Clinical trial NCT02514239
Conditions: Multiple Myeloma
Sponsor: Boehringer Ingelheim
Start date: 2015-07-08; Completion date: 2020-07-02
Enrollment: 43 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this trial is to determine the maximum tolerated dose (MTD) of BI 836909 administered by continuous i.v. infusion in patients with relapsed and/or refractory multiple myeloma. If the MTD is not reached based on safety findings, a recommended dose for further development will be determined. This will depend on the safety data, pharmacokinetic/pharmacodynamics data and potentially preliminary efficacy data. Secondary objectives are to document the safety and tolerability of BI 836909, to perform pharmacokinetic and pharmacodynamic analyses and to evaluate relevant biological effects in terms of parameters of efficacy.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: None arm 9: None arm 10: None arm 11: None arm 12: None arm 13: None
Interventions: intervention 1: BI 836909
Intervention descriptions: intervention 1: Intravenous Infusion of BI 836909.

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02587386-05
EudraCT No.:
BI Trial No.:
2014-004896-22
1351.1
BI Investigational
Product(s):
BI 836909
Title:
An open label, phase I, dose escalation study to characterize the safety, 
tolerability, pharmacokinetics, and pharmacodynamics of intravenous 
doses of BI 836909 in relapsed and/or refractory multiple myeloma
patients
Clinical Phase:
Phase I
Clinical Trial 
Leader:
Phone:+
Fax: +
Co-ordinating 
Investigator:
Phone: + 
Fax: +
Status:
Final Protocol (Revised Protocol (based on global amendment 4))
Version and Date:
Version 5.0
Date: 26 Nov 2018
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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 836909
Protocol date:
Trial 
number:
Revision date:
26 Nov 2018
10 Feb 2015
1351.1
Title of trial:
An open label, phase I, dose escalation study to characterize the safety, 
tolerability, pharmacokinetics, and pharmacodynamics of intravenous doses 
of BI 836909 in relapsed and/or refractory multiple myeloma patients
Co-ordinating Investigator:
Trial site(s):
Multi-centre
Clinical phase:
I
Objective(s):
Primary objective:
To determine the maximum tolerated dose (MTD) as well as the dose 
limiting toxicities (DLT) of a 6-week regimen of BI 836909 given as
continuous intravenous infusion in patients with relapsed and/or refractory 
multiple myeloma.
Secondary objectives:

Recommended dose for further development

To provide preliminary findings on the safety profile and assess 
pharmacokinetic profile of BI 836909 

To assess pharmacodynamic and anti-tumoral activity of BI 836909

To evaluate immunogenicity of BI 836909
Methodology:

Phase I dose escalation trial of BI 836909 given as intravenous 
infusion. 

Starting dose: 0.20 µg/day

A 6-week regimen will be tested (4 weeks of continuous intravenous 
administration of BI 836909 followed by a 2 weeks off-period).


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Name of company
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 836909
Protocol date:
Trial 
number:
Revision date:
26 Nov 2018
10 Feb 2015
1351.1
Methodology:
For the dose levels of 0.2 to 1.6 µg/day single patient cohorts are entered. 
The following dose cohorts will be tested within the above-mentioned dose 
range:

0.2, 0.4, 0.8 and 1.6 µg/day

The DLT observation period for the single patient cohorts will be 2 
weeks. If a patient has been on treatment in one of the above-
mentioned dose cohorts for 2 weeks without DLT or other relevant 
safety findings the first patient of the next higher dose cohort will be 
entered if agreed on by the safety committee. If a patient has 
reached DLT, then the safety committee recommends 3 + 3 cohorts. 
Patients may not proceed to the next higher dose level before 
completion of 6 patients. 
One intra-patient dose escalation is allowed within the single patient dose 
cohorts if the initial dose is tolerated and no DLT occurs during 1st cycle. In 
case of DLT additional patients will be entered into this cohort following a 3 
+ 3 design. 
For the dose levels ≥3.2 µg/day 3-6 patients will be treated per dose level
and observed for 4 weeks during the first cycle before decision for dose 
escalation to the next dose cohort is made. 
The following dose cohorts will be tested within the above-mentioned dose 
range:
3.2, 6.5, 13, 25, 50, 100, 200 ,400 and 800 µg/day.. Intermediate dose cohorts 
with 50% increments of previous dose will be entered if determined by 
thesafetycommittee. Increments to the next higher dose will not exceed 2-
fold increases.
The DLT observation period will be extended to 4 weeks for all future 
cohorts before decision for dose escalation within the next dose cohort is 
made:

Per dose level 1 patient will be enrolled and treated for 1 week
before all remaining patients for this cohort can be entered. 
Additional patients should not start treatment before the previous 
patient has been treated for 48 hours in order to monitor initial 
transient toxicities due to cytokine release syndrome.

Once the MTD of BI 836909 is determined up to 6 additional 
patients will be treated at the MTD or the recommended dose for 
confirmation of safety.


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Name of company
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 836909
Protocol date:
Trial 
number:
Revision date:
26 Nov 2018
10 Feb 2015
1351.1
Number of patients
total entered:
Each treatment:
Up to 50 patients depending on dose level reached
Dose escalation:
Number of patients will depend on the number of dose levels to be tested 
before MTD determination or determination of the recommended 
dose. Based on preclinical data, it is expected that > 5 dose levels in addition 
to the 4 single-patient doses will be tested. Up to 50 patients will be treated 
during the dose escalation phase. Up to 6 additional patients will be treated 
with MTD or recommended dose.
Diagnosis :
Patients with relapsed and/or refractory multiple myeloma
Main criteria
for inclusion:
Patients with relapsed and/or refractory multiple myeloma and progression 
after ≥ 2 prior treatment lines (including proteasome inhibitor and immune-
modulatory drugs).
Patients with significant comorbidities such as impaired renal function, 
cardiovascular diseases (i.e. uncontrolled hypertension, unstable angina, 
history of infarction within past 6 months, congestive heart failure > NYHA 
II), active infection requiring treatment, or active autoimmune disease will be 
excluded.
Test product(s):
BI 836909 in vials for continuous intra-venous infusion
Comparator products:
N/A
Duration of treatment:
Treatment will continue for up to 5 cycles or until:

Disease progression or start of further anticancer treatment

Non-acceptable toxicity

Patient decision to withdraw consent

Investigator’s  decision
In case of ongoing clinical benefit after five courses additional 5 courses may 
be given if considered indicated by the treating investigator.


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Name of company
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 836909
Protocol date:
Trial 
number:
Revision date:
26 Nov 2018
10 Feb 2015
1351.1
Criteria for efficacy: 
Efficacy evaluation will be based on the response criteria of the 
International Myeloma Working Group (IMWG, 2006)
Secondary endpoints for efficacy:
Objective response rate (percentage of patients with sCR, CR, PR and 
VGPR) 

Duration of response (DOR) 

Minimal residual disease (MRD) response rate 

Duration of MRD response 

Progression free survival (PFS)
Criteria for pharmacokinetics:
Pharmacokinetic endpoints are secondary or further endpoints
Secondary endpoint:
Concentration at steady state after i.v. infusion (Css))
Criteria for safety:
Primary endpoint:

Maximum tolerated dose (MTD) of BI 836909: MTD is defined as 
the highest dose of the dose level tested where ≤ 1 patient out of 6 
develops dose limiting toxicity (DLT). 

Number of patients with dose limiting toxicities (DLTs) will be 
reported.
The safety of BI 836909 will be assessed by a descriptive analysis of 
incidence and intensity of adverse events graded according to CTCAE 
(version 4.03), the incidence of dose limiting toxicity (DLT), laboratory data 
and results of physical examination.
If MTD cannot be determined based on safety findings, a recommended 
biologically active dose for further development will be determined based on 
pharmacokinetic and pharmaco-dynamic data.
Statistical methods:
Patients with DLT, objective response rate, MRD will be explored and 
summarized by descriptive statistics. Kaplan-Meier methods will be used for 
time to event endpoints.


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Name of company
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 836909
Protocol date:
Trial 
number:
Revision date:
26 Nov 2018
10 Feb 2015
1351.1
Statistical methods:
The pharmacokinetic parameters Css, 
 
 
will be descriptively explored. 


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FLOW CHART: BI 836909 CONTINUOUS INTRAVENOUS INFUSION
Trial Periods
Screen
Treatment courses1
EOT2
FU3
Course1
1
2 – 4
5 or last cycle4
Week
1 - 4
5 - 6
1 - 4
5 - 6
1 - 4
Visit 6
Screen5
1
2
3
4
5
6
1
2
3
4
5
6
1
2
3
4
5
Days6
-21 to -1
1-47
8
15
22
29- 30
36
1
8
15
22
29
36
1
8
15
22
29
0 - 7
Informed consent /IWRS call
X
Informed consent for pharmacogenetics and biomarkers
X
Bone Marrow Aspirate8
X
X
X
Minimal residual disease assessment in bone marrow (MRD)9
X
X
Bio-Banking of bone marrow
X10
X
Blood for pharmacogenetics
See separate flow chart
Biomarker in urine
See separate flow chart
Demographics
X
Medical history
X
Review of in-/exclusion criteria/ IWRS call
X
Height
X
Weight
X
X
X
X
Physical examination16
X
X
X
X
X
X
X
Body temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood pressure (with heart rate)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG (local)11
X
X
X
X
General safety laboratory parameters12
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Screening for HCV, HBV, HIV
X
Serum pregnancy test
X
X
X
X
Hospitalisation 7
X
X7
X
X
Home Care Support13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Eligibility for treatment 
X
X
X
Administration of BI 836909
X
c.i.v.
X
X
c.i.v. 
X
X
c.i.v.
X
Disease / response assessment (clinical/MRI) 14
X
X
X
X
Pharmacokinetics15
see separate flow chart
Reason for treatment discontinuation / IWRS call
X
Next line of anti-cancer therapy
X
Patient status
X
1
each course has a duration of 6 weeks, 4 weeks of continuous infusion of BI 836909 and 2 weeks break.


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2 
EOT will be performed after permanent discontinuation of trial medication or as soon as possible but no later than 1 week after discontinuation of trial drug (Section 
6.2.5.1)
3
Follow up visit should be performed 30 days after the EOT (REP visit). In case of ongoing clinical benefit, patients can be followed up to collect data for duration of 
response. Follow-up visits for responders will be at 3, 6 and 12 months after EOT if a patient did not progress, started a new anti-cancer treatment, died, or withdrew 
informed consent.
Follow up visit after EOT: report all AEs, SAEs, AESIs regardless of relatedness. This includes all deaths unless due to underlying disease (Section 6.2.5.2)
Extended follow up: report related SAEs and AESIs.
Please note: Death should always be reported as SAE in this trial unless due to underlying disease.
4
in case of clinical benefit a maximum of 5 cycles is administered. In case of ongoing clinical benefit up to a maximum of 5 additional treatment cycles can be given if 
considered indicated by the investigator (Section 4.1.5), visit 6 at day 36 must be performed for all cycles except the last one. 
5
results from routine assessments (MRI) for multiple myeloma are accepted for screening if performed no later than 28 days before start of treatment (Section 6.2.2)
6
± 3 days
7
patients will be hospitalized in the first cycle for 3 or 4 days if first bag change will be performed in the clinic, on day 1 of cycle 2 for 24 hours, in patients within intra-
patient dose escalation at the time when dose is escalated also for 24 hours and in all subsequent cycles for 8 hours on day 1 of each cycle; patients will also be 
hospitalized at the end of cycle 1 (day 29); hospitalization may be prolonged in case a patient experiences a cytokine release syndrome or a severe AE (Section 6.2.1).
8
within 14 days before day 1 cycle 1 or on day 1 cycle 1 before start of treatment, when M protein/ Free kappa/lambda light chain (FLC) becomes undetectable during 
treatment, on day 29 of cycle 3 and at EOT
Karyotyping: recent analysis will be accepted for screening before start of treatment if performed within 3 months prior to start of study medication and in case that no 
therapy has been given between assessment of karyotyping and study medication; otherwise, a baseline karyotype should be performed at screening; subsequent 
karyotyping could also be performed in subsequent marrow samples (tests to be done locally).
Percentage (%) of plasma cells in bone marrow should be assessed locally according to institutional standards and documented in eCRF. 
9
MRD (minimal residual disease assessment): when M protein/FLC becomes undetectable during treatment; day 29 of cycle 3 and EOT (tests to be done centrally).
10
Optional collection and bio-banking of a baseline bone marrow sample and a bone marrow sample on treatment when a complete response is reached. 
11
at screening and at the beginning of each cycle (except for cycle 1).
12
at screening and at each visit and at EOT; during hospitalization in cycle 1 safety lab should be done before start of 
treatment on day 1 and repeated in the evening of 
day 1 as well as in the morning of days 2 and 3; in cycle 2 safety lab should be done before start of treatment on day 1 and in the morning of day 2.
On day 29 of cycle 1 blood draw for safety lab should be done before the end of the infusion.
13
Infusion bag will have to be exchanged during continuous infusion of BI 836909 approximately every 4 days; patients should either come to the clinic or bag change will 
be done by a home care service.
14
Clinical disease assessment must be performed:
At screening, at start of each cycle as well as at EOT.
MRI must be performed: 
At screening and at start of each other cycle at or within 14 days before day 1, cycle 3; day 1, cycle 5; day1, cycle 7; day 1… and/or at time of progression based on 
IMWG response criteria or start of further anticancer therapy; Results from routine assessments (MRI) for multiple myeloma are accepted for screening if performed 
within 28 days before start of treatment. 
Clinical disease status will be assessed at screening and at the start of each new cycle (e.g, before cycle 2, 3, 4 and 5 etc.) as well as at EOT.
15
see separate Flow chart; Appendix 10.2.
16
Orienting neurological examination should be performed at screening as well as at EOT and daily during hospitalization required by the protocol. 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART: BI 836909 CONTINUOUS INTRAVENOUS 
INFUSION ...................................................................................................7
TABLE OF CONTENTS ................................................................................ 11
ABBREVIATIONS.......................................................................................... 16
1. INTRODUCTION........................................................................................ 20
1.1
MEDICAL BACKGROUND............................................................................20
1.2
DRUG PROFILE...............................................................................................21
2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 24
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................24
2.2
TRIAL OBJECTIVES.......................................................................................24
2.3
BENEFIT - RISK ASSESSMENT ...................................................................24
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 27
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................27
3.1.1
Administrative structure of the trial...................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................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.............................35
3.3.4.1
Removal of individual patients................................................35
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(s) .38
4.1.1.1
Description of portable pump for continuous intravenous infusion 
of BI 836909 ............................................................................39
4.1.2
Method of assigning patients to treatment groups ............................39


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4.1.3
Selection of doses in the trial................................................................39
4.1.4
Drug assignment and administration of doses for each patient .......39
4.1.4.1
Prophylactic measures .............................................................41
4.1.4.1.1Premedication ..........................................................................41
4.1.4.1.2Monitoring for infusion-related reactions and cytokine release 
syndromes ................................................................................41
4.1.4.1.3 
Tumour lysis syndrome .......................................................41
4.1.4.1.4Handling of infusion-related reactions or cytokine release
syndromes ................................................................................42
4.1.4.2
Continuation of Treatment during a Course ............................45
4.1.4.3
Dose reductions and dose delays .............................................45
4.1.4.4
Permanent discontinuation of BI 836909 ................................45
4.1.4.5
Temporary treatment interruption of BI 863909 .....................46
4.1.5
Blinding and procedures for unblinding ............................................46
4.1.5.1
Blinding....................................................................................46
4.1.5.2
Procedures for emergency unblinding .....................................46
4.1.6
Packaging, labelling, and re-supply ....................................................46
4.1.7
Storage conditions.................................................................................47
4.1.8
Drug accountability ..............................................................................47
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................48
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................48
4.2.1.1
Rescue medication ..................................................................48
4.2.1.2
Supportive care .......................................................................48
4.2.1.2.1Treatment of Myeloma Bone Disease, Hypercalcemia, Pain and 
Renal Failure............................................................................48
4.2.1.2.2Growth factors .........................................................................48
4.2.1.2.3Infections..................................................................................48
4.2.1.3
Concomitant medication.........................................................49
4.2.2
Restrictions............................................................................................49
4.2.2.1
Restrictions regarding concomitant treatment .........................49
4.2.2.2
Restrictions on diet and life style.............................................50
4.3
TREATMENT COMPLIANCE.......................................................................50
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 51
5.1
EFFICACY - CLINICAL PHARMACOLOGY OR 
PHARMACODYNAMICS................................................................................51
5.1.1
Endpoint(s) of efficacy..........................................................................51
5.1.2
Assessment of Efficacy..........................................................................51
5.1.2.1
Laboratory parameters ............................................................51
5.1.2.2
Objective response rate............................................................52


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5.1.2.3
Duration of response (DOR)...................................................53
5.1.2.4
Minimal Residual Disease (MRD) response............................53
5.1.2.5
Duration of MRD response.....................................................53
5.1.2.6
Progression...............................................................................53
5.1.2.7
Progression free survival (PFS) ...............................................53
5.2
SAFETY..............................................................................................................54
5.2.1
Endpoint(s) of safety.............................................................................54
5.2.1.1
Dose limiting toxicity ..............................................................54
5.2.2
Assessment of adverse events...............................................................55
5.2.2.1
Definitions of adverse events...................................................55
5.2.3
Adverse event collection and reporting...............................................58
5.2.4
Assessment of safety laboratory parameters......................................61
5.2.4.1
General safety laboratory parameters ......................................61
5.2.4.2
Screening for laboratory evidence of tumour lysis syndrome .61
5.2.4.3
Virology...................................................................................62
5.2.4.3.1Screening for hepatitis B, hepatitis C and human 
immunodeficiency virus...........................................................62
5.2.5
Electrocardiogram................................................................................62
5.2.6
Assessment of other safety parameters...............................................63
5.2.6.1
Vital signs ................................................................................63
5.2.6.2
Physical examination ...............................................................63
5.3
OTHER...............................................................................................................63
5.3.2
Other assessment(s) ..............................................................................63
5.3.2.1
Demographics and history .......................................................63
5.3.2.2
Concomitant diagnoses............................................................64
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................64
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................65
5.5.1
Pharmacokinetic endpoint(s)...............................................................65
5.5.2
Methods of sample collection and storage ..........................................66
5.5.2.1
Blood sampling for pharmacokinetic analysis........................66
5.5.2.2 Analytical determinations of samples......................................66


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5.6.1.4 Immunophenotyping ..................................................................68
6.
INVESTIGATIONAL PLAN.................................................................. 73
6.1
VISIT SCHEDULE............................................................................................73
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................73
6.2.1
Hospitalisation.......................................................................................73
6.2.2
Disease and Response Assessments for Multiple Myeloma...............73
6.2.3
Screening and run-in period(s)............................................................74
6.2.4
Treatment period(s)..............................................................................78
6.2.4.1 Cycle 1 .....................................................................................78
6.2.4.2 Cycle 2 – 5 (or further cycles in case more than 5 cycles are 
administered)............................................................................82
6.2.5
Follow-Up Period ..................................................................................86
6.2.5.1 End of treatment visit (EOT)......................................................86
6.2.5.2
Residual effect period (REP) ...................................................88
6.2.5.3
Extended follow up..................................................................88
7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE......................................................................................... 89
7.1
STATISTICAL DESIGN – MODEL ...............................................................89
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................89
7.3
PLANNED ANALYSES....................................................................................89
7.3.1
Primary endpoint analyses...................................................................89
7.3.2
Secondary endpoint analyses ...............................................................89
7.3.4
Safety analyses.......................................................................................90
7.3.5
Pharmacokinetic analyses ....................................................................90
7.4
INTERIM ANALYSES .....................................................................................91
7.5
HANDLING OF MISSING DATA ..................................................................92
7.5.1
Safety......................................................................................................92
7.5.2 Plasma concentration – time profiles..................................................92
7.5.3 Pharmacokinetic assessment................................................................92
7.6
RANDOMISATION ..........................................................................................93
7.7
DETERMINATION OF SAMPLE SIZE ........................................................93


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS ................................................................................................ 94
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................94
8.2
DATA QUALITY ASSURANCE .....................................................................95
8.3
RECORDS..........................................................................................................95
8.3.1
Source documents .................................................................................95
8.3.2
Direct access to source data and documents.......................................96
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS96
8.4.1
Listedness...............................................................................................96
8.4.2
Expedited reporting to health authorities and IECs/IRBs................96
8.5
STATEMENT OF CONFIDENTIALITY.......................................................96
8.6
END OF TRIAL.................................................................................................96
9.
REFERENCES......................................................................................... 98
9.1
PUBLISHED REFERENCES...........................................................................98
9.2
UNPUBLISHED REFERENCES..................................................................101
10. APPENDICES ........................................................................................ 102
10.1 INTERNATIONAL MYELOMA WORKING GROUP (IMWG) UNIFORM 
RESPONSE CRITERIA FOR MULTIPLE MYELOMA...........................102
10.2
FLOW CHART PHARMACOKINETIC ASSESSMENTS........................104
10.3 DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS 
SYNDROM.......................................................................................................106
10.4 CREATININE CLEARANCE ESTIMATED BY THE 
COCKCROFTGAULT (C-G) EQUATION..................................................107
10.5
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE SCORE .............................................................................107
10.6
CLINICAL EVALUATION OF LIVER INJURY .......................................108
10.6.1 Introduction.........................................................................................108
10.6.2 Procedures ...........................................................................................108
11. DESCRIPTION OF GLOBAL AMENDMENT(S)............................ 110


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ABBREVIATIONS
ADA
AE
ALT
AESI
Anti-HBs
Anti-HBc
Anti-HCV
AP
APRIL
aPTT
AST
Anti-Drug Antibody
Adverse Event
Alanine Aminotransferase
Adverse Event of Special Interest
Hepatitis B Surface Antibody
Hepatistis B Core Antibody
Hepatitis C Antibody
Alkaline Phosphatase
A Proliferation inducing Ligand
Activated Partial Thromboplastin Time
Aspartate aminotransferase
BAFF
BI
BiTE
BCMA
BIRDS
BLQ
BSA
CA
CAR
CBA
CD
CHO
COPD
B cell activating factor
Boehringer-Ingelheim
Bi-specific T-cell enhancer
B-cell Maturation Antigen 
Regulatory Documents for Submission
Below the limit of quantification
Body Surface Area
Competent authority
Chimeric antigen receptor
Cytometric Bead Array
Classification determinant
Chinese hamster ovary
Chronic obstructive pulmonary disease
CI
c.i.v.
cv
Css
Confidence Interval
Continuous intravenous infusion
Continuous infusion
Concentration at steady state after i.v. infusion
CML
CNS
Local Clinical Monitor 
Central nervous system
CRA
CRAB
Clinical Research Associate
CRAB criteria in MM (Hypercalcemia renal insufficiency, anemia and 
ostelytic lesions)
CRF
CRO
CR
CRS
Case Report Form
Clinical Research Organisation
Complete Remission
Cytokine release syndrome 


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CT
Computer Tomography
CTCAE
CTL
Common Terminology Criteria for Adverse Events
Cytotoxic T lymphocyte
CTP
Clinical Trial Protocol
CTR
dL
DLT
DILI
Clinical Trial Report
Deciliter
Dose Limiting Toxicity
Drug induced liver toxicity
DMC
DNA
DOR
Data Monitoring Committee
Desoxyribonucleic Acid
Duration of response
eCRF
EC50
Electronic Case Report Form
Half maximal effective concentration
EDC
ECG
ECOG
e.g.
Electronic Data Capture
Electrocardiography
Eastern Cooperative Oncology Group
For example
EudraCT
EOR
EOT
FACS
European Clinical Trials Database
End of Residual Effect Period
End of Trial
Fluorescence Activated Cell Sorting 
FLC
FS
FU
Free light chain
Factor for Sex
Follow up visit
GCP
G-CSF
GFR
GM1-antibody
H
HBV
HBsAg
HCL
HCV RNA
HCV
HNSTD
HIV
Good Clinical Practice
Granulocte Colony Stimulating Factor
Glomerular filtration rate
Antiganglioside antibody 1
Hour
Hepatitis B Virus
Hepatitis B Surface Antigen
Hydrogen chloride
Hepatitis C Ribonucleic Acid
Hepatitis C Virus
Highest Non-Severely Toxic Dose
Human immunodeficiency virus
IB
ICH
Investigator’s Brochure
International Conference on Harmonisation
IEC
IgA
IgG
IgM
IL-2
IL6R
IMiDs
INN
Independent Ethics Committee
Immunoglobulin A
Immunoglobulin G
Immunoglobulin M
Interleukine-2
Interleukine -6 receptor
Immunomodulators
International Nonproprietary Name


