI 836858, adverse events and safety laboratory will be 
assessed.  To continue treatment with further administrations, all of the following criteria 
must be met:
Refractory or relapsed AML patients
(1)
Neutrophils ≥500 /μL (0.5 x 109/L) and platelets ≥25,000 /μL (25 x 109/L), unless 
CTCAE Grade 4 neutropenia or thrombocytopenia was preexistent prior to trial 
entry. Patients with active leukemia who go from Grade 3 neutropenia to Grade 4 
neutropenia after treatment may continue on study provided there is no evidence 
of infection or febrile neutropenia. Patients with active leukemia who go from 


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Grade 3 to Grade 4 thrombocytopenia after treatment may continue on study 
provided that post-transfusion platelet count is at least 20,000/µL before therapy is 
given.
(2)
Acceptable tolerability (in case of an AE at the planned start of a further 
administration, patients may continue therapy only after recovery to a level which 
would allow further therapy, i.e. CTCAE grade 1 or pre-treatment value); no 
febrile neutropenia (≥38.5°C and ANC <1000/µL) and no uncontrolled infection. 
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.
AML patients in CR
(1)
Neutrophils ≥750 /μL (0.75 x 109/L) and platelets ≥50,000 /μL (50 x 109/L). 
(2)
Acceptable tolerability (in case of an AE at the planned start of a further 
administration, patients may continue therapy only after recovery to a level which 
would allow further therapy, i.e. CTCAE grade 1 or baseline value.)
(3)
Patients with GvHD, with a CTCAE grade 1 or 2 and taking steroids, may 
continue further administration.  GvHD patients with a steroid-refractory (≥2 
mg/Kg) CTCAE grade 3 or higher, independent of receiving steroids, should be 
discontinued from study.
In case criteria 1 and 2 are not fulfilled, blood counts and/or the adverse event should be 
re-evaluated for up to three weeks.  In case of a treatment delay, the Sponsor must be 
notified. If criterion 1 is not fulfilled and the patient has <5% blasts in the bone marrow, 
absence of myelodysplastic changes, and/or absence of evidence of disease by flow 
cytometry in the bone marrow then no further treatment should be administered until 
discussion with the Sponsor.
Administration of the trial drug has to be stopped temporarily in case of a DLT (see 
Section 5.2.1.1).  Patients may continue therapy only after recovery from the DLT to a 
CTCAE level which allows further therapy based on Investigator assessment and only with a 
reduced dose of BI 836858.  The new dose of BI 836858 must be finally agreed on between 
the Sponsor and the Investigator.  The reduced dose will be valid for all following treatment 
cycles in the individual patient.  A reduction of the dose will be allowed only once for an 
individual patient during the whole trial.  In case a patient experiences a second episode of 
DLT with the reduced BI 836858 dose, the treatment has to be permanently discontinued.  
Likewise, treatment has to be discontinued in case the DLT is not reversible.
Intra-patient dose escalation
Intra-patient dose escalation may be considered in agreement between investigator and 
sponsor for selected patients. It is restricted to patients who have received at least 3 treatment 
cycles and tolerate the treatment well at the time of dose escalation. Intra-patient dose 
escalation can only be performed at a time when the next higher dose cohort has been 


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reviewed and considered safe by the sponsor and investigators. 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 hours after 
the end of the infusion, including safety laboratory 24 hours after the first administration of 
the escalated dose of BI 836858.
A log of all patients enrolled into the study (i.e. having given informed consent) will be 
maintained in the Investigator Site File (ISF) at the investigational site irrespective of 
whether they have been treated with investigational drug or not.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This Phase I trial will be performed according to an open label, single arm design.  It will 
recruit two separate patient populations: 1) Patients with relapsed and refractory AML and 
active disease; and 2) AML patients in CR with high risk to relapse.  This trial will be 
handled in an open fashion by the Sponsor throughout, i.e. also for the purpose of data 
cleaning and preparation of the analysis.  The eCRF will contain information on the treatment 
and the dose.
4.1.5.2
Procedures for emergency unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
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.
4.1.7
Storage conditions
BI 836858 has to be stored in a limited access area at the temperature indicated on the trial 
drug label - stored in a refrigerator 36-46°F (2-8°C); do not freeze.  If the storage conditions 
are found to be outside the specified range, immediately contact the local clinical monitor 
(CML) as provided in the list of contacts.  For more details on BI 836858, please refer to the 
Investigator’s Brochure (IB) and the ISF.


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4.1.8
Drug accountability
Drug supplies of BI 836858, which will be provided by the Sponsor or a Clinical Research 
Organization (CRO) appointed by the Sponsor, must be kept in a secure, limited access 
storage area under the storage conditions defined by the Sponsor.  A temperature log must be 
maintained to make certain that the drug supplies are stored at the correct temperature.
Each Investigator and/or pharmacist will receive the investigational drugs delivered by the 
Sponsor when the following requirements are fulfilled:

approval of the study protocol by the IRB / ethics committee,

availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal Investigator,

availability of a signed and dated CTP or immediately imminent signing of the CTP,

availability of the proof of a medical licence for the principal investigator,

availability of the Form 1572.
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients.  The 
Investigator and/or pharmacist must maintain records of the product’s delivery to the trial 
site, the inventory at the site, the use for each patient, and the return to the Sponsor or 
alternative disposition of unused product.  The Investigator/pharmacist will maintain records 
that document adequately that the patients were provided these doses specified by the CTP 
and reconcile all investigational product received from the Sponsor. At the time of return to 
the sponsor, the investigator must verify that all unused or partially used drug supplies have 
been returned by the clinical trial patient and that no remaining supplies are in the 
investigator’s possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
Rescue medication to reverse the action of BI 836858 is not available.  Potential side effects 
of BI 836858 have to be treated symptomatically.  Patients should receive supportive care 
according to the local guidelines regarding treatment of infusion-related reactions, blood 
product support, antibiotics, antivirals, analgesics, skin and mouth care, etc.  The use of 
growth factors such as granulocyte colony stimulating factor (G-CSF) will be allowed, but 
growth factors should be avoided during the first 2 cycles for better assessment of safety and 
response parameters. 
Anti- bacterial and fungal prophylaxis should be given according to local standards or 
available guidelines.


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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.
Concomitant therapy will be recorded in the eCRF during the screening and treatment period, 
starting at the date of signature of informed consent, and ending at the EOT-visit.  After the 
EOT-visit, only concomitant therapy indicated for treatment of an adverse event needs to be 
reported.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Prior anti-leukemia therapy must have been discontinued at least two weeks before the first 
administration of the trial drug (Hydroxyurea may be given during study participation) and 
the patient must have recovered from all clinically relevant reversible toxicities as determined 
by the investigator.  A time interval of at least 2 weeks (four weeks for biologics) must have 
elapsed from the last administration of any other investigational treatment for AML to the 
first administration of BI 836858.
For peripheral blood blast control, as this may correlate with the risk of occurrence of 
infusion related symptoms, hydroxyurea will be allowed (maximum dose of hydroxyurea 
3gm daily) before and during study participation. Blasts must be ≤ 5,000/µl at start of each 
administration of BI 836858. 
No other anti-neoplastic therapy concomitantly is allowed.
Short term glucocorticoid medications may be used up to 20 mg per/day continuously are  
allowed (see exclusion criterion 4) and up to 2 mg/kg bodyweight for short term. 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 (CNS) 
involvement is allowed but must be discussed and agreed upon between Investigator and 
Sponsor.  All concomitant therapy will be recorded in the eCRF.
4.2.2.2
Restrictions on diet and life style
No restrictions apply with regard to diet or life style.


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4.3
TREATMENT COMPLIANCE
BI 836858 will be administered as a single intravenous infusion under supervision of the 
Investigator or dedicated clinic personnel.  Compliance may also be verified by 
pharmacokinetic assessment.  Any discrepancies will be explained in the eCRF by the 
Investigator or designee.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY – PHARMACODYNAMICS
5.1.1
Endpoints of efficacy
The efficacy endpoints will be assessed at the time points specified in the Flow Charts.  
Efficacy endpoints will be secondary 
 in this trial.
Secondary endpoints of efficacy are:
For patients with refractory or relapsed AML:

Best overall response according to International Working Group (IWG) criteria 
(please see Section 5.1.2.3) (R06-0452)

Progression free survival

Time to treatment failure
For AML patients in CR with high risk to relapse:

Progression free survival

Time to treatment failure
 
5.1.2
Assessment of efficacy
 


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5.1.2.3
Assessment and definition of best overall response
For patients with refractory or relapsed AML, response will be assessed according to the 
criteria from the IWG based on laboratory data from the peripheral blood, bone marrow 
examination, clinical examination (at the end of each cycle), at the evaluation for further 
treatment-visit and the EOT-visit. Bone marrow examination will be performed before the 
Cycle 3 and Cycle 5 (5th and 9th administration of BI 836858) (i.e., BM performed on Day 1 
(+/-1) of cycles 3 and 5 and treatment started on Day 1 (up to +3) of cycles 3 and 5) and at 
the discretion of the Investigator, e.g. in case clinical and laboratory examinations of 
peripheral blood demonstrate that a CR has been achieved, or for assessment of persistent 
neutropenia, anemia or thrombocytopenia. 
For AML patients in CR, response will be assessed clinically and in the peripheral blood (on 
Day 1 of each cycle). In the case of suspected relapse based on peripheral blood counts a 
bone marrow examination will be performed. 
Assessment and definition of best overall response
Response will be evaluated according to the following criteria (modified from the IWG
criteria, R06-0452):

Complete remission (CR)
Morphologically leukemia free state (i.e. bone marrow with <5% blasts by 
morphologic criteria and no blasts with Auer rods, no evidence of extramedullary 
leukemia) and absolute neutrophil count ≥1000 /μL and platelets ≥100,000 /μL.  
Patient must be independent of transfusions (no transfusion for 1 week prior to the 
assessment).

Complete remission with incomplete blood count recovery (CRi)
All of the above criteria for CR must be met, except that absolute neutrophils 
<1000 /μL or platelets <100,000 /μL in the blood.  

Partial remission (PR)
All of the criteria for CR must be met, except that leukemic blasts in the bone marrow 
may range from 5 to 25% as long as the count has decreased by at least 50% from 
pre-study treatment, or <5% blasts in the presence of Auer rods or abnormal 
morphology.

Stable disease (SD)
Patient alive with no CR, CRi, PR or PD.


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
Treatment failure (TF)
Patient survives >7 days following completion of initial 2 treatment cycles (e.g. 
28 days) with persistent leukemia in the last peripheral blood smear or bone marrow 
(>25% blasts), or with persistent extramedullary disease, but without further clinical 
deterioration due to leukemia or increase of blast population in the bone marrow or 
peripheral blood.
Resistant disease: Patient survives >7 days post-course of treatment; persistent 
leukemia in blood or bone marrow.
Aplasia: Patient survives >7 days post-course of treatment; death while cytopenic, 
with aplastic bone marrow
Indeterminate cause: Patients who die < 7 days post therapy. Patients who die > 7 
days post therapy with no peripheral blood blasts, but no bone marrow examination.
Patients who do not complete the first course of therapy.
Morphologic relapse (recurrence): Reappearance of blasts post-CR or CRi in 
peripheral blood or bone marrow. That is, 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.

Progressive disease (PD)
Patient survives >7 days following completion of initial 2 treatment cycles (e.g. 
28 days) with increase of blast population in the bone marrow or peripheral blood by 
>50% or aggravation or new development of extramedullary disease or further 
deterioration or death due to leukemia.  Patients with a global deterioration of health 
status requiring discontinuation of treatment without objective evidence of PD at that 
time should be classified as having ‘clinically progressive disease’.  Every effort 
should be made to document the objective PD even after discontinuation of treatment.
Definition of best overall response
Best overall response is defined as the best overall response (CR, CRi, PR, TF, PD or not 
evaluable in this order) recorded since first administration of BI 836858.
5.1.2.4
Progression free survival (PFS)

PFS is defined as the time from first treatment with BI 836858 until disease 
progression, relapse or death.

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 


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progression/relapse was observed. For patients who did not progress, relapse, or die, 
PFS will be censored at the date of last disease assessment.
5.1.2.5
Time to treatment failure (TTF)
Some patients will receive the next line of therapy, although no formal PD may be diagnosed 
at the time when the next treatment is indicated according to Investigator assessment.  In 
addition to PFS, the TTF will be calculated.

TTF is defined as the time from first treatment with BI 836858 until objective disease 
progression, relapse or death or start of next AML therapy.

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, die, or 
receive next AML therapy TTF will be censored at the date of last disease assessment.
 
 
 
 
 
 
 
 
  
 


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5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoints:

Maximum tolerated dose (MTD)

Number of patients with Dose Limiting Toxicity (DLT) during the MTD evaluation 
period:
o
For patients with refractory or relapsed AML, the first two cycles (i.e. patient 
has received at least 4 administrations of BI 836858 and reached end of cycle 
2). 
o
For AML patients in CR with high risk to relapse, the first two cycles (i.e. 
patient has received at least 2 administrations of BI 836858 and reached end of 
cycle 2).
 
As this trial is the first in human use of BI 836858, the primary objective is to determine the 
MTD of BI 836858 and assess the safety of the drug in humans.  For details on determination 
of MTD, please refer to Section 3.1, Section 5.2.1.1 and Section 7.3.1.
The safety of BI 836858 will be assessed by a descriptive analysis of incidence and intensity 
of adverse events (AE) graded according to the CTCAE version 4.0, the incidence of DLT, 
laboratory data and results of physical examination.
The Sponsor will review the safety data with the participating Investigators at regular 
intervals and as ad hoc if needed.
The safety endpoints will be assessed in a descriptive way without confirmatory analyses.
5.2.1.1
Dose limiting toxicity (DLT) for refractory or relapsed AML patients
DLT is defined as any non-disease-related non-hematological AE of CTCAE grade 3 or 
higher. Expected non-hematological disease related AE´s such as complications resulting 
from haematological AEs include:

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


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
constitutional symptoms due to anemia as defined by the investigator 
Infusion-related reactions (IRRs, CTCAE grade 3 or higher) associated with the 
administration of BI 836858 should be reported as Adverse Event of Special Interest (AESI, 
refer to Section 5.2.2.1), 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).
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. 
Hematological AEs, e.g. neutropenia, thrombocytopenia and anemia are frequently 
pre-existing in AML patients and are therefore AEs not considered as DLT. Failure to 
recover neutrophil count (ANC>500/uL) or platelet count (>25000/uL) at the first bone 
marrow evaluation after 2 cycles of BI 836858 in patients with < 5% blasts in the bone 
marrow, absence of myelodysplastic changes, and/or absence of evidence of disease by flow 
cytometry in the bone marrow will be considered a DLT. For patients with > 5% blasts, 
myelodysplastic changes, or evidence of disease by flow cytometry/cytogenetics, failure to 
recover neutrophil or platelet count may not be considered DLT as this could be the result of 
persistent disease. 
Patients who have not completed at least 4 administrations (2 cycles) of BI 836858 due to BI 
836858 related toxicity will be considered as a DLT.
5.2.1.2
Dose limiting toxicity (DLT) for AML patients in CR
DLT is defined as any non-disease-related AE of CTCAE grade 3 or higher. Patients in 
remission are not expected to have disease-related AEs.  In case of any hematological AE of 
CTCAE grade 3 or higher, relapse of AML has to be excluded. Infusion-related reactions 
(IRRs) associated with the administration of BI 836858 should be reported as Adverse Events 
of Special Interest (AESI, refer to Section 5.2.2.1), 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).
Occurrence of and/or worsening of GvHD will not be considered as a DLT; however, these 
cases will be reviewed carefully during the safety assessment meetings.
AML patients in CR who have not completed at least 2 administrations (2 cycles) of BI 
836858 due to BI 836858 related toxicity will be considered as a DLT.
Once each patient of a cohort has completed 2 treatment cycles of BI 836858 all available 
safety data will be reviewed by the Sponsor, Coordinating Investigator and other participating 
Investigators who enrolled at least one patient. Safety data will be discussed via a 


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teleconference, initiated by Sponsor, to reach a consensus on DLT, in order to allow dose 
escalation, cohort expansion or suspension of further dose escalation.
All DLTs occurring at any time will be reported as an adverse event of special interest (AESI, 
see Sections 5.2.2.1 for definitions and 5.2.2.2 for reporting requirements).
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
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, this 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.