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INR
ISF
IMWG
International Normalised Ratio
Investigator Site File
International Myeloma Working Group
IRB
IRR
IUD
Institutional Review Board
Infusion-related reactions
Intrauterine Device
ISF
Investigator Site File
i.v.
intravenous
IWRS
Kg
LDH
LUC
MCP-1
Interactive Web-based Response System
Kilogram
Lactate Dehydrogenase
Large Unstained Count
Monocyte Chemoattractant Protein-1
MedDRA
ml
m2
µg
Medical Dictionary for Drug Regulatory Activities
Mililiter
Square meter
Microgram 
MM
MPT
MRD
mRNA
MRT/MRI
MSD
MTD
n.a.
NaCL
NC
NCI
NBE
NK
NOA
NOD
NOR
NOS
NYHA
Multiple Myeloma
Melphalan-Thalidomide-Prednisone
Minimal Residual Disease
Messenger Ribonucleic acid
Magnet resonance tomography/ Magnet resonance imaging
Meso Scale Discovery
Maximum Tolerated Dose
Not applicable
Natrium Chloride
Non Compliance
National Cancer Institute
New biological entity
Natural Killer Cell
Not analysed
Non-obese diabetic
No valid result
No sample available
New York Heart Association
OPU
OR
OS
PAD
PBMC
PD
PET
PFS
Pg
Operative Unit
Overall response
Overall survival
Pharmacologically active dose
Peripheral blood mononuclear cell
Progressive disease
Positronen-Emissions-Tomography
Progression Free Survival
Pictogram


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PI
PLT
PK/PD
Principle Investigator
Platelet
Pharmacokinetics/Pharmacodynamics
p.o.
per os (oral)
PR
PT
Partial Response
Prothrombin Time
q.d.
RBC
RDC
REP
RNA
quaque die (once a day)
Red Blood Count
Remote Data Capturing 
Residual Effect Period
Ribonucleic Acid
SAE
Serious Adverse Event
SC
ScFv
SD
SCID
sCR
SNP
SOP
Safety Committee
Single chain fragment variable
Stable Disease
Severe combined immune deficiency
Stringent Sesponse
Single nucleotide polymorphism
Standard Operating Procedure
T-cell
T lymphocyte
TCM
Trial Clinical Monitor
TLS
Tumour Lysis Syndrom
TNF
TNFRSF17
Tumour necrosis factor
Tumor necrosis factor receptor superfamily member 17
TSL
ULN
VGPR
VH
VL
WBC
WFI
Tumour lysis syndrome
Upper Limit of Normal
Very Good Partial Response
Heavy chain
Light chain
White blood count
Water for injection


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1. INTRODUCTION
1.1
MEDICAL BACKGROUND
Multiple Myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone 
marrow leading to bone destruction and marrow failure. The age adjusted annual incidence is 
increasing with approximately 6 new cases per 100,000. The incidence is twice as high in the 
black US population compared to Caucasians. MM is sensitive to a variety of cytotoxic drugs 
both as initial treatment or as treatment for relapsed disease. The 5-year survival rate for MM 
has improved from ~ 25% for newly diagnosed patients in 1975 to ~ 45% in 2006 (R14-3715). 
This is mainly attributed to new drugs such as proteasome inhibitors and immunomodulators 
(IMiDs). However, responses are transient and MM is not considered curable with current 
approaches. Patients refractory to proteasome inhibitors and IMiDs have a poor prognosis with a 
median overall survival of 9 months with further treatment and 3 months without (R14-3714).
Outcome is particularly poor in molecularly defined populations such as the high risk subgroup 
del17p13 positive MM (R14-3712). New treatment options are therefore urgently required.
Although many NBEs are in clinical development for MM no antibody or antibody fragment has 
yet been registered.
MM patients presenting with active symptomatic disease are initially treated with primary 
induction therapy followed by high dose chemotherapy with autologous stem cell support in 
selected patients. Patients eligible for intensive treatment are identified by age (with 65 to 75 
years constituting the upper limit), lack of comorbidities and preserved renal function. Although 
this modality has improved survival of younger and fit patients, the median duration of response 
does not exceed 3 years and few patients remain free of the disease for more than 10 years (R14-
3753). Relapses are due to the failure of high-dose chemotherapy to eradicate residual disease. 
Consolidation and maintenance approaches have been tested in order to increase the depth and 
duration of remission. Since maintenance approaches have been hampered by lack of efficacy or 
tolerability there is still the option of improving survival outcome in the transplant setting by 
adding novel modalities to induction, consolidation or maintenance regimens. Patients not 
eligible for high dose therapy usually receive similar induction regimens as the transplant 
candidates based on the proteasome inhibitor Bortezomib or a Melphalan based combination 
with Thalidomide. Median OS of Melphalan-Thalidomide-Prednisone (MPT) in elderly patients 
is 40 months (P11-05130). Lenalidomide in combination with Dexamethasone is the standard 
regimen for relapsed/refractory MM but may move to the first line setting in transplant 
ineligible patients based on recent trial results (R14-15304). Other established strategies in the 
relapsed setting are repeat induction regimens or bortezomib or IMiD based salvage 
combinations with alkylating agents. An improvement of outcome (PFS and OS) is clearly 
needed in the relapsed setting. The patients who have become refractory to established 
treatments and progressed on treatment or within 60 days of completing their last therapy have a 
dismal prognosis of 9 months OS on treatment and 3 months without (R14-3714). The unmet 
need is highest in this population.


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1.2
DRUG PROFILE
B cell maturation antigen (BCMA, TNFRSF17, CD269) is a transmembrane protein belonging 
to the TNF receptor super family. BCMA expression is selectively induced during late stage 
plasma cell differentiation and is absent on naïve and memory B cells (R14-2907). Upon binding 
to its ligands, B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL), the 
survival of the bone marrow plasma cells and plasmablasts is promoted (R14-2906). BCMA 
does not maintain normal B cell homeostasis but is required for the survival of long lived plasma 
cells. Studies in BCMA -/- mice showed that the survival of long lived bone marrow plasma 
cells was impaired but B cell development and early humoral immune responses were 
indistinguishable from wild type mice (R14-2905). The mRNA expression of BCMA is highly 
elevated in malignant plasma cell disorders. By contrast, mRNA expression in normal tissues is 
very low and restricted to lymphoid tissues where normal long lived plasma cells are located. 
BCMA protein expression is reported to be restricted to plasma cells only. Neither T–cells, 
myeloid cells (R14-4494) nor CD34+ hematopoietic stem cells (R14-2794) express BCMA. The 
selective expression of BCMA makes it a very attractive target for antibody-based and chimeric 
antigen receptor (CAR)-based therapies (R14-2794).
BI 836909 consists of two single chain variable scFv fragments (scFv) that bind to B-cell 
maturation antigen (BCMA) on tumor cells and CD3 on T-cells. Each of the scFv fragments 
consists of a VH and VL domain connected with a Glycine/Serine linker. The two scFv 
fragments are connected with a short Glycine/Serine linker. 
 


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2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Several publications demonstrate that BCMA is universally expressed on the cell surface of MM 
cells (R14-2906, R14-3798, R14-3711). A recently published prevalence study showed that 
12/67 MM patients had high, 52/67 patients had intermediate and only 3/67 MM patients had 
low to negative BCMA surface expression. There was no correlation between BCMA expression 
and disease stage, response to last treatment and time from diagnosis, but, there was a trend 
towards higher BCMA expression levels in tumors with adverse genetics (R14-3711). 
Expression of BCMA is restricted to plasmablasts and long lived plasma cells and is absent on 
normal human tissues (R14-2794, R14-2906). Pretesting for BCMA expression is not a 
requirement for myeloma patients to be entered into the trial.
BI 836909 is an Anti-BCMA Bi-Specific T-cell Engager (BiTE) which binds to BCMA on MM 
cells as well as CD3ɛ on T-cells. It is a bispecific new biological entity (NBE) and functions as a 
bridge between MM cells and cytotoxic T lymphocytes (CTLs) and directs the cytolytic activity 
of CTLs to MM cells. The BiTE concept has successfully been tested for the CD19xCD3 BiTE 
blinatumomab which is in late stage clinical development at this time (R14-3640).
BI 836909 has not yet been tested in humans. 
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to determine the maximum tolerated dose (MTD) of 
BI 836909 administered by continuous i.v. infusion in patients with relapsed and/or refractory 
multiple myeloma. If the MTD is not reached based on safety findings, a recommended dose for 
further development will be determined. This will depend on the safety data, pharmacokinetic/
pharmacodynamics data and potentially preliminary efficacy data. Secondary objectives are to 
document the safety and tolerability of BI 836909, to perform pharmacokinetic and 
pharmacodynamic analyses and to evaluate relevant biological effects in terms of parameters of 
efficacy. The starting dose is based on a Pharmacologically Active Dose (PAD) estimated from 
the EC50 of the most sensitive in vitro cytotoxicity assay and pharmacokinetic modelling. 
Assuming an average body surface area (BSA) of 1.7 m2 the proposed starting dose of 0.12 μg/ 
m2/day translates into a starting dose of 0.20 µg/d given by continuous intravenous injection. In 
the clinical trial the administered doses will not be BSA-adapted. The proposed starting dose is 
4500 fold lower than the HNSTD (540 µg/m2/day) and 1500 fold lower than the dose (180 
µg/m2/day) that did not result in cytokine release in the 4-week toxicology study in cynomolgus
monkeys.
2.3
BENEFIT - RISK ASSESSMENT
Progress in understanding the biological behavior of MM has been achieved and effective 
treatment regimens have been developed. However, these treatments are not curative and most 
patients with MM still die of their disease. In particular, patients with relapsed and/or refractory 
multiple myeloma have a need for new therapeutic options.


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BI 836909 is a Bi-specific T-cell Engager that binds to BCMA on MM cells and on CD3ε on T-
cells and therefore functions as a bridge between cancer cells and CTLs and directs the cytolytic
activity to the MM cells. 
BI 836909 shows strong binding to human BCMA, and comparable cross reactive binding to 
cynomolgus BCMA. Cells of a bone marrow aspirate of a MM patient containing BCMA 
positive target cells as well as T autologous cells were incubated for 48 hours with BI 836909. 
The number of BCMA/CD38 positive cells was determined by flow cytometry over time. The 
number of viable BCMA/CD38 positive cells decreased in the samples incubated with 
BI 836909. The cell number in the untreated samples was not reduced. 
At time of protocol preparation, BI 836909 has not previously been tested in humans. BCMA is 
not expressed on other cells than plasma cells. The anticipated side effect profile of BI 836909 
based on preclinical studies comprise predominantly depletion of plasma cells and alterations of 
lymphatic tissues. Changes in WBC (decreases of lymphocytes and monocytes, increases of 
neutrophils) may occur. Lymphocytopenia may predispose to infections. Given the mode of 
action cytokine release syndromes may happen. Cytokine release can be associated with clinical 
symptoms such as fever, chills, nausea, vomiting, hypotension, dyspnoea, tachypnea, headache, 
tachycardia, rash, and/or hypoxia. CNS toxicities were observed with blinatumomab, the 
CD19xCD3 BiTE molecule. Whether this side effect is restricted to the CD19 target is still 
unclear. Considering the experience with other monoclonal antibodies in different indications, 
infusion-related reactions as well as cytokine release syndrome may occur and have to be 
differentiated from tumour lysis syndrome. Adverse events like these are frequently reported in 
patients with malignant diseases and may be due to the underlying disease, the treatment or both. 
Autoimmune phenomena in terms of anti-drug antibodies may occur. Prophylactic measures will 
be implemented in this protocol for primary prevention, supportive treatments are available (see 
Sections 4.1.4.1 and 4.2.1.2). 
Current therapy for MM often cause remissions, but nearly all patients eventually relapse and 
die. There is substantial evidence of an immune-mediated elimination of myeloma cells in the 
setting of allogeneic hematopoietic stem cell transplantation. There is clearly a great need for 
new immunotherapies for multiple myeloma and targeting BCMA on MM cells and directing the 
cytolytic activity of CTLs to MM cells by a BCMA-BiTE might be a major advance in treating 
patient with refractory or relapsed MM.
Patients with MM may benefit from treatment with BI 836909 in terms of tumour cell reduction,
tumour stabilisation, control of tumour-related symptoms and improved survival as BI 836909 
targets an epitope of MM cells which has not previously been targeted. The potential benefit of 
therapy with BI 836909 is expected to outweigh the treatment-related risks. 
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and follow-up 
of laboratory alterations in selected liver laboratory parameters to ensure patients’ safety, see 
also Section 5.2.2. Advanced and pretreated MM patients may present with elevated liver 
enzymes at study entry due to liver involvement or pretreatment with hepatotoxic regimen. 
Transaminase elevations may also occur during treatment with BI 836909 in the context of 
infusional reactions or cytokine release syndromes which can be managed by experienced 


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investigators.  Therefore the definitions for hepatic injury have been modified to reflect the 
disease state of MM patients entering the trial. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations in selected liver laboratory parameters to 
ensure patients’ safety, see also Section 5.2.2.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The trial is an open-label, non-randomized phase I dose-escalation trial with modified 3+3 
design to evaluate the tolerability and safety of BI 836909 given as continuous intravenous 
infusion as well as to determine the MTD or to establish the recommended dose for further 
development of BI 836909 administered as continuous intravenous infusion. 
MTD is defined as the highest dose of the dose level tested where ≤ 1 patient out of 6 develops
dose limiting toxicity. If MTD cannot be determined based on safety findings, a recommended 
dose for further development will be determined based on pharmacokinetic and 
pharmacodynamics data. 
Figure 3.1: 1 Overall study design (In case of ongoing clinical benefit, patients can be followed 
up to collect data for duration of response. Follow-up visits for responders will be 
at 3, 6 and 12 months after EOT if a patient did not progress, started a new anti-
cancer treatment, died, or withdrew informed consent.)
The study consists of the following phases:

Screening period (day – 21 to day -1): baseline assessments will be performed as well as 
in- and exclusion criteria will be evaluated

Treatment period: Treatment will continue for up to five 6-week cycles or until:
-
Disease progression/start of further anticancer treatment


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-
Non-acceptable toxicity
-
Patient decision to withdraw consent
-
Investigator’s decision
In case of ongoing clinical benefit after five courses additional 5 courses may be given if 
considered indicated by the investigator.

End of treatment (EOT): this visit will take place as soon as possible after 
discontinuation of study medication but no later than 1 week after discontinuation of  
trial drug

Follow up visit (FU): follow up visit should be performed 30 days after the EOT (REP 
visit). Patients will be treated for a maximum of 10 cycles. In case of ongoing clinical 
benefit, patients can be followed up to collect data for duration of response. Follow-up 
visits for responders will be at 3, 6 and 12 months after EOT if a patient did not progress, 
started a new anti-cancer treatment, died, or withdrew informed consent. Last patient out 
is defined as the REPlast visit completed by the last patient. This will be the end of the 
trial. 
For patients who have entered the trial before the approval of the second revision last 
visit would be defined as the last follow up visit after the approval date.
For patients who have re-consented after the approval of the fourth revision last visit 
would be defined as above.
The following dose levels will be tested:
Table 3.1: 1
Dose escalation scheme
Dose level
Dose µg/d
Patients per cohort
Approximate 
increment to next 
dose
1
0.2
1
2x
2
0.4
1
2x
3
0.8
1
2x
4
1.6
1
2x
5
3.2
3 (+3)
2x
6
6.5
3 (+3)
2x
7
13
3 (+3)
2x
8
25
3 (+3)
2x
9
50
3 (+3)
2x 
10
100*
3 (+3)
2x 
11
200*
3 (+3)
2x
12
400*
3 (+3)
2x
13
800*
3 (+3)
2x
*Intermediate dose cohorts with up to 50% increment versus the previous cohort will be entered if determined by the safety 
committee,in case that the dose of a cohort  exceeds MTD (> 1 patient out of 6 with DLT) and the previous cohort is 
well tolerated. 
For example:


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- 75µg/day in case a dose of 100µg/day exceeds MTD
150µg/day in case a dose of 200µg/day exceeds MTD
- 300µg/day in case a dose of 400µg/day exceeds MTD
- 600µg/day in case a dose of 800µg/day exceeds MTD
The above-mentioned intermediate dose cohorts will follow the 3 (+3) design. The starting dose will be 0.20 
µg/day given as a continuous intravenous infusion for 4 weeks. 
An every 6-week regimen will be tested (4 weeks of continuous intravenous administration of 
BI 836909 followed by a 2 weeks off-period).
For the dose levels 0.2 to 1.6 µg/day single patient cohorts are entered since no clinical activity 
is expected at these doses. 
If a patient has been on treatment in one of the above-mentioned dose cohorts for 2 weeks 
without DLT the first patient of the next higher dose cohort will be entered if agreed on by the 
safety committee. If a patient has reached DLT, then the safety committee recommends the 
switch to a 3 + 3 cohort for the dose level at which the DLT occurred. Patients may not proceed 
to the next higher dose level before completion of 6 patients.
One intra-patient dose escalation is allowed within the single patient dose cohorts if the initial 
dose is tolerated well and no DLT occurs during 1st cycle. In case of DLT additional patients will 
be entered into this cohort following a 3+3 design.
For the dose levels ≥ 3.2 µg/day 3-6 patients will be treated per dose level and observed for 4 
weeks during the first cycle before decision for dose escalation to the next dose cohort is made.
Per dose level 1 patient will be enrolled and treated for 1 week, then further patients will be 
enrolled. Patients should be entered sequentially. Additional patients should not start treatment 
before the previous patient has been treated for 48 hours in order to monitor initial transient 
toxicities due to cytokine release syndrome.
In the dose escalation part the trial safety committee (for details see Section 3.1.1) can determine 
to enter additional and intermediate dose cohorts at any time e.g. if DLTs or other safety events, 
pharmacodynamics activity or antitumor efficacy occur. The safety committee will also 
determine to switch from single patient cohorts to a 3+3 design at doses below 3.2µg/d if DLTs, 
pharmacodynamic activity or antitumor efficacy occur. 
PK/PD data might be taken into account for dose escalation decisions if available.
Patients should be entered sequentially. Treatment initiation of more than 1 new patient per day 
will not be permitted during the dose escalation phase.
Once the MTD or the recommended dose for better characterization of safety and early 
evaluation of anti-tumour activity is determined up to 6 additional patients will be treated with 
MTD or the recommended dose.


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3.1.1
Administrative structure of the trial
This study is sponsored by Boehringer Ingelheim. A Coordinating Investigator as specified on 
the cover page of this protocol will be nominated and will be responsible to coordinate 
investigators at different centres participating in this multicentre trial. Tasks and responsibilities 
for the Coordinating Investigator will be defined in a contract. Documents on participating 
(Principal) Investigators and other important participants, especially their curricula vitae, will be 
filed in Boehringer Ingelheim Regulatory Documents for Submission (BIRDS). Details on 
handling of the trial supplies including responsible institutions are given in Section 4 of this 
protocol. The target group of Principal Investigators will be haemato-oncologists experienced 
and specialized in the treatment of MM and in the conduct of phase I trials. The Principal 
Investigator (PI) at each site will be responsible for assuring the proper conduct of the trial, 
patient care, and safety at the site. The investigator or in some cases one or more sub-
investigators will be responsible for the daily conduct of the trial, patient visits, eCRF 
completion, and for assisting the CRAs in site monitoring.
Site personnel authorized by the Investigator must enter the information required by the protocol 
into the eCRF. A Study Monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between the source data and those entered onto the eCRF will be addressed by qualified site 
personnel. When a data discrepancy warrants a correction, that correction will be made by 
authorized site personnel. Data collection procedures will be discussed with the study site at the 
site initiation visit and/or at the Investigator’s Meeting. 
The study sites will use a validated electronic data capture (EDC) system to enter subjects’ data 
from source documents onto electronic eCRFs. Password-protected access to the EDC system 
will be via a secure website. Data clarification forms and data corrections will be handled 
through the same system. All transactions within the EDC system must be fully documented
within an electronic audit trial. Each set of completed eCRFs must be reviewed and 
electronically signed and dated by the Investigator. In compliance with remote data retention 
requirements, the study sites will be provided with a CD-ROM containing the eCRFs and the 
complete audit trail in PDF format, subsequent to database lock.
A complete list of investigators and other persons whose participation materially will affect the 
conduct of the trial will be filed in BIRDS and provided in the Clinical Trial Report (CTR).
The study may be outsourced for responsibilities that include site monitoring, study medication 
logistics and processing of safety reports, among others.
Boehringer Ingelheim has appointed a Trial Clinical Monitor (TCM), responsible for 
coordinating all required activities to

Manage the trial in accordance with applicable regulations and internal SOPs,

Direct the clinical trial team in the preparation, conduct and reporting of the trial,

Order the materials as needed for the trial

Ensure appropriate training and information of local monitors (CML), Clinical Research 
Associates (CRAs) and Investigators of participating countries.


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The safety laboratory investigations (haematological, biochemical, coagulation, and urine) and 
specific biomarkers (Section 5.1.2, 5.2.4 and 5.3.3) will be performed at the investigator site and 
no central laboratory will be used for these parameters. Only standard laboratory investigations 
are required by the protocol for safety laboratory investigations. The certification and/or 
accreditation for each laboratory or evidence that it participates in an established quality 
program must be provided by the investigator and filed at the Sponsor and the local ISF of the 
site, as well as the normal ranges of each test performed.
All trial relevant documentation will be stored in BIRDS. Trial relevant documentation which 
has to be at the trial site will be filed in the ISF at the investigator site. The ISF document will be 
kept in print-out version at the sites as far as required by local regulation and BI-SOP.
A safety committee (SC) of the investigators in cooperation with the responsible trial monitor 
and the medical project leader of the sponsor as well as medical representatives from Amgen 
will be implemented to analyse ongoing safety information and decide on further steps in dose 
finding. Prior to escalating the dose to the next higher dose cohort there will be a safety 
teleconference or meeting between trial investigators and the medical project leader of the 
sponsor to discuss any findings in the ongoing and already recruited cohorts, this means that all 
available clinical and safety data including repeated cycles of prior dose cohorts will be taken 
into consideration for assessments and decision making. Participation of the coordinating 
investigator or 
 deputy is a mandatory requirement for this committee to establish a quorum. 
After the defined observation period of each cohort this safety committee will discuss the need 
to enter additional patients or dose cohorts or release the next dose cohort and dose increment as 
per protocol. The same is true for the decision to switch from single patient cohorts to the 3+3 
design. Step dosing may be implemented based on cytokine release syndrome qualifying for 
DLT following the following guidance:

Restart with previous dose level for 4 days (one bag) and then escalate to current dose 
level until the end of the cycle. 
The composition of the SC will be documented in BIRDS. The tasks and responsibilities will be 
agreed in contracts between the SC members and the Sponsor. SC will decide on the switch from 
single patient cohorts to the 3+3 design independently from defined dose cohorts based on 
clinical activity (antitumor response) and/or clinically relevant safety or pharmacodynamics 
findings. 
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be defined 
according to BI SOPs. A list of responsible persons and relevant local information can be found 
in the ISF.
Summary of assessments (see corresponding Flow charts):


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At screening, blood samples are drawn, a physical examination and a routine MRI scan are 
performed, and the patient is evaluated for eligibility in the trial. Bone marrow aspirate/biopsy 
will be performed. In case karyotyping of bone marrow aspirate/biopsy has been performed after 
the latest therapy within 3 months before start of trial medication, it should be recorded.
Clinical disease status will be assessed at screening and at the start of each new cycle (e.g, 
before cycle 2, 3, 4 and 5 etc.) as well as at EOT with physical examination and clinical 
assessment of the multiple myeloma. MRI scans in this trial will be performed prior to treatment, 
at screening and every other cycle at day 1, cycle 3, day 1, cycle 5, day1, cycle 7, day 1 and/or at 
time of progression or start of further anticancer therapy.
Results from routine assessments (MRI) for multiple myeloma are accepted for screening if 
performed no later than 28 days before start of treatment. 
Bone marrow examination, MRI scan and additional CT scans will be performed at time points 
outlined in the Flow chart. Results of MRI scans, additional CT scans, optional PET scan or 
bone marrow examination performed during the conduct of the trial should be reported in the 
eCRF. After the EOT visit which must occur immediately at time of permanent discontinuation 
of study medication but no later than 7 days after last drug administration, the patient will have a 
follow up visit within 30 days after EOT (REP visit) for assessment of AEs /SAEs, patient status 
and further anti-cancer treatment. In case of ongoing clinical benefit, patients can be followed up 
to collect data for duration of response. Follow-up visits for responders will be at 3, 6 and 12 
months after EOT if a patient did not progress, started a new anti-cancer treatment, died, or 
withdrew informed consent and will assess related SAEs and AESIs.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The primary objective of this trial is to determine the MTD. The most important secondary 
objective is to assess the safety of BI 836909 given as continuous intravenous infusion. 
For the first 4 doses up to and including 1.6µg/d dose cohorts single patient cohorts have been 
chosen since no clinical benefit is expected at these low doses.
For the remaining dose cohorts a standard 3+3 design has been chosen as this is an established
standard approach in phase I studies in oncology:
The following dose cohorts will be tested as single patient cohorts: 0.2, 0.4, 0.8 and 1.6 µg/day.
If a patient has been on treatment in one of the above-mentioned dose cohorts for 2 weeks 
without DLT the first patient of the next higher dose cohort will be entered. In case that a DLT 
has been observed in the single patient cohorts 5 additional patients will be entered on this actual 
dose level. 
Intra-patient dose escalation is allowed once to the next higher dose within the first 4 above-
mentioned dose cohorts up to 1.6µg/d.
In case that no DLTs have been observed during the first cycle within the single patient dose 
cohorts the patient can be treated at the next higher dose level in subsequent cycles. Only one 


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intra-patient dose escalation step is allowed. This approach of intra-patient dose escalation 
reduces the number of patients treated at pharmacologically inactive doses to a minimum and 
increases the likelihood of treatment benefit for patients entered at low dose. 
Prior to treatment of a patient at the next higher cohort a safety committee quorum needs to be 
obtained to oversee the observation period of this dose level to make sure that no additional 
patients must be entered at that dose level and that a patient can be entered at the next higher 
dose level. If the safety committee recommends treatment of additional patients at the lower 
dose level 2 additional patients must be entered at the lower dose level first. The 3 + 3 design 
will then be followed. 
For the dose levels ≥ 3.2 µg/day 3-6 patients (3+3 design) will be treated per dose level and 
observed for 4 weeks before decision for dose escalation to the next dose cohort is made.
If one patient of the cohort of three patients experiences a dose limiting toxicity (DLT) (for 
definition see 5.2.1.1) within the first cycle (4 weeks of continuous infusion), three additional 
patients will be treated at the same dose level according to a standard 3+3 design. 
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 de-escalated until a dose level is reached in which at most one 
DLT out of six patients is observed (R01-0028). 
3.3
SELECTION OF TRIAL POPULATION
A total number of approximately 50 patients is expected to be entered into the trial. The number 
of patients depends on the number of dose escalation steps. A total of 5 sites will participate; this 
means that a total number of approximately 6 to 10 patients should be entered per site.
A comprehensive review of all relevant medical factors including patient characteristics (e.g. 
age, performance score, concomitant diagnoses, organ dysfunctions) as well as disease 
characteristics will be the basis for the decision of the investigator on whether a patient is 
eligible or not.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The eligible patients for the trial are patients with relapsed and/or refractory multiple myeloma 
who have progression of disease after at least 2 prior treatment lines (including proteasome 
inhibitors and at least one regimen containing an immune - modulatory drug [IMiD]). Patients 
must have measurable disease at time of screening as defined in Section 3.3.2. 
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements pertaining 
to the in-and exclusion criteria.  


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3.3.2
Inclusion criteria
1. Patients with a documented diagnosis of relapsed and/or refractory multiple myeloma
who progressed after at least two prior treatment regimens, including both a proteasome 
inhibitor as well as an immune - modulatory drug at time of screening
2. Must have measurable disease, defined by one or more of following at time of screening:

a serum M protein > 0.5 g/dl measured by serum protein electrophoresis

urinary M protein excretion > 200 mg/24 hours

serum free light chain (FLC) measurement > 10 mg/dl, provided that the serum 
FLC ratio is abnormal
3. Relapse or progression of disease with an indication for therapy as per investigator`s 
judgment at time of screening
4. Life expectancy of at least 6 months as per investigator`s judgment at time of screening
5. ECOG Performance Status 0, 1 or 2 at time of screening
6. Age ≥ 18 years at time of screening
7. Written informed consent which is consistent with ICH-GCP guidelines and local 
legislation.
8. Able to adhere to the study visit schedule e.g. ability to come to the clinic and adhere to 
other protocol requirements
9. Indwelling central venous catheter or willingness to undergo intra venous central line
placement
3.3.3
Exclusion criteria
1. Plasma cell leukemia
2. Extramedullary relapse of multiple myeloma
3. Known central nervous system involvement by multiple myeloma
4. Last anticancer treatment < 2 weeks prior to visit 1
5. Last treatment with a therapeutic antibody less than 6 weeks prior to visit 1
6. Prior allogeneic stem cell transplantation or solid organ transplantation
7. Autologous stem cell transplantation < than 90 days at time of treatment start
8. Last corticosteroid < 2 weeks prior to visit 1 unless the dose is ≤10 mg/day prednisolone 
or equivalent
9. AST or ALT >3 x upper limit of normal (CTCAE version 4.03 grade 2 or higher) at time 
of screening
10. Total conjugated bilirubin >1.5 x upper limit of normal (CTCAE version 4.03 grade 2 or 
higher) at time of screening
11. Absolute neutrophil count <1.0 x 109/L (without growth factor support) at time of 
screening
12. Platelets <25 x 109/L (without transfusions) at time of screening
13. Calculated GFR <30 mL/min (Cockroft-Gault Formula; see Appendix 10.4) at time of 
screening
14. Clinical relevant concurrent medical disease or condition which according to the 
investigator’s judgment would either compromise patient safety or interfere with the 
evaluation of the safety of the test drug, e.g. symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia requiring therapy at time of screening


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15. Clinically not controlled chronic or ongoing infectious disease requiring treatment at the 
time of enrolment or within the previous two weeks
16. Active hepatitis B or hepatitis C, or laboratory evidence for a chronic infection with 
hepatitis B or C (see Section 5.2.4.3.1) at time of screening; HIV infection at time of 
screening
17. Women of childbearing potential not using a highly effective method of birth control 
during the trial until one year after the last dose. Highly effective methods of birth 
control are defined as those which result in a low failure rate (i.e. less than 1% per year) 
when used consistently and correctly used such as implants, injectables, combined oral 
contraceptives, intrauterine devices (IUDs), sexual abstinence or vasectomised partner. 
Barrier methods of contraception are accepted if condom or occlusive cap is used 
together with spermicides (e.g. foam, gel). Female patients will be considered to be of 
childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal 
ligation/salpingectomy, or postmenopausal (12 months with no menses without an 
alternative medical cause)
18. Male patients with partners of childbearing potential who are unwilling to use condoms 
in combination with a second medically acceptable method of contraception during the 
trial and for a minimum of 6 months after treatment.
19. Pregnancy or breast feeding
20. Known or suspected active alcohol or drug abuse as per investigator’s judgment
21. Treatment with another investigational drug within the past four weeks before start of 
therapy or concomitantly with this trial
22. Patients with a known hypersensitivity to any component of the study drug 
23. Patients with other malignancies within 5 years at time of screening (except basal cell or 
squamous cell carcinoma of the skin or carcinoma in situ treated with curative therapy)
24. Known autoimmune diseases requiring systemic treatment in past 5 years and interfering 
with evaluation of study drug. 
25. Pre-existing disorders of the central nervous system.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
The investigator or patient themselves may stop treatment at any time for safety or personal 
reasons.

The patient withdraws consent for study treatment or study participation, without the 
need to justify the decision.

The patient needs to take concomitant drugs that interfere with the investigational 
product (See Section 4.2).

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy)

Relapse or Progressive Disease (PD), including deterioration of general condition due to 
disease progression or relapse (for definition see Appendix 10.1) or start of further anti-
cancer therapy

The patient fails to follow protocol requirements/directions and represent a safety issue 
for patient


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
Eligibility criteria are violated and represent a safety issue for patient

AEs that cannot be managed by dose reduction or adequate treatment

Further dose reductions considered necessary but not allowed according to the protocol 
(see Section 4.1.4.3)

The patient is found to be pregnant during program participation (please refer to Section 
5.2.3)

A change in the patient’s status creating an unfavourable risk/benefit in favour to stop 
study medication. 
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow chart and Section 6.2. For all patients the 
reason for withdrawal (e.g. adverse event) must be recorded in the eCRF. These data will be 
included in the trial database and reported.  
For safety reasons it is recommended that the patient is encouraged to return for at least the 
follow-up visit.
When discontinuation is due to a serious AE (SAE) the treating investigator must follow the 
event until it is resolved, becomes chronic, or remains stable with no resolution expected.  
If a woman becomes pregnant after having taken study medication, the treating investigator must 
report immediately any drug exposure during pregnancy to the sponsor. Drug exposure during 
pregnancy has to be reported immediately (within 24 hours) to the defined unique entry point for 
SAE forms of the respective BI OPU (country-specific contact details will be provided on the 
fax cover page). 
For cases of paternal exposure to the BI product during the clinical trial, the pregnancy (mother 
is not a participant in the clinical trial) has also to be reported to BI, if the father (participant in
the clinical trial) voluntarily reports it to the investigator.
In both cases the outcome of the pregnancy associated with the drug exposure during pregnancy 
must be followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for the 
clinical trial and not the SAE form is to be completed. 
The Pregnancy Monitoring Form for the clinical trial (Part A and Part B) will be provided by the 
sponsor with the clinical trial documentation.
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:

Failure to meet expected enrolment goals overall or at a particular trial site

Emergence of any efficacy/safety information invalidating the earlier positive benefit-risk-
assessment that could significantly affect the continuation of the trial

Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial

Discontinuation or modification of the clinical development program with BI 836909 for any 
reason.


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
The Investigator/the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product and comparator product(s)
Substance (INN):
BI 836909
Pharmaceutical form: 
Powder for solution for infusion after dilution in water
plus 5 ml bag-diluent
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
75 µg lyophilisate 
Daily dose:
See Section 4.1.5
Duration of use:
BI 836909 will be administered as a continuous 4-week infusion 
followed by a 2-week break for 5 cycles or until progression, 
unacceptable adverse events or other reason necessitating 
withdrawal. In case of ongoing clinical benefit a maximum of 5 
additional treatment cycles can be given if considered indicated by 
the treating investigator. This means that a maximum of 10 cycles 
can be given to a patient. 
Route of administration:
Intravenous infusion
Posology:
Rate controlled infusion; the flow rate is set to 2.6 ml/h (250 ml in 
96 hours).
Substance (INN):
Bag Diluent for BI 836909
Pharmaceutical form: 
5 ml diluent
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
N.A.
Daily dose:
N.A. 
Duration of use:
5 ml bag diluent will be added to each bag independent of dose 
given and will be administered as a continuous 4-week infusion 
followed by a 2-week break for 5 cycles or until progression, 
unacceptable adverse events or other reason necessitating 
withdrawal. 
Route of administration:
Intravenous infusion


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Posology:
Rate controlled infusion; the flow rate is set to 2.6 ml/h (250 ml in 
96 hours).
4.1.1.1
Description of portable pump for continuous intravenous infusion of BI 836909
BodyGuardTM 323 Multi-Therapy Ambulatory Infusion Pump (Ceasarea Medical Electronics 
GmbH; 72805 Lichtenstein; Germany) will be used in the trial for the 4 –week continuous rate 
controlled intravenous infusion. Site personnel will be trained on the use of the pump by the 
vendor. Detailed instructions will be available in the ISF.
4.1.2
Method of assigning patients to treatment groups
This is a single arm, open-label, dose-escalation trial. Assignment of a patient to a dose has to be 
confirmed by the investigator with the clinical monitor of the sponsor as described below in 
Section 4.1.4.
4.1.3
Selection of doses in the trial
This is the first in man study with BI 836909 and the starting dose will be a Pharmacologically 
Active Dose (PAD) estimated from the EC50 of the most sensitive in vitro cytotoxicity assay 
and pharmacokinetic modelling. Based on this modelling, the starting dose for Phase I for 
continuous intravenous injection is 0.20µg/d.  The proposed starting dose is 4500 fold lower 
than the HNSTD (540 µg/m2/day) and 1500 fold lower than the dose (180 µg/m2/day) that did 
not result in cytokine release in the 4-week toxicology study in cynomolgus monkeys.  For 
planned dose cohorts see Table 4.1.4.1.
4.1.4
Drug assignment and administration of doses for each patient
Dose allocation will be controlled by the sponsor to ensure safety monitoring and the dose-
escalation schedule is adhered to in the interest of the safety of the patients. 
Each investigational site must notify the sponsor when an eligible patient is identified. Prior to 
inclusion of a new patient during the dose-escalation phase the investigator has to confirm the 
actual dose tier of BI 836909 for the patient with the clinical monitor of the sponsor who 
oversees the dose-escalation steps and the safety data of patients from all trial sites. Enrolment 
will only be possible after the sponsor has notified the site by written confirmation of the dose 
and earliest possible date of first administration. Drug assignment to a patient will be done via 
the inter-active Webb response system (IWRS). 
BI 836909 will be administered as a continuous intravenous infusion.
An every 6 week regimen will be tested (4 weeks of continuous intravenous administration of
BI 836909 followed by a 2-week off-period).


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Start of infusion of BI 836909 may be at any time during the day. However, to facilitate blood 
sampling for pharmacokinetic (PK) and pharmacodynamic analyses, it is recommended to start 
the infusion during the morning hours.
Preparation of solution for infusion will be done by the pharmacist at the site (for details, see ISF 
and pharmacy file). Pre-filled 250 ml bags with 0.9% NaCl will be used for the 4-day infusion. 
In a first step 5 ml bag diluent will be added to the normal saline containing bag and then the 
diluted solution of BI 836909 in a concentration according to actual dose level will be added. 
Bag exchange must occur every 4 days either in the hospital or at patient`s home by the home 
care service (for details see corresponding manuals). Once the infusion line has been 
disconnected from patient`s implanted port the port should be flushed with normal saline before 
a new catheter will be accessed. Catheter must be flushed at the beginning of the infusion with 
normal saline. 
Table 4.1.4: 1
Dose escalation scheme
Dose µg/day
Patients 
per cohort
Observation time of ongoing patients 
before enrolment/entry of next 
patient/cohort
0.2
1
2 weeks, then enrol next cohort
0.4
1
As in previous cohort
0.8
1
As in previous cohort
1.6
1
As in previous cohort
3.2
3 (+3)
1 week for first patient, then enter next two 
patients; additional patients should not 
start treatment before the previous patient 
has been treated for 48 hours in order to 
monitor initial transient toxicities due to 
cytokine release syndrome. All 3 must 
have completed 4 weeks before enrolling 
next cohort
6.5
3 (+3)
As in previous cohort
13
3 (+3)
As in previous cohort
25
3 (+3)
As in previous cohort
50
3 (+3)
As in previous cohort
100
3 (+3)
As in previous cohort
200
3 (+3)
As in previous cohort
400
3 (+3)
As in previous cohort
800
3 (+3)
As in previous cohort
*Intermediate dose cohorts may be added based on decision of the safety committee (see table 3.1:1) and will follow the above-
mentioned rules. 
For details see Section 3.1. 
During the dose-escalation phase, each patient will receive a continuous infusion of BI 836909 
given for 4 weeks followed by observation for 2 weeks after termination of the continuous 


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infusion. Treatment is given until progression according to IMWG response criteria (see 
Appendix 10.1), non-acceptable toxicity, patient decision to withdraw consent, investigator’s 
decision. In case of clinical benefit a maximum of 5 cycles is administered. In case of ongoing 
clinical benefit additional 5 treatment cycles can be given if considered indicated by the treating 
investigator. 
4.1.4.1
Prophylactic measures
4.1.4.1.1 Premedication
Premedication is mandatory 30-120 minutes prior to start of administration of BI 836909 to 
prevent/reduce severity of infusion-related reactions and before increasing the dose in case of an 
intra-patient dose escalation, unless a contraindication for premedication exists. The 
premedication for before start of each cycle should include

Acetaminophen/paracetamol 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 or 16 mg dexamethasone
If BI 836909 has been well tolerated without signs of infusion-related reactions during the first
cycle, glucocorticoid premedication may be reduced to 50% of the administered dose before first 
cycle, i.e. glucocorticoid i.v., equivalent to prednisolone 50 mg at start of second cycle. If 
tolerated well the investigator may decide to further reduce or do without premedication in 
repeated treatment cycles.
4.1.4.1.2 Monitoring for infusion-related reactions and cytokine release syndromes
Close monitoring of the patient during and after the infusion of BI 836909 is required for 
evaluation of infusion-related risks. The measures of monitoring include:

Hospitalization of patients with access to intensive care days 1–4 of cycle 1 and in case 
of intra-patient dose escalation within the first cycle of dose escalation.

Hospitalization of patients with access to intensive care on day 1 of cycle 2 (for a total of 
24 hours) and in case of intra-patient dose escalation within the first cycle of dose 
escalation.

Frequent measurements and documentation of blood pressure and heart rate (see Section
5.2.6.1).
In courses 2 and higher the patients are required to be hospitalized under close surveillance
with access to intensive care days 1-3 again in case of infusion related events in earlier treatment 
courses. If no infusion related events occurred in earlier treatment courses an observation period 
of 4 - 8 hours in the hospital will suffice at start of each continuous infusion of BI 836909 in 
courses 3 and higher.
4.1.4.1.3 Tumour lysis syndrome
All patients have to be monitored for clinical or laboratory evidence of tumour lysis syndrome 
(see Appendix 10.3). To prevent tumour lysis syndrome, all patients should receive appropriate 


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hydration and supportive measures (e.g. rasburicase) according to local standards or available 
guidelines (R10-4517). In addition, close monitoring of laboratory parameters to allow for early 
diagnosis of a possible tumour lysis syndrome is recommended, for details please refer to 
Section 5.2.4.2 CTCAE version 4.03 classifies TLS in grade 3 (present), grade 4 (life threatening 
consequences; urgent intervention indicated) and grade 5 (death). Presence of TLS is not clearly 
defined by CTCAE version 4.03 (R10-4848). For this trial the Cairo-Bishop classification will 
be used to define presence of TLS, i.e. presence of clinical TLS (R10-4517).
4.1.4.1.4 Handling of infusion-related reactions or cytokine release syndromes
In case of an infusion-related reaction or cytokine release syndrome, appropriate measures 
depending on the type and severity of the reaction should be taken by the investigator according 
to best medical judgement and local guidelines. Supportive therapy including steroids may be 
used as clinically indicated. For supportive treatment of severe CRS interleukin 6 receptor 
(IL6R) antagonists may be used (R15-0031).
Changes of the infusion rate and temporary interruptions of the infusion have to be recorded in 
the eCRF.
Infusion-related reactions or cytokine release syndromes CTCAE version 4.03 grade 3 and 4 are 
defined to be adverse events of special interest and have to be reported according to the rules 
defined for SAE-reporting (see Section 5.2.2.1).
The following recommendations for the management of infusion-related reactions or cytokine 
release syndromes (Table 4.1.4.1.4: 1) should be considered by the investigator as guidance:

In the case of an infusion-related reaction CTCAE version 4.03 grade 1 or 2, the infusion
of BI 836909 should be temporarily interrupted and resumed as soon as considered 
clinically manageable by the investigator.

In the case of an infusion-related reaction CTCAE version 4.03 grade 3 or 4, the infusion 
has to be stopped immediately. These patients should not be re-exposed to BI 836909.


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Table 4.1.4.1.4: 1
Grading and management of cytokine release syndrome
CRS 
grade
Description of 
severitya
(CTCAE v4)
Interruption
Minimum expected 
intervention
Re-start 
guidance
Permanent 
discontinuation
1
Mild reaction; 
infusion 
interruption not 
indicated; 
intervention not 
indicated
n/a
Administer symptomatic 
treatment (e.g. 
paracetamol/
acetaminophen for fever).
Monitor for CRS 
symptoms including vital 
signs and pulse oximetry 
at least Q2 hours for 12 h 
or until resolution, 
whichever is earlier.
n/a
n/a
2
Therapy or 
infusion 
interruption 
indicated but 
responds 
promptly to 
symptomatic 
treatment (e.g. 
antihistamines, 
NSAIDS, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for 
≤24 h 
Immediately 
interrupt BI 
836909 until 
event has 
improved to 
CRS grade 
≤1, but for no 
less than 72 
h. 
Administer: 
• Symptomatic treatment 
(e.g. paracetamol/ 
acetaminophen for 
fever)
• Supplemental oxygen 
when oxygen saturation 
is <90% on room air 
• Intravenous fluids or 
low dose vasopressor for 
hypotension when 
systolic blood pressure 
is <85 mmHg. Persistent 
tachycardia (e.g. >120 
bpm) may also indicate 
the need for intervention 
for hypotension. 
Monitor for CRS 
symptoms including vital 
signs and pulse oximetry 
at least Q2 hours for 12 
hours or until resolution to 
CRS grade ≤1, whichever 
is earlier. 
Investigators may also use 
tocilizumabc as an 
additional therapy in this 
setting at a dose of 4-8 
mg/kg as a single dose, 
particularly if CRS does 
not improve to grade ≤1 
within 4 h after dose 
interruption. 
For subjects with 
extensive co-morbidities 
or poor performance 
status, manage per grade 3 
CRS guidance below. 
• Re-start 
possible, if 
successfully 
managed and 
improvement to 
CRS grade ≤1 
within 7 days, 
• Consult with 
Boehringer 
Ingelheim 
medical monitor 
first. 
• Hospitalization: 
48 h 
In the event of 
2 consecutive 
cases of CRS 
of grade 2, 
consider 
reducing dose 
to 200 μg/d for 
subjects 
originally 
receiving 400 
μg/d 
• Additional 
measures: 
additional 
assessments 
and 
premedication 
as indicated in 
CTP
• If there is no 
improvement 
to CRS ≤grade 
1 within 7 days 
• If interruption 
is >14 days 
• In case of 
repeat grade 2 
event despite 
dose reduction


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Table 4.1.4.1.4: 1 (cont’d)
Grading and management of cytokine release syndrome
3
Prolonged (e.g. 
not rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following 
initial 
improvement; 
hospitalization 
indicated for 
clinical 
sequelae (e.g. 
renal 
impairment, 
pulmonary 
infiltrates)
Immediately 
interrupt/ 
delay BI 
836909 until 
event has 
improved to 
CRS grade 
≤1. 
Admit to intensive care 
unit for close clinical and 
vital sign monitoring per 
institutional guidelines. 
Administer 
dexamethasone (or 
equivalent) IV at a dose 
maximum of 3 doses of 8 
mg (24 mg/d). The dose 
should then be reduced 
step-wise.
AND/OR 
Investigators should also 
consider use of 
tocilizumabc as an 
additional therapy in this 
setting at a dose of 4-8 
mg/kg as a single dose. 
As for CRS grade 
2 
• If there is no 
improvement 
to CRS ≤grade 
2 within 5 days 
and CRS 
≤grade 1 
within 7 days.
• In case of 2 
separate grade 
3 CRS events. 
• If interruption 
is >14 days 
4
Life-
threatening 
symptoms 
• Requirement 
for ventilator 
support OR 
• Grade 4 
organ toxicity 
(excluding 
transaminitis) 
per CTCAE 
criteria 
n/a
Admit to intensive care 
unit for close clinical and 
vital sign monitoring per 
institutional guidelines. 
Administer 
dexamethasone (or 
equivalent) IV at a dose 
maximum of 3 doses of 8 
mg (24 mg/day). Further 
corticosteroid use should 
be discussed with the 
Boehringer Ingelheim 
medical monitor. 
Additionally, tocilizumabc
should be administered at 
a dose of 4-8 mg/kg as a 
single dose and may be 
repeated once within 24 to 
48 h based on clinical 
assessment. 
n/a
Immediately 
stop the infusion 
(if applicable) 
and permanently 
discontinue BI 
836909 therapy.
CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous 
a CTCAE v4 grading used, therapy adapted using the revised grading system for cytokine release syndrome (R16-
2323)
b High dose vasopressors (all doses are required for ≥3 h): norepinephrine monotherapy ≥20 μg/min, dopamine 
monotherapy ≥10 μg/kg/min, phenylephrine monotherapy ≥200 μg/min, epinephrine monotherapy ≥10 μg/min; if 
on vasopressin, vasopressin + norepinephrine equivalent of ≥10 μg/min; if on combination vasopressors (not 
vasopressin), norepinephrine equivalent of ≥20 μg/min. 
c All sites will ensure that CRS rescue medications are available on-site, including corticosteroids and 2 doses of 
tocilizumab per study subject.