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 jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
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 


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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”
Every new occurrence of cancer of new histology must be reported as a serious event 
regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC system. A copy of the latest 
list of “Always Serious AEs” will be provided to you upon request. These events should 
always be reported as SAEs as described above.
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, please see above.
The following are considered as AESIs:

infusion-related reactions (CTCAE grade 3 or higher),

any event that qualifies for DLT, and

hepatic injury (DILI).
Hepatic injury
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


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These lab findings constitute a hepatic injury alert and the patients showing these lab 
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 lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed
Intensity of AEs
The intensity of adverse events should be classified and recorded in the CRF according to the 
Common Terminology Criteria for Adverse Events (CTCAE, version 4.0, 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, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
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.


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•
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 study drug treatment continues or remains 
unchanged.
5.2.2.2
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 CRF(s) by the 
Investigator:

From signing the informed consent onwards through the Residual Effect Period 
(REP), until individual patient’s end of trial: 
All AEs (serious and non-serious) and all AESIs. 

However, if an individual patient discontinues trial medication prematurely but stays 
in the trial (i.e. if further visits incl. telephone visits, or vital status assessments are 
planned) from then on and until the individual patient’s end of the trial the 
Investigator must report related SAEs and related AESIs. 

After the individual patient’s end of 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.


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The REP is defined as 30 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as “on 
treatment,” please see Section 7.3.3. 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 hours ) 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 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication and any possible interactions between the investigational drug(s) and a 
Non-Investigational Medicinal Product (NIMP) / Auxiliary Medicinal Product (AMP).
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions 
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 characterised, 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. 


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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 in oncology trials is a study endpoint for analysis of efficacy, and as such is 
exempted from being reported as an SAE. 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. 
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 and the 
progression of the underlying malignancy, the event must be reported as an (S)AE on the SAE 
Form and on the eCRF. 
5.2.3
Assessment of safety laboratory parameters
5.2.3.1
General safety laboratory parameters
Blood samples and urine have to be collected at the time points specified in the Flow Charts.  
Safety laboratory examinations will include hematology, biochemistry, coagulation and 
qualitative urine analysis:
Hematology
Hemoglobin, white blood cell count (WBC) with differential, 
platelets (PLT)
Reticulocytes have to be measured only at Visit 1 of every 
second cycle, EOT, Visit 1 of every second cycle in FTE, at 
the EOFT visit (in refractory or relapsed AML patients) and 


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during follow-up.
Biochemistry
Glucose, sodium, potassium, calcium, inorganic phosphate, 
creatinine, AST, ALT, alkaline phosphatase (AP), lactate 
dehydrogenase (LDH), bilirubin, urea, total protein, albumin, 
uric acid
Serum immunoglobulin levels (IgG, IgM, IgA) and direct 
antiglobulin test have to be measured only every 8 weeks, at 
the EOT visit and during follow-up.
Coagulation
Activated partial thromboplastin time (aPTT), prothrombin 
time (PT), international normalised ratio (INR) where 
indicated (e.g. treatment with vitamin K antagonists)
Urine
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be 
analysed by dipstick and reported as semiquantitative 
measurements. In case of pathological findings, further 
evaluation should be performed and results documented.
Pregnancy test
A serum pregnancy test needs to be obtained at the time 
points indicated in the Flow Chart in patients of childbearing 
potential. 
An additional safety lab will be collected on day 2 of Cycle 1 (i.e., 24 hours after the first 
administration of BI 836858). Other lab tests to be included: haptoglobin, direct antiglobulin
test, bilirubin (direct and indirect) and free hemoglobin. Non pre-existing abnormal 
laboratory values (CTCAE Grade 3 or higher) will be followed up every 48 hours until these 
laboratory values are back to at least CTCAE Grade 1.
In case an administration is delayed due to an AE, the patient should visit the site at least 
once a week for assessment of safety laboratory and AEs. More frequent visits may be 
appropriate as assessed by the Investigator.
 
 
  
 
5.2.4
Electrocardiogram
A 12-lead resting ECG will be performed in all patients according to the schedule in the Flow 
Charts.  The ECG will be assessed for pathological results (to be recorded as either 
concomitant disease or AE) by the Investigator.  Additional examinations should be done 
whenever the Investigator deems necessary.


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5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Vital signs (blood pressure, heart rate and body temperature) will be recorded at every visit 
during screening, treatment (including the EOT visit) and follow-up. Additional time points 
for blood pressure and heart rate at the day of administration of BI 836858 are: prior to the 
start of premedication, prior to the start of BI 836858 infusion, and in 30 (±10) minute 
intervals throughout the course of the infusion of BI 836858 and 60 (±10) minutes after the 
end of the infusion, thereafter every 4-8 hours until at least 24 hours after start of the
infusion. In case of an infusion-related reaction, the Investigator should decide whether to 
intensify or prolong monitoring of vital signs of the patient.
Beginning with infusion 2, blood pressure and heart rate will be assessed at the same time
points as during infusion 1 with the exception that they will not be assessed every 4-8 hours 
until at least 24 hours after the start of the infusion.
5.2.5.2
Physical examination
A physical examination including height, weight and ECOG performance score will be 
performed at screening and at the time points specified in the Flow Charts. During the 
physical examination, the patient should be assessed for possible AEs.
 
 
 
 
 
 
 
 
5.4
APPROPRIATENESS OF MEASUREMENTS
Determination of MTD is based on toxicities graded according to CTCAE (R09-2850). The
CTCAE criteria are commonly used in the assessment of AEs in cancer patients. The criteria 


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to be used for evaluation of response (R06-0452) are well established and scientifically 
accepted.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
During the treatment phase, patients with refractory or relapsed AML will receive 
administration with BI 836858 every 7 days.  For AML patients in CR, The first three 
administrations will be given once every second week on day 1 of Cycles 1, 2 and 3. From 
the 4th administration onwards, patients will receive monthly (every second cycle) infusions 
of BI 836858 (i.e. 4th infusion on Cycle 5 Day 1, 5th infusion on Cycle 7 Day 1 …) for overall 
up to 12 months of treatment.
Patients are required to be hospitalized under close surveillance with access to intensive care 
for at least 24 hours after the first administration of BI 836858 to allow close monitoring for 
infusion-related reactions or other AEs.  After good tolerability of the first administration of 
BI 836858, the Investigator may evaluate the risk for an infusion-related reaction and other 
AEs in view of relevant co morbidities 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 within one treatment cycle and the patient comes to the clinic 
between the missed and the next scheduled visit, the delayed visit should be scheduled as 
soon as possible and documented with the actual date and the reason for the delayed visit. 
The next visit, should still take place at the time it was originally scheduled in this treatment 
cycle.
However, in case the day of treatment administration (Visit 1 of a cycle) is delayed, all 
subsequent visits of a cycle will be recalculated based on the actual date of Visit 1 of the 
delayed cycle.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations as outlined in the Flow Charts A and B 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 (Visit 1), i.e. the phase after informed consent and before the first 
administration of the trial drug, may be as long as 14 days.
The following parameters and investigations will be obtained and / or performed for both
patient populations:

Informed consent

Informed consent for pharmacogenetics 

Demographics (sex, birth date, race) and baseline conditions

Medical history (oncological and relevant non-oncological)

Review of inclusion and exclusion criteria (patient eligibility)


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
Dose assignment (during cohort dose escalation phase only, before the first administration 
of the trial drug and after informed consent and review of in- and exclusion criteria)

Safety laboratory (hematology, biochemistry including serum immunoglobulin levels and 
direct antiglobulin test, coagulation, urine; for details please refer to Section 5.2.3.1)

Physical examination, height, weight, vital signs and ECOG performance score

Serum pregnancy test in women of childbearing potential

12-lead ECG

Concomitant therapy

Bone marrow aspiration for disease assessment (for refractory or relapsed AML patients)
6.2.1.1    Re-screening
Sites will be allowed to re-screen patients after 1 week from when they screen failed. If more 
than 4 weeks have elapsed prior to re-screening, all screening procedures must be repeated.
6.2.2
Treatment periods for refractory or relapsed AML patients
6.2.2.1
Visit 1 and Visit 3 – day of BI 836858 administration (administrations 1-8)
On the treatment days, the following parameters and investigations will be obtained and / or 
performed:

Review of inclusion and exclusion criteria (patient eligibility), prior to the first 
administration only

Safety lab parameters before trial drug administration as specified in Section 5.2.3.1. An 
additional safety lab will be collected on day 2 of Cycle 1 (i.e., 24 hours after the first 
administration of BI 836858). Other lab tests to be included: haptoglobin, direct
antiglobulin test, bilirubin (direct and indirect) and free hemoglobin. Non pre-existing 
abnormal laboratory values (CTCAE Grade 3 or higher) will be followed up every 48 
hours until these laboratory values are back to at least CTCAE Grade 1.

Physical examination 
 completed every second cycle 
beginning with cycle 1. Physical exam may be completed up to 2 days prior to 
administration and ECOG must be completed on the day of the administration. Height 
and weight (only at Day 1 of first cycle). If the first administration is completed within 3 
days of the screening visit, these examinations do not need to be repeated.

Vital signs at time points specified in Section 5.2.5.1

Serum pregnancy test in women of childbearing potential (required at odd-numbered 
administrations e.g. 1, 3, 5, 7).

12-lead ECG (required at Visit 1 of each cycle)

Adverse events (AEs)


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
Changes in concomitant therapies

Bone marrow aspiration (Required before the 5th and 9th administration of BI 836858 and 
at the discretion of the Investigator).
 
 
 
 

Administration of BI 836858 after final confirmation of dose tier

Eligibility for further administration may be performed up to 2 days prior to this visit (at 
administration 2 and beyond).
6.2.2.2
Visit 2 and Visit 4 (+ 1 day window allowed beginning in Cycle 3), following 
administration of BI 836858
In Cycles 1 and 2, visits will occur at Day 4 and Day 11 after the administration.  Beginning 
in Cycle 3 and thereafter, patients will come to the clinic only for infusions and will not be 
required to complete the visits on Day 4 and Day 11 unless medically indicated.  On the 
Visit 2 and Visit 4 days, the following parameters and investigations will be obtained and / or
performed:

Safety lab parameters before trial drug administration as specified in Section 5.2.3.1

Vital signs at time points specified in Section 5.2.5.1

Adverse events (AEs)

Changes in concomitant therapies
 
6.2.3
End of treatment and follow-up period for refractory or relapsed AML 
patients
6.2.3.1
EOT visit
This visit includes an evaluation for further treatment.  Those patients with clinical benefit
after 8 administrations and who are tolerating the infusions well may continue until PD or 
other criteria for withdrawal are met as noted in Section 3.3.4.1. For those patients who will 
receive more than 8 administrations, this visit is to be performed 7 days (+ 2 days) after the 
8th administration of BI 836858.  For those patients who receive <8 administrations, this visit 
is to be performed 14 days (+ 2 days) after the last administration of BI 836858.
If the patient concludes the trial within a treatment cycle not at the end of a treatment cycle, 
the information required to be collected at the EOT visit should be obtained immediately.  


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The following parameters and investigations will be obtained and /or performed:

Safety lab parameters and urine analysis as specified in Section 5.2.3.1

Physical examination, weight 
  

Vital signs at time points specified in Section 5.2.5.1

Serum pregnancy test in women of childbearing potential.

12-lead ECG

Adverse events (AEs)

Changes in concomitant therapies

Bone marrow aspiration.
 
 

Eligibility for further administration may be performed up to 2 days prior to this visit.

End of active trial treatment.  This will include the reason for conclusion of trial if 
applicable, premature discontinuation of trial, and date of last administration of the trial 
drug.
6.2.3.2
Further treatment (Visit 1 and Visit 2)
These visits are only for those patients with clinical benefit after 8 administrations and who 
are tolerating the infusions well.  Patients can receive further treatment once the result from 
the bone marrow assessment from EOT is available. Procedures already done at EOT (i.e., 
safety lab, pregnancy test) do not need to be repeated at FTE if FTE visit is within 7 days 
from EOT.  The patients will continue to receive weekly infusions until PD or other criteria 
for withdrawal are met as noted in Section 3.3.4.1.  
Prior to each infusion, the following parameters and investigations will be obtained and /or 
performed:

Safety lab parameters before trial drug administration as specified in Section 5.2.3.1

Physical examination every other cycle starting with cycle 5 (may be completed up to 
2 days prior) and ECOG performance score.  

Vital signs at time points specified in Section 5.2.5.1

Serum pregnancy test in women of childbearing potential (required at odd-numbered 
administrations e.g. 9, 11, 13 etc.)

Adverse events (AEs)

Changes in concomitant therapies

Administration with BI 836858

Eligibility for further administration may be performed up to 2 days prior to this visit.


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6.2.3.3
End of further treatment 
This visit is only for those patients who received administrations in further treatment and
should be performed 14 days (+ 2 days) after the last administration of BI 836858.
ECG, bone marrow aspiration, 
 will be performed at EOFT 
only if the patient has completed at least 2 cycles (e.g. received 4 administrations) since the 
EOT visit.
The following parameters and investigations will be obtained and /or performed:

Safety lab parameters and urine analysis as specified in Section 5.2.3.1

Physical examination including weight (may be completed up to 2 days prior) 
 
  

Vital signs at time points specified in Section 5.2.5.1

Serum pregnancy test in women of childbearing potential 

12 lead ECG (completed only in patients who receive at least 4 administrations since 
EOT visit)

Adverse events (AEs)

Changes in concomitant therapies

Bone marrow aspirate (completed only in patients who receive at least 4 administrations 
since EOT visit)
 
6.2.4
Treatment period for AML patients in CR
6.2.4.1
Visit 1– Day 1 of BI 836858 administration (administrations 1-3)
On the treatment days, the following parameters and investigations will be obtained and / or 
performed:

Review of inclusion and exclusion criteria (patient eligibility), prior to the first 
administration only

Safety lab parameters before trial drug administration as specified in Section 5.2.3.1. An 
additional safety lab will be collected on day 2 of Cycle 1 (i.e., 24 hours after the first 
administration of BI 836858). Other lab tests to be included: haptoglobin, direct 
antiglobulin test, bilirubin (direct and indirect) and free hemoglobin. Non pre-existing 
abnormal laboratory values (CTCAE Grade 3 or higher) will be followed up every 48 
hours until these laboratory values are back to at least CTCAE Grade 1.