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4.1.4.2
Continuation of Treatment during a Course
Adverse events and laboratory values will be evaluated continuously by the investigator and the 
sponsor. Prior to start of each new cycle of BI 863909, adverse events and safety laboratory will 
be assessed. To continue treatment with a further infusion of BI 863909 all of the following 
criteria must be met:
(1)
Neutrophils ≥500 /μL (0.5 x 109/L) and platelets ≥25 000 /μL (25 x 109/L), with or 
without growth factor support or transfusions.
(2)
Acceptable tolerability (in case of an adverse event at the planned start of a treatment 
course, patients may continue therapy only after recovery to a level which would 
allow further therapy, i.e. CTCAE version 4.03 grade 1 or pre-treatment value.)
A log of all patients enrolled into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
4.1.4.3
Dose reductions and dose delays
Related SAEs/AEs of ≥ grade 2 or non-drug related SAEs/AEs of ≥ grade 2 deemed intolerable 
by the patient or the treating physician and not responding to appropriate medical management 
will result in a pause until resolution to baseline or grade 1. A pause of a maximum duration of 
14 days and a dose reduction to the next lower dose level is allowed if clinically indicated. Only 
one dose de-escalation step is allowed. 
DLT events in any cycle, cases meeting the pre-defined hepatic injury criteria (ref. 5.2.2.1) and 
infusion related reactions or cytokine release syndromes ≥ grade 3 will lead to permanent 
discontinuation in the dose escalation phases. After recovery to baseline or grade 1 continuation 
of the cycle at the next lower dose tier is allowed. Only one dose de-escalation step is allowed.
CNS events ≥ grade 2 irrespective of relatedness that have not resolved to baseline or grade 1 
within one week despite treatment interruption will lead to permanent discontinuation in the 
dose escalation phase. CNS events that have resolved to baseline or grade 1 within one week can 
be continued at the next lower dose level. Only one dose de-escalation step is allowed. 
In case of dose reductions all future courses will also be at the reduced dose level.
4.1.4.4
Permanent discontinuation of BI 836909
Patients treated at the initial dose cohort of 0.2µg/d who require a dose reduction will be 
permanently discontinued. 
A pause of treatment or delayed start of treatment of more than 2 weeks or several interruptions 
exceeding a total of 14 days of treatment per cycle due to SAEs/AEs will lead to permanent 
treatment discontinuation.


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4.1.4.5
Temporary treatment interruption of BI 863909
If a pause of treatment < 14 days occurs within a cycle then the cycle will be restarted at the 
same or the next lower dose (if clinically indicated) and continued until the pre-scheduled end of 
the cycle. This dose will be continued in subsequent cycles. 
If a pause of treatment occurs and less than 7 days of treatment would remain after restart of the 
cycle there is an option to skip the last treatment days and continue with the next course as 
scheduled. However, treatment should not be given for less than 14 days per cycle. 
Patients who permanently discontinue treatment for reasons other than DLT will be replaced. 
Only patients who will receive at least 14 days of treatment in the first course will be evaluable 
for the primary analysis unless they develop DLT.
For dose levels 2 and higher the trial safety committee may decide to start the subsequent cycles 
of the affected patient and potentially new patients at this and higher dose cohorts in a stepwise 
fashion: treatment will be started at 10-30% of the target dose for the first week (but not earlier 
than 4 days after the stop of infusion in retreated patients). On day 9 the dose may be escalated 
to the target dose.
The re-start of the infusion should be performed in the hospital under supervision of the 
investigator.
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 
patients with relapsed and/or refractory MM. This open-label 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 836909 will be supplied in lyophilized vials containing 75µg BI 836909 to be reconstituted 
with 1ml water for injection (WFI). Water for injection will not be provided. One pack of
medication contains 1 vial of lyophilized BI 836909 and 1 vial of 5 ml bag diluent. 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.
Re-supply will be managed by IWRS system. 


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4.1.7
Storage conditions
BI 836909 which will be provided by the sponsor must be kept in a secure, limited access 
storage area under the storage conditions defined by the sponsor and at the temperature indicated 
on the trial drug label. BI 836909 as well as the bag diluent must be stored in a refrigerator at 2 –
8oC and should not be frozen. Drug supplies will be kept in their original packaging. A 
temperature log must be maintained for documentation.  
If the storage conditions are found to be outside the specified range, immediately contact the 
local clinical monitor or the CRA as provided in the list of contacts. For more details on 
BI 836909, please refer to the IB (c02942358) and the ISF.
In-use stability of BI 836909 and Bag Diluent refers can be found in the "Instruction for 
Pharmacists". These will be provided within the ISF and pharmacy file. 
4.1.8
Drug accountability
The 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 the investigational site,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal investigator,

availability of a signed and dated clinical trial protocol 

Reference ranges for local laboratory values.
The Investigator/pharmacist/investigational storage drug manager will receive the investigational 
drugs delivered by the sponsor after the IRB/ethics committee approval of the trial and 
completion of a clinical trial contact between the Sponsor and the Head of Trial Center.  
The Investigator and/or pharmacist and/or investigational drug storage manager must maintain 
records of the product’s delivery to the trial site, the inventory at the site, the use by each patient, 
and the alternative disposition of unused products.
These records will include dates of receipt, quantities, batch/serial numbers, expiry (‘use by’) 
dates, and the unique code numbers assigned to the investigational products and trial patients. 
The investigator/pharmacists/investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator/pharmacists/investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
patient or homecare service to the trial site and that no remaining supplies are in the 
investigator’s possession.


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The Investigator/pharmacist/investigational storage drug manager will receive the investigational 
drugs delivered by the sponsor after the IRB/ethics committee approval of the trial and 
completion of a clinical trial contact between the Sponsor and the Head of Trial Center.  
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
4.2.1.1
Rescue medication
Rescue medication in term of an antidote to reverse the action of BI 836909 is not available. 
Potential side effects of BI 836909 have to be treated symptomatically. 
All concomitant or rescue treatment(s) taken during the course of the trial must be recorded in 
the source documents (e.g. patient files) and in eCRF. 
4.2.1.2
Supportive care
Patients should receive supportive care according to local guidelines regarding treatment of 
infusion-related reactions (Section 4.1.4.1.2), blood product support, antibiotics, antivirals, 
analgesics, etc. In the case of a tumour lysis syndrome, supportive therapy including rasburicase 
may be used as clinically indicated at the investigator's discretion. 
4.2.1.2.1 Treatment of Myeloma Bone Disease, Hypercalcemia, Pain and Renal Failure
Treatment of myeloma bone disease, hypercalcemia, pain and renal failure should be done 
according to institutional standards.
4.2.1.2.2 Growth factors
The use of growth factors such as Erythropoiesis-Stimulating Proteins as well as granulocyte 
colony stimulating factor (G-CSF) will be allowed during therapy. However, growth factors are 
not allowed at inclusion and should be avoided, if patient`s condition allows, in the first 
treatment course for better assessment of safety parameters. 
4.2.1.2.3 Infections
Prophylactic antibiotics, antifungal and antivirals are allowed and should be given according to 
institutional standards. Pneumocystis prophylaxis should also be given according to institutional 
standards. For patients who are considered to have an increased risk for herpes infections, the 
prophylaxis is mandatory unless medically contraindicated. Subjects who may experience 
neutropenia for 7 days or longer are at a high risk for infectious complications. As appropriate, 
these subjects will be administered prophylactic antibacterial, antifungal, and antiviral 
medications. These subjects will be monitored for early signs of breakthrough infections after 
the initiation of antibacterial therapy to prompt additional evaluation and possible therapy 
modification. 


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Patients who develop fever >38.3°C or a sustained temperature of >38°C ≥1 h will be 
hospitalised, undergo the following diagnostic work-up and started on empirical treatment with 
broad spectrum i.v. antibiotics according to institutional standards:
-
Blood cultures from central line and peripheral veins 
-
Urine culture 
-
CT-Thorax low dose 
-
Respiratory virus by pharyngeal wash (Parainfluenza 1-4, Influenza A + B, Adenovirus, 
Metapneumovirus, Echovirus, Rhinovirus, Bocavirus, Coronavirus, Entrovirus und RSV by 
multiplex PCR) 
Subjects with active systemic infections requiring IV antibiotics, antivirals, or antifungals should 
not be dosed with BI 836909 until infection has resolved and if being treated with an anti-
infectious therapy, the course of such therapy should have been completed. 
Patients requiring interruption of treatment for >14 days due to active infection will be
permanently discontinued.
4.2.1.3
Concomitant medication
All concomitant therapies to provide adequate care may be given as clinically necessary, unless 
given as anti-myeloma therapy. Bis-phosphonates can be given as clinically indicated. All 
concomitant treatments should be recorded in the eCRF except for vitamins or nutrient 
supplements. Trade names, indication and dates of administration of concomitant therapies will 
be documented. For parenteral nutrition during the trial, the components not need to be specified 
in detail. It should just be indicated as “parenteral nutrition”. If a patient needs general 
anaesthesia, it will be sufficient to indicate “general anaesthesia” without specifying the details.
Concomitant therapy should 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 EOT 
visit, only concomitant therapy indicated for treatment of an adverse event has to be reported or 
if given as anti-myeloma therapy. 
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Previous therapies for multiple myeloma must have been discontinued at least two weeks before 
the first administration of trial drug (see exclusion criteria Section 3.3.3 for details) and patient 
must have recovered from all clinically relevant toxicities. A time interval of at least four weeks 
must have elapsed from the last administration of any other investigational treatment for 
multiple myeloma to the first administration of BI 836909. 
No anti-neoplastic therapy concomitantly is allowed.
No other investigational therapy concomitantly is allowed.


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Additional glucocorticoid medications may be used as clinically indicated to treat infusion-
related reactions at any dose. Short term systemic glucocorticoid for lung disease (for example 
asthma or COPD) may be used. Daily oral steroid treatment may be administered at doses 
equivalent to prednisolone 10 mg per day. All other indications for steroids have to be discussed 
and agreed upon between investigator and sponsor. 
4.2.2.2
Restrictions on diet and life style
No restrictions apply with regards to diet or life style unless based on restrictions due to the 
portable pump used within the study. 
4.3
TREATMENT COMPLIANCE
BI 836909 will be administered as a continuous intravenous infusion (c.i.v.) via infusion pump 
over a period of 4 weeks. Infusion bags will have to be exchanged approximately every 4 days 
either at site or by a trained care provider. Persons involved in exchange of the bag will 
document compliance. Compliance may also be verified by pharmacokinetic assessments. Any 
discrepancies will be explained in the eCRF by the investigator or his/her deputy. 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY OR PHARMACODYNAMICS
5.1.1
Endpoint(s) of efficacy
The efficacy endpoints will be assessed at the time points specified in the flowcharts. Efficacy 
endpoints will be secondary or further endpoints in the trial and will be evaluated according to 
the response criteria of the International Myeloma Working Group (IMWG, 2006; Appendix 
10.1).
Secondary endpoints of efficacy are:

Objective response rate (percentage of patients with stringent complete response (sCR), 
complete response (CR), partial response (PR) and very good partial response (VGPR) )

Duration of response (DOR)

Minimal residual disease (MRD) response rate

Duration of MRD response. 

Progression-free survival (PFS)
5.1.2
Assessment of Efficacy
5.1.2.1
Laboratory parameters 
The following laboratory parameters must be evaluated to assess response of treatment:

Multiple myeloma (MM) cells in bone marrow
Analysis of myeloma cells in bone marrow will be conducted using a diagnostic FACS panel 
including markers for CD45, CD38, CD19, CD138, CD56 and kappa/lambda chains. 
Scheduled sampling time points will be as follows (see flow charts): within 14 days before
day 1 cycle 1or in cycle 1, day 1 before start of treatment, when M protein/FLC becomes 
undetectable during treatment, on day 29 of cycle 3 and at EOT. The analysis will be 
performed centrally.
Percentage (%) of plasma cells in bone marrow should be assessed locally according to 
institutional standards and documented in eCRF at each timepoint. 

M protein will be measured in serum at the beginning and at the end of each treatment 
period, i.e. at baseline (screening or Cycle 1 Day 1) and at Cycle 1 Day 29, Cycle 2 Day 
1 and Cycle 2 Day 29 and Cycle X Day 1, Cycle X Day 29 and at EOT. M protein 
measurements in urine will only be followed up if positive for M protein in serum at 


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baseline (Cycle 1 Day 1). Time points for urine analysis for M protein will be the same 
as for serum. Measurements will be performed locally.

Free Light Chains (FLC)
In case of free kappa/lambda light chain (FLC) multiple myeloma (M protein negative 
cases) FLC will be analysed in serum and urine at the same time points as for M protein
described above. Measurements will be performed locally. Levels of 
involved/uninvolved FLC, ratio of monoclonal lambda FLC / kappa FLC and ratio of 
monoclonal kappa FLC /lambda FLC will be determined. Measurements will be 
performed locally.

The analysis of immunoglobulins (IgG, IgA, IgM) will be performed at baseline, 
followed by intervals of two weeks and at EOT. Measurements will be performed 
locally.

ß2-microglobulin will be measured in serum as recommended for M protein described 
above. In urine, measurements will be done at baseline and every 6 weeks and at EOT. 
Measurements will be performed locally.

Total calcium levels will be investigated at baseline, before start of treatment and at the 
end of each treatment cycle, i.e.: Cycle X Day 1, Cycle X day 29 and EOT. 
Measurements will be performed locally.
5.1.2.2
Objective response rate
Objective response rate is defined as the percentage of patients achieving a sCR, CR, PR and 
VGPR and will be evaluated according to the response criteria of the International Myeloma 
Working Group (IMWG, 2006; Appendix 10.1).

Stringent complete response (sCR)
CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow 
by immunohistochemistry or immunofluorescence.

Complete response (CR)
Complete response is defined as negative immunofixation on the serum and urine and 
disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow.

Very good partial response (VGPR)
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 
90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h.

Partial response (PR)
Partial response is defined as a > 50% reduction of serum M-protein and reduction in 24 
hours urinary M-protein by >90% or to < 200 mg/24 h.


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If the serum and urine M-protein are unmeasurable a > 50% decrease in the difference between 
involved and uninvolved FLC levels is required in place of the M-protein criteria.
If serum and urine M-protein are not measurable, and serum free light assay is also not 
measureable, a > 50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was > 30%.
In addition to the above listed criteria, if present at baseline, a > 50% reduction in the size of soft 
tissue plasmacytomas is also required.
5.1.2.3
Duration of response (DOR)
The duration of response (DOR) is calculated from the time of first recorded achievement of a
response level, that is sCR, CR, PR and VGPR until documented progression or death.
5.1.2.4
Minimal Residual Disease (MRD) response
MRD Response is defined as < 1 tumour cell within 104 normal cells in bone marrow using 
FACS analysis.
MRD response rate is calculated by the percentage of patients achieving MRD response.
5.1.2.5
Duration of MRD response
Duration of MRD response is calculated from the time of first recorded achievement of a MRD 
response to progression or death.
5.1.2.6
Progression
Progression is defined as an increase of > 25% from lowest response value in any one or more of 
the following:

Serum M-component and/or (the absolute increase must be > 0.5 g/dL)

Urine M-component and/or (the absolute increase must be > 200 mg/24 h)
Only in patients without measurable serum and urine M-protein levels; the difference between 
involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL

Bone marrow plasma cell percentage; the absolute percentage must be > 10%

Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas

Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 
mmol/L) that can be attributed solely to the plasma cell proliferative disorder
5.1.2.7
Progression free survival (PFS)
PFS is defined as the time from first treatment with BI 836909 until disease progression or 
death.


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5.2
SAFETY
5.2.1
Endpoint(s) of safety
The primary objective is to assess the safety of the drug in humans and to determine the MTD of
BI 836909. 
Primary Endpoints are the following:

Maximum tolerated dose (MTD) of BI 836909
MTD is defined as the highest dose level tested where ≤1 patient out of 6 develop dose 
limiting toxicity. If MTD cannot be determined based on safety findings, a recommended 
dose for further development will be determined based on pharmacokinetic and 
pharmacodynamic data.
The MTD will be defined on the basis of DLT observed during cycle 1. However, for 
those patients who receive more than one cycle of BI 836909, all adverse events 
corresponding to the definition of DLT (Section 5.2.1.1) will be considered for the 
purpose of confirming the MTD and for the selection of the recommended dose for 
further development. In regular intervals, all available safety data including adverse 
events qualifying for DLT will be reviewed by the safety committee.

Number of patients with dose limiting toxicities
The safety of BI 836909 will be assessed by a descriptive analysis of incidence and intensity of 
adverse events graded according to CTCAE (version 4.03), the incidence dose limiting toxicity 
(DLT), laboratory data and results of physical examination.
Further endpoint of safety is

Immunogenicity of BI 836909 (frequency of patients developing anti-drug antibodies)
The safety data will be reviewed in regular intervals as well 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
Dose limiting toxicity (DLT) is defined as any drug-related non-haematological adverse event 
CTCAE version 4.03 grade 3 or higher. The following grade 3 events will not be considered 


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DLT: febrile neutropenia and infection responding to antibiotic/anti-infective treatment within 
48 hours, fatigue, headache, insomnia, fever, hypotension.
Laboratory parameters of grade ≥3 but not considered clinically relevant and/or responding to 
routine medical management, will not be considered dose limiting toxicities.
Additional events that are considered DLT include:

Persistent grade 4 neutropenia or thrombocytopenia until day 56 in the absence of 
detectable Multiple Myeloma as it may reflect a marrow toxic effect of BI 836909.
If infusion related reactions (IRR) or cytokine release syndromes (CRS) ≥ grade 2 occur or 
constitute DLT events the safety committee may decide to switch to step dosing for the 
respective and any higher dose cohort.  In that case the infusion will be started at 10(-30)% of 
the target dose on day 1 of the course and will be escalated to the full target dose from day 9 of 
course 1 on for the remainder of the course. Patients will be hospitalized and pre-medicated for 
the dose increase the same way they are for start of treatment. Once the safety committee 
decides to switch to step dosing patients that may have developed DLT due to IRR or CRS 
events may be replaced at the respective cohort by additional patients who will receive treatment 
with the adapted administration schedule (step dosing).
Although hematological adverse events (e.g. anemia, thrombocytopenia, neutropenia, 
lymphopenia) will not be considered DLT, complications resulting from hematological events, 
e.g. bleeding due to thrombocytopenia or grade 4 infection due to neutropenia are classified as 
non-hematological adverse events and are covered by the above definition of DLT. Nevertheless, 
hematological adverse events will be considered for definition of the dose for further 
development.
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding) symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.  
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalization or prolongation of existing hospitalization, 


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
results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect,
or

is to be deemed serious of any other reason it is an important medical event when based 
upon appropriate medical judgement which may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definitions.  
Life-threatening in this context refer to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if 
more severe.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has setup a list of AEs, which by their nature, can always be considered to 
be “serious” even though they may not have met the criteria of an SAE as given above.  
The latest list of “Always Serious AEs” can be found in the RDC system. These events should 
always be reported as SAEs as described in Section 5.2.3.
Adverse Events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being of 
particular concern for prospective safety monitoring and safety assessment within this trial, e.g. 
the potential for AEs based on knowledge from other compounds in the same class.  AESI need
to be reported to the Sponsor’s Pharmacovigilance Department within the same timeframe that 
applies to SAE, see Section 5.2.3.
The following are considered AESIs:

Infusion-related reactions and cytokine release syndromes (CTCAE version 4.03 grade 3 
or higher)

Tumour lysis syndrome

CNS adverse events grade 2 or higher

Any event that qualifies for DLT (refer to Section 5.2.1.1)

Hepatic Injury 
A hepatic injury is defined by the following alterations of hepatic laboratory parameters 
(Appendix 10.6): 

an elevation of AST and/or ALT ≥5 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN (if ratio of conjugated/total bilirubin is > 0.5) 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 via the RDC-
system. 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 theses 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.
Work-up as outlined in the “DILI-checklist” will serve to confirm the initial abnormality, obtain 
a comprehensive history and medical assessment, assess the severity of liver injury, evaluate 
data for potential alternative causes and decide on management of trial drug. When performing 
all of the required examinations, the investigator is encouraged to use clinical judgement, based 
on the patient’s disease, comorbidities, clinical situation, past viral infections and risk for 
reactivation, exposure, prior therapy for malignant disease, co-medications and other factors as 
applicable. The sequence of tests in the DILI checklist may be used as guidance. The findings 
from the hepatic imaging (including comparison to prior imaging if available) must be made 
available as soon as possible as part of the adverse event reporting process and/or on the 
respective CRF pages. In the event the aetiology of the abnormal liver test results is not 
identified based on the imaging (e.g. biliary tract, pancreatic or intrahepatic pathology), the 
“DILI checklist” must be completed. Virus reactivation should be assessed by viral load and 
PCR testing where possible. Diagnostics for auto-immune hepatitis, Wilson’s disease and 
haemochromatosis can be completed at the end of all assessments, as these examinations will not 
change within a short time period but can be considered proof of a long persisting chronic 
condition. In case a laboratory parameter of the DILI checklist cannot be performed, the 
investigator should provide a comment including a brief assessment of the relevance of this 
parameter for the overall evaluation of DILI.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 in the (e)CRF.
Causal relationship of adverse events
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history. 
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 


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No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
The causal relationship must be provided by the Investigator for all potential trial drugs, i.e. the 
BI trial drug and for all other trial drugs (such as any active comparator or placebo and for trial 
procedure).  
5.2.3
Adverse event collection and reporting
AE Collection 
The following must be collected and documented on the appropriate eCRF by the Investigator:

From signing the informed consent onwards through the Residual Effect period (REP) 
which is 30 day after EOT until the end of REP all AEs (serious and non-serious) and 
AESIs must be reported

After the end of REP until trial completion all related SAEs and related AESIs must be 
reported.
The REP is defined as 30 days after the last administration of study medication. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on treatment 
please. Events which occurred after the REP will be considered as post treatment events.  
After the last per protocol contact the Investigator does not need to actively monitor patients for 
AEs. However, if the Investigator becomes aware of SAEs or AESIs that occurred after the last 
per protocol contact, the SAEs and AESIs should be reported by the Investigator to the Sponsor 
if considered relevant by the investigator.
Patients may be hospitalized during selected phases of the study as required per protocol, e.g., 
monitoring of trial drug administration, collection of blood for pharmacokinetic purposes, or for 
administrative reasons. Hospitalizations for administrative reasons and other hospitalizations 
already planned at the screening visit need not be reported as a SAE in case they are performed 
"as planned".


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The investigator must report the following events via telephone/fax using the SAE form 
immediately (within 24 hours) to the sponsor: SAEs and non-serious AEs occurring at the same 
time as an SAE and/or which are medically related to the SAE(s), and Protocol-specified adverse 
event of special interest. With receipt of any further information to these events, a follow-up 
SAE report has to be provided. SAEs and non-serious AEs must include a causal relationship 
assessment made by the investigator.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File) or by using the 
electronic submission process. This immediate report is required irrespective of whether the 
investigational product has been administered or not and irrespective of causal relationship. It 
also applies if new information to existing SAEs or AESIs becomes available. 
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF).  In 
specific occasions the Investigator could inform the Sponsor upfront via telephone.  This does 
not replace the requirement to complete and fax the BI SAE form.
Information Required
For each AE, the investigator will provide information requested on the appropriate eCRF pages 
and the BI SAE form, e.g. onset, end date, intensity, treatment required, outcome, seriousness, 
and action taken with the investigational drug(s). The investigator should determine the causal 
relationship to the trial medication, the trial procedures outlined under Section 6.2.
The following should also be records as an SAE in the eCRF and SAE form (if applicable):

Worsening of pre-existing conditions unless due to underlying disease

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
Screening Failures
SAEs occurring in patients having discontinued the trial due to screening failures, i.e. after the 
screening period and who did not receive any trial medication, are to be reported if the 
Investigator considered the SAE related to the screening procedure.  SAEs which occurred 
during the screening period are to be reported according to standard procedures.  
Pregnancy


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In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (country-specific
contact details will be provided in the ISF). The Pregnancy Monitoring Form for Clinical Trials 
(Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring Form 
for Clinical Trials (Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, only 
the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be completed. If 
there is an SAE associated with the pregnancy then the SAE has to be reported on the SAE form 
in addition.
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
Exemption to SAE Reporting
Disease Progression in oncology trials is a study endpoint for analysis of efficacy. Disease 
progression (malignant neoplasm progression, neoplasm progression) is exempted from 
reporting as a (S)AE. Progression of the subject's underlying malignancy will be recorded in the 
appropriate pages of the (e)CRF as part of efficacy data collection. Death due to disease 
progression is to be recorded on the appropriate CRF page and not on a SAE form.
Examples of exempted events of PD are:

Progression of underlying malignancy (Progressive disease PD): if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by the 
respective response criteria. 

Hospitalization/Procedures due solely to the progression of underlying malignancy (PD)
Clinical symptoms and/or signs of progression (with or without confirmation by objective 
criteria e.g. imaging, clinical measurement): if the symptom can exclusively be determined to be 
due to the progression of the underlying malignancy and does meet the expected pattern of 
progression for the disease under study.
Please note, when there is evidence suggesting a causal relationship between the drug and the 
progression of the underlying disease, the event must be reported as (S)AE.
Exempted events are monitored at appropriate intervals by an independent committee such as the 
Safety Monitoring Committee. All SAEs, including those persisting after trial completion must 
be followed up until they have resolved, have been sufficiently characterized, or no further 
information can be obtained.  