Physical examination and ECOG performance score completed every second cycle 
beginning with cycle 1. Physical exam may be completed up to 2 days prior to 
administration and ECOG must be completed on the day of the administration. Height 
and weight (only at Day 1 of first cycle). If the first administration is completed within 3 
days of the screening visit, these examinations do not need to be repeated.


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
Vital signs at time points specified in Section 5.2.5.1

Serum pregnancy test in women of childbearing potential (required at odd-numbered 
administrations e.g. 1, 3, 5, 7).

12-lead ECG (required at Visit 1 of each cycle)

Adverse events (AEs)

Changes in concomitant therapies

Bone marrow aspiration (at the discretion of the Investigator).
 

Peripheral blood for disease assessment. If suspicion of relapse, bone marrow aspiration 
(or biopsy) for disease assessment is to be performed.
 
 

Administration of BI 836858 after final confirmation of dose tier 

Eligibility for further administration may be performed up to 2 days prior to this visit (at 
administration 2 and beyond).
6.2.4.2
Further treatment 
These visits are only for those patients who have received 3 infusions and are tolerating the 
infusions well.  Patients can receive further treatment every second cycle (i.e., Cycle 5 Day 1, 
Cycle 7 Day 1, etc.). The patients will continue to receive monthly infusions for overall up to 
one year of treatment or until PD or other criteria for withdrawal are met (as noted in Section 
3.3.4.1).  
Prior to each infusion, the following parameters and investigations will be obtained and /or 
performed:

Safety lab parameters before trial drug administration as specified in Section 5.2.3.1

Physical examination every other cycle starting with cycle 5 (may be completed up to 
2 days prior) 
  

Vital signs at time points specified in Section 5.2.5.1

12-lead ECG (required at Visit 1 of each cycle)

Serum pregnancy test in women of childbearing potential (required at odd-numbered 
administrations e.g. 5, 7, 9 etc.)

Adverse events (AEs)

Changes in concomitant therapies

Peripheral blood for disease assessment. If suspicion of relapse, bone marrow aspiration 
(or biopsy) for disease assessment is to be performed.

Administration with BI 836858

Eligibility for further administration may be performed up to 2 days prior to this visit.


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6.2.4.3
End of Treatment (EOT) visit
The EOT visit will be performed as soon as possible but no later than one week (7 days) after
permanent discontinuation of trial medication  for any reason, or when the Investigator 
decides with the patient to permanently discontinue the trial medication. 
If the patient concludes the trial within a treatment cycle not at the end of a treatment cycle, 
the information required to be collected at the EOT visit should be obtained immediately.  
The following parameters and investigations will be obtained and /or performed:

Safety lab parameters and urine analysis as specified in Section 5.2.3.1

Physical examination, weight 
  

Vital signs at time points specified in Section 5.2.5.1

Serum pregnancy test in women of childbearing potential.

12-lead ECG

Adverse events (AEs)

Changes in concomitant therapies

Bone marrow aspiration.

Peripheral blood for disease assessment. If suspicion of relapse, bone marrow aspiration 
(or biopsy) for disease assessment is to be performed.
 
 

End of active trial treatment.  This will include the reason for conclusion of trial if 
applicable, premature discontinuation of trial, and date of last administration of the trial 
drug.

In case the patient receives further anti-cancer treatment: regimen, drug name and start 
and stop dates
6.2.4.4
End of Residual Effect Period visit (EoR) 
The REP is defined in Section 5.2.2.2. The End of REP (EoR) visit should not be performed
earlier than 30 days after permanent discontinuation of the trial medication. The information
collected at this visit should include all new reportable AEs that occurred after EOT and a
follow-up of adverse events ongoing at EOT.
The following parameters and investigations will be obtained and / or performed:

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


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
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
6.2.5
Follow up
Follow up (FU) visits will be performed for both patient populations.  These visits will occur 
after the patient has completed treatment according to protocol or is not eligible for further 
treatment cycles.  These follow-up visits will begin 4 weeks after the last infusion with BI 
836858.  In patients with AML in CR, follow-up visit 1 (FU1) is the same as EoR. Follow up 
will end in case the patient is lost to follow-up or in case the Investigator and Sponsor agree 
not to pursue further follow up visits.  Follow up visits should be performed at 4 week 
intervals or earlier if appropriate as determined by the Investigator.
Follow-up visits should be completed at the investigational site but may be performed by 
telephone interview in case the patient is unable to visit the Investigator.  Follow-up visits 
should be performed for 6 months after the last infusion with BI 836858.  At the last follow-
up visit, and end of trial assessment will be performed and documented in the eCRF.  For 
follow-up of patients with adverse events which have not recovered at the last planned 
follow-up visit please refer to Section 5.2.2.2.
The following will be obtained and / or performed:

Safety laboratory (hematology, biochemistry including serum immunoglobulin levels and 
direct antiglobulin test, coagulation, urine; for details please refer to Section 5.2.3.1)

Physical examination, 
 vital signs.

AEs since last visit in case they occurred during the observational period (42 days after 
the last trial drug administration in refractory or relapsed AML patients) or residual effect 
period (REP, 30 days after the last trial drug administration) or are considered drug-
related (see Section 5.2.2.1)

Concomitant therapy indicated for treatment of an AE

Follow-up of AEs in case they were not yet recovered at EOT

Bone marrow aspirate, if indicated

Treatment with any other anti-leukemia drug (report date of treatment and drug)

Vital status evaluated at each follow up visit
6.2.6
End of the whole trial
The clinical trial will be analysed and reported after the last patient has completed 4 treatment 
cycles or stopped treatment prior to completion of cycle 4.  In case the trial is ended by the 


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Sponsor when patients are still being treated with BI 836858 when the final report of the trial 
is being prepared, the patients will either be included in a follow-up trial or alternatively kept 
on treatment in this trial.  Those patients will then be reported in a revised report and it will 
be noted in the original report that such a revised report will be written.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This trial will be performed as an open-label study.  The primary objective of the trial is to 
determine the MTD of BI 836858 for both patient populations separately.  To determine the 
MTD, patients are entered sequentially into escalating dose tiers using the 3+3 design (see 
Section 3.1).  After the MTD has been determined, up to 12 patients for each patient 
population are additionally entered at this dose level to better characterize the safety of BI 
836858.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory. No formal statistical tests will be 
performed.
7.3
PLANNED ANALYSES
For the determination of the MTD, only MTD evaluable (i.e. non-replaced patients) will be 
considered. 
For the analysis of secondary 
 all patients in the 
treated set (i.e. patients treated with at least one dose of BI 836858) will be included in the 
analysis, including the patients who have been replaced for any reason (see Section 3.3.4.1).
7.3.1
Primary analyses
The primary objective for this study is to identify the MTD (for both patient populations 
separately) and to investigate the safety profile of BI 836858. MTD is defined in Section 3.1, 
and will be identified by the occurrence of DLT in the dose escalation scheme. In order to 
identify the MTD, the number of patients with a DLT during the first two cycles at each dose 
level will be presented. Patients who discontinue during the first two treatment cycles for 
reasons other than DLT will be excluded from the determination of MTD. 
However, for those patients who receive more than two cycles of BI 836858, all AEs that 
constitute a DLT will be taken into consideration for the purpose of determining the 
recommended dose for the expansion cohort or the recommended dose for subsequent phase
II trial(s).
DLT is defined in Section 5.2.1.1. For the analysis of the tolerability and safety, please refer 
to Section 7.3.3.
The primary analysis will take place when all patients from the dose escalation and dose 
expansion cohorts have had a minimum of 4 cycles or have discontinued from the trial prior 
to reaching end of cycle 4 due to meeting the criteria for withdrawal as outlined in Section 
3.3.4.1.


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In case patients are still being treated at the time of the primary analysis, a revised clinical 
trial report (CTR) will be created when the last patient has completed his/her last visit,
including all primary and secondary analyses.
7.3.2
Secondary analyses
This section outlines the analyses for the secondary 
 as 
defined in Section 5.1.1.
 
 
7.3.2.3
Best overall response
Each patient will be assigned to one of the response categories described in Section 5.1.2.3. 
Each patient’s best overall response will be used as a primary measure. To describe response 
over time, the proportion of patients in each response category will be tabulated at specified 
time intervals. The number of patients with objective response (best response of CR, CRi, or 
PR) will be summarized. Patients will be followed up for assessment of response and 
progression until they progress, receive any other anti-leukemia therapy, die, or until the trial 
ends. The observed length of follow-up and the number of patients available for analysis at 
each time point will determine the period of time covered in tables and figures.  Frequency 
distribution and other descriptive statistical measures will be used to examine these variables.
7.3.2.4
Progression free survival, time to treatment failure
These time-to-event variables will be analyzed with the Kaplan-Meier method.
In case there is no occurrence of death, progression or treatment failure until the last visit of 
the trial the time will be censored.  The percentage of patients who are event free will be 
displayed at monthly or greater time intervals as appropriate.  Details of censoring rules will 
be provided in the statistical analysis plan.
The cause of death will be summarized, along with whether death was plausible related to 
disease progression.


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7.3.3
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 a period of 30 days after the last dose of trial. Adverse events that start 
before first drug intake and deteriorate under treatment will also be considered as ‘treatment-
emergent’.
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).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.4
Interim analyses
The sponsor will continuously monitor safety. The dose escalation design foresees that 
regular safety evaluations are performed. These evaluations will be un-blinded to dose.
No formal interim analysis of efficacy data is foreseen, although efficacy data when available 
may be considered as part of the safety evaluations.


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As patients with refractory or relapsed AML are known to have low monocyte counts and 
functional abnormalities of NK cells, both of which are required for the mode of action of   
BI 836858 (see Section 2.1), detailed evaluations will be performed to ensure a positive 
benefit-risk assessment in this patient population. If considered unjustifiable, treatment of 
patients with refractory or relapsed AML may be terminated based on these interim 
evaluations. 
Results of this evaluation of patients with refractory or relapsed AML will be documented 
and stored.  If applicable, the format and the detailed content of the analysis will be defined 
in the statistical analysis plan.
If considered necessary, a preliminary safety evaluation may also be performed in AML 
patients in CR.  This analysis will have no impact on the further conduct of the trial but can 
become necessary for internal project purposes.  Results of this evaluation will be 
documented and stored.  If applicable the format and the detailed content of such a 
preliminary analysis will be defined in the statistical analysis plan.
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.4
HANDLING OF MISSING DATA
Every effort will be made to obtain complete information on all AEs, with particular 
emphasis on potential DLT.
If not stated otherwise, missing data will not be imputed and remain missing. Potential 
outliers will be reported and analyzed as observed.
The occurrence of missing data should be minimized by follow-up of patients for both 
disease progression and mortality after end of trial for an individual patient. Both response 
and progression status for patients who are lost to follow-up or who die before progression 
has been documented, will be assessed at the end of the trial. 
Missing baseline laboratory values will be imputed by respective values from the screening 
visit.


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7.5
RANDOMISATION
This is a non-randomized Phase I trial. All the patients will receive BI 836858.
7.6
DETERMINATION OF SAMPLE SIZE
Patients with refractory or relapsed AML:
Assuming 4 cohorts of 3 patients (i.e. no patients with DLT at given level) and 2 cohorts of 
6 patients (i.e. 1 DLT witnessed in first 3 patients so further 3 patients exposed with no 
DLTs), 24 evaluable patients will be necessary for the dose escalation part.
Together with an assumed number of 12 additional patients for the expansion cohort this 
leads to an expected sample size of 36 evaluable patients.
AML patients in CR:
Assuming 1 cohort of 3 patients (i.e. no patients with DLT at given level) and 2 cohorts of 
6 patients (i.e. 1 DLT witnessed in first 3 patients so further 3 patients exposed with no 
DLTs), 15 evaluable patients will be necessary for the dose escalation part in this patient 
population.
Together with an assumed number of 12 additional patients for the expansion cohort this 
leads to an expected sample size of 27 evaluable AML patients in CR.
Note that in general, the sample size is induced by the 3+3 design and is subject to different 
random factors.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator should inform the Sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches
of the protocol/ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorized 
CML/Clinical Research Associate (CRA) or Clinical Quality Assurance auditors appointed 
by Boehringer Ingelheim, by appropriate IEC members, and by inspectors from regulatory 
authorities.
8.2
DATA QUALITY ASSURANCE
The trial will be conducted in compliance with the protocol, the principles laid down in the
Declaration of Helsinki (please, refer to Section 8), local law and according to the principles 
of GCP and the company SOPs. To inform all Investigators about the trial drugs and the 


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procedures of the trial, either an Investigator meeting will be performed prior to start of the 
trial, or each Investigator will be visited individually by the Clinical Monitor and the CRA. 
Each Investigator will receive an ISF with all information relevant for the performance of the 
trial. Investigators will be visited at regular intervals for on-site monitoring by a Boehringer
Ingelheim employee or a CRA authorised by BI. At these occasions, source data verification
(SDV) will be performed and a check will be done whether the eCRFs are kept current. The
information in the eCRF and information in source documents will be cross-checked as
described in Section 8.3.1.
The data management procedures to ensure the quality of the data are described in detail in
the trial data management and analysis plan (TDMAP) available in the Clinical Trial Master 
File (CTMF). Coding of the data obtained will be done by using the medical dictionary for 
regulatory activities (MedDRA) and the WHO dictionary for concomitant medication. Data 
quality review meetings will be performed at regular intervals to evaluate the quality of the 
data collected. Discrepancies in data will be queried. 
A quality assurance audit/inspection of this trial may be conducted by the Sponsor or 
Sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance
auditor will have access to all medical records, the Investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the Sponsor via remote 
data capture. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent
with the source documents or the discrepancies must be explained. The Investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The CRA / on site monitor 
and auditor may review all CRFs/eCRFs, and written informed consents. The accuracy of the 
data will be verified by reviewing the documents described in Section 8.3.1.


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8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For BI 836858 this is the current version of the IB (c02324887-03). The current versions of 
these reference documents are provided in the ISF. 
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of SAEs, e.g. suspected unexpected serious adverse reactions (SUSARs) 
to health authorities and IECs/IRBs, will be done according to local regulatory requirements. 
Further details regarding this reporting procedure are provided in the ISF.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IEC and the regulatory authority.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
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Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Willman CL, Estey EH, 
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Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J 
Clin Oncol. 2003. 21(24): 4642-4649.
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Stone RM, O'Donnell MR, Sekeres MA. Acute myeloid leukemia. 
Hematology. 2004: 98–117.
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Estey E, Doehner H. Acute myeloid leukaemia. Lancet. 2006. 368: 1894-1907.
R07-2769
NCCN Clinical Practice Guidelines in Oncology: acute myeloid leukemia 
(V.1.2006). www.nccn.org ; National Comprehensive Cancer Network 2005.
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Froehling S, Schlenk RF, Kayser S, Morhardt M, Benner A, Doehner K, et.al. 
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acute myeloid leukemia patients older than 60 years: results from AMLSG 
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myelodysplastic syndrome in patients not considered fit for intensive 
treatment. Cancer. 2007. 109(6): 1114–1124.
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Estey E. Acute myeloid leukemia and myelodysplastic syndromes in older 
patients. J Clin Oncol. 2007. 25(14): 1908–1915.