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5.2.4
Assessment of safety laboratory parameters
5.2.4.1
General safety laboratory parameters
Blood samples and urine have to be collected at the time points specified in the flowchart. Safety 
laboratory examinations will include haematology, biochemistry, coagulation and qualitative 
urine analysis. The measurements will be performed locally.
Haematology
Haemoglobin, red blood cell count (RBC), white blood cell count 
(WBC) with differential, platelets (PLT)
Biochemistry
Glucose, sodium, potassium, total calcium, inorganic phosphate, 
creatinine, aspartate amino transferase (AST), alanine amino 
transferase (ALT), alkaline phosphatase (AP), lactate 
dehydrogenase (LDH), total bilirubin (if elevated provide direct 
bilirubin), urea, total protein, albumin, uric acid, Ferritin (at 
baseline of cycle 1 only).
Serum immunoglobulin levels (IgG, IgM, IgA) at baseline, day 15 
and day 29 of each cycle only
Coagulation
Activated partial thromboplastin time (aPTT), prothrombin time 
(PT)/international normalised ratio (INR), fibrinogen and D-
Dimers in cycle 1 and 2; thereafter on day 1 of each of the 
following cycles only.
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.
A serum pregnancy test needs to be obtained at the time points indicated in the flowchart in 
patients of childbearing potential. 
In case a treatment course is delayed due to an adverse event, the patient should visit the site at 
least once a week for assessment of safety laboratory and adverse events. More frequent visits 
may be appropriate as assessed by the investigator.
5.2.4.2
Screening for laboratory evidence of tumour lysis syndrome
Tumour lysis syndrome (TLS) is characterized by metabolic derangements caused by the 
massive and abrupt release of cellular components into the blood after rapid lysis of malignant 
cells. The release of the intracellular metabolites can overwhelm normal homeostatic 
mechanisms, potentially leading to hyperuricemia, hyperkalemia, hyperphosphatemia, 
hypocalcemia, and uremia. This can result in impaired renal function, and in some cases, in 
acute renal failure and even death (R10-4517). To allow for early treatment in case TLS 
develops, vigilant monitoring is recommended if clinically indicated. During the first 48 hours 
after the start of the first infusion/injection of BI 836909 in course 1, and during the first 24 


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hours after the start of the first infusion/injection in course 2, the below listed laboratory 
parameters need to be determined to screen for evidence of a tumour lysis syndrome monitored 
frequently, i.e. every 4-8 hours between the time points at which a complete safety laboratory 
has to be performed. The actual date and time of the blood samples should be recorded in the 
eCRF.
Haematology
haemoglobin, haematocrit, red blood cell count (RBC), white 
blood cell count (WBC),+ differential, platelets (PLT)
Biochemistry
uric acid, potassium, calcium, inorganic phosphate, lactate 
dehydrogenase (LDH), creatinine, urea, ferritin. 
Coagulation
Activated partial thromboplastin time (aPTT), prothrombin time 
(PT)/international normalised ratio (INR), fibrinogen, D-dimer.
5.2.4.3
Virology
5.2.4.3.1 Screening for hepatitis B, hepatitis C and human immunodeficiency virus
Patients with active hepatitis B (HBV), hepatitis C (HCV) or laboratory evidence of a chronic 
infection have to be excluded from the trial, i.e. antigen or antibody positive. The same applies 
to patients with a human immunodeficiency virus (HIV) infection.
The following laboratory parameters have to be determined at the screening visit and reported in 
the eCRF: hepatitis B surface antigen (HbsAg), hepatitis B surface antibody (anti-HBs), hepatitis 
B core antibody (anti-HBc), hepatitis C antibody (anti-HCV), HCV RNA.
Screening for HIV infection should be performed according to local standards. The result of the 
HIV assessment has to be reported in the eCRF.
5.2.5
Electrocardiogram
A 12-lead resting electrocardiogram (ECG) will be performed in all patients at the screening 
visit and at the beginning of each cycle (except for cycle 1) and at the EOT visit. The ECG will 
be assessed for pathological results (to be recorded as either baseline condition, concomitant 
disease or AE) by the investigator. Additional examinations should be done whenever the 
investigator deems necessary.
For safety monitoring 12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using 
an electrocardiograph.
All ECGs will be recorded for a 10 second duration after the subjects have rested for at least 5 
min in a supine position. 


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5.2.6
Assessment of other safety parameters
5.2.6.1
Vital signs
Vital signs (blood pressure, pulse rate and body temperature) will be recorded at every visit 
during screening, treatment and EOT. Additional time points for blood pressure, heart rate and 
body temperature at the day of start of administration of BI 836909 are: prior to the start of 
premedication and infusion, then every 30 (±10) minutes after start of the infusion of BI 836909 
for a total of 4 hours and thereafter 3 times a day during hospitalisation or in case of cytokine 
release syndrome and at each visit. In case of an infusion-related reaction, the investigator 
should decide whether to intensify or prolong monitoring of vital signs of the patient. 
Continuous cardiac monitoring should be performed during the hospitalisation for administration 
of BI 836909, patient surveillance may be modified by the investigator according to tolerability 
of the infusion during subsequent applications.
5.2.6.2
Physical examination
A physical examination including height (screening only), weight and ECOG performance score 
including an orienting neurological examination will be performed at screening and at the time 
points specified in the Flow Chart. The orienting neurological examination should be performed 
at screening as well as at EOT and daily during hospitalisation (see Flow charts). 
During the physical examination, the patient should be assessed for possible adverse events.
5.3
OTHER
5.3.2
Other assessment(s)
5.3.2.1
Demographics and history
Demographics (sex, birth date, race), and baseline conditions will be collected during the 
screening visit. A detailed cancer history will be obtained. The date of first diagnosis of MM
(month and year may be sufficient) will be recorded in the eCRF. The stage at diagnosis
according to the response criteria of the International Myeloma Working Group (IMWG, 2006)
at screening should be recorded (see Appendix 10.1). Previously administered chemo- and 
immunotherapy will be documented, including start and end dates (year and month may be 
sufficient), the treatment regimen/protocol with the number of courses (chemo-, 
immunotherapy), the best response obtained and the date of progression after each prior therapy 
(year and month may be sufficient). If the patient has received chemotherapy with autologous 
stem cell support, procedural details, including the treatment regimen prior to stem cell support 
should be collected. Documentation of previous radiotherapy should include the total radiation 
dose and radiation field(s). Any myeloma-related previous surgeries which may affect tumour 


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assessment in this trial according to the investigator within the past five years should be 
documented in the eCRF.
5.3.2.2
Concomitant diagnoses
Concomitant diagnoses present at study entry and/or during screening and relevant to the 
patient’s safety during the trial as judged by the investigator will be recorded in the eCRF.
5.4
APPROPRIATENESS OF MEASUREMENTS
Determination of MTD is based on toxicities graded according to CTCAE 4.03 (R10-4848). The 
CTCAE criteria are commonly used in the assessment of adverse events in cancer patients. The 
criteria to be used for evaluation of response (Appendix 10.1) are well established and 
scientifically accepted. 


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5.5
DRUG CONCENTRATION MEASUREMENTS AND PHARMACOKINETICS
Blood samples during and at the end of infusion must be taken from the arm opposite to the 
infusion arm. For patients having a central venous access, PK samples obtained from either 
forearm. In order not to confound ECG recording, PK samples should be taken after performing 
the ECG.
If the infusion duration deviates from the scheduled time, the exact start and end times should be 
recorded in the eCRF. If the infusion stops in between, the stop time and the time when it is 
started again need to be documented in the eCRF. If the duration of infusion is prolonged or 
shortened, all following time points of PK and biomarker sampling should be adapted to the time 
when the i.v. infusion or s.c. injections has ended. Any changes in the rate of infusion should be 
documented in the eCRF.
Blood for pharmacokinetic analysis will be collected at specified time points during the 
corresponding treatment cycles (see corresponding Flow Charts; Appendix 10. 2) to determine 
the concentration of BI 836909. The blood samples for PK analysis will be processed to serum 
the same way as the ADA samples. The actual sampling date and time for blood samples should 
be documented in the eCRF. These actual sampling times will be used for determination of 
pharmacokinetic parameters. The exact clock time of trial medication administration and blood 
sampling as well as timing of any changes to the infusion flow rate will be documented in the 
eCRF. 
Generally, PK serum samples for BI 836909 determination will be labelled with the study 
number, subject number, cycle number, visit number, protocol (planned) time and the sample
number (according to Flow Charts; Appendix 10.2).
Detailed handling instructions for serum samples are provided in the ISF as well as the lab-
manual.
5.5.1
Pharmacokinetic endpoint(s)
If data allow, the following pharmacokinetic parameters will be evaluated using non-
compartmental analysis methods according to the internal BI Standard Operating Procedure
(SOP).
Secondary pharmacokinetic endpoint is: 

Serum concentration at steady state (Css) for c.i.v. 


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5.5.2
Methods of sample collection and storage
5.5.2.1
Blood sampling for pharmacokinetic analysis
2,5 mL blood will be taken from a forearm vein or a central venous access in a vacutainer tube 
containing SSTII separation gel. The vacutainer should be carefully inverted 5 times after 
sample collection (an inversion is one complete turn of the wrist, 180 degrees and back). Tubes 
should stand upright for minimum 30 minutes but for a maximum of 2 hours at ambient 
temperature. The tube should be centrifuged for 10 min at 3,500-4,500 rpm. The specimen has 
been sufficiently centrifuged when the solid blood components and the liquid are approximately 
equally separated. The serum must be transferred with a pipette into a cryovial with colored cap 
(blue cap for PK) and immediately frozen at -20°C until shipment.
After the analysis has been performed the samples will be stored for 5 years and then destroyed. 
5.5.2.2 Analytical determinations of samples
A detailed description of the validated assay will be available prior to the start of sample 
analysis.
The remainder samples may be used for immunogenicity assessment if needed.


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5.6.1.4 Immunophenotyping
Diagnostic multiple myeloma flow cytometry including MRD
Analysis of myeloma cells in bone marrow will be conducted using a diagnostic flow cytometry 
panel including markers for CD45, CD38, CD19, CD138, CD56 and kappa/lambda chains. The 
analysis will be performed centrally. In order to assess minimal residual disease the flow 
cytometric panel may include 6-color-analysis such as cytIgλ /cytIg/CD19/CD56/CD38/CD45 
and cytIgλ/CD19/cytIg/CD138/CD38/CD45 (R14-4637). Modifications according to updated 
guidance are possible. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients must comply with all inclusion and exclusion criteria prior to the patient enters the study 
(see Section 3.3).
All patients should adhere to the visit schedule as specified in the Flow chart. However, in case a 
patient misses a visit and the patient reports to the investigator between the missed and the next 
scheduled visit, the procedures that were planned at the missed visit should be done and the 
actual date and the reason for the delay should be documented in the eCRF. Subsequent visits 
should follow the original visit schedule of the ongoing cycle unless a treatment pause > one 
week occurred. Then the next scheduled cycle should be started. 
Some flexibility is allowed in scheduling the visits according to the time window specified in the 
Flow chart (± 3 days).
If pathological laboratory values or other issues require an additional unscheduled visit, a new 
eCRF page will be created for the unscheduled visit. At the unscheduled visit, it is sufficient to 
record only the clinical relevant labs/examinations performed.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Hospitalisation
Patients will be hospitalised for 3 – 4 days during cycle 1 as well as in the cycle when dose is 
escalated within one patient (single patient cohorts). In case that a step dosing approach is 
applied patient will also be hospitalised when dose is escalated to the normal dose (see Section 
5.2.1). Patients will be hospitalised at start of cycle 2 for 24 hours and in all subsequent cycles 
for 8 hours in an outpatient setting. 
6.2.2
Disease and Response Assessments for Multiple Myeloma
Clinical disease status for multiple myeloma will be assessed at screening, at the start of each 
cycle as well as at EOT. 
At screening and subsequently the evaluation of multiple myeloma will be done according to 
IMWG (2006).
If a patient has clinical symptoms of multiple myeloma at screening, they should be recorded as 
baseline conditions.
Biomarkers in blood and urine will be done according to specific Flow chart for biomarkers.
Total body MRI should be performed within 14 days before day 1, cycle 1; results from routine 
assessments (MRI) for multiple myeloma are accepted if performed no later than 28 days before 
start of treatment.


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Total body MRI should be performed at or within 14 days before day 1, cycle 3; day 1, cycle 5;
day 1, cycle 7 as well as every other cycle thereafter and at time of EOT.
Bone marrow aspirates will be done within 14 days before day 1 cycle 1 or at cycle 1, day 1 
before start of treatment, when M protein/FLC becomes undetectable during treatment, at day 29 
of cycle 3 and at EOT. 
For karyotyping the recent analysis will be accepted if performed within 3 months prior to start 
of study medication in case that no therapy has been given between assessment of karyotyping 
and study medication; otherwise, a baseline karyotype should be performed at screening; 
subsequent karyotyping could be performed in subsequent marrow samples.
The biomarker assessments will be performed as specified in the Flow charts. A bone marrow 
biopsy should be performed if aspirate could not be obtained (punctio sicca).
One sample of bone marrow will be provided for DNA banking in case that the patient has given 
consent for pharmacogenetic testing (baseline bone marrow, a bone marrow sample on treatment 
when a complete response is reached). 
6.2.3
Screening and run-in period(s)
The examinations required for the screening visit may be conducted within a time interval of 21
days prior to the first study drug administration.
If for administrative or medical reasons, the patient is not entered within the defined screening 
period, it is allowed to re screen a patient. There is no maximum time period defined for re-
screening.
If the patient has been determined eligible by the investigator to enter the trial (refer to Section 
3.3), the investigator will assign one or more medication number(s) to the patient through the 
IWRS system at Visit 1 (Section 4.1.2). First dose of BI 836909 will be administered at the 
beginning of Visit 1 at the trial site (Day 1, cycle 1).


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Table 6.2.3: 1
Screening Visit (Day -21 to -1)
Informed consent
Obtain written informed consent prior to enrolment in the trial
and before any study-specific screening assessments are
performed.
Separate consent is required for none pre-specified 
pharmacogenetics and biomarker testing in bone marrow and 
blood. 
Demographic data
Demographics and patient characteristics including detailed 
documentation of co-morbidities/concomitant diagnoses. 
Gender, date of birth/year of birth, race if allowed by local
law will also be recorded.
Medical History
Oncological and relevant non-oncological baseline conditions
will be recorded.
Physical examination
(Section 5.2.6.2)
A general physical examination including blood pressure, heart 
rateand temperature as well as an orientated neurological 
examination will be performed, preferably by the same
investigator throughout the study to enable comparability.
ECOG performance score
(Section 5.2.6.2)
ECOG performance score will be assessed and documented.
Weight and Height
(Section 5.2.6.2)
Height is measured at screening only.
Weight is measured: preferably, the same weight scale should
be used throughout the study to ensure consistency of data
collected.
12-lead ECG (Section
5.2.5)
Resting 12-lead ECG (digital) is performed and analysed 
locally. 
Safety laboratory as well as 
screening for HCV, HBV 
and HIV
(Section 5.2.4)
Haematology (including differential), biochemistry, 
coagulation parameters and urinalysis (dipstick), as well as 
screening for HCV, HBV and HIV


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Table 6.2.3: 1 (cont’d)
Screening Visit (Day -21 to -1)
Bone marrow aspirate for 
disease assessment and 
DNA banking of bone 
marrow
(Section 5.6.1)
Karyotyping: recent analysis will be accepted if performed 
within 3 months prior to start of study medication in case that 
no therapy has been given between assessment of 
karyotyping and study medication; otherwise, a baseline 
karyotype should be performed at screening; subsequent 
karyotyping could be performed in subsequent marrow 
samples.
The following assessments will be performed (see Flow 
charts): 

MM cells in bone marrow; percentage (%) of plasma 
cells in bone marrow should be assessed locally 
according to institutional standards and documented 
in eCRF.

BCMA expression by myeloma cells in bone marrow
Obtain bone marrow biopsy if aspirate could not be obtained
(punctio sicca).
One sample of bone marrow will be provided for DNA 
banking.
Disease assessment:
Clinical/MRI and
blood/urine
(Section 5.6.1)
Evaluation of multiple myeloma according to IMWG (2006)
Clinical: if patient has clinical symptoms of Multiple
Myeloma, they should be recorded as baseline conditions.
Total body MRI should be performed; results from routine 
assessments (MRI) for multiple myeloma are accepted if 
performed no later than 28 days before start of treatment.
Adverse events
(Section 5.2.2)
Occurrence of AEs since signing the Informed Consent Form 
will be documented. For patients who become screen 
failures, if an AE occurs during this period, the patient should 
be followed until the PI determines the patient is a screen 
failure.


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Table 6.2.3: 1 (cont’d) 
Screening Visit (Day -21 to -1)
Concomitant therapies
(Section 4.2)
All concomitant therapies (including transfusions and anti-
infectives) at trial entry and/or during screening will be 
recorded in the eCRF.
Review of inclusion/
exclusion criteria
(Section 3.3.2 & 3.3.3)
Patient eligibility for the trial according to in- and
exclusion criteria. In case of ineligibility, documentation of 
the reason(s) in patients source data why the patient is not 
eligible for the trial.
Serum pregnancy test 
(Section 5.2.4.1)
Serum pregnancy test in women of childbearing potential


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6.2.4
Treatment period(s)
The first study drug dose should occur at the latest at Day 21 after the first screening procedure 
has been performed. A treatment cycle is defined as 6 weeks of duration. If initiation of a 
subsequent cycle is delayed due to medical reasons, additional visits beyond Day 36 may be 
necessary and may be performed at investigator’s discretion, and should be recorded in the 
eCRF.
Patients may continue treatment in case of clinical benefit for 5 cycles. In case of ongoing 
clinical benefit up to a maximum of 5 additional treatment cycles can be given if considered 
indicated by the treating investigator.
6.2.4.1 Cycle 1
Patients will be hospitalized for the first 3 – 4 days.
Table 6.2.4.1: 1
Visit 1 (Day 1-3 or 4)
Physical examination
(Section 5.2.6.2)
A general physical examination will be performed, preferably by 
the same investigator through the study to enable comparability.
This includes blood pressure, heart rate and temperature.
Additional time points for blood pressure, heart rate and body 
temperature at the day of start of administration of BI 836909 are: 
prior to the start of premedication and infusion, then every 30 
(±10) minutes after start of the infusion of BI 836909 for the first 
4 hours and additionally 3 times during hospitalisation (in the 
evening of day 1 as well as in the morning of day 2 and 3).
Orienting neurological examination daily during hospitalisation. 
Weight
(Section 5.2.6.2)
Weight is measured; preferably, the same weight scale should be
used throughout the study to ensure consistency of data collected.
PK samples
(Section 5.5 and 5.2.5)
For PK sampling, see separate Flow chart as well as section 5.5
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation parameters and urinalysis 
(dipstick).
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant therapies
(Section 4.2)
Any new or any change in concomitant therapies since the last
visit, will be recorded in the eCRF.


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Table 6.2.4.1: 1 (cont’d)
Visit 1 (Day 1-3 or 4)
Disease assessment:
clinical and blood and 
urine markers
(Section 5.6.1)
Clinical: if patient has any new clinical symptoms of
multiple myeloma, these should be recorded in the “disease
assessment” page and as an AE when applicable (see
Section 5.2.2.1).
Administration of 
BI 836909
(Section 4.1)
4 weeks continuous intravenous infusion via infusion pump.
Infusion bags must be exchanged approximately every 4 days.
Call IWRS/
Administer BI 836909
The IWRS system needs to be accessed (see Section 4.1.4) before 
any BI 836909 is administered to the patient. Dispense medication 
for the first course of treatment (see Section 4.1.4), as directed by 
the IWRS system.


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Table 6.2.4.1: 2
Visit 2 – Visit 4 (Day 8 to day 22)
Home care service will be provided for bag exchange. 
Assessments to be performed at start of each cycle: 
Body temperature, Blood 
pressure, heart rate
(Section 5.2.6.2)
Serum pregnancy test 
(Section 5.2.3)
This examination includes blood pressure, heart rate and 
temperature.
Serum pregnancy test in women of childbearing potential
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation parameters and 
urinalysis (dipstick).
Immunoglobulins will be measured at visit 3 (day 15)
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant therapies
(Section 4.2)
Any new or any change in concomitant therapies since the last
visit, will be recorded in the eCRF.
Administration of 
BI 836909
(Section 4.1)
4 weeks continuous intravenous infusion via infusion pump. 
Infusion bags must be exchanged approximately every 4 days
Call IWRS/
Administer BI 836909
The IWRS system needs to be accessed (see Section 4.1.4.2) 
before any BI 836909 is administered to the patient. Dispense 
medication for the first course of treatment (see Section 
4.1.4), as directed by the IRT system.


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Table 6.2.4.1: 3
Visit 5 (Day 29 and day 30)
Physical examination
and
 
(Section 5.2.6.2)
A general physical examination will be performed, preferably 
by the same investigator through the study to enable 
comparability. This includes blood pressure, heart rate and 
temperature.
PK samples
(Section 5.5 and 5.2.5)
For PK sampling, see separate Flow chart and Section 5.6.

10 minutes before the end of continuous infusion

24 hours after stop of treatment (day 30)
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation parameters and 
urinalysis (dipstick).
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant therapies
(Section 4.2)
Any new or any change in concomitant therapies since the last
visit, will be recorded in the eCRF.
Body temperature, Blood 
pressure, heart rate
(Section 5.2.6.2)
This examination includes blood pressure, heart rate and 
temperature.
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation parameters and 
urinalysis (dipstick).
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant therapies
(Section 4.2)
Any new or any change in concomitant therapies since the last 
visit, will be recorded in the eCRF.


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6.2.4.2
Cycle 2 – 5 (or further cycles in case more than 5 cycles are administered)
Table 6.2.4.2: 1
Cycle 2 – 5 (or further cycles): Visit 1 (day 1)
Patient will be hospitalised for at least 24 hours.
Physical examination
(Section 5.2.6.2)
A general physical examination will be performed, preferably
by the same investigator through the study to enable
comparability. This includes blood pressure, heart rate and 
temperature. Orienting neurological examination daily during 
hospitalisation. 
Weight
(Section 5.2.6.2)
Weight is measured; preferably, the same weight scale should
be used throughout the study to ensure consistency of data
collected.
ECG/PK samples
(Section 5.5 and 5.2.5)
For PK sampling, see separate Flow chart and Section 5.5. A 
12-lead ECG will be done at the start of each cycle. 
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation parameters and 
urinalysis (dipstick).
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant therapies
(Section 4.2)
Any new or any change in concomitant therapies since the last
visit, will be recorded in the eCRF.


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Table 6.2.4.2: 1 (cont`d)
Cycle 2 – 5 (or further cycles): Visit 1 (day 1)
Disease assessment:
Clinical, MRI and blood 
and urine markers
(Section 5.6.1)
Clinical: if patient has any new clinical symptoms of
multiple myeloma, these should be recorded in the “disease
assessment” page and as an AE when applicable (see
Section 5.2.2.1).
MRI should be performed every other cycle:
at or within 14 days before cycle 3, 
day 1, cycle 5, day1, cycle 7, day 1… 
and/or at time of progression or start of further anticancer 
therapy;
Administration of 
BI 836909
(Section 4.1)
4 weeks continuous intravenous infusion via infusion pump.
Infusion bags must be exchanged approximately every 4 days 
Call IWRS/
Administer BI 836909
The IWRS system needs to be accessed (see
Section 4.1.4.2) before any BI 836909 is administered to the 
patient. Dispense medication for the first course of treatment 
(see Section 4.1.4), as directed by the IRT system.


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Table 6.2.4.2: 2
Cycle 2 – 5 (or further cycles): Visit 2 - 4
Physical examination
(Section 5.2.6.2)
A general physical examination will be performed, preferably
by the same investigator through the study to enable
comparability. This includes blood pressure, heart rate and 
temperature.
Weight
(Section 5.2.6.2)
Weight is measured; preferably, the same weight scale should
be used throughout the study to ensure consistency of data
collected.
ECG/PK samples
(Section 5.5 and 5.2.5)
For PK sampling, see separate Flow chart and Section 5.5. A 
12-lead ECG will be done at the start of each cycle.
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation parameters and 
urinalysis (dipstick).
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant therapies
(Section 4.2)
Any new or any change in concomitant therapies since the last
visit, will be recorded in the eCRF.
Disease assessment:
clinical and blood and 
urine markers
(Section 5.6.1)
Clinical: if patient has any new clinical symptoms of
multiple myeloma, these should be recorded in the “disease
assessment” page and as an AE when applicable (see
Section 5.2.2.1).


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Table 6.2.4.2: 2 (cont`d)
Cycle 2 – 5 (or further cycles): Visit 2 - 4
Administration of 
BI 836909
(Section 4.1)
4 weeks continuous intravenous infusion via infusion pump.
Infusion bags must be exchanged approximately every 4 days.
Call IWRS/
Administer BI 836909
The IWRS system needs to be accessed (see
Section 4.1.4.2) before any BI 836909 is administered to the 
patient. Dispense medication for the first course of treatment 
(see Section 4.1.4), as directed by the IWRS system.
Bone Marrow
Bone marrow aspirate will be done on day 29 of cycle 3:
The following assessments will be performed:

MM cells in bone marrow; percentage (%) of plasma cells 
in bone marrow should be assessed locally according to 
institutional standards and documented in eCRF.

BCMA expression by myeloma cells in bone marrow

MRD (in case M protein/FLC becomes undetectable)
Obtain bone marrow biopsy if aspirate could not be obtained 
(punctio sicca).
One sample of bone marrow will be provided for DNA 
banking.


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Table 6.2.4.2: 3
Cycle 2 – 5 (or further cycles): Visit 6 (Day 36)
For all cycles except for last cycle
Body temperature, Blood 
pressure, heart rate
(Section 5.2.6.2)
This examination includes blood pressure, heart rate and 
temperature.
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation parameters and 
urinalysis (dipstick).
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant therapies
(Section 4.2)
Any new or any change in concomitant therapies since the last 
visit, will be recorded in the eCRF.
6.2.5
Follow-Up Period
6.2.5.1 End of treatment visit (EOT)
The EOT visit will be performed after permanent discontinuation of trial medication for any 
reason as soon as possible but no later 1 week after permanent discontinuation of the trial 
medication or when the investigator decided with the patient to permanently discontinue the trial 
medication or became aware that the trial medication had been terminated.


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Table 6.2.5.1: 1
Visit at the End of Treatment (EOT)
ECG
(Section 5.2.5)
Resting 12-lead ECG (digital)
Physical examination
(Section 5.2.6.2)
A general physical examination as well as an orientated 
neurological examination will be performed, preferably by the
same investigator throughout the study to enable
comparability. This includes blood pressure, heart rate and 
temperature
Weight
(Section 5.2.6.2)
Weight is measured; preferably, the same weight scale should
be used throughout the study to ensure consistency of data
collected.
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation parameters, and 
urinalysis (dipstick).
Disease assessment:
clinical and blood/MRI
(Section 5.5.1)
Clinical: if patient has any new clinical symptoms of
multiple myeloma, these should be recorded in the “disease
assessment” page and as an AE when applicable (see Section 
5.2.2.1).
Total body MRA should be performed.
Bone Marrow aspirate
(Section 5.6.1)
The following assessments will be performed:

MM cells in bone marrow; percentage (%) of plasma cells
      in bone marrow should be assessed locally according to
      institutional standards and documented in eCRF.

BCMA expression by myeloma cells in bone marrow

MRD (in case M protein/FLC becomes undetectable)
Obtain bone marrow biopsy if aspirate could not be obtained 
(punctio sicca).
One sample of bone marrow will be provided for DNA 
banking.


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Table 6.2.5.1: 1 (cont`d)
Visit at the End of Treatment (EOT)
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant therapies
(Section 4.2)
Any new or any change in concomitant therapies since the last
visit, will be recorded in the eCRF.
IWRS
Contact IWRS to register EOT.
Termination of Trial
Medication
Including reason for conclusion, date of last administration of 
the trial drug.
6.2.5.2
Residual effect period (REP)
The REP is defined in Section 5.2.3. 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 AEs that occurred after EOT and a follow-up of 
adverse events ongoing at EOT. Any subsequent anti-cancer therapy administered between EOT 
and REP visit must be documented to allow an assessment of newly reported AEs as well as 
patient`s status. 
Table 6.2.5.3: 1
Residual effect period (REP)
Adverse events
(Section 5.2.2)
All AEs, SAEs, AESIs regardless of related ness. This 
includes all deaths.
Patient status
Collect information for progression or relapse, death, lost to 
follow-up.
Other therapy for 
Multiple Myeloma
In case the patient receives other therapy for Multiple 
Myeloma
6.2.5.3
Extended follow up
In case of ongoing clinical benefit, patients can be followed up to collect data for duration of 
response. Follow-up visits for responders will be at 3, 6 and 12 months after EOT if a patient did 
not progress, started a new anti-cancer treatment, died, or withdrew informed consent and will 
assess related SAEs and AESIs.


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE
7.1
STATISTICAL DESIGN – MODEL
The dose escalation procedure is described in Section 3.1.1. Cohorts of patients will be entered 
sequentially into escalating dosage tiers with the aim to identify the maximum tolerated dose of 
BI 836909.
This study is open-label, which allows the safety of each dosage of BI 836909 to be assessed 
before treating additional patients with higher doses. Patients will not be randomized; they will 
be assigned to the cohort that is being filled at the time the patient is ready to enter the trial.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory by nature. No formal statistical tests 
will be performed.
7.3
PLANNED ANALYSES
Only one analysis population (the treated set, see definition below) will be considered for 
efficacy and safety analyses. No Per protocol population will be used for analyses. However 
important protocol violations will be described.
Treated Set consists of all patients who received at least one application of BI 836909.
7.3.1
Primary endpoint analyses
In order to identify the MTD, the number of patients with DLTs during the first course at each 
dose level will be displayed descriptively by dose level. 
In addition, the number of patients with all DLTs during any treatment course will be analysed. 
Analysis of other adverse events and laboratory parameters is described in Section 7.3.4.
7.3.2
Secondary endpoint analyses
Objective response rate (patients with sCR, CR, VGPR, or PR), and MRD response rate will be 
analysed descriptively. Progression free survival (PFS), duration of response (DOR) and 
duration of MRD response will be analysed using the Kaplan-Meier method. Details of 
censoring rules will be provided in the statistical analysis plan.
Refer to Section 7.3.5 for the planned analyses of secondary pharmacokinetic endpoints.


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary. Standard BI summary tables and listings will be produced. 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
(“REP”; see definition in Section 5.2.3) will be considered ‘treatment-emergent’. Adverse events 
that start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
Key measures of safety will include:

The incidence and intensity (according to CTCAE criteria version 4.03) of adverse events;

Time course and distribution of patients by maximum CTCAE grade according to version 
4.03;

Time course of laboratory changes
The severity and timing of adverse events will indicate the tolerability of the treatment regimen. 
Adverse events will be evaluated using the CTCAE grading scheme version 4.03. The overall 
incidence and intensity of adverse events, as well as relatedness of adverse events to treatment 
with BI 836909 will be reported for all dose cohorts. Serious adverse events will be tabulated. In 
addition, events leading to dose reduction or treatment discontinuation will be examined, but 
may not be reported as individual tables, depending upon the extent of overlap with the 
occurrence of DLT.
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. 
7.3.5
Pharmacokinetic analyses
The secondary pharmacokinetic endpoint Css
will be descriptively explored, and if possible, dose proportionality will also 
be explored descriptively. Attainment of steady state will be determined by visual examination 
of the data.
Refer to Section 5.5.1 for pharmacokinetic parameters to be calculated. The derivation of the 
parameters will be according to sponsor’s standard operating procedures. 
All evaluable patients will be included in the pharmacokinetic analysis. Patients who are 
considered as not evaluable will be listed with their individual plasma concentrations and 
individual pharmacokinetic parameters, however, will not be included in descriptive statistics for 
plasma concentrations, pharmacokinetic parameters or other statistical assessment. A patient is 
considered not evaluable if the subject has an important protocol violation relevant to the 
evaluation of pharmacokinetics or has insufficient data. 


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Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report. Only concentrations within the validated concentration range will be used 
for the calculation of pharmacokinetic parameters. Plasma concentrations will be plotted 
graphically versus time for all subjects as listed in the drug plasma concentration-time tables. 
For the presentation of the mean profiles, the geometric and arithmetic mean and the planned 
blood sampling times will be used. If the actual sampling time deviates significantly from the 
planned time, the corresponding plasma concentration will be excluded from the calculation of 
descriptive statistics.
Pharmacokinetic analyses of the plasma concentration-time data will be performed using a 
validated software program (e.g., Phoenix Winnonlin) and for this purpose the actual sampling 
time for pre-dose samples will be set to zero.
Pharmacokinetic parameters will be compared in a descriptive manner. The following 
descriptive statistics will be calculated for analyte concentrations as well as for all 
pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, median, 
maximum, arithmetic coefficient of variation, geometric mean, and geometric coefficient of 
variation. The data format for descriptive statistics of concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of pharmacokinetic 
parameters will be calculated using the individual values with the number of decimal places as 
provided by the evaluation program. Then the individual values as well as the descriptive 
statistics will be reported with three significant digits in the clinical trial report.


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7.5
HANDLING OF MISSING DATA
No imputation will be performed on missing efficacy data. Missing baseline laboratory values 
will be imputed by the respective values from the screening visit. No other imputations will be 
performed on missing data although every effort will be made to obtain complete information on 
all adverse events, with particular emphasis on potential dose limiting toxicities.
7.5.1
Safety
With respect to safety evaluations, it is not planned to impute missing values although every 
effort will be made to obtain complete information on all adverse events, with particular 
emphasis on potential dose limiting toxicities.
7.5.2
Plasma concentration – time profiles
Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not 
analysed), BLQ (below the limit of quantification), and NOP (no peak detectable) will be 
ignored and not replaced by zero at any time point (applies also to the lag phase including the 
pre-dose value). Descriptive statistics of concentrations at specific time points will be calculated 
only when at least 2/3 of the individuals have concentrations within the validated concentration 
range. The overall sample size to decide whether the “2/3 rule” is fulfilled will be based on the 
total number of samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS, NOA, 
NOP are included).
7.5.3
Pharmacokinetic assessment
In the noncompartmental analysis, concentration data identified with NOS, NOR, and NOA will 
not be considered. BLQ and NOP values in the lag phase will be set to zero. The lag phase is 
defined as the period between time zero and the first time point with a concentration above the 
quantification limit. All other BLQ/NOP values of the profile will be ignored. If the predose 
concentration is less than or equal to 5% of Css value in that subject, the subject’s data without 
any adjustments can be included in all pharmacokinetic measurements and calculations (i.e. the 
predose value will not be changed to zero). If the predose value is greater than 5% of Css, the 
subject should be dropped from all statistical evaluations. The individual pharmacokinetic 
parameters can be calculated and listed separately.
Every effort will be made to include all concentration data in an analysis. If not possible, a case 
to case decision is required whether the value should only be excluded from half-life estimation 
or the complete analysis. If a concentration is only excluded from half-life determination, it will 
be used for all other calculations (e.g. descriptive statistics) and for graphical presentation. If a 
concentration value is excluded from all calculations, it will not be presented graphically or used 
for the calculation of descriptive statistics and parameter determination. However the excluded 
concentration itself will be listed in the clinical trial report associated with an appropriate flag. If 
the actual sampling time will not be recorded or will be missing for a certain time point, the 
planned time will generally be used for this time point instead. Pharmacokinetic parameters 
which cannot be determined will be identified by "not calculated" (NC). 


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7.6
RANDOMISATION
No randomisation will be performed. Patients will be assigned into escalating dose groups by 
order of admission into the trial.
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of up to 50 subjects in this trial. The planned sample size is not 
based on a power calculation. 


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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 investigator of the patient.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the investigator 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.
The certificate of insurance cover is made available to the investigator and the patients, and is 
stored in the ISF (Investigator Site File). 
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be personally 
dated by each signatory and the informed consent and any additional patient-information form 
retained by the investigator as part of the trial records. A signed copy of the informed consent 
and any additional patient information must be given to each patient or the patient’s legally 
accepted representative.
The Investigator must give a full explanation to trial patients including the items listed below in 
association with the use of the patient information form, which is prepared avoiding the use of 
technical terms and expressions. The patient is given sufficient time to consider participation in 
the trial. The Investigator obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
Investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or places a 
seal on) and dates the informed consent.


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The patient must be informed that his/her personal trial-related data will be used by Boehringer 
Ingelheim in accordance with the local data protection law. The level of disclosure must also be 
explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or sponsor’s 
designees or by IRBs/IECs or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on 
paper or 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 reported on the 
eCRF must be consistent with the source data or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
trial; current medical records must also be available.
For the eCRF, the following data need to be derived from source documents:

Patient identification (gender, date of birth)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Originals or copies of the imaging diagnostics

ECG results (original or copies of the printouts)

Adverse events and outcome events (onset date (mandatory), and end date (if applicable))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results (in validated electronic format, if available)

Completion of Patient’s Participation in the trial

Prior to allocation of a patient to a treatment into a clinical trial, there must be document 
evidence in the source data (e.g. medical records) that the trial participant meets all 
inclusion criteria and does not meet any exclusion criteria.  The absence of records 


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(either medical records or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review and 
regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents
described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore a unique reference document for the evaluation of listedness needs to be provided. For
the BI 863909 this is the current version of the Investigator’s Brochure (c02942358). 
The current versions of these reference documents are provided in the ISF. No AE are classified 
as listed for trial design, or invasive procedures
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered confidential 
and disclosure to third parties is prohibited with the exceptions noted below. Patient
confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate medical 
personnel responsible for the patient’s welfare. Data generated as a result of the trial need to be 
available for inspection on request by the participating physicians, the sponsor’s representatives, 
by the IRB / IEC and the regulatory authorities. 
8.6
END OF TRIAL
The end of the trial is defined as the last follow up visit of the last patient.


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The IEC / competent authority in each participating EU member state needs to be notified about 
the end of the trial or early termination of the trial.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R01-0028
Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. 
Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer 
Inst 1997. 89(15):1138-1147.
R01-0787
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone 
PP. Toxicity and response criteria of the Eastern Cooparative Oncology Group. 
Am J Clin Oncol 5, 649 – 655 (1982)
R06-1037
Guidance for industry: estimating the maximum safe starting dose in initial 
clinical trials for therapeutics in adult healthy volunteers. U.S.Department of 
Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER) 2005
R10-4517
Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the 
management of pediatric and aldult tu,or lysis syndrome: an evidence-based 
review. J Clin Oncol 2008; 26(16): 2767 – 2778.
R10-4848
Common terminology criteria for adverse events (CTCAE): version 4.0 (NIH 
publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 2010), revised 
June 2010, reprinted June 2010). 
R11-5034
Guidance for industry: S9 nonclinical evaluation for anticancer pharmaceuticals 
(ICH, March 2010). Rockville: U.S. Department of Health and Human Services, 
Food and Drug Administration, Center for Drug Evaluation and Research 
(CDER), Center for Biologics Evaluation and Research (CBER) (2010)
R14-2794 
Carpenter RO, Evbuomwan MO, Pittaluga S, Rose JJ, Raffeld M, Yang S, Gress 
RE, Hakim FT, Kochenderfer JN B-cell maturation antigen is a promising target 
for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res 19 (8), 2048 -
2060 (2013)
R14-2905 
O'Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, Lin 
LL, Mantchev GT, Bram RJ, Noelle RJ. BCMA is essential for the survival of 
long-lived bone marrow plasma cells. J Exp Med 2004. 199(1):91-97.
R14-2906 
Tai YT, Mayes PA, Acharya C, Zhong MY, Cea M, Cagnetta A, Craigen J, Yates 
J, Gliddon L, Fieles W, Hoang B, Tunstead J, Christie AL, Kung AL, Richardson 
P, Munshi NC, Anderson KC. Novel anti-B-cell maturation antigen antibody-
drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. 
Blood 2014. 123(20):3128-3138.
R14-2907 
Chiu A, Xu W, He B, Dillon SR, Gross JA, Sievers E, Qiao X, Santini R, Hyjek 
E, Lee J, Cesarman E, Chadburn A, Knowles DM, Cerutti A. Hodgkin lymphoma 


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cells express TACI and BCMA receptors and generate survival and proliferation 
signals in response to BAFF and APRIL. Blood 2007. 109(2):729-739.
R14-3640 
Nagorsen D, Kufer P, Baeuerle PA, Bargou R. Blinatumomab: a historical 
perspective. Pharmacol Ther 2012. 136(3):334-342.
R14-3711 
Yong KL, Germaschewski FM, Rodriguez-Justo M, Bounds D, LeeL, Mayes PA, 
Sully K, Seestaller-Wehr LM, Fieles WE, Tunstead JR, McCahon L, Paterson J, 
Herledan G, Craigen JL Evaluation of BCMA as a therapeutic target in multiple 
myeloma using an antibody-drug conjugate. 55th Ann Mtg of the American 
Society of Hematology (ASH), New Orleans, 7-10 Dec 2013 Blood 122 (21),, 
Abstr 4447 (2013)
R14-3712
Avet-Loiseau H, Attal, M, Moreau, P, Charbonnel, C,Garban, F,Hulin, C, 
Leyvraz, S, et al. Genetic abnormalities and survival in multiple myeloma: the 
experience of the Intergroupe Francophone du Myelome. Blood 2007 Apr 15;109 
(8): 3489 – 3495.
R14-3714 
Kumar, SK, Lee JH, Morgan, G, Richardson, PG, Crowley, J, Haessler, J, 
Hoering, A et al. Risk of progression and survival in multiple myeloma relapsing 
after therapy with IMiDs and bortezomib: A multicenter international myeloma 
working group study. Leukemia. 2012 Jul 29;26:149-157.
R14-3715 
SEER Stat fact sheets: myeloma. U.S. Department of Health & Human Services, 
National Institutes of Health, National Cancer Institute, Surveillance 
Epidemiology and End Results (SEER) (2014).
R14-3753 
Attal M, Lauwers-Cances V, Marit G,Caillot D,Moreau P, Facon T, Stoppa, AM 
et al, IFM InvestigatorsLenalidomide maintenance after stem-cell transplantation 
for multiple myeloma.N Engl J Med 2012 Jun 10; 366 (19): 1782 – 1791.
R14-3786
Sanchez E. et al. Serum B-cell maturation antigen is elevated in multiple 
myeloma and correlates with disease status and survival. British Journal of 
Haematology, Volume 158, Issue 6, pages 727–738, September 2012  
R14-3798
Quinn J, Glassford J, Percy L, Munson P, Marafioti T, Rodriguez-Justo M, Yong 
K. APRIL promotes cell-cycle progression in primary multiple myeloma cells: 
influence of D-type cyclin group and translocation status. Blood 2011. 
117(3):890-901.
R14-4478
BGM Durie et al. International uniform response criteria for multiple. Leukemia 
2006. 20, 1467 – 1473. 
R14-4494
Ng LG1, Sutherland AP, Newton R, Qian F, Cachero TG, Scott ML, Thompson 
JS, Wheway J, Chtanova T, Groom J, Sutton IJ, Xin C, Tangye SG, Kalled SL, 
Mackay F, Mackay CR. B cell-activating factor belonging to the TNF family 
(BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of
circulating T and B cells. J Immunol. 2004 Jul 15;173(2):807-17.


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R14-4637
Rawstron AC1, Bennett FL, O'Connor SJ, Kwok M, Fenton JA, Plummer M, de 
Tute R, Owen RG, Richards SJ, Jack AS, Hillmen P. Monoclonal B-cell 
lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008 Aug 7;
359(6):575-83
R14-4644
K Giannopoulos, W Kaminska, I Hus and A Dmoszynska. The frequency of T 
regulatory cells modulates the survival of multiple myeloma patients: detailed 
characterisation of immune status in multiple myeloma Open. Br J Cancer 106: 
546-552; advance online publication, January 5, 2012; doi:10.1038/bjc.2011.575
R14-4645
Feyler, S et al. CD4+CD25+FoxP3+ regulatory T cells are increased whilst 
CD3+CD4−CD8−αβTCR+ Double Negative T cells are decreased in the 
peripheral blood of patients with multiple myeloma which correlates with disease 
burden. British Journal of Haematology Volume 144, Issue 5, pages 686–695, 
March 2009    
R14-4646
Atanackovic D, Cao Y, Luetkens T, Panse J, Faltz C, Arfsten J, Bartels K, 
Wolschke C, Eiermann T, Zander AR, Fehse B, Bokemeyer C, Kroger N. 
CD4+CD25+FOXP3+ T regulatory cells reconstitute and accumulate in the bone 
marrow of patients with multiple myeloma following allogeneic stem cell 
transplantation. Haematologica. 2008 Mar;93(3):423-30. doi: 
10.3324/haematol.11897. Epub 2008 Feb 20
R14-15304 
Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch AR, Hulin C, 
Cavo, M. Initial phase 3 results of the first (frontline investigation of 
lenalidomide + dexamethasone versus standard thalidomide) trial (MM-020/IFM 
07 01) in newly diagnosed multiple myeloma (NDMM) patients (pts) ineligible 
for stem cell transplantation (SCT). 55th Ann Mtg of the American Society of 
Hematology (ASH), New Orleans, 7-10 Dec 2013 abstract.
P11-05130
Wijermans P, Schaaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, 
Sinnige H, Zweegman S. Phase III study of the value of thalidomide added to 
melphalan plus prednisone in elderly patients with newly diagnosed multiple 
myeloma: the HOVON 49 study. J Clin Onc 2010 Jul 1: 28 (19):3160-65
R15-0031
Maude SL, Barrett D, Teachey DT, Grupp SA:Managing cytokine release 
syndrome associated with novel T cell-engaging therapies.Cancer J 2014 
(Sudbury) 20 (2), 119 – 122.
R15-0269
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and 
response assessment of multiple myeloma. Leukemia 2009, 23:3 – 9. 
R16-2323
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current 
concepts in the diagnosis and management of cytokine release syndrome. Blood 
2014, 124(2):188-95.


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9.2
UNPUBLISHED REFERENCES
c02942358
 Investigator Brochure 863909, Version 1


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10.
APPENDICES
10.1 
INTERNATIONAL MYELOMA WORKING GROUP (IMWG) UNIFORM 
RESPONSE CRITERIA FOR MULTIPLE MYELOMA
Response
IMWG criteria1
sCR
CR as defined below plus normal FLC ratio and absence of clonal cells in 
bone marrow2 by immunohistochemistry or immunofluorescence3
CR
Negative immunofixation on the serum and urine and disappearance of any 
soft tissue plasmacytomas and < 5% plasma cells in bone marrow3
VGPR
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or > 90% reduction in serum M-protein plus urine M-
protein level < 100 mg/24 h
PR
> 50% reduction of serum M-protein and reduction in 24 hours urinary M-
protein by >90% or to < 200 mg/24 h
If the serum and urine M-protein are unmeasurable,5 a > 50% decrease in 
the difference between involved and uninvolved FLC levels is required in 
place of the M-protein criteria
If serum and urine M-protein are not measurable, and serum free light assay 
is also not measureable, > 50% reduction in plasma cells is required in 
place of M-protein, provided baseline bone marrow plasma cell percentage 
was > 30%
In addition to the above listed criteria, if present at baseline, a > 50% 
reduction in the size of soft tissue plasmacytomas is also required
SD
Not meeting criteria for CR, VGPR, PR, or progressive disease
Progressive 
disease4
Increase of > 25% from lowest response value in any one or more of the 
following:
Serum M-component and/or (the absolute increase must be > 0.5 g/dL)5
Urine M-component and/or (the absolute increase must be > 200 mg/24 h)
Only in patients without measurable serum and urine M-protein levels; the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL
Bone marrow plasma cell percentage; the absolute percentage must be > 
10%6
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas
Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 
2.65 mmol/L) that can be attributed solely to the plasma cell proliferative 
disorder
Relapse
Clinical relapse requires one or more of:
Direct indicators of increasing disease and/or end organ dysfunction 
(CRAB features) 5. It is not used in calculation of time to progression or 
progression-free survival but is listed here as something that can be 
reported optionally or for use in clinical practice
Development of new soft tissue plasmacytomas or bone lesions


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Definite increase in the size of existing plasmacytomas or bone lesions. A 
definite increase is defined as a 50% (and at least 1 cm) increase as 
measured serially by the sum of the products of the cross-diameters of the 
measurable lesion
Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L]
Decrease in haemoglobin of > 2 g/dL [1.25 mmol/L]
Rise in serum creatinine by 2 mg/dL or more [177 mmol/L or more]
Relapse from 
CR5 (To be used 
only if the end 
point studied is 
DFS)7
Any one or more of the following:
Reappearance of serum or urine M-protein by immunofixation or 
electrophoresis
Development of > 5% plasma cells in the bone marrow6
Appearance of any other sign of progression (i.e., new plasmacytoma, lytic 
bone lesion, or hypercalcaemia)
1Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473 (R14-4478); and Kyle RA, Rajkumar SV. Leukemia 2009;
23:3-9 (R15-0269). 
Note: A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only measurable disease is 
by serum FLC levels: CR in such patients is defined as a normal FLC ratio of 0.26–1.65 in addition to CR criteria 
listed above. VGPR in such patients is defined as a >90% decrease in the difference between involved and uninvolved 
free light chain (FLC) levels. 
2 Confirmation with repeat bone marrow biopsy not needed.
3 Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal kappa/lambda ratio by 
immunohistochemistry and/or immunofluorescence requires a minimum of 100 plasma cells for analysis. An abnormal 
ratio reflecting presence of an abnormal clone is kappa/lambda of > 4:1 or < 1:2.
4 All relapse categories require two consecutive assessments made at any time before classification as relapse or disease 
progression and/or the institution of any new therapy. In the IMWG criteria, CR patients must also meet the criteria for 
progressive disease shown here to be classified as progressive disease for the purposes of calculating time to 
progression and progression-free survival. The definitions of relapse, clinical relapse and relapse from CR are not to be 
used in calculation of time to progression or progression-free survival. 
5 For progressive disease, serum M-component increases of >1 gm/dL are sufficient to define relapse if starting M-component is 
>5 g/dL.
6 Relapse from CR has the 5% cut-off versus 10% for other categories of relapse.
7 For purposes of calculating time to progression and progression-free survival, CR patients should also be evaluated using 
criteria listed above for progressive disease.