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R07-2773
Menzin J, Lang K, Earle CC, Kerney D, Mallick R. The outcomes and costs of 
acute myeloid leukemia among the elderly. Arch Intern Med. 2002. 162: 
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Mrozek K, Bloomfield CD. Chromosome aberrations, gene mutations and 
expression changes, and prognosis in adult acute myeloid leukemia. 
Hematology. 2006:169–177.
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Becker C, Ali HA, Krahl R, Poenisch W, Wedding U, Fiedler, F, et.al. High 
complete remission rate in patients with acute myeloid leukemia (AML) above 
the age of 60 years: a report of the AML97#38 study of the East German 
Hematology and Oncology Study Group. Blood. 2004. 104(11): Abstr 880.
R09-2850
Common terminology criteria for adverse events (CTCAE) version 4.0 
(publish date: May 28, 2009). U.S.Department of Health and Human Services, 
National Institutes of Health, National Cancer Institute (2009).
R10-2947
Dohner H, et.al. Diagnosis and management of acute myeloid leukemia in 
adults: recommendations from an international expert panel, on behalf of the 
European LeukemiaNet. Blood, 21 January 2010, Volume 115, Number 3.
R10-4428
Chung CH. Managing premedications and the risk for reactions to infusional 
monoclonal antibody therapy. Oncologist. 2008. 13: 725-732.
R10-4517
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the 
management of pediatric and adult tumor lysis syndrome: an evidence-based 
review. J Clin Oncol. 2008. 26(16): 2767-2778.
R10-6267
Wang DD, Zhang S, Zhao H, Men AY, Parivar K.  Fixed dosing versus body 
size-based dosing of monoclonal antibodies in adult clinical trials. J Clin 
Pharmacol. 2009. 49: 1012-1024.
R11-1467
Crocker PR, Zhang J. New I-type lectins of the CD33-related Siglec subgroup 
identified through genomics. Biochem Soc Symp. 2002. 69: 83-84.R11-1468
R11-1468
Scheinberg DA, Tanimoto M, McKenzie S, Strife A, Old LJ, Clarkson BD. 
Monoclonal Antibody M195: A Diagnostic Marker for Acute Myelogenous 
Leukemia. Leukemia. 1989. 3: 440-445.
R11-1469
Hauswirth AW, Florian S, Printz D, Sotlar K, Krauth MT, Fritsch G, et.al. 
Expression of the target receptor CD33 in CD43+/CD38-/CD123+ AML stem 
cells. Eur J Clin Invest. 2007. 37: 73-82.
R11-1470
Plesa C, Chelghoum Y, Plesa A, Elhamri M, Tidaud I, Michallet M, et.al. 
Prognostic Value of Immunophenotyping in Elderly Patients with Acute 
Myeloid Leukemia. Cancer. 2007. 112(3): 572-580.


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R11-1471
Raza A, Jurcic JG, Roboz GJ, Maris M, Stephenson JJ, Wood BL, et.al. 
Complete remission observed in acute myeloid leukaemia following prolonged 
exposure to lintuzumab: a phase I trial. Leukemia & Lymphoma. 2009: 1-9.
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Lapusan S, Vidriales MB, Thomas X, de Botton S, Vekhoff A, Tang R, 
Dumontet C, et.al. Phase I studies of AVE9633, an anti-CD33 antibody-
maytansinoid conjugate, in adult patients with relapsed/refractory acute 
myeloid leukemia. Invest New Drugs. 2011 Apr 26.
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Taussig DC, Pearce DJ, Simpson C, Rohatiner AZ, Lister TA, Kelly G, et.al. 
Hematopoietic stem cells express multiple myeloid markers: implications for 
the origin and targeted therapy of acute myeloid leukemia. Blood. 2005. 106: 
4086-4092.
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Caron PC, Dumont L, Scheinberg DA. Supersaturating Infusional Humanized 
Anti-CD33 Monoclonal Antibody HuM195 in Myelogenous Leukemia. 
Clinical Cancer Research. 1998. 4: 1421-1428.
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Raza A, Jurcic JG, Roboz GJ, Maris M, Stephenson JJ, Wood BL, et.al. 
Complete remissions observed in acute myeloid leukemia following prolonged 
exposure to lintuzumab: a phase 1 trial. Leukemia & Lymphoma. 2009 Aug. 
50(8): 1336-1344.
R11-2960
Webber BA, Cushing MM, Li S. Prognostic significance of flow cytometric 
immunophenotyping in acute myeloid leukemia. Int J Clin Exp Pathol. 2008. 
1(2): 124-133.
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Caron PC, Co MS, Bull MK, Avdalovic NM, Queen C, Scheinberg DA. 
Biological and immunological features of humanized M195 (anti-CD33) 
monoclonal antibodies. Cancer Res. 1992. 52: 6761-6767.
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Jurcic, JG, et.al. Molecular Remission Induction with Retinoic Acid and Anti-
CD33 Monoclonal Antibody HuM195 in Acute Promyelocytic Leukemia. Clin 
can res. February 2000. Vol. 6, 372–380.
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Stringaris K, Sekine T, Khoder A, Alsuliman A, Razzaghi B, Sargeant R, 
Pavlu J, Brisley G, Lavallade H de, Sarvaria A, Marin D, Mielke S, Apperley 
JF, Shpall EJ, Rezvani K. Leukemia-induced phenotypic and functional 
defects in natural killer cells predict failure to achieve remission in acute 
myeloid leukemia. Haematologica. 2014. 99 (5), 836 – 847.


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9.2
UNPUBLISHED REFERENCES
 
 
 
 
 
 
U11-2766-01
 Investigator’s Brochure: BI 836858 (Version 1.0). 09 December 
2011.
c02324887-03
 Investigator’s Brochure: BI 836858 (Version 5.0). 14 Aug 2015.


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10.
APPENDICES
10.1
PUBLICATION POLICIES
Boehringer Ingelheim is as much as possible dedicated to support process of free exchange of 
relevant scientific information.  Any publication of the result of this trial must be consistent 
with the Boehringer Ingelheim publication policy. The rights of the Investigator and of the 
Sponsor with regard to publication of the results of this trial are described in the Investigator
contract. As a general rule, no trial results should be published prior to finalisation of the 
Clinical Trial Report (CTR).
The present trial will be published in a clinical trial registry indicating the trial dates and 
indication as well as the number of sites and location.
10.2       EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
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


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10.3
CLINICAL EVALUATION OF LIVER DISEASE
10.3.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (Protocol-Specified 
Significant Events), are to be further evaluated using the following procedures:
10.3.2
Procedures
Repeat the following lab tests: ALT, AST, and bilirubin (total and direct) - within 48 to 
72 hours. If ALT and/or AST >3-fold ULN combined with an elevation of total bilirubin 
>2-fold ULN are confirmed, results of the laboratory parameters described below must be 
made available to the Investigator and to BI as soon as possible.
In addition,

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “Drug Induced Liver Injury (DILI) checklist” provided in the 
ISF

obtain history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets according to the “DILI checklist” provided in the ISF; 

obtain a history of exposure to environmental chemical agents (consider home and 
work place exposure) according to the “DILI checklist” provided in the ISF; and 
report these via the CRF.
Clinical chemistry
Alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C 
(Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E 
(Anti-HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody
(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, 
Antimitochondrial antibody
Hormones, tumor marker
TSH
Haematology
Thrombocytes, eosinophils

Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic
pathology, e.g. bile duct stones or neoplasm.


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
Initiate close observation of subjects by repeat testing of ALT, AST, and total 
bilirubin (with fractionation by total and direct) at least weekly until the laboratory 
ALT and/or AST abnormalities stabilize or return to normal, then according to the 
protocol. Depending on further laboratory changes, additional parameters identified 
e.g. by reflex testing will be followed up based on medical judgment and Good 
Clinical Practice (GCP).


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
01
Date of CTP revision
13 April 2012
EudraCT number
N/A
BI Trial number
1315.1
BI Investigational Product(s)
BI 836858
Title of protocol
A Phase I, open, cohort dose escalation trial with 
BI 836858 in patients with refractory or relapsed 
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
Section to be changed
Title page 
Description of change
Change of TCM and contact information; 
Status: “Final Protocol” has been removed and 
“Revised Protocol (based on Global Amendment 
01)” has been added
Version and Date: Version 1.0 has been replaced 
with Version 2.0   
Rationale for change
Clarification and update
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
The following exclusion criterion has been added:
Patients who are candidates for allogeneic stem 
cell transplantation.
Rationale for change
Clarification that all eligible patients  should have 


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Number of global amendment
01
received all standard therapies available for AML, 
before participating in a first in human trial
Section to be changed
Section 4.1.3 Selection of doses in the trial and 
Table 4.1.3: 1 Entry of patients into trial, by 
cohort
Description of change
Section 4.1.3: Clarification of the cohort dose 
escalation phase for enrolment of patients into the 
first dose cohort of 10 mg
Table 4.1.3: 1: Addition of footnote for 
clarification of cohort dose escalation phase for 
enrolment of patients into the first dose cohort of 
10 mg
Rationale for change
Clarification


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Number of global amendment
02
Date of CTP revision
14 Jun 2013
EudraCT number
N/A
BI Trial number
1315.1
BI Investigational Product(s)
BI 836858
Title of protocol
A Phase I, open, cohort dose escalation trial with BI 
836858 in patients with refractory or relapsed 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
Section to be changed
Title page
Description of change
Status: “Revised Protocol (based on Global 
Amendment 01)” has been updated to be “Revised 
Protocol (based on Global Amendments 01 and 02)”
Version and Date: Version 2.0 has been replaced 
with Version 3.0
Rationale for change
Clarification and update
Section to be changed
Protocol Synopsis
Description of change
Objective: “refractory or relapsed” has been added
Mode of admin: the time period of the infusion 
“over 3 hours” was deleted
Duration of treatment: Language has been updated 
from “Those patients with partial response (PR) or 
complete response (CR) after 8 administrations and 
who are tolerating the infusions may continue until 
progressive disease (PD)” to read “Those patients 
with clinical benefit as defined by International 
Working Group (IWG) objective response (partial 


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Number of global amendment
02
remission (PR) or complete remission (CR) or 
complete remission with incomplete blood recovery 
(CRi)) or subjective response (in the absence of 
objective response) after 8 administrations and who 
are tolerating the infusions may continue until 
progressive disease (PD).”
Criteria for safety: The following parameters have
been added: “vital signs, ECG, physical 
examination and”
Rationale for change
Clarification and update
Section to be changed
Flow Chart
Description of change
Trial Period: “Demographics” has been updated to 
“Demographics and baseline conditions”, “Adverse 
events” has been marked to be collected at 
screening, “Pharmacokinetics” and “Anti-drug 
antibodies” have been marked to be collected at 
further treatment visits, and “Vital Status” has been 
added.
Footnotes: EOT footnote replaced “CR” with “CRi 
or CR”
** section has replaced “CR” with “CRi or CR”
Footnote 3 has removed “footnote 1” and replaced 
with “footnote 2”
Footnote 4 wording has been added: “An additional 
safety lab will be collected on day 2 (i.e., 24 hours 
after the first administration of BI 836858).Other 
lab tests to be included: haptoglobin, direct Coombs 
test, and bilirubin (direct and indirect)”.
Footnote 10 has been updated to: Bone marrow 
aspirate to assess efficacy before 5th and 9th
administrations “(i.e., BM performed on Day 1 (+/-
1) of cycles 3 and 5 and treatment started on day 1 
(up to +3)  of cycles 3 and 5)”
Footnote 14 has removed “Cycle 1 Day 9, Cycle 2 
Day 2, and Cycle 2 Day 9 in addition to those” and 
been updated to “Sampling at the time points 
specified in Tables 1 and 2.  As noted in Tables 1 
and 2 PK sampling timepoints specify visits on 
Cycles 1 and 2  Days 1, 2, 4, 8, 9 and 11 and EOT 
and on Cycle ≥3 Days 1 and 8 and EOT/EOFT as 
noted in the Flow Chart.
Footnote 17 has been updated to “After the 8th 
infusion, at the end of treatment visit, patients will 
be evaluated to determine if they have clinical 


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Number of global amendment
02
benefit, as defined by IWG objective response (PR, 
CRi or CR) or subjective response (in the absence 
of objective response) and are tolerating the 
infusions well and who would like to continue to 
receive infusions until PD or other criteria for 
withdrawal are met as noted in Section 3.3.4.1.  For 
each infusion past the 8th administration, patients 
will continue to be assessed after each cycle for 
clinical benefit (objective or subjective response), 
and that they are tolerating the infusions well and 
would like to continue until PD or other criteria for 
withdrawal are met as noted in Section 3.3.4.1.”
Rationale for change
Clarification and update. 
For footnote 4, an additional safety lab was added 
on day 2, 24 hours after the first administration of 
BI 836858. The aim is to observe elevated 
laboratory values earlier and, with additional 
parameters (e.g. liver enzymes) to better understand 
the cause of the laboratory values. 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.
Section to be changed
Table 1 and Table 2
Description of change
Blood sampling timepoints have been updated in 
both tables. For Table 2, additional blood sampling 
timepoints have been added for cycles≥3
Rationale for change
Update
 
 
 
 
 
 


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Number of global amendment
02
The schedule to investigate cytokine levels at 
specific timepoints was adapted following the FDA 
guidance (Draft Guidance for Industry 
Immunogenicity Assessment for Therapeutic 
Protein Products).
Section to be changed
Abbreviations
Description of change
“ASCT Allogeneic stem cell transplantation” was 
added.
In CRi abbreviation, “marrow” was removed and 
“blood” was added.
“NK Natural Killer (cells)” was added.
Rationale for change
Clarification and update
Section to be changed
Section 1.1 Medical Background
Description of change
“Objective response was defined as either CR, CRi 
or PR” was added
Rationale for change
Clarification and update
Section to be changed
Section 2.2 Trial Objectives
Description of change
Section was revised to read as follows: The primary 
objective of this trial is to determine the maximum 
tolerated dose (MTD) of BI 836858.  BI 836858 is a 
new biological entity (NBE) and the MTD may not 
be reached.  Even if no MTD is reached the highest 
dose of BI 836858 that may be tested is 800 mg. To 
learn more about the safety and preliminary efficacy
there will be an expansion cohort either at the MTD 
or 800mg. “the highest tested dose (e.g. 320 mg).”   
Rationale for change
Clarification and Update
Section to be changed
Sections Flow Chart- EOT footnote, 2.2, 3.3.3, 
3.3.4.1, 5.5.1, 5.5.2.1, 5.5.3.2, 5.6, 5.6.2, 5.6.3, 
6.2.2.2, 6.2.3.1, 7.3, 7.3.2.4, 10.3
Description of change
Grammatical and spelling updates
Rationale for change
Grammatical and spelling updates
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
Text was revised and dose levels were modified as 
follows: 
“The dose is planned to be escalated in cohorts at 
pre-defined dose levels based on a multiplication 
factor of 2. 3 in the low dose range, and a factor of 
approximately 2 at doses higher than 90 mg. The 
dose levels are 10 mg, 20 mg, 40 mg, 80 mg, 160 
mg, and 320 mg 10 mg, 30 mg, 90 mg, 200 mg, 400 
mg, and 800 mg as outlined in Section 4.1.3.  
However, Intermediate dose levels and levels
higher than 320 mg may be investigated if agreed 


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Number of global amendment
02
upon between Investigator and Sponsor.”  
“In case no MTD is reached up to the highest 
planned dose (e.g., 320 mg), of  800 mg, 12 
additional patients will be treated with once weekly 
highest test dose (i.e., 320 mg) 800 mg of 
BI 836858.”
Clarification of treatment in the dose escalation 
phase of the trial as follows:
“During the dose escalation phase, each patient 
will receive up to 2 repeated treatment cycles. In 
patients who show clinical benefit as defined by 
IWG objective response (CR, CRi, PR), or 
subjective response (in the absence of objective 
response) as defined by the Investigator after 2 
cycles, the number of cycles on the same dose level 
may be increased to 4 (8 administrations) upon 
agreement between Investigator and Sponsor. This 
includes Cycle three (administration of BI 836858 
on Days 29 and 36) and cycle four (administration 
of BI 836858 on Days 43 and 50). Continuation of 
treatment will be discussed between Investigators 
and Sponsor at each cycle.”
Text has been revised as follows:
Patients who show “clinical benefit”, (CR, CRi, PR, 
or subjective response) clinical benefit as defined by 
the Investigator after 4 cycles “(each cycle 
individually evaluated)),” and who are tolerating 
the infusions well may continue to receive 
additional cycles upon agreement between 
Investigator and Sponsor until the patient meets any 
of the criteria for withdrawal as outlined in Section 
3.3.4.1.”
Rationale for change
Clarification and Update and Safety. 
To mitigate the risk of dose dependent side effects, 
all dose levels will be based on a multiplication 
factor of two (x2) and the doses pre-defined i.e. 10,
20, 40, 80, 160 and 320 mg of BI 836858.


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Number of global amendment
02
Section to be changed
Section 3.2 DISCUSSION OF TRIAL DESIGN, 
INCLUDING THE CHOICE OF CONTROL 
GROUP
Description of change
The text was revised as follows:
In case no MTD is reached up to the highest 
planned dose (e.g., 320 mg), of 800mg, 12 
additional patients will be treated with once weekly 
of the highest tested dose (e.g., 320 mg) 800 mg of 
BI 836858.  
“And pharmacologic/pharmacodynamic” has been 
removed from this section.
Rationale for change
Clarification and Update
Section to be changed
Section 3.3 Selection of trial population
Description of change
“About” was added to target of 10 patients.
Rationale for change
Clarification
Section to be changed
Section 3.3.2 Inclusion Criteria
Description of change
Inclusion criteria #2 added “per central laboratory 
assessment at the Ohio State University”.
Inclusion criteria #3 added “See Section 10.2”.
Inclusion criteria #4 removed “>” and replaced with 
“≥”.
Rationale for change
Clarification
Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
Exclusion criterion #2 – text was revised: “Patients 
with >30,000 leukocytes/μl in the peripheral blood 
was changed to “Patients with >5,000 leukocytes/μl 
in the peripheral blood”. 
Exclusion criterion #3- text was removed and 
updated for clarification: “Anti-leukemia therapy 
within two weeks before first treatment with BI 
836858; however, parallel treatment with 
Hydroxyurea is allowed. (Hydroxyurea may be 
given until 48 hours before the first treatment with 
BI 836858) (See Section 4.2.2.1)”
Exclusion criterion #13 has removed “the evaluation 
of efficacy or safety of the trial drug and reads as 
follows: “Concomitant intercurrent illness, or any 
condition which in the opinion of the Investigator, 
would compromise safe participation in the study, 
e.g. active severe infection, unstable angina 
pectoris, new onset of exacerbation of a cardiac 
arrhythmia”


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Number of global amendment
02
Rationale for change
Clarification, update and safety.
To control the WBC, a treatment with hydroxyurea 
is allowed (as noted in Exclusion #3). The parallel 
use of hydroxyurea may allow patients with a 
proliferative disease to remain on study. This may 
also reduce the number of early study withdrawals, 
especially in the lower dose cohorts, as disease 
progression may be controlled. 
Section to be changed
Section 3.3.4.1 Removal of individual patients
Description of change
“4 administrations (1 cycle)” has been replaced by 
“4 administrations (2 cycles)”.
Rationale for change
Clarification and correction
Section to be changed
Section 4.1 TREATMENTS TO BE ADMINISTERED
Description of change
Text was revised to read as follows: BI 836858 will 
be administered as an as a rate-controlled 
intravenous infusion.
Text was deleted for clarification: (Volume:  250 
mL), Rate:  see Table 4.1.1:1 below)
Rationale for change
Posology was revised - update
Section to be changed
Section 4.1.1 Identity of BI investigational product 
and comparator product
Description of change
Posology was revised from “Infusion over 3 hours” 
to “Rate controlled infusion”.
Table 4.1.1: 1 was removed and text was added as 
explanation for infusion rate as follows:
“The first and second infusion will be started at a 
rate of 10 mL/h. The infusion rate should be 
increased every 30 (+/-10) minutes by 10 mL/h to a 
maximum of 80 mL/h as long as tolerated by the 
patient. If considered safe by the Investigator, the 
stepwise increase of infusion rate during the third 
and subsequent infusions may be faster or steps may 
be omitted, but the maximum infusion rate must not 
exceed 120 mL/h. If symptoms of an infusion-related 
reaction occur, the infusion should be temporarily 
stopped. Upon recovery, it should be infused at 50% 
of the rate at which the reaction occurred and 
should not be dose escalated from this dose for at 
least 30 minutes. Lower rates may be selected if 
clinically indicated. Depending on the time of 
occurrence and the severity of the reaction, the 
investigator may consider administering additional 


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Number of global amendment
02
supportive medication, e.g. corticosteroids. A 
stepwise re-increase of the infusion rate to a 
maximum of 80 mL/h is possible. For medical 
reasons, in case a patient experiences an adverse 
event during the infusion, the duration of the 
infusion may be expanded until the use-by date and 
use-by time indicated on the label is reached. The 
actual duration of the infusions and the infusion 
steps need to be documented in the eCRF including 
actual start and end time, actual time points for 
interruption and restart of the infusion and the 
actual infusion rates.”
Rationale for change
Clarification and Update.
The stepwise increase of the infusion rate of BI 
836858 was adapted and an upper limit of 80ml/hr 
is defined in the protocol amendment. However,
some flexibility is given in case the first four 
administrations of BI 836858 are well tolerated.
Section to be changed
Section 4.1.3 Selection of doses in the trial
Description of change
Text was modified as follows: “BI 836858 will be 
administered as a rate-controlled, intravenous 
infusion as noted in Table 4.1.1: 1 over 3 hours 
every 7 days.”
The text referring to dose levels was modified: “The 
dose is planned to be escalated in cohorts at pre-
defined dose levels based on a multiplication factor 
of 2. 3 in the low dose range, and a factor of 
approximately 2 at doses higher than 90 mg.  The 
dose levels are 10 mg, 30 mg, 90 mg, 200 mg, 400 
mg, and 800 mg. However, The dose levels are 10 
mg, 20 mg, 40 mg, 80 mg, 160 mg, and 320 mg.
Intermediate dose levels and dose levels higher 
than 320 mg may be investigated if agreed upon 
between Investigator and Sponsor.  
Clarification that enrolment into the next highest 
dose cohort has been corrected from “14 days” to 
“28 days”.
Text was modified: In case no MTD is reached up 
to the highest planned tested dose (e.g. 320 mg), of 
800 mg, 12 additional patients will be treated with 


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Number of global amendment
02
once weekly with the highest tested dose (e.g. 320 
mg) 800 mg of BI 836858 in the expansion cohort.
Rationale for change
Clarification and update
To mitigate the risk of dose dependent site effects, 
all dose levels will be based on a multiplication 
factor of two (x2) and the doses pre-defined i.e. 10, 
20, 40, 80, 160 and 320 mg of BI 836858.
Section to be changed
Section 4.1.4 Drug assignment and administration 
of doses for each patient
Description of change
Updated glucocorticoid i.v., equivalent to 
prednisolone dose from “50mg” to “100mg”
Language updated to read as follows:
“If BI 836858 has been well tolerated without signs 
of infusion-related reactions in the first 
administration, glucocorticoid premedication may 
be reduced to a dose equivalent to 25 50 mg 
prednisolone for the second through fourth
administrations, and in case this is well tolerated 
reduce the steroids with the 5th infusion (25 mg 
with 5th and 0 mg with the 6th infusion.) However, 
in case an administration of BI 836858 was not 
well tolerated the premedication with prednisolone 
can be re-escalated up to 100 mg.”
Rationale for change
Update.
To further mitigate the risk of infusion related 
symptoms, the prophylaxis, given before each 
infusion of BI 836858, was adapted
Section to be changed
Section 4.1.4 Drug assignment and administration 
of doses for each patient
Description of change
Text added for clarification: Neutrophils ≥500 /μL 
(0.5 x 109/L) and platelets ≥25,000 /μL (25 x 109/L), 
unless CTCAE Grade 4 neutropenia or 
thrombocytopenia was preexistent prior to trial 
entry. “Patients with active leukemia who go from 
Grade 3 neutropenia to Grade 4 neutropenia after 
treatment may continue on study provided there is 
no evidence of infection or febrile neutropenia. 
Patients with active leukemia who go from Grade 3 
to Grade 4 thrombocytopenia after treatment may 
continue on study provided that post-transfusion 
platelet count is at least 20,000/uL before therapy is 
given.”


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Number of global amendment
02
Rationale for change
Clarification
Section to be changed
Section 4.1.7 Storage conditions
Description of change
Added “- stored in a refrigerator 36-46°F (2-8°C); 
do not freeze”.
Rationale for change
Clarification
Section to be changed
Section 4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
The word “the” was removed from text
Text was modified and added to allow use of 
Hydroxyurea as follows: “Prior anti-leukemia 
therapy must have been discontinued at least two 
weeks before the first administration of the trial 
drug (Hydroxyurea may be given during study 
participation) until 48 hours before the first 
treatment with BI 836858) and the patient must 
have recovered from all clinically relevant 
reversible toxicities as determined by the 
investigator.  
“For peripheral blood blast control, as this may 
correlate with the risk of occurrence of infusion 
related symptoms, hydroxyurea will be allowed 
(maximum dose of hydroxyurea 3gm daily) before 
and during study participation. Leukocyte must be 
≤ 5,000/µl at start of each administration of BI 
836858. During the first two dose cohorts, if in the 
first cycle more than 2 patients who receive 
BI 836858 experience a leukocyte count over 
40,000/µl indicative of disease progression, then 
hydroxyurea will be allowed (maximum dose of 
hydroxyurea 3gm daily) during the week after the 
first infusion of BI 836858 for all subsequent 
patients.
If the change of permitting hydroxyurea is 
implemented and more than 2 of the next 6 patients 
experience the leukocytosis (40,000/µl indicative of 
disease progression) and discontinue the due to 
disease progression in the first cycle, then the 
eligibility criteria will be modified such that patients 
requiring hydroxyurea within a week of study entry 
to maintain WBC <30,000/ul will no longer be 
eligible.  


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Number of global amendment
02
Rationale for change
Clarification and update.
To control the WBC, a treatment with hydroxyurea 
will be allowed. The parallel use of hydroxyurea 
may allow patients with a proliferative disease to 
remain on the study. This may also reduce the 
number of early study withdrawals, especially in the 
lower dose cohorts, as disease progression may be 
controlled. 
Section to be changed
Section 5.1.2.3 Assessment and definition of best 
overall response
Description of change
Language updated for clarification to read as 
follows: “Response will be assessed according to 
the criteria from the IWG based on laboratory data 
from the peripheral blood, bone marrow 
examination, and clinical examination (at the end of 
each cycle), e.g. prior to the next dose of BI 836858,
at the evaluation for further treatment-visit and, the 
EOT-visit., and at all follow up visits.  Bone marrow 
examination will be performed before the Cycle 3 
and Cycle 5 (5th and 9th administration of BI 
836858) (i.e., BM performed on Day 1 (+/-1) of 
cycles 3 and 5 and treatment started on Day 1 (up 
to +3) of cycles 3 and 5) and at the discretion of the 
Investigator, e.g. in case clinical and laboratory 
examinations of peripheral blood demonstrate that 
a CR has been achieved, or for assessment of 
persistent neutropenia, anemia or 
thrombocytopenia.”
Treatment Failure: added " Resistant disease: 
Patient survives ≥7 days post-course of treatment; 
persistent leukemia in blood or bone marrow.
Aplasia: Patient survives ≥7 days post-course of 
treatment; death while cytopenic, with aplastic bone 
marrow
Indeterminate cause: Patients who die < 7 days 
posttherapy. Patients who die > 7 days posttherapy 
with no peripheral blood blasts, but no bone marrow 
examination. Patients who do not complete the first 
course of therapy.
Morphologic relapse: Reappearance of blasts post-
CR in peripheral blood or bone marrow.”
Progressive Disease: removed “10%” for increase of 


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Number of global amendment
02
blast population in bone marrow or peripheral blood 
and replaced with “50%”.
Rationale for change
Clarification and update
Section to be changed
Rationale for change
Updated
Section to be changed
Section 5.2.2.1 Definitions of adverse events
Description of change
Protocol-specified significant events: Updated for 
patients with impaired liver function at baseline 
“2.5” was removed and replaced with “5.0” times 
ULN for AST or ALT is considered a protocol-
specified significant event.  And “1.5” was removed 
and replaced with “2.0”ULN for bilirubin protocol-
specified significant event.
Clarification added that SAEs should be reported 
“(within 24 hours or the next business day 
whichever is shorter)”.
Change of spelling in the word DILI
Rationale for change
Clarification and update
Section to be changed
Section 5.2.3.1 General safety laboratory parameters
Description of change
Text added: “An additional safety lab will be 
collected on day 2 of Cycle 1 (i.e., 24 hours after the 
first administration of BI 836858). Other lab tests to 
be included: haptoglobin, direct Coombs test, 
bilirubin (direct and indirect) and free hemoglobin. 
Non pre-existing abnormal laboratory values 
(CTCAE Grade 3 or higher) will be followed up 
every 48 hours until these laboratory values are 
back to at least CTCAE Grade 1.”
Rationale for change
Update
 
 
 
 
 
 
 
 
Section to be changed
Section 5.2.5.1 Vital signs


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Number of global amendment
02
Description of change
Text was updated: Additional time points for blood 
pressure and heart rate at the day of administration 
of BI 836858 are: prior to the start of premedication, 
prior to the start of BI 836858 infusion, and in 30 
(±10) minute intervals throughout the course of the
and 30 (±10), 60 (±10), 90 (±10), 120 (±10), 150 
(±10) and 180 (±10) minutes after start of the
infusion of BI 836858 and 60 (±10) minutes after 
the end of the infusion, thereafter every 4-8 hours 
until at least 24 hours after the start of the infusion.
Rationale for change
Clarification and update
Section to be changed
Section 5.2.5.2 Physical examination
Description of change
Added “height” for clarification of procedures to be 
performed during a PE.
Rationale for change
Clarification
Section to be changed
Section 5.3.2.1 Demographics and history
Description of change
Updated to include “CRi”.
Rationale for change
Clarification
 