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10.2
FLOW CHART PHARMACOKINETIC ASSESSMENTS 
BLOOD SAMPLING TIMES FOR PHARMACOKINETICS
Course
Week
Visit
Day
Time point after 
dose (h:min)
CRF time
Sample 
number
BI 836909 
analysis in 
serum
ADA**
analysis
1
1
1
1
Before start of 
infusion
0:00
S1-A
X
X
1:00
S2-A
X
2:00
S3-A
X
4:00
S4-A
X
8:00
S5-A
X
2
24:00
S6-A
X
3
48:00
S7-A
X
1
1
2
8
168h after start of 
infusion 
168:00
S8-A
X
1
2
3
15
336h after start of 
infusion
336:00
S9-A
X
X
1
3
4
22
504 h after start of 
infusion 
504:00
S10-A
X
1
4
5
29
Before end of 
infusion in cycle 1*
671:50
S11-A
X
673:00
S12-A
X
674:00
S13-A
X
676:00
S14-A
X
680:00
S15-A
X
30
696:00
S16-A
X
X
2
1
1
1
Before start of 
infusion
0:00
S17-A
X
2
2
3
15
14 days after start of 
infusion 
336:00
S18-A
X
X


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Course
Week
Visit
Day
Time point after 
dose (h:min)
CRF time
Sample 
number
BI 836909 
analysis in 
serum
ADA**
analysis
2
3
4
22
22 days after start of 
infusion 
504:00
S19-A
X
2
4
5
29
Before stop of 
infusion
671:50*
S20-A
X
X
3
1
1
1
Before start of 
infusion 
0:00
S21-A
X
3
2
3
15
14 days after start of 
infusion 
336:00
S22-A
X
X
3
3
4
22
22 days after start of 
infusion
504
S23-A
X
3
4
5
29
Before stop of 
infusion 
672:00*
S24-A
X
X
4
1
1
1
Before start of 
infusion 
0:00
S25-A
X
4
2
3
15
14 days after start of 
infusion 
336:00
S26-A
X
X
4
3
4
22
22 days after start of 
infusion
504:00
S27-A
X
4
4
5
29
Before stop of 
infusion 
671:50*
S28-A
X
X
5
1
1
1
Before start of 
infusion 
0:00
S29-A
X
5
2
3
15
14 days after start of 
infusion 
336:00
S30-A
X
X
5
3
4
22
22 days after start of 
infusion
504:00
S31-A
X
5
4
5
29
Before stop of 
infusion 
671:50*
S32-A
X
X
*10 minutes before stop of infusion
** Anti Drug Antibodies


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10.3
DEFINITIONS OF LABORATORY AND CLINICAL TUMOR LYSIS 
SYNDROM
Metabolic 
Abnormality
Criteria for Classification 
of Laboratory Tumor 
Lysis Syndrome
Criteria for Classification of Clinical Tumor Lysis 
Syndrome
Hyperuricemia
Uric acid >8.0 mg/dl (475.8 
μmol/liter) in adults or 
above the upper limit of the 
normal range for age in 
children
Hyperphosphatemia
Phosphorus >4.5 mg/dl (1.5 
mmol/liter) in adults or >6.5 
mg/dl (2.1 mmol/liter) in 
children
Hyperkalemia
Potassium >6.0 mmol/liter
Cardiac dysrhythmia or sudden death probably or definitely 
caused by hyperkalemia
Hypocalcemia
Corrected calcium <7.0 
mg/dl (1.75 mmol/liter) or 
ionized calcium <1.12 (0.3 
mmol/liter) †
Cardiac dysrhythmia, sudden death, seizure, neuromuscular 
irritability (tetany, paresthesias, muscle twitching, 
carpopedal spasm, Trousseau’s sign, Chvostek’s sign, 
laryngospasm, or bronchospasm), hypotension, or heart 
failure probably or definitely caused by hypocalcemia
Acute kidney 
injury†
Not applicable
Increase in the serum creatinine level of 0.3 mg/dl (26.5 
μmol/liter) (or a single value >1.5 times the upper limit of 
the age-appropriate normal range if no baseline creatinine 
measurement is available) or the presence of oliguria, 
defined as an average urine output of <0.5 ml/kg/hr for 6 hr
*In laboratory tumor lysis syndrome, two or more metabolic abnormalities must be present during the same 24-hour period 
within 3 days before the start of therapy or up to 7 days afterward. Clinical tumor lysis syndrome requires the presence 
of laboratory tumor lysis syndrome plus an increased creatinine level, seizures, cardiac dysrhythmia, or death.
†The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × (4 − 
albumin in grams per deciliter).
‡Acute kidney injury is defined as an increase in the creatinine level of at least 0.3 mg per deciliter (26.5 μmol per liter) or a 
period of oliguria lasting 6 hours or more. By definition, if acute kidney injury is present, the patient has clinical tumor 
lysis syndrome. 


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10.4
CREATININE CLEARANCE ESTIMATED BY THE COCKCROFTGAULT 
(C-G) EQUATION
Estimated creatinine clearance rate (eCCR) using Cockcroft-Gault formula.
(140 - age) x weight x FS
eCCR =
______________________
Serum Creatinine x 72
Units: GFR [ml/min], age [years], weight [kg], estimated creatinine clearance rate [mg/dl],
FS is a correction Factor for Sex: in males FS = 1, in females FS = 0.85
Please refer to the ISF for local country formula in case you don't use the same units (kg, ml/min 
or mg/dl).
10.5
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
SCORE
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g. light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
Reference: R01-0787


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10.6
CLINICAL EVALUATION OF LIVER INJURY
10.6.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (Protocol-specified 
adverse event of special interest), are to be further evaluated using the following procedures: 
10.6.2
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 “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, Anti-mitochondrial 
antibody
<project dependent:> Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), 
herpes simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), toxoplasmosis 
(IgG, IgM)>
Hormones, tumormarker
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 judgement and Good Clinical Practices 
(GCP).


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
21 May 2015
EudraCT number
2014-004896-22
BI Trial number
1351.1
BI Investigational Product(s)
BI 863909
Title of protocol
An open label, phase I, dose escalation study to 
characterize the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of 
intravenous and subcutaneous doses of BI 836909 
in relapsed and/or refractory multiple myeloma 
patients
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Sections to be changed
1. Synopsis Methodology and number of 
patients
2. Footnote 12 of Flow charts for part A and 
part B
3. Section 3.1
4. Section 3.2
5. Section 3.3.3
6. Section 4.1.4
7. Section 5.2.4.1
8. Section 5.2.4.2
9. Section 7.4
Description of change
1.Synopsis Methodology and number of 
patients
….
For the dose levels of 0.2 to 1.6 µg/day single 


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Number of global amendment
1
patient cohorts are entered. The following dose 
cohorts will be tested within the above-mentioned 
dose range:
• 0.2, 0.4, 0.8 and 1.6 µg/day
• The DLT observation period for the single 
patient cohorts will be 2 weeks. If a patient has 
been on treatment in one of the above-mentioned 
dose cohorts for 2 weeks without DLT or other 
relevant safety findings the first patient of the 
next higher dose cohort will be entered if agreed 
on by the safety committee. If a patient has 
reached DLT, then the safety committee 
recommends 3 + 3 cohorts. Patients may not 
proceed to the next higher dose level before 
completion of 6 patients. 
One intra-patient dose escalation is allowed 
within the single patient dose cohorts if the 
initial dose is tolerated and no DLT occurs 
during 1st cycle. In case of DLT additional 
patients will be entered into this cohort 
following a 3 + 3 design. 
For the dose levels ≥ 3.2 µg/day 3-6 patients 
will be treated per dose level and observed for 
4 weeks during the first cycle before decision 
for dose escalation to the next dose cohort is 
made. 
The following dose cohorts will be tested within 
the above-mentioned dose range:
• 3.2, 6.5, 13, 25, 50 and 100 µg/day and higher 
if MTD has not yet been established. Additional 
and intermediate dose cohorts will be entered if 
determined by the safety committee.
Increments to the next higher dose will not 
exceed 2-fold increases.
The DLT observation period will be extended to 4  
weeks for all future cohorts before decision for 
dose escalation within the next dose cohort is 
made:
• Per dose level 1 patient will be enrolled and 
treated for 1 week before all remaining patients 
for this cohort can be entered. Additional 
patients should not start treatment before the 
previous patient has been treated for 48 hours 
in order to monitor initial transient toxicities 


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1
due to cytokine release syndrome.
Number of patients:
….
Part A: Number of patients will depend on the 
number of dose levels to be tested before MTD 
determination or determination of the 
recommended dose. Based on preclinical data, it 
is expected that > 5 dose levels in addition to the 
4 single-patient doses will be tested. Around 20 
to 40 patients will be treated during the dose 
escalation phase.
….
2.Footnote 12 for part A and part B
at screening and at each visit and at EOT; during 
hospitalization in cycle 1 safety lab should be 
done before start of treatment on day 1 and 
repeated in the evening of day 1 as well as in 
the morning of days 2 and 3; in cycle 2 safety 
lab should be done before start of treatment on 
day 1 and in the morning of day 2.
On day 29 of cycle 1 blood draw for safety lab 
should be done before the end of the infusion.
3.Section 3.1
Table 3.1.1
Dose 
level
Dose 
µg/d
Patients 
per cohort
Approximate 
increment to 
next dose
1
0.2
1
2x
2
0.4
1
2x
3
0.8
1
2x
4
1.6
1
2x
5
3.2
3 (+3)
2x
6
6.5
3 (+3)
2x
7
13
3 (+3)
2x
8
25
3 (+3)
2x
9
50
3 (+3)
2x 
10
100…..
3 (+3)
2x 
…..
For the dose levels 0.20 to 1.6 µg/day single 
patient cohorts are entered since no clinical 


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activity is expected at these doses. 
If a patient has been on treatment in one of the 
above-mentioned dose cohorts for 2 weeks 
without DLT the first patient of the next higher 
dose cohort will be entered if agreed on by the 
safety committee. If a patient has reached 
DLT, then the safety committee recommends 
the switch to a 3 + 3 cohort for the dose level at 
which the DLT occurred. Patients may not 
proceed to the next higher dose level before 
completion of 6 patients.
One intra-patient dose escalation is allowed 
within the single patient dose cohorts if the initial 
dose is tolerated well and no DLT occurs during 
1st cycle. In case of DLT additional patients will 
be entered into this cohort following a 3+3 
design.
For the dose levels ≥ 3.2 µg/day 3-6 patients 
will be treated per dose level and observed for 
4 weeks during the first cycle before decision 
for dose escalation to the next dose cohort is 
made.
Per dose level 1 patient will be enrolled and 
treated for 1 week, than further patients will be 
enrolled. Patients should be entered sequentially. 
Additional patients should not start treatment 
before the previous patient has been treated 
for 48 hours in order to monitor initial 
transient toxicities due to cytokine release 
syndrome.
….
4.Section 3.2
…
Part A: 
The following dose cohorts will be tested as 
single patient cohorts: 0.2, 0.4, 0.8 and 1.6 
µg/day.
If a patient has been on treatment in one of the 
above-mentioned dose cohorts for 2 weeks 
without DLT the first patient of the next higher 
dose cohort will be entered. In case that a DLT 
has been observed in the single patient cohorts 5 
additional patients will be entered on this actual 
dose level. 


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Intra-patient dose escalation is allowed once to 
the next higher dose within the first 4 above-
mentioned dose cohorts up to 1.6µg/d.
In case that no DLTs have been observed during 
the first cycle within the single patient dose 
cohorts the patient can be treated at the next 
higher dose level in subsequent cycles. Only one 
intra-patient dose escalation step is allowed. This 
approach of intra-patient dose escalation reduces 
the number of patients treated at 
pharmacologically inactive doses to a minimum 
and increases the likelihood of treatment benefit 
for patients entered at low dose. 
Prior to treatment of a patient at the next higher 
cohort a safety committee quorum needs to be 
obtained to oversee the observation period of this 
dose level to make sure that no additional patients 
must be entered at that dose level and that a 
patient can be entered at the next higher dose 
level. If the safety committee recommends 
treatment of additional patients at the lower dose 
level 2 additional patients must be entered at the 
lower dose level first. The 3 + 3 design will then 
be followed. 
For the dose levels ≥ 3.2 µg/day 3-6 patients (3+3 
design) will be treated per dose level and 
observed for 4 weeks before decision for dose 
escalation to the next dose cohort is made.
...
5.Section 3.3.3
was changed to
…
5.
Last treatment with a therapeutic 
antibody less than 6 weeks prior to visit 1
6.
Prior allogeneic stem cell 
transplantation or solid organ transplantation
7.
Autologous stem cell transplantation < 
than 90 days at time of treatment start
…..
was added
22.
Patients with a known hypersensitivity 
to any component of the study drug 
23.
Patients with other malignancies within 
5 years at time of screening (except basal cell 
or squamous cell carcinoma of the skin or 


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carcinoma in situ treated with curative 
therapy)
6.Section 4.1.4; table 4.1.4.1
Dose 
µg/day
Patients 
per 
cohort
Observation time of 
ongoing patients before 
enrolment/entry of next 
patient/cohort
0.2
1
2 weeks, then enrol next 
cohort
0.4
1
As in previous cohort
0.8
1
As in previous cohort
1.6
1
As in previous cohort
3.2
3 (+3)
1 week for first patient, 
then enter next two 
patients; additional 
patients should not 
start treatment before 
the previous patient has 
been treated for 48 
hours in order to 
monitor initial transient 
toxicities due to 
cytokine release 
syndrome. All 3 must 
have completed 4 weeks
before enrolling next 
cohort
6.5
3 (+3)
As in previous cohort
13
3 (+3)
As in previous cohort
25
3 (+3)
As in previous cohort
50
3 (+3)
As in previous cohort
100….
3 (+3)
As in previous cohort
7.Section 5.2.4.1
…..
Haematology Haemoglobin, red blood cell count 
(RBC), white blood cell count (WBC) with 
differential, platelets (PLT)
Biochemistry Glucose, sodium, potassium, total 
calcium, inorganic phosphate, creatinine, 
aspartate amino transferase (AST), alanine amino 
transferase (ALT), alkaline phosphatase (AP), 


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lactate dehydrogenase (LDH), total bilirubin (if 
elevated provide direct bilirubin), urea, total 
protein, albumin, uric acid, Ferritin (at baseline 
of cycle 1 only).
Serum immunoglobulin levels (IgG, IgM, IgA) at 
baseline, day 15 and day 29 of each cycle only
Coagulation
Activated partial thromboplastin 
time (aPTT), prothrombin time (PT)/international 
normalised ratio (INR), ), fibrinogen and D-
Dimers in cycle 1 and 2; thereafter on day 1 of 
each of the following cycles only.
…..
8.Section 5.2.4.2
Tumour lysis syndrome (TLS) is characterized by 
metabolic derangements caused by the massive 
and abrupt release of cellular components into the 
blood after rapid lysis of malignant cells. The 
release of the intracellular metabolites can 
overwhelm normal homeostatic mechanisms, 
potentially leading to hyperuricemia, 
hyperkalemia, hyperphosphatemia, hypocalcemia, 
and uremia. This can result in impaired renal 
function, and in some cases, in acute renal failure 
and even death (R10-4517). To allow for early 
treatment in case TLS develops, vigilant 
monitoring is recommended if clinically 
indicated. During the first 48 hours after the 
start of the first infusion/injection of BI 836909 
in course 1, and during the first 24 hours after 
the start of the first infusion/injection in course 
2, the below listed laboratory parameters need 
to be determined to screen for evidence of a 
tumour lysis syndrome monitored frequently, 
i.e. every 4-8 hours between the time points at 
which a complete safety laboratory has to be 
performed. The actual date and time of the 
blood samples should be recorded in the eCRF.
Haematology haemoglobin, haematocrit, red 
blood cell count (RBC), white blood cell count 
(WBC),+ differential, platelets (PLT)


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Biochemistry uric acid, potassium, calcium, 
inorganic phosphate, lactate dehydrogenase 
(LDH), creatinine, urea, ferritin. 
Coagulation
Activated partial thromboplastin 
time (aPTT), prothrombin time (PT)/international 
normalised ratio (INR), fibrinogen, D-dimer.
9.Section 7.4
…..
1. Preliminary analysis after the four first 
cohorts from part A (for a minimum of 4 
patients) to check the PK/PD behaviour of BI 
836909. In case BI 836909 shows undue 
difference from predicted exposure, if needed, the 
dosing escalation scheme of BI 836909 might be 
adapted.
…..
Rationale for change
Changes 1 to 6 and 9 have been requested by the 
German Authority during the approval process
Changes7 and 8 was done for clarification only. 


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Date of CTP revision
28 December 2016
EudraCT number
2014-004896-22
BI Trial number
1351.1
BI Investigational 
Product(s)
BI 863909
Title of protocol
An open label, phase I, dose escalation study to characterize the 
safety, tolerability, pharmacokinetics, and pharmacodynamics of 
intravenous doses of BI 836909 in relapsed and/or refractory 
multiple myeloma patients
To be implemented 
only after approval 
of the 
IRB/IEC/Competent 
Authorities
X
To be implemented 
immediately in order 
to eliminate hazard –
IRB / IEC / 
Competent 
Authority to be 
notified of change 
with request for 
approval
Can be implemented 
without IRB/IEC/ 
Competent 
Authority approval 
as changes involve 
logistical or 
administrative 
aspects only
Sections to be 
changed
1. PROTOCOL TITLE
2. CLINICAL TRIAL PROTOCOL SYNOPSIS
3. FLOW CHARTS and FOOTNOTES
4. 2.2 TRIAL OBJECTIVES
5. 3.1 OVERALL TRIAL DESIGN AND PLAN
6. 3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE 
CHOICE OF CONTROL GROUP(S)
7. 3.3 SELECTION OF TRIAL POPULATION
8. 4. TREATMENTS
9. 5. VARIABLES AND THEIR ASSESSMENT
10. 6. INVESTIGATIONAL PLAN


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11.7. STATISTICAL METHODS AND DETERMINATION 
OF SAMPLE SIZE
12.10.2 FLOW CHART PHARMACOKINETIC 
ASSESSMENTS
All part B, expansion cohorts as well as follow up visits beyond the 
REP visit related items have been deleted in all corresponding parts 
of the protocol. Minor changes have been made for consistency 
between the different chapters of the protocol. 
Additional cohorts have been included because no DLTs occurred 
up to now and more cohorts to detect MTD may be needed. The 
corresponding parts of the protocol have been updated accordingly.
Corresponding sections were changed to:
1.PROTOCOL TITLE
An open label, phase I, dose escalation study to characterize the 
safety, tolerability, pharmacokinetics, and pharmacodynamics of 
intravenous doses of BI 836909 in relapsed and/or refractory 
multiple myeloma patients
2. CLINICAL TRIAL PROTOCOL SYNOPSIS
Objective(s):
Primary objective:
To determine the maximum tolerated dose (MTD) as well as the 
dose limiting toxicities (DLT) of a 6-week regimen of BI 836909 
given as continuous intravenous infusion in patients with relapsed 
and/or refractory multiple myeloma.
Secondary objectives:
Recommended dose for further development 
To provide preliminary findings on the safety profile and assess 
pharmacokinetic profile of BI 836909 
To assess pharmacodynamic and anti-tumoral activity of BI 836909
To evaluate immunogenicity of BI 836909
Methodology:
Phase I dose escalation trial of BI 836909 given as intravenous 
infusion.
Starting dose: 0.20 µg/day
A 6-week regimen will be tested (4 weeks of continuous 
intravenous administration of BI 836909 followed by a 2 weeks off-
period). […]
Description of 
change
For the dose levels ≥ 3.2 µg/day 3-6 patients will be treated per dose 
level and observed for 4 weeks during the first cycle before decision 
for dose escalation to the next dose cohort is made.
The following dose cohorts will be tested within the above-
mentioned dose range:


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
3.2, 6.5, 13, 25, 50, 100, 200 and 400 µg/day and higher 
doses if MTD has not yet been established. Additional and 
intermediate dose cohorts will be entered if determined by 
the safety committee.

[…]

Once the MTD of BI 836909 is determined up to 6 
additional patients will be treated at the MTD or the 
recommended dose for confirmation of safety.
Number of patients total entered:
Up to 50 patients depending on dose level reached
Dose escalation:
Number of patients will depend on the number of dose levels to be 
tested before MTD determination or determination of the 
recommended dose. Based on preclinical data, it is expected that > 5 
dose levels in addition to the 4 single-patient doses will be tested. 
Up to 50 patients will be treated during the dose escalation 
phase. Up to 6 additional patients will be treated with MTD or 
recommended dose.
Test product(s):
BI 836909 in vials for continuous intra-venous infusion.
Criteria for pharmacokinetics: 

Concentration at steady state after i.v. infusion (Css)).
Statistical methods:
Patients with DLT, objective response rate, MRD will be explored 
and summarized by descriptive statistics. Kaplan-Meier methods 
will be used for time to event endpoints.
The pharmacokinetic parameters Css,
 
 
 
 
 
 
will be descriptively explored.
3. FLOW CHARTS and FOOTNOTES
FLOW CHART: BI 836909 CONTINUOUS ITRAVENOUS 
INFUSION
“Triplicate ECG for QTc assessment” as well as footnote 16 was 
deleted because expansion cohorts have been cancelled.
Footnote 3:Follow up visit should be performed 30 days after the EOT (REP visit). Follow 


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up visit after EOT: report all AEs, SAEs, AESIs regardless of relatedness. This 
includes all deaths unless due to underlying disease (Section 6.2.5.2)
Please note: Death should always be reported as SAE in this trial unless due to 
underlying disease.
Footnote 8: within 14 days before day 1 cycle 1 or on day 1 cycle 1 before start of 
treatment, when M protein/ Free kappa/lambda light chain (FLC) becomes 
undetectable during treatment, on day 29 of cycle 3 and at EOT.
Karyotyping: recent analysis will be accepted for screening before start of 
treatment if performed within 3 months prior to start of study medication and in 
case that no therapy has been given between assessment of karyotyping and 
study medication; otherwise, a baseline karyotype should be performed at 
screening; subsequent karyotyping could also be performed in subsequent 
marrow samples (tests to be done locally).
Footnote 9: MRD (minimal residual disease assessment): when M protein/FLC becomes 
undetectable during treatment; day 29 of cycle 3 and EOT (tests to be done 
centrally). 
Footnote 10: Optional collection and bio-banking of a baseline bone marrow sample and a 
bone marrow sample on treatment when a complete response is reached.
Footnote 13: Infusion bag will have to be exchanged during continuous infusion of BI 
836909 approximately every 4 days; patients should either come to the clinic or 
bag change will be done by a home care service.
Footnote 14: Clinical disease assessment must be performed: At screening, at start of each 
cycle as well as at EOT. […]
Old footnote 16 was deleted
Former Footnote 17 was changed to 16: Orienting neurological examination should be 
performed at screening as well as at EOT and daily during hospitalization 
required by the protocol.
4. 2.2 TRIAL OBJECTIVES
The primary objective of this trial is to determine the maximum 
tolerated dose (MTD) of BI 836909 administered by continuous i.v. 
infusion in patients with relapsed and/or refractory multiple 
myeloma. If the MTD is not reached based on safety findings, a 
recommended dose for further development will be determined. 
This will depend on the safety data, pharmacokinetic/ 
pharmacodynamics data and potentially preliminary efficacy data. 
Secondary objectives are to document the safety and tolerability of 
BI 836909, to perform pharmacokinetic and pharmacodynamic 
analyses and to evaluate relevant biological effects in terms of 


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parameters of efficacy. The starting dose is based on a 
Pharmacologically Active Dose (PAD) estimated from the EC50 of 
the most sensitive in vitro cytotoxicity assay and pharmacokinetic 
modelling. Assuming an average body surface area (BSA) of 1.7 m2
the proposed starting dose of 0.12 μg/ m2/day translates into a 
starting dose of 0.20 µg/d given by continuous intravenous 
injection. In the clinical trial the administered doses will not be 
BSA-adapted. The proposed starting dose is 4500 fold lower than 
the HNSTD (540 µg/m2/day) and 1500 fold lower than the dose 
(180 µg/m2/day) that did not result in cytokine release in the 4-week 
toxicology study in cynomolgus monkeys.
5. 3.1 OVERALL TRIAL DESIGN AND PLAN
The trial is an open-label, non-randomized phase I dose-escalation 
trial with modified 3+3 design to evaluate the tolerability and safety 
of BI 836909 given as continuous intravenous infusion as well as to 
determine the MTD or to establish the recommended dose for 
further development of BI 836909 administered as continuous 
intravenous infusion. 
MTD is defined as the highest dose of the dose level tested where ≤ 
1 patient out of 6 develops dose limiting toxicity. If MTD cannot be 
determined based on safety findings, a recommended dose for 
further development will be determined based on pharmacokinetic 
and pharmacodynamics data. 
Overall study design:
The study consists of the following phases:
[…]

Follow up visit (FU): follow up visit should be performed 30 
days after the EOT (REP visit). 