 
 
 
 
Section to be changed
Section 5.4 Appropriateness of measurements
Description of change
References updated removing “R10-4429” and 
replacing with “R06-0452”.
Rationale for change
Update
Section to be changed
Section 5.5.1 
 
 
 
 


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Number of global amendment
02
Operating Procedure (SOP) 001-MCS-36-472_RD-
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Number of global amendment
02
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Section to be changed
Section 6.2.1 Screening and run-in period
Description of change
Updated to be consistent with Flow Chart:             
“Visit 0” revised to “Visit 1”                                  
“and baseline conditions” was added to 
Demographics 
 
Rationale for change
Clarification


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Number of global amendment
02
Section to be changed
Added Section 6.2.1.1 Rescreening
Description of change
Added to include rescreening of patients for the trial
Rationale for change
Update
Section to be changed
Section 6.2.2.1 Visit 1 and Visit 3 – day of BI 
836858 administration (administrations 1-8)
Description of change
Safety lab was updated as follows: “An additional 
safety lab will be collected on day 2 (i.e., 24 hours 
after the first administration of BI 836858).Other 
lab tests to be included: haptoglobin, direct 
Coombs test, bilirubin (direct and indirect) and 
free hemoglobin. Non pre-existing abnormal 
laboratory values (CTCAE Grade 3 or higher) will 
be followed up every 48 hours until these 
laboratory values are back to at least CTCAE 
Grade 1.”
Physical examination and ECOG text modified for 
clarification: 
Physical examination “and ECOG performance 
score completed” every second cycle beginning 
with cycle 1. (Physical exam may be completed up 
to 2 days prior to administration and ECOG must be 
completed on the day of the administration.), Height 
and weight (only at Day 1 of first cycle). and ECOG 
performance score.  If the first administration is 
completed within 3 days of the screening visit, these 
examinations do not need to be repeated.
Biomarkers updated with reference to collection 
time points in Table 3
Rationale for change
Clarification and update.
The aim is to observe elevated laboratory values 
earlier and, with additional parameters (e.g. liver 
enzymes) to better understand the cause of the 
laboratory values. 
 
 
Section to be changed
Section 6.2.3.1 EOT visit
Description of change
“, PR or CR ” deleted


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Number of global amendment
02
Rationale for change
Update
Section to be changed
Section 6.2.3.2 Further treatment (Visit 1 and Visit 
2)
Description of change
Language updated to: “These visits are only for 
those patients with clinical benefit, PR, or CR after 
8 administrations and who are tolerating the 
infusions well.  Patients can receive further 
treatment once the result from the bone marrow 
assessment from EOT is available. Procedures 
already done at EOT (i.e., safety lab, pregnancy 
test) do not need to be repeated at FTE if FTE visit 
is within 7 days from EOT.”
Rationale for change
Clarification and update
Section to be changed
Section 6.2.3.3 End of further treatment
Description of change
Physical examination language clarification to 
include “weight”
Rationale for change
Clarification
Section to be changed
Section 6.2.3.4 Follow up
Description of change
Text added: “Vital status evaluated at each follow 
up visit.”
Rationale for change
Updated
Section to be changed
Section 7.3.2.3 Best overall response
Description of change
Updated with “or PR” for consistency and 
clarification
Rationale for change
Clarification
Section to be changed
Section 7.3.3 Safety analyses
Description of change
MTD determination clarification to be completed 
after 2 cycles
Rationale for change
Clarification
Section to be changed
 
 
 
Rationale for change
Clarification
Section to be changed
Section 9.1 Published References
Description of change
Reference removed (R10-4429) and added (R01-
0787)
Rationale for change
Update
Section to be changed
Section 10.2 EASTERN COOPERATIVE
ONCOLOGY GROUP (ECOG) Performance


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Number of global amendment
02
Status
Description of change
Section/Table added for clarification
Rationale for change
Clarification


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Number of global amendment
03
Date of CTP revision
28 April 2016
EudraCT number
N/A
BI Trial number
1315.1
BI Investigational Product(s)
BI 836858
Title of protocol
A Phase I, open label, cohort dose escalation trial 
with BI 836858 in patients with refractory or 
relapsed acute myeloid leukemia and patients 
with acute myeloid leukemia in complete 
remission with high risk to relapse
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title Page 
Description of change
Title of trial updated
Rationale for change
Updated to include new patient population
“Patients with AML in complete remission  (CR) 
with high risk to relapse”
Section to be changed
Synopsis: title of trial, objectives, No. of patients, 
inclusion criteria, test product, duration of 
treatment, criteria for efficacy  
Description of change
Protocol synopsis sections updated to include new 
patient population
Rationale for change
Revised to include new patient population
Section to be changed
Flow Chart
Description of change
A new Flow Chart was added for the new patient
population.  To differentiate them, now labelled 
“Flow Chart A” and “Flow Chart B” plus patient 
population.  Footnote section in FC - A updated.
Rationale for change
Updated to include new patient population


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Number of global amendment
03
 
 
Section to be changed
Abbreviations
Description of change
Updated with new abbreviations; abbreviation 
definitions revised; abbreviation deleted
Rationale for change
Update
Section to be changed
1.1 Medical Background
Description of change
New patient population information added and 
differentiated from refractory/relapsed patients.
Deletion of language to update section.
Rationale for change
Updated to include new patient population and 
medical background information
Section to be changed
1.1 Medical Background
Description of change
Addition of lintuzumab paragraph
Rationale for change
To update medical background information
Section to be changed
1.2 Drug Profile
Description of change
Investigator brochure reference updated; 
preliminary data from current study added
Rationale for change
Updated with new information
Section to be changed
2.1 Rationale for Performing the Trial
Description of change
Section updated and preliminary data added to 
include new patient population
Rationale for change
Updated to support rationale of new patient 
population 
Section to be changed
2.1 Rationale for Performing the Trial
Description of change
Addition of lintuzumab paragraph
Rationale for change
Update
Section to be changed
2.2 Trial Objectives
Description of change
Language revised since there will be more than 1 
MTD
Rationale for change
clarification
Section to be changed
2.3 Benefit – Risk Assessment
Description of change
Text updated with new patient population; section 
updated/language deleted; new clinical data added 
Rationale for change
Updated to support addition of new patient 
population
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
Text added/deleted and updated to differentiate 
both patient populations
Rationale for change
Updated to include new patient population


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Number of global amendment
03
Section to be changed
3.1.1, 4.1.6, 5.2.3.2, 5.2.4, 5.2.5.2, 7.3.2.3, 7.3.6, 
and 10.3.2
Description of change
Grammatical and spelling updates
Rationale for change
Updates
Section to be changed
3.2 Discussion of Trial Design, Including the 
Choice of Control Group
Description of change
Text added/deleted and updated to differentiate 
both patient populations
Rationale for change
Updated to include new patient population
Section to be changed
3.3 Selection of Trial Population
Description of change
Text added/deleted to differentiate both patient 
populations; number of patients screened and 
entered updated
Rationale for change
Updated to include new patient population
Section to be changed
3.3.1 Main Diagnosis for Study Entry
Description of change
Text added to differentiate both patient 
populations; text deleted
Rationale for change
Updated to include new patient population
Section to be changed
3.3.2 Inclusion criteria
Description of change
Text added to differentiate both patient 
populations
Rationale for change
Updated to include new patient population
Section to be changed
3.3.3 Exclusion criteria
Description of change
Text added/deleted and updated in exclusions # 1, 
# 2, # 3, and # 5 to differentiate both patient 
populations
Rationale for change
Updated to include new patient population
Section to be changed
3.3.3 Exclusion criteria
Description of change
Text updated in exclusions # 4 and #19 for 
clarification
Rationale for change
Clarification and update
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
Text added/updated to differentiate expectations 
in both patient populations
Rationale for change
Updated to include new patient population
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
Vital status collection added for clarification
Rationale for change
Clarification
Section to be changed
4.1.1 Identity of BI investigational product and 
comparator product
Description of change
Text added to clarify days when drug 
administered 
Rationale for change
Updated as per new patient population


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Number of global amendment
03
Section to be changed
4.1.3 Selection of doses in the trial
Description of change
Text added/deleted to differentiate both patient 
populations; new IB reference # included 
Rationale for change
Text added/deleted to differentiate both patient 
populations
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change
Text added/deleted to differentiate both patient 
populations; text updated in premedication and 
retreatment sections; text added regarding intra-
patient dose escalation
Rationale for change
Updated to include new patient population and to 
allow intra-patient dose escalation
Section to be changed
4.1.5.1 Blinding
Description of change
Text added to differentiate both patient 
populations
Rationale for change
Updated to include new patient population
Section to be changed
4.1.8 Drug accountability
Description of change
Drug substance added to text for clarification
Rationale for change
Updated for clarification
Section to be changed
4.2.1 Rescue medication, emergency procedures, 
and additional treatments
Description of change
Text deleted for clarification
Rationale for change
Updated for clarification
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Text updated for clarification
Rationale for change
Clarification
Section to be changed
5.1.1 Endpoints of efficacy
Description of change
Endpoints modified to differentiate between 
patient populations; endpoints deleted; secondary 
endpoints changed to further endpoints.
Deleted supportive care endpoint and change 
secondary endpoints to further endpoints
Rationale for change
Updated to differentiate both patient populations 
and to clarify study intended endpoints
Section to be changed
5.1.1 Endpoints of efficacy
Description of change
Language on supportive care requirements was 
deleted to update endpoints
Rationale for change
update
 
 


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Number of global amendment
03
 
Section to be changed
5.1.2.3 Assessment and definition of best overall 
response
Description of change
Text added for clarification and differentiation of 
patient populations; addition of stable disease and 
morphologic relapse as it was previously omitted 
in error
Rationale for change
Updated to differentiate both patient populations 
and for further clarification
Section to be changed
5.1.2.3 Assessment and definition of best overall 
response
Description of change
Language on Stable Disease added for update
Rationale for change
Update
Section to be changed
5.1.2.4 Progression free survival (PFS)
Description of change
Text added to clarify date of progression/relapse 
for clarification 
Rationale for change
Updated for clarification
Section to be changed
5.1.2.5 Time to treatment failure (TTF)
Description of change
Text added/deleted to clarify date of 
progression/relapse
Rationale for change
Updated for clarification
Section to be changed
Description of change
Text added for clarification
Rationale for change
Updated to clarify date of progression/relapse
Section to be changed
5.1.2.8 Supportive care requirements 
Description of change
Section deleted
Rationale for change
Deleted as "supportive care requirements" is no 
longer an endpoint
Section to be changed
5.1.2.9 ECOG Performance status
Description of change
Section # changed from 5.1.2.9 to 5.1.2.8 
Rationale for change
Revised as per deletion of the “supportive care 
requirements” 
Section to be changed
5.2.1 Endpoints of safety
Description of change
Text added/deleted to specify primary and further
safety endpoints


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Trial Protocol
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Number of global amendment
03
Rationale for change
Updated for clarification
Section to be changed
5.2.1.1 Dose Limiting Toxicity (DLT)
Description of change
Section subtitle updated with refractory/relapsed 
patient population; Text added/deleted for 
clarification
Rationale for change
Updated to reflect text relevant to refractory/ 
relapsed patients
Section to be changed
5.2.1.2 Dose Limiting Toxicity (DLT) for AML 
patients in CR
Description of change
Section added for inclusion of this patient 
population; text added/deleted for clarification 
and differentiation of each patient population
Rationale for change
Updated to include new patient population
Section to be changed
Section 5.2.2 Assessment of adverse events, 
5.2.2.1, 5.2.2.2 
Description of change
Sections updated as per new protocol template
Rationale for change
Update
Section to be changed
5.2.3.1 General safety laboratory parameters
Description of change
Text updated to reflect the new flow chart and 
change or clarification in lab test
Rationale for change
Clarification
Section to be changed
5.3.2.1 Demographics and history
Description of change
Text added/deleted to differentiate patient 
population 
Rationale for change
Updated
 
 
 
 


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Doc. No.: c02543230-04
Trial Protocol
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Number of global amendment
03
 
 
 
Section to be changed
6. Investigational Plan sections (6.1, 6.2, 6.2.1, 
6.2.2, 6.2.2.1, 6.2.2.2, 6.2.3 subtitle, 6.2.3.1, 
6.2.3.2, 6.2.4, 6.2.4.1, 6.2.4.2, 6.2.4.3, 6.2.4.4, 
6.2.4.5, 6.2.5 (former 6.2.3.4) and 6.2.6 (former 
6.2.3.5)  
Description of change
Text in these sections were added/updated to 
differentiate procedures to be performed with 
each patient population and to reflect new flow 
chart and tables
Rationale for change
Update and clarification
Section to be changed
7.1 statistical Design - Model
Description of change
Text added to differentiate both patient 
populations
Rationale for change
Update
Section to be changed
7.3 Planned Analyses
Description of change
Text updated for clarification
Rationale for change
Update
Section to be changed
7.3.1 & 7.3.2 Primary and secondary analyses
Description of change
Text updated to include both patient populations
Rationale for change
Update
Section to be changed
7.3.2.6 Supportive care requirements
Description of change
Section deleted 
Rationale for change
Section deleted as "supportive care requirements" 
is no longer an endpoint
Section to be changed
7.3.2.7 ECOG score
Description of change
Section # changed from 7.3.2.7 to 7.3.2.6 due to 
deletion of previous section
Rationale for change
Update
Section to be changed
7.3.3 Safety analyses
Description of change
Text updated as per new protocol template 
language
Rationale for change
Update
Section to be changed
7.3.4 Interim analyses
Description of change
Text updated as per new preliminary data 
obtained from the refractory /relapsed patient 
population


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Number of global amendment
03
Rationale for change
Update
Section to be changed
7.6 Determination of Sample Size
Description of change
Text added and updated to differentiate both 
patient populations
Rationale for change
Update
Section to be changed
8.4.1 Listedness
Description of change
IB reference # updated
Rationale for change
Update
Section to be changed
9.1 & 9.2 Published  and Unpublished References
Description of change
References added:R10-2947, R11-4695, and 
c02324887-03
Rationale for change
Update
Section to be changed
10.2 ECOG
Description of change
Reference # added for clarification
Rationale for change
Update


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02543230
1.0
clinical-trial-protocol-rev3
A Phase I, open, cohort dose escalation trial with BI 836858 in patients with
refractory or relapsed acute myeloid leukemia
Approval–Clinical Monitor
28 Apr 2016 22:06 CEST
Author-Trial Statistician
29 Apr 2016 11:47 CEST
Approval-Therapeutic Area 
29 Apr 2016 14:19 CEST
Approval-Translational Medicine
Expert
29 Apr 2016 14:37 CEST
Approval-Team Member Medicine
29 Apr 2016 17:02 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02543230
1.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c01837068-03
BI Trial No.:
1315.1
Title:
A Phase I, open-label, cohort dose escalation trial with BI 836858 in 
patients with refractory or relapsed acute myeloid leukemia and 
patients with acute myeloid leukemia in complete remission with 
high risk to relapse
Including:
Protocol Amendment 1 [U11-3713-02] 
Protocol Amendment 2 [U11-3713-03]
Protocol Amendment 3 [c02543230-04]
Investigational
Product(s):
BI 836858
Responsible trial 
statistician(s):
Telephone:
Fax: 
Date of statistical 
analysis plan:
09 APR 2018 REVISED
Version:
“Revised”
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1
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................3
2
LIST OF ABBREVIATIONS ...............................................................4
3
INTRODUCTION..................................................................................6
4
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......7
5
ENDPOINTS ..........................................................................................8
5.1
PRIMARY ENDPOINTS....................................................................................8
5.2
SECONDARY ENDPOINTS..............................................................................9
5.2.1
Key secondary endpoints................................................................................9
5.2.2
Secondary endpoints .......................................................................................9
........................................11
........................................15
........................................15
........................................16
........................................17
6
GENERAL ANALYSIS DEFINITIONS...........................................18
6.1
TREATMENTS..................................................................................................18
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................19
6.3
PATIENT SETS ANALYSED..........................................................................21
....................................................................................................21
6.5
POOLING OF CENTERS ................................................................................21
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................21
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS .................22
7
PLANNED ANALYSES......................................................................23
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........23
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................23
7.3
TREATMENT COMPLIANCE .......................................................................24
7.4
PRIMARY ENDPOINTS..................................................................................24
7.5
SECONDARY ENDPOINTS............................................................................24
7.5.1
Key secondary endpoint(s) ...........................................................................24
7.5.2
Other secondary endpoint(s)........................................................................24
................................................................................25
7.7
EXTENT OF EXPOSURE................................................................................25
7.8
SAFETY ANALYSIS.........................................................................................25
7.8.1
Adverse events ...............................................................................................25
7.8.2
Laboratory data.............................................................................................31
7.8.3
Vital signs.......................................................................................................32
7.8.4
ECG ................................................................................................................32
8
REFERENCES.....................................................................................33
...............................................................34
10
HISTORY TABLE...............................................................................35


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LIST OF TABLES
Table 5.2.2: 1: Derivation rules for PFS....................................................................................9
Table 5.2.2: 2: Derivation rules for TTF..................................................................................11
........................................................................13
........................................................................14
Table 6.1:1: Definition of analysing treatment periods ...........................................................18
Table 6.2: 1 Important protocol violations ..............................................................................19
Table 7.8.1: 1: Definition of user defined AE categories (UDAEC) for Adverse Events.......27
Table 7.8.1: 2: User defined AE category (UDAEC) Cardiac Failure ....................................30
Table 10: 1
History table ....................................................................................................35


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2
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
ATC classification
Anatomical, Therapeutic, Chemical classification
BI
Boehringer Ingelheim
BM
Bone marrow
BMI
Body Mass Index
BSA
Body Surface Area
BRPM
Blinded report planning meeting
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
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EoT
End-of-Text
ICH
International Conference on Harmonisation
iPV
Important protocol violation
IRR
Infusion related reaction
LLQ
Lower limit of quantification
LVSI
Laboratory values of special interest
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical and Quality Review Meeting


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MTD 
Maximum Tolerated Dose
NE
Not evaluable
PB
Peripheral blood
PD
Progressive disease
PFS
Progression free survival
PK
Pharmacokinetics
PKS
Pharmacokinetic set
PR
Partial remission
PT
Preferred term
PV
Protocol violation
REP
Residual effect period
RP2D
Recommended phase II dose
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listings
SOC
System organ class
SOP
Standard Operating Procedure
SS
Screened set
SSC
Special search category
TCM
Trial Clinical Monitor
TF
Treatment failure
TOC
Table of contents
TS
Treated set
TSAP
Trial statistical analysis plan
TTF
Time to treatment failure


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3
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This 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 (1).
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. 
SAS Version 9.2 or later version will be used for all analyses.
Version 1 of this TSAP(c01837068-02) fully specified the planned analyses for the 
population of patients with refractory or relapsed AML. Further enrolment of this population 
was stopped as of 10-JUN-2016 (for more details refer to CTP amendment 3 and the 
authorisation letter to continue study cohort 3 in AML patients in complete remission with 
high risk to relapse). In January 2018, the trial was terminated because of low patient 
recruitment into the CR population. This version now includes the specifications as to how 
the data from the CR population will be summarized a final CTR that will includes the 
analyses for both populations.


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4
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Clarification of Residual Effect Period (REP):
According to CTP section 6.2.5, for refractory or relapsed AML patients the reporting period 
for adverse events is defined until 6 weeks (42 days) after last administration of study drug.
However, the residual effect period (REP) for BI 836858 is defined as 30 days. Therefore, for 
all safety analyses defined in this TSAP, all events occurring between first drug 
administration until 30 days after last drug administration will be considered on treatment. A 
separate table or listing will be provided with adverse events outside the on-treatment period. 
See TSAP section 7.8 for details.
For AML patients in CR a REP of 30 days was defined in the CTP.
For the CR patients, an abbreviated set of tables and listings will be included consisting of:

Patient disposition

Patient demographics

Baseline disease characteristics

Exposure

Medication compliance

Summary table of Adverse Events

Frequency table of adverse events by highest CTCAE grade

Frequency table of user defined adverse events by highest CTCAE grade

Overall summary of infusion related reactions

Listing of patients with dose related toxicities

A frequency table of AEs by treatment,  system organ class, and preferred term

Hepatic injury (DILI)

Listing of hepatic enzymes and bilirubin

Summary of haemalytic laboratory values
Listings of all clinical efficacy, safety, laboratory and biomarker data will be provided.
 
 


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5
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary endpoints are the maximum tolerated dose (MTD) and the number of patients 
with of dose limiting toxicity (DLT) during the MTD evaluation period.
Maximum tolerated dose (MTD):
MTD is defined as the highest dose studied for which the incidence of dose-limiting toxicity 
is no more than 17% (i.e., 1/6 patients) during the MTD evaluation period. The MTD will be 
defined on the basis of DLTs occurring during the MTD evaluation period of dose escalation 
cohorts. 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).
MTD evaluation period:
FOR PATIENTS WITH REFRACTORY OR RELAPSED AML,
the MTD evaluation period is defined as the time from the first administration of BI 836858 
to start of  the fifth administration, excluding the day of fifth administration. In case the fifth 
infusion will not be started, the evaluation period ends 30 days after the last administration. 
FOR AML PATIENTS IN CR WITH HIGH RISK TO RELAPSE,
the MTD evaluation period is defined as the time from the first administration of BI 836858 
to start of the third administration, excluding the day of third administration. In case the third 
infusion will not be started, the evaluation period ends 30 days after the last administration. 
In case a patient has not completed the required number of administrations due to BI 836858 
related toxicity, he/she will not be replaced and this will be considered as DLT. However, 
patients who have not completed the required number of administrations of BI 836858 for 
reasons other than BI 836858 related toxicity will be replaced. 
That is, a patient will be considered evaluable for MTD assessment if he/she received at least 
4 (refractory or relapsed patients) or 2 (patients in CR) administrations of BI 836858 or if 
he/she received less than 4 (refractory or relapsed patients) or 2 (patients in CR) 
administrations due to DLT. 
The MTD estimate after the dose escalation part of the trial will be obtained on the basis of 
DLTs observed during the MTD evaluation period. However, for those patients who receive 
more than 4 (refractory or relapsed patients) or 2 (patients in CR) administrations of BI 
836858, all AEs that constitute a DLT will be considered in the final determination of the 
dose recommended for Phase II. 
The list of patients evaluable for MTD will be confirmed by the Trial Clinical Monitor 
(TCM) no later than at the last blinded report planning meeting (BRPM) before database lock 
(DBL) for the clinical trial report (CTR).


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5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
FOR PATIENTS WITH REFRACTORY OR RELAPSED AML:
Best overall response
The different categories possible for overall response (at a specific timepoint) are Complete 
remission (CR), Complete remission with incomplete blood count recovery (CRi), Partial 
remission (PR), Treatment failure (TF) (i.e. Resistant disease, Aplasia, Indeterminate cause, 
or morphologic relapse), Progressive disease (PD), and Not evaluable (NE). 
Best overall response is defined as the best overall response (CR, CRi, PR, TF, PD or NE in 
this order) recorded since randomisation (first administration of trial medication in non-
randomised trials) until the earliest of progressive disease (PD), death or last adequate disease 
assessment before new anti-cancer therapy.
In order to evaluate the best overall response, the investigator's assessment as given in the 
eCRF will be taken into account (no central review and no check versus bone marrow 
measurement is planned). 
Progression free survival (PFS)
For patients with 'event' as outcome for PFS:

PFS [days] = date of outcome - date of randomisation (date of first administration of 
trial medication in non-randomised trials) +1.
For patients with 'censoring' as outcome for PFS:

PFS (censored) [days] = date of outcome - date of randomisation (date of first 
administration of trial medication in non-randomised trials) +1.
The censoring rules and dates of event or censoring for PFS under different scenarios are 
specified in Table 5.2.2:1.
Table 5.2.2: 1: Derivation rules for PFS
Situation
Outcome (event or 
censored)
Date of outcome
Progressed according to 
disease assessment 
event
Date of disease assessment 
of progression
Death without progression
event
Date of death 


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Table 5.2.2: 1: Derivation rules for PFS (cont.)
Situation
Outcome (event or 
censored)
Date of outcome
Alive and not progressed 
censored
Date of last disease 
assessment
No disease assessment 
performed post-baseline, 
vital status is unknown or 
patient is known to be alive
censored
Date of randomisation (or 
first treatment 
administration, in non-
randomised trials)
Subsequent anti-cancer therapy before progression or death (check interval 
between start of new medication and earliest of subsequent PD or death )
Interval <= 7 days
event
Earliest date of disease 
assessment of progression 
or death
Interval > 7 days
censored
Date of last disease 
assessment before initiation 
of subsequent anti-cancer 
therapy
Time to treatment failure (TTF)
As some patients will receive the next line of therapy, although no formal PD may be 
diagnosed at the time when the next treatment is indicated, the Time to treatment failure 
(TTF) will be derived similarly to PFS, but will consider PD, death or start of next anti-AML 
therapy as events.
For patients with 'event' as outcome for TTF:

TTF [days] = date of outcome - date of randomisation (date of first administration of 
trial medication in non-randomised trials) +1.
For patients with 'censoring' as outcome for TTF:

TTF (censored) [days] = date of outcome - date of randomisation (date of first 
administration of trial medication in non-randomised trials) +1.
The censoring rules and dates of event or censoring for TTF under different scenarios are 
specified in Table 5.2.2:2.


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Table 5.2.2: 2: Derivation rules for TTF
Situation
Outcome (event or 
censored)
Date of outcome
Progressed according to 
disease assessment, no 
subsequent anti-cancer 
therapy
event
Date of disease assessment 
of progression
Death without progression, 
no subsequent anti-cancer 
therapy
event
Date of death 
Subsequent anti-cancer 
therapy before progression 
or death
event
Date of first administration 
of subsequent anti-cancer 
therapy
Alive and not progressed, 
no subsequent anti-cancer 
therapy
censored
Date of last disease 
assessment
No disease assessment 
performed post-baseline, 
vital status is unknown or 
patient is known to be alive, 
no subsequent anti-cancer 
therapy 
censored
Date of randomisation (or 
first treatment 
administration, in non-
randomised trials)
FOR AML PATIENTS IN CR WITH HIGH RISK TO RELAPSE:
Progression free survival (PFS)
Defined as for refractory/relapsed AML patients, see above.
Time to treatment failure (TTF)
Defined as for refractory/relapsed AML patients, see above.


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6
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
In this Phase I trial, treatments are not randomised (open-label, dose escalation). Different 
dose levels of the investigational medicinal product can arise. The data will be presented for 
all dose cohorts separately, in particular patients will be analysed by the treatment group 
initially assigned in the first treatment course.
“Analysing treatment” will be used for reporting of treatment emergent adverse events (AE) 
and to differentiate between screening, on-treatment, post-treatment and post-study safety 
data. The inequalities start date ≤ onset date of AE < stop date will determine whether the AE 
will be assigned to the “analysing treatment” or not. Table 6.1: 1 defines the “analysing 
treatment period(s)” which will be used for reporting of treatment emergent AEs and safety 
laboratory parameters. 
Table 6.1:1: Definition of analysing treatment periods
Analysing treatment 
period
Start date (including)
Stop date (excluding)
Screening
Date of informed consent
Date of first administration of trial 
medication
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 patient status 
obtained / last date patient 
known to be alive + 1 (if 
patient is lost to follow-up) 
/ date of refusal + 1 day / 
the date patient died + 1
During the trial: open / empty; after 
database lock (DBL): DBL + 1 day
MTD evaluation period
Date of first administration 
of trial medication
For patients with 
refractory/relapsed AML:
Date of fifth infusion or (if the fifth 
infusion was not administered) 
Date of last administration of trial 
medication + 30 days + 1 day
For AML patients in CR:
Date of third infusion or (if the 
third infusion was not 
administered) Date of last 
administration of trial medication + 
30 days + 1 day


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Data recorded between the first administration of trial medication until up to 30 days 
(Residual effect period; REP) after the last administration of trial medication will be 
considered as on-treatment.
In addition, to  justify the MTD determination, AEs occurring during the MTD evaluation 
period will be presented separately from those occurring during the complete on-treatment 
period.
The actual treatment codes are defined in the document entitled “5-05-o-c-treatment-setup”, 
which can be found in the trial's DMS Section 5 within BIRDS. Labels of each analysing 
treatment period and analysis numbers are provided in the TSAP technical documents “ADS 
Plan” and "Data guide".
6.2
IMPORTANT PROTOCOL VIOLATIONS
Even though no per protocol population is defined, patients with potentially important 
protocol violations (iPV) will be identified and documented.
Potentially important protocol violations are defined in Table 6.2:1. The final list of iPVs will 
be confirmed at the last blinded report planning meeting (BRPM) before the database lock at 
the time of the CTR.
Two separate iPV tables will be created for patients treated before and after the clinical hold 
and separately for patients with refractory/relapsed AML patients and AML patients in CR.
Table 6.2: 1 Important protocol violations
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
None
A1.2
Patient has laboratory assessments 
that may cause additional risk.
EX 2, EX 8-11
None
A1.3 
Patient is unable to comply with the 
protocol
EX 14, EX 21
None
A1.4
Patient has condition that may 
interfere with evaluation of safety 
(and/or efficacy)
EX 3-4, EX 6, EX 12, EX 13, 
EX15, EX 19, 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 1-3, EX 1, EX 5
None
B
Legal criteria


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Table 6.2: 1 Important protocol violations (cont.)
Category/
Code
Description
Comment/Example
Excluded from
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 18
None
B5
Patient’s age < 18
IN 4
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
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), see 
CTP section 4.1.4
None
C3
Unjustified intra-patient dose-
escalation
Create listing, decision at 
MQRM / RPM, see CTP section 
4.1.4
None
C4
Withdrawal of patient not performed 
according to CTP
Create listing, decision at 
MQRM / RPM, see CTP section 
3.3.4 
None
C5
Discontinuation of trial drug not 
performed according to CTP
Create listing, decision at 
MQRM / RPM, see CTP section 
3.3.4
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 (section 4.2.2.1 
and exclusion criteria #3, #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


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6.3
PATIENT SETS ANALYSED

Screened set (SS): This patient set includes all patients who have signed the informed 
consent. The SS will be used for patient disposition tables.

Treated set (TS): This patient set includes all patients who were documented to have 
received at least one dose of trial medication. The TS will be used for all efficacy and 
safety analyses.
 
 
 
 
 

MTD evaluable set: The MTD set consists of all patients who were entered, treated 
and considered evaluable for MTD determination. 
The above patient sets will be defined separately for refractory/relapsed AML patients and 
AML patients in CR. However, due to the early enrolment stop of the refractory/relapsed 
AML patients, the MTD (RP2D) set is not applicable for this patient population. No 
combined safety analysis of both patient populations is foreseen on trial level. If deemed 
necessary, this will be performed on project level.
No per protocol population will be used for analyses. 
6.5
POOLING OF CENTERS
Not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
If not stated otherwise, missing data will not be imputed and remain missing. Potential 
outliers will be reported and analysed as observed.
Missing or incomplete AE dates are imputed according to BI standards (2).
 
For missing laboratory data at Visit 1 (before the very first administration of study 
medication) data from preceding visits will be used.


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6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS
Study days and visits will be labelled according to the CTP's flow chart.
Unless otherwise specified, baseline is defined as the time-point closest to but prior to first 
administration of trial medication in course 1. Note that for some trial procedures (for 
example body weight, vital signs, laboratory tests) this may be the value measured on the 
same day trial medication was started. In these cases it will be assumed that the 
measurements were taken according to protocol, i.e. prior to first intake of any trial 
medication. 
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 ANALYSES
The labelling and display format of statistical parameters will follow the guideline “Reporting 
of Clinical Trials and Project Summaries” (3).
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, and percentiles will be presented to one more decimal place than 
the raw data and SDs will be presented to two more decimal places. Minima and maxima will 
be presented to the same number of decimal places as the raw data.
For time-to-event analysis tables, the set of statistics is: Number of patients [N(%)], Number 
of patients with event [N(%)], Number of patients censored [N(%)], <Time to event> 
[<unit>] followed by P25 (25th percentile), median + CI, P75 (75th percentile). If not 
specified otherwise, the duration as well as the time to event will be displayed in months and 
a final decision will be made at the last RPM.
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 
patients in the respective treatment group (unless otherwise specified, all patients in the 
respective patient set whether they have non-missing values or not). Percentages will be 
rounded to one decimal place. The category missing will be displayed only if there are 
actually missing values.
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.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. 


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Concomitant diseases will be coded similarly as adverse events based on the most current 
MedDRA version. Concomitant therapies will be coded according to WHO DD. Concomitant 
therapies (CT) will be classified according to the Anatomical, Therapeutic, Chemical (ATC) 
classification system. The third ATC level will be used to categorise 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, patients 
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 ENDPOINTS
The primary endpoints are the MTD and the occurrence of DLT. The MTD is determined 
from the number of non-replaced patients with DLT during the MTD evaluation period (for 
the definition of MTD evaluation period refer to section 5.1). 
An overall summary of patients with DLT(s) which occurred during the MTD evaluation 
period and the on-treatment period will be provided for each dose cohort. 
Patients who were treated but replaced 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 patients will be 
provided. This will include the initial dose of the investigational medicinal product, patient 
number, treatment start date, DLT in MTD evaluation period [y/n], Evaluable for MTD [y/n] 
and will be sorted by treatment start date.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Other secondary endpoint(s)
Best overall response:
Best overall response will be analysed descriptively. The number of treated patients and the 
frequency of patients by best overall response category including the corresponding 
percentages will be presented.
Progression-free survival (PFS) and Time to treatment failure (TTF):
PFS and TTF will be assessed based on the Kaplan-Meier method. Point estimates together 
with confidence intervals (based on Greenwood's method) will be provided for median PFS 
(if applicable). The Breslow method for handling ties will be used. The censoring rules for 
PFS are as stated in Section 5.2.2.


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7.7
EXTENT OF EXPOSURE
Standard descriptive analyses over all treatment courses will be performed. This will include 
a summary of the variables defined in section 5.4.1 and will comprise a mixture of frequency 
and percentages, as well as summary statistics.
7.8
SAFETY ANALYSIS
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 patients with AEs and NOT the number of AEs.
The analyses will be based on BI standards. Adverse events will be coded with the most 
recent version of MedDRA. The severity of AEs will be scaled according to CTCAE version 
4.03.
Reporting will be done according to version 5 of the AE guideline (6).


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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 patient, all episodes with the same preferred term (PT) (system organ class, SOC) 
will be condensed to one AE record using a worst case approach for all AE attributes 
including CTCAE grading. 
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events, where a treatment emergent AE has an onset in the analyzing treatment period. All 
adverse events occurring before first intake of trial medication will be assigned to ‘screening’ 
and all adverse events occurring after last intake of trial medication + 30 days will be 
assigned to ‘follow-up” (in randomised 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 5.2.2.1 as infusion 
related rections (IRRs) of CTCAE grade >= 3, DLTs (occurring during the MTD evaluation 
period or repeated treatment courses) and hepatic 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 
patients with AEs by worst CTCAE grade. 
The frequency of patients with adverse events will be summarised 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):
IRRs will be the object of special attention.


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Patients with any IRR will be tabulated by treatment and worst CTCAE grade. In addition, 
the number of infusions and the number of IRRs will be displayed by treatment.
The duration of IRR [h] and the time since start of the respective infusion [min] together with 
IRR related symtoms 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.
Fatal AEs:
AEs leading to death during the on-treatment period will be tabulated. Reported fatal AEs 
that occurred in the post-treatment phase will be listed.
Additionally, a table summarizing the information on deaths collected on the AE eCRF and 
the Patient Status eCRF will be provided.
User defined AE categories (UDAEC):
User defined AE categories (UDAEC) for adverse events are defined in in Table 7.8.1:1. For 
user defined AE categories which contain sub-searches and/or two sensitivity levels (broad 
and narrow) all possibilities will be displayed on the UDAEC level in tables, e.g. for infusion 
related reactions, tables will include the UDAECs “Infusion related reactions broad” and 
“Infusion related reactions narrow”, similarly for Bleeding: “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 (UDAEC) for Adverse Events
Topic
UDAEC
MedDRA 
code
(Sub-)searches
Sensitivity
Infusion 
related 
reactions
Infusion related 
reactions
20000021
SMQ Anaphylactic reaction + 
PT Infusion related reaction1
Narrow & 
broad 
(Algorithm)
Bleeding
Bleeding - SMQ 
Haemorrhage 
laboratory terms
20000040
SMQ Haemorrhage 
laboratory terms 
Narrow & 
broad
Bleeding - SMQ 
Haemorrhage 
terms (excl. 
laboratory terms)
20000039
SMQ Haemorrhage terms 
(excl. laboratory terms) 
Narrow 
Tumor lysis 
syndrome 
Tumor lysis 
syndrome
20000219
SMQ Tumor lysis syndrome
Narrow & 
broad
(Algorithm)


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Table 7.8.1: 1: Definition of user defined AE categories (UDAEC) for Adverse Events (cont.)
Nausea 
Nausea
BIcMQ 
Narrow 
&
broad
Vomiting 
Vomiting
BIcMQ 
Narrow 
& 
broad
Drug related 
hepatic 
disorders
Drug related 
hepatic disorders
20000006
SMQ Drug related hepatic 
disorders plus the following 
sub-searches: 
Narrow 
& 
broad
Drug related 
hepatic disorders 
- SMQ 
Cholestasis and 
jaundice of 
hepatic origin
20000009
Cholestasis and jaundice of 
hepatic origin (SMQ)
Narrow 
& 
broad
Drug related 
hepatic disorders 
-SMQ Drug 
related hepatic 
disorders -
severe events 
only
20000007
Drug related hepatic disorders 
- severe events only (SMQ)
Narrow 
& 
broad
Drug related 
hepatic disorders 
- SMQ Liver 
related 
investigations, 
signs and 
symptoms
20000008
Liver related investigations, 
signs and symptoms (SMQ)
Narrow 
& 
broad
Drug related 
hepatic disorders 
- SMQ Liver-
related 
coagulation and 
bleeding 
disturbances
20000015
Liver-related coagulation and 
bleeding disturbances (SMQ)
Narrow 
& 
broad


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Table 7.8.1: 1: Definition of user defined AE categories (UDAEC) for Adverse Events (cont.)
Cardiac safety
Cardiac safety -
Cardiac failure 
(tailored SMQ)²
20000004
Cardiac failure (tailored 
SMQ)²
   Cardiac safety -
   SMQ Cardiac 
   arrhythmia 
20000049
SMQ Cardiac arrhythmia 
Broad
Cardiac safety -
SMQ Ischemia 
heart disease
20000043
SMQ Ischemia heart disease 
Broad
ALT
ALT
BIcMQ Elevated Specific 
Liver Function Parameters 
sub-search1
Narrow & 
broad
AST
AST
BIcMQ Elevated Specific 
Liver Function Parameters 
sub-search2
Narrow 
& 
broad
ALKP
ALKP
BIcMQ Elevated Specific 
Liver Function Parameters 
sub-search3
Narrow 
& 
broad
Bilirubin
Bilirubin
BIcMQ Elevated Specific 
Liver Function Parameters 
sub-search5
Narrow 
& 
broad
Neutropenia3
Neutropenia
BIcMQ3
Broad
1 The PT Infusion related reaction as collected in the eCRF will be included on both 
sensitivity levels (broad and narrow).
2 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.
3 Neutropenia as defined by the BIcMQ “Haematopoietic Cytopenias”, Subsearch1.1.


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Table 7.8.1: 2: User defined AE category (UDAEC) Cardiac Failure
Selected PTs for Cardiac Failure
Cardiac asthma
Cardiac failure
Cardiac failure acute
Cardiac failure chronic
Cardiac failure congestive
Cardiac failure high output
Cardiac index decreased
Cardiac output decreased
Cardiogenic shock
Cardiomegaly
Cardiothoracic ratio increased
Dilatation ventricular
Left ventricular failure
Low cardiac output syndrome
Right ventricular failure
Oedema due to cardiac disease
Left ventricular dysfunction
Ejection fraction decreased
Cardiopulmonary failure
Diastolic dysfunction
Cardiac ventriculogram right abnormal
Cardiac ventriculogram abnormal
Cardiac ventriculogram left abnormal
Cardiac cirrhosis
Right ventricular dysfunction
Ventricular dysfunction
Cardiac resynchronisation therapy
Ventricular failure
Acute left ventricular failure
Acute right ventricular failure
Chronic left ventricular failure
Chronic right ventricular failure
Myocardial depression
Ventricular dyssynchrony
Systolic dysfunction
Neonatal cardiac failure


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (7). The same on-treatment period as considered for the analysis of AEs will be 
applied for laboratory values. Patients having at least one post-baseline laboratory value will 
be displayed in the descriptive analyses.
Descriptive statistics, including change from baseline and frequency of patients with 
transitions relative to the reference range, will be provided. CTCAE grades for applicable 
laboratory parameters will be calculated according to CTCAE version 4.03. The following 
outputs will be presented:

Worst CTCAE grade experienced during the on-treatment phase.

Transitions of CTCAE grade from baseline to worst laboratory value, from worst to 
last laboratory value during the on-treatment phase, and from baseline to last 
laboratory value.
Patients with missing CTCAE grade at baseline or no baseline value but post baseline values 
will be displayed in the category “Missing CTCAE grade at baseline”.
Possible clinically significant abnormal laboratory values:
Possible clinically significant abnormal laboratory values are defined as those laboratory 
values that are of CTCAE Grade ≥ 2 and show an increase from baseline value by at least one 
CTCAE grade. For those parameters for which no CTCAE has been defined, BI standard 
definition will be used to determine possible clinical significance. Frequency of patients with 
possible clinically significant abnormal laboratory values will be provided whenever 
applicable. If no baseline value is available but the patient has a post-baseline laboratory 
value of CTCAE Grade ≥ 2 an increase from baseline will be assumed, i.e. the laboratory 
value considered as possible clinically significant.
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
In addition, the following definition of potential Hy’s law cases was discussed with the FDA 
at the Pre-NDA meeting of the NSCLC submissions of the nintedanib trials 1199.13 and 
1199.14 and was agreed by the authorities. Please also refer to the FDA guideline Guidance 
for Industry Drug- Induced Liver Injury: Premarketing Clinical Evaluation, version of July 
2009.
These are defined as those cases where a combination of all of the following events occurred: 
any on-treatment value of ALT or AST (or both) > 3 times upper limit of normal (3 x ULN) 
with total bilirubin ≥ 2 x ULN and ALKP < 2 x ULN. The events can occur in any order, but 
must occur within 14 days of the previous event, i.e. the second event must occur within 14 
days of the first event, and the third event must occur within 14 days of the second event, etc. 


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All of the above combinations of elevated liver enzymes will be analysed, i.e. DILI cases as 
defined in the CTP and additionally the definition of potential Hy's law cases which was 
discussed with the FDA by the nintedanib project. 
Handling of laboratory parameters with CTCAE grade -1:
For Uric Acid, Glomerular filtration rate (GFR) and Hypokalemia, the CTCAE grade cannot 
always be assigned by the laboratory parameter itself as two different CTCAE grades have 
the same laboratory constellation, but are distinguished by additional clinical parameter. In 
this case a CTCAE grade of "-1" will be assigned initially. For all analyses patients with a 
CTCAE grade of "-1" will be treated as

Grade 1 for Uric Acid

Grade 3 for GFR

Grade 1 for Hypokalemia (Only when CTCAE version 4.03 is used)
Handling of Urine protein (UPROZ)
With CTCAE version 4, the CTCAE grade 3 for proteinuria is defined based on 24 hrs values 
[g/24 hrs] only; no dipstick definition is available based on quantitative results. 
High values of UPROZ (+++, ++++; labstd = 3, 4) would therefore be assigned to CTCAE 
grade -9, which by default is equivalent to CTCAE grade 0. To circumvent this, high values 
of UPROZ (+++, ++++; labstd = 3, 4) will be assigned to CTCAE grade 2.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
12-lead resting ECGs are done throughout the trial and are assessed for clinically relevant 
results which are to be recorded as either concomitant disease or AE by the Investigator. No 
further ECG analysis is planned.


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8
REFERENCES
1
001-MCG-160_RD-01: "TSAP annotations", current version; IDEA for CON.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
3
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current 
version; IDEA for CON.
4
001-MCS-36-472: "Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
5
001-MCS-36-472_RD-01: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; IDEA for CON.
6
001-MCG-156: “Handling and summarization of adverse event data for clinical 
trial reports and integrated summaries”, current version; IDEA for CON.
7
001-MCG-157: “Handling, Display and Analysis of Laboratory Data”, current 
version; IDEA for CON.


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10 HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
14-July-16
None
This is the final TSAP without any 
modification
Revision
09-Apr-18
4
Added specifications for final report to 
include CR patients