Patients will be treated for a maximum of 10 cycles. Last 
patient out is defined as the REP visit completed by the last 
patient. This will be the end of the trial. 
For patients who have entered the trial before the approval of 
the second revision last visit would be defined as the last follow 
up visit after the approval date.
The following dose levels will be tested: 


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Table 3.1.1 Dose escalation scheme
Dose 
level
Dose µg/d
Patients per 
cohort
Approximate 
increment to next 
dose
1
0.2
1
2x
2
0.4
1
2x
3
0.8
1
2x
4
1.6
1
2x
5
3.2
3 (+3)
2x
6
6.5
3 (+3)
2x
7
13
3 (+3)
2x
8
25
3 (+3)
2x
9
50
3 (+3)
2x 
10
100
3 (+3)
2x 
11
200
3 (+3)
2x
12
400*
3 (+3)
2x
*further doses will be tested in case that MTD could not be confirmed at a dose level of 
400 µg/day. Intermediate dose cohorts will be entered if determined by the safety 
committee, for example, in case that the dose cohort 400 µg/day exceeds MTD 
(> 1 patient out of 6 with DLT) and no DLT is observed on 200 µg/day consider 
300 µg/day.
[…]
In the dose escalation part the trial safety committee (for details see 
Section 3.1.1) can determine to enter additional and intermediate 
dose cohorts at any time e.g. if DLTs or other safety events, 
pharmacodynamics activity or antitumor efficacy occur. The 
safety committee will also determine to switch from single patient 
cohorts to a 3+3 design at doses below 3.2µg/d if DLTs, 
pharmacodynamic activity or antitumor efficacy occur. 
PK/PD data might be taken into account for dose escalation 
decisions if available.
Patients should be entered sequentially. Treatment initiation of more 
than 1 new patient per day will not be permitted during the dose 
escalation phase.
Once the MTD or the recommended dose for better characterization 
of safety and early evaluation of anti-tumour activity is determined
up to 6 additional patients will be treated with MTD or the 
recommended dose. […]
3.1.1 Administrative structure of the trial
[…]


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A safety committee (SC) of the investigators in cooperation with the 
responsible trial monitor and the medical project leader of the 
sponsor as well as medical representatives from Amgen will be 
implemented to analyse ongoing safety information and decide on 
further steps in dose finding. Prior to escalating the dose to the next 
higher dose cohort there will be a safety teleconference or meeting 
between trial investigators and the medical project leader of the 
sponsor to discuss any findings in the ongoing and already recruited 
cohorts, this means that all available clinical and safety data 
including repeated cycles of prior dose cohorts will be taken into 
consideration for assessments and decision making. Participation of 
the coordinating investigator or 
 deputy is a mandatory 
requirement for this committee to establish a quorum. After the 
defined observation period of each cohort this safety committee will 
discuss the need to enter additional patients or dose cohorts or 
release the next dose cohort and dose increment as per protocol. The 
same is true for the decision to switch from single patient cohorts to 
the 3+3 design. Step dosing may be implemented based on 
cytokine release syndrome qualifying for DLT following the 
following guidance:
- Restart with previous dose level for 4 days (one bag) and then 
escalate to current dose level until the end of the cycle.
The composition of the SC will be documented in BIRDS. The tasks 
and responsibilities will be agreed in contracts between the SC 
members and the Sponsor. SC will decide on the switch from single 
patient cohorts to the 3+3 design independently from defined dose 
cohorts based on clinical activity (antitumor response) and/or 
clinically relevant safety or pharmacodynamics findings. […]
Clinical disease status will be assessed at screening and at the start 
of each new cycle (e.g, before cycle 2, 3, 4 and 5 etc.) as well as at 
EOT with physical examination and clinical assessment of the 
multiple myeloma. MRI scans in this trial will be performed prior to 
treatment, at screening and every other cycle at day 1, cycle 3, day 
1, cycle 5, day1, cycle 7, day 1 and/or at time of progression or start 
of further anticancer therapy.
Results from routine assessments (MRI) for multiple myeloma are 
accepted for screening if performed no later than 28 days before 
start of treatment. 
Bone marrow examination, MRI scan and additional CT scans will 
be performed at time points outlined in the Flow chart. Results of 
MRI scans, additional CT scans, optional PET scan or bone marrow 


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2
examination performed during the conduct of the trial should be 
reported in the eCRF. After the EOT visit which must occur 
immediately at time of permanent discontinuation of study 
medication but no later than 7 days after last drug administration, 
the patient will have a follow up visit within 30 days after EOT 
(REP visit) for assessment of AEs /SAEs, patient status and
further anti-cancer treatment.
6. 3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE 
CHOICE OF CONTROL GROUP(S)
The primary objective of this trial is to determine the MTD. The 
most important secondary objective is to assess the safety of BI 
836909 given as continuous intravenous infusion. 
For the first 4 doses up to and including 1.6µg/d dose cohorts single 
patient cohorts have been chosen since no clinical benefit is 
expected at these low doses.
For the remaining dose cohorts a standard 3+3 design has been 
chosen as this is an established standard approach in phase I studies 
in oncology:
The following dose cohorts will be tested as single patient cohorts: 
0.2, 0.4, 0.8 and 1.6 µg/day. […]
7. 3.3 SELECTION OF TRIAL POPULATION
A total number of approximately 50 patients is expected to be 
entered into the trial. The number of patients depends on the number 
of dose escalation steps. A total of 5 sites will participate; this 
means that a total number of approximately 6 to 10 patients should 
be entered per site. […]
8. 4. TREATMENTS
4.1.1.1 Description of portable pump for continuous intravenous 
infusion of BI 836909
BodyGuardTM 323 Multi-Therapy Ambulatory Infusion Pump 
(Ceasarea Medical Electronics GmbH; 72805 Lichtenstein; 
Germany) will be used in this trial for the 4 –week continuous rate 
controlled intravenous infusion. Site personnel will be trained on the 
use of the pump by the vendor. Detailed instructions will be 
available in the ISF. […] 
4.1.4
Drug assignment and administration of doses for each 
patient
[…]


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Table 4.1.4.1: Dose escalation scheme
Dose 
µg/day
Patients 
per cohort
Observation time of ongoing patients 
before enrolment/entry of next 
patient/cohort
0.2
1
2 weeks, then enrol next cohort
0.4
1
As in previous cohort
0.8
1
As in previous cohort
1.6
1
As in previous cohort
3.2
3 (+3)
1 week for first patient, then enter next 
two patients; additional patients should 
not start treatment before the previous 
patient has been treated for 48 hours in 
order to monitor initial transient 
toxicities due to cytokine release 
syndrome. All 3 must have completed 
4 weeks before enrolling next cohort
6.5
3 (+3)
As in previous cohort
13
3 (+3)
As in previous cohort
25
3 (+3)
As in previous cohort
50
3 (+3)
As in previous cohort
100
3 (+3)
As in previous cohort
200
3 (+3)
As in previous cohort
400….*
3 (+3)
As in previous cohort
*further and intermediate dose cohorts may be added […]
4.1.4.1.2 Monitoring for infusion-related reactions and cytokine 
release syndromes
Close monitoring of the patient during and after the infusion of BI 
836909 is required for evaluation of infusion-related risks. The 
measures of monitoring include:

Hospitalization of patients with access to intensive care days 1–
4 of cycle 1 and in case of intra-patient dose escalation 
within 
the first cycle of dose escalation.

Hospitalization of patients with access to intensive care on day 1 
of cycle 2 (for a total of 24 hours) and in case of intra-patient 
dose escalation within the first cycle of dose escalation.

Frequent measurements and documentation of blood pressure 
and heart rate (see Section 5.2.6.1).

In courses 2 and higher the patients are required to be 
hospitalized under close surveillance with access to intensive 
care days 1-3 again in case of infusion related events in 
earlier 
treatment courses. If no infusion related events 
occurred in 
earlier treatment courses an observation 


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period of 4 - 8 hours in 
the hospital will suffice at start of each 
continuous infusion of 
BI 836909 in courses 3 and higher.
[…]
4.1.4.3 Dose reductions and dose delays
Related SAEs/AEs of ≥ grade 2 or non-drug related SAEs/AEs of ≥ 
grade 2 deemed intolerable by the patient or the treating physician 
and not responding to appropriate medical management will result 
in a pause until resolution to baseline or grade 1. A pause of a 
maximum duration of 14 days and a dose reduction to the next 
lower dose level is allowed if clinically indicated. Only one dose de-
escalation step is allowed. 
DLT events in any cycle, cases meeting the pre-defined hepatic 
injury criteria (ref. 5.2.2.1) and infusion related reactions or 
cytokine release syndromes ≥ grade 3 will lead to permanent 
discontinuation in the dose escalation phases. After recovery to 
baseline or grade 1 continuation of the cycle at the next lower dose 
tier is allowed. Only one dose de-escalation step is allowed.
CNS events ≥ grade 2 irrespective of relatedness that have not 
resolved to baseline or grade 1 within one week despite treatment 
interruption will lead to permanent discontinuation in the dose 
escalation phase. CNS events that have resolved to baseline or grade 
1 within one week can be continued at the next lower dose level. 
Only one dose de-escalation step is allowed. 
In case of dose reductions all future courses will also be at the 
reduced dose level. […]
4.2.2.2 Restrictions on diet and life style
No restrictions apply with regards to diet or life style unless based 
on restrictions due to the portable pump used within the study. 
4.3 TREATMENT COMPLIANCE
BI 836909 will be administered as a continuous intravenous 
infusion (c.i.v.) via infusion pump over a period of 4 weeks. 
Infusion bags will have to be exchanged approximately every 4 
days either at site or by a trained care provider. Persons involved in 
exchange of the bag will document compliance. Compliance may 
also be verified by pharmacokinetic assessments. Any discrepancies 
will be explained in the CRF by the investigator or his/her deputy.
9. 5. VARIABLES AND THEIR ASSESSMENT
[…]
5.1.1
Endpoint(s) of efficacy


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The efficacy endpoints will be assessed at the time points specified 
in the flowcharts. Efficacy endpoints will be secondary or further 
endpoints in the trial and will be evaluated according to the 
response criteria of the International Myeloma Working Group 
(IMWG, 2006; Appendix 10.1).
Secondary endpoints of efficacy are:

Objective response rate (percentage of patients with stringent 
complete response (sCR), complete response (CR), partial 
response (PR) and very good partial response (VGPR) )

Duration of response (DOR)

Minimal residual disease (MRD) response rate

Duration of MRD response. 

Progression-free survival (PFS)
5.1.2
Assessment of Efficacy
5.1.2.1
Laboratory parameters 
The following laboratory parameters must be evaluated to assess 
response of treatment:

Multiple myeloma (MM) cells in bone marrow
Analysis of myeloma cells in bone marrow will be 
conducted using a diagnostic FACS panel including markers for 
CD45, 
CD38, CD19, CD138, CD56 and kappa/lambda 
chains. 
Scheduled sampling time points will be as follows 
(see flow charts): within 14 days before day 1 cycle 1 or in 
cycle 1, day 1 
before start of treatment, when M 
protein/FLC  becomes 
undetectable during treatment, on day 
29 of cycle 3 and at EOT. 
The analysis will be 
performed centrally. […]
5.1.2.8 Overall survival (OS) was deleted
5.1.2.9 Supportive care requirement: was deleted 
5.2.1
Endpoint(s) of safety


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The primary objective is to assess the safety of the drug in humans 
and to determine the MTD of BI 836909. 
Primary Endpoints are the following:

Maximum tolerated dose (MTD) of BI 836909
MTD is defined as the highest dose level tested where ≤ 1 
patient out of 6 develop dose limiting toxicity. If MTD 
cannot 
be determined based on safety findings, a 
recommended dose 
for further development will be 
determined based on 
pharmacokinetic and 
pharmacodynamic data.
The MTD will be defined on the basis of DLT observed during 
cycle 1. However, for those patients who receive more than one 
cycle of BI 836909, all adverse events corresponding to the 
definition of DLT (Section 5.2.1.1) will be considered for the 
purpose of confirming the MTD and for the selection of the 
recommended dose for further development. In regular intervals, all 
available safety data including adverse events qualifying for DLT 
will be reviewed by the safety committee.

Number of patients with dose limiting toxicities
The safety of BI 836909 will be assessed by a descriptive 
analysis of incidence and intensity of adverse events graded 
according to CTCAE (version 4.03), the incidence dose 
limiting 
toxicity (DLT), laboratory data and results of 
physical 
examination.
Further endpoint of safety:

Immunogenicity of BI 836909 (frequency of patients developing 
anti-drug antibodies)
The safety data will be reviewed in regular intervals as well as ad 
hoc if needed.
The safety endpoints will be assessed in a descriptive way without 
confirmatory analyses.
5.2.3. Adverse event collection and reporting
[…]
Examples of exempted events of PD are:

Progression of underlying malignancy (Progressive disease PD):  
if PD is clearly consistent with the suspected progression of 
the 
underlying malignancy as defined by the respective 
response criteria. 

Hospitalization/Procedures due solely to the progression of 
underlying malignancy (PD)


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
Clinical symptoms and/or signs of progression (with or without 
confirmation by objective criteria e.g. imaging, clinical 
measurement): if the symptom can exclusively be 
determined to 
be due to the progression of the underlying 
malignancy and does 
meet the expected pattern of 
progression for the disease under 
study.
Please note, when there is evidence suggesting a causal relationship 
between the drug and the progression of the underlying disease, the 
event must be reported as (S)AE.
Exempted events are monitored at appropriate intervals by an 
independent committee such as the Safety Monitoring Committee. 
[…]
5.2.5
Electrocardiogram
A 12-lead resting electrocardiogram (ECG) will be performed in all 
patients at the screening visit and at the beginning of each cycle 
(except for cycle 1) and at the EOT visit. The ECG will be assessed 
for pathological results (to be recorded as either baseline condition, 
concomitant disease or AE) by the investigator. Additional 
examinations should be done whenever the investigator deems 
necessary.
For safety monitoring 12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 -
V6) will be recorded using an electrocardiograph.
All ECGs will be recorded for a 10 second duration after the 
subjects have rested for at least 5 min in a supine position. […]
5.5.1
Pharmacokinetic endpoint(s)
If data allow, the following pharmacokinetic parameters will be 
evaluated using non-compartmental analysis methods according to 
the internal BI Standard Operating Procedure
(SOP).
Secondary pharmacokinetic endpoint is: 

Serum concentration at steady state (Css) for c.i.v. 


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5.6.1.4 Immunophenotyping
Diagnostic multiple myeloma flow cytometry including MRD
Analysis of myeloma cells in bone marrow will be conducted using 
a diagnostic flow cytometry panel including markers for CD45, 
CD38, CD19, CD138, CD56 and kappa/lambda chains. The analysis 
will be performed centrally. In order to assess minimal residual 
disease the flow cytometric panel may include 6-color-analysis such 
as cytIgλ /cytIgkappa/CD19/CD56/CD38/CD45 and 
cytIgλ/CD19/cytIg kappa/CD138/CD38/CD45 (R14-4637). 
Modifications according to updated guidance are possible. 


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10 6 INVESTIGATIONAL PLAN
[…]
6.2.2
Disease and Response Assessments for Multiple Myeloma
Clinical disease status for multiple myeloma will be assessed at 
screening, at the start of each cycle as well as at EOT. 
At screening and subsequently the evaluation of multiple myeloma 
will be done according to IMWG (2006).
If a patient has clinical symptoms of multiple myeloma at screening, 
they should be recorded as baseline conditions.
Biomarkers in blood and urine will be done according to specific 
Flow chart for biomarkers.
Total body MRI should be performed within 14 days before day 1, 
cycle 1; results from routine assessments (MRI) for multiple 
myeloma are accepted if performed no later than 28 days before 
start of treatment.
Total body MRI should be performed at or within 14 days before 
day 1, cycle 3; day 1, cycle 5; day 1, cycle 7 as well as every other 
cycle thereafter and at time of EOT or at time of progression or start 
of further anticancer therapy.
Bone marrow aspirates will be done within 14 days before day 1 
cycle 1 or at cycle 1, day 1 before start of treatment, when M 
protein/FLC becomes undetectable during treatment, at day 29 of 
cycle 3 and at EOT. 
For karyotyping the recent analysis will be accepted if performed 
within 3 months prior to start of study medication in case that no 
therapy has been given between assessment of karyotyping and 
study medication; otherwise, a baseline karyotype should be 
performed at screening; subsequent karyotyping could be performed 
in subsequent marrow samples.
The biomarker assessments will be performed as specified in the 
Flow charts. A bone marrow biopsy should be performed if aspirate 
could not be obtained (punctio sicca).
One sample of bone marrow will be provided for DNA banking in 
case that the patient has given consent for pharmacogenetic testing 
(baseline bone marrow, a bone marrow sample on treatment when a 
complete response is reached as well as during follow up). […]
6.2.4.1 
Cycle 1
Patients will be hospitalized for the first 3 – 4 days.
Table 6.2.4.1: 1
Visit 1 (Day 1-3 or 4)


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Physical
examination
(Section 5.2.6.2)
A general physical examination will be
performed, preferably by the same investigator
through the study to enable comparability.
This includes blood pressure, heart rate and 
temperature.
Additional time points for blood pressure, 
heart rate and body temperature at the day of 
start of administration of BI 836909 are: prior 
to the start of premedication and infusion, then 
every 30 (±10) minutes after start of the 
infusion of BI 836909 for the first 4 hours and 
additionally 3 times during hospitalisation (in 
the evening of day 1 as well as in the morning 
of day 2 and 3). 
Orienting neurological examination daily 
during hospitalisation.
Weight
(Section 5.2.6.2)
Weight is measured; preferably, the same
weight scale should be used throughout the
study to ensure consistency of data collected.
PK samples
(Section 5.5 and 
Section 5.2.5)
For PK sampling, see separate Flow chart and 
Section 5.5
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation
parameters and urinalysis (dipstick).
Adverse events
(section 5.2.2)
Occurance of AEs since last visit. 
[…]
Table 6.2.4.1: 3
Visit 5 (Day 29 and day 30)
Physical 
examination
and 
 
A general physical examination will be 
performed, preferably by the same 
investigator through the study to enable 
comparability. This includes blood pressure, 
heart rate and temperature.


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PK samples
(Section 5.5 and 
Section 5.2.5)
For PK sampling, see separate Flow chart and 
Section 5.6.

10 minutes before the end of continuous 
infusion or 

24 hours after stop of treatment (day 30)
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation
parameters and urinalysis (dipstick).
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant
therapies
(Section 4.2)
Any new or any change in concomitant
therapies since the last visit, will be recorded
in the eCRF.
[…]
6.2.4.2 
Cycle 2 – 5 (or further cycles in case more than 5 
cycles are administered)
Table 6.2.4.2: 1 Cycle 2 – 5 (or further cycles): Visit 1 (day 1)
Patient will be hospitalized for at least 24 hours.
Physical
examination
(Section 5.2.6.2)
A general physical examination will be
performed, preferably by the same investigator
through the study to enable comparability.
This includes blood pressure, heart rate and 
temperature. Orienting neurological 
examination daily during hospitalisation. 


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Weight
(Section 5.2.6.2)
Weight is measured; preferably, the same
weight scale should be used throughout the
study to ensure consistency of data collected.
ECG/PK samples
(Section 5.5 and 
Section 5.2.5)
For PK sampling, see separate Flow chart and 
Section 5.5. A 12-lead ECG will be done at 
the start of each cycle. 
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation
parameters and urinalysis (dipstick).
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant
therapies
(Section 4.2)
Any new or any change in concomitant
therapies since the last visit, will be recorded
in the eCRF.


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Disease assessment:
Clinical, MRI and 
blood and urine 
markers
(Section 5.6.1)
Clinical: if patient has any new clinical
symptoms of multiple myeloma, these should
be recorded in the “disease
assessment” page and as an AE when 
applicable (see
Section 5.2.2.1).
MRI should be performed every other cycle:
at or within 14 days before cycle 3, 
day 1, cycle 5, day1, cycle 7, day 1… 
and/or at time of progression or start of further 
anticancer therapy;
Administration of 
BI 836909
(Section 4.1)
4 weeks continuous intravenous infusion via 
infusion pump. Infusion bags must be 
exchanged approximately every 4 days 
Call IWRS/
Administer BI 
836909
The IWRS system needs to be accessed (see
Section 4.1.4.2) before any BI 836909 is 
administered to the patient. Dispense medication 
for the first course of treatment (see  Section  
4.1.4), as directed by the IRT system.
[…]
6.2.5.2 Residual effect period (REP)
The REP is defined in Section 5.2.3. 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 AEs that occurred after EOT and a 
follow-up of adverse events ongoing at EOT. Any subsequent anti-
cancer therapy administered between EOT and REP visit must be 
documented to allow an assessment of newly reported AEs as well 
as patient`s status. .


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Table 6.2.5.3: 1
Residual effect period (REP)
Adverse events
(Section 5.2.2)
All AEs, SAEs, AESIs regardless of 
relatedness. This includes all deaths.
Patient status
Collect information for progression or relapse,
death, lost to follow-up.
Other therapy for 
Multiple Myeloma
In case the patient receives other therapy for 
Multiple Myeloma
11 7. STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
[…]
7.3
PLANNED ANALYSES
Only one analysis population (the treated set, see definition below) 
will be considered for efficacy and safety analyses. No Per 
protocol population will be used for analyses. However important
protocol violations will be described.
Treated Set consists of all patients who received at least one 
application of BI 836909.
7.3.1 Primary endpoint analyses
In order to identify the MTD, the number of patients with DLTs 
during the first course at each dose level will be displayed 
descriptively by dose level. 
In addition, the number of patients with all DLTs during any 
treatment course will be analysed. Analysis of other adverse events 
and laboratory parameters is described in Section 7.3.4. […]
7.3.5 Pharmacokinetic analyses
The secondary pharmacokinetic endpoint Css
 
will be 
descriptively explored, and if possible, dose proportionality will 
also be explored descriptively. Attainment of steady state will be 
determined by visual examination of the data. […]


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7.4
INTERIM ANALYSES
An interim analysis will be performed as soon as the MTD is 
determined. To be specific, the date of Last Patient Out is defined 
by the date when the subject number 6 treated at MTD has 
completed cycle 1 including 2 weeks off-period before 6 additional 
subjects enter. This analysis will be restricted to the following 
aspects: 

Safety evaluations including summary of patients with DLT 
(See Sections 7.3.4 and 7.3.1).

Pharmacokinetic evaluations (See Section 7.3.5).

Preliminary efficacy evaluations on objective response rate (See 
Section 7.3.2).
The analyses will be in descriptive nature. No inferential statistical 
analyses will be performed
Results of this evaluation will be documented within an interim 
report and archived. The analysis will be defined in more detail in 
the Trial Statistical Analysis Plan.
The sponsor will continuously monitor the safety. The sponsor and 
the investigators will perform safety evaluations regularly, and if 
considered necessary at additional ad hoc meetings. The evaluations 
will be unblinded to dose.
7.5.3 Pharmacokinetic assessment
In the noncompartmental analysis, concentration data identified 
with NOS, NOR, and NOA will not be considered. BLQ and NOP 
values in the lag phase will be set to zero. The lag phase is defined 
as the period between time zero and the first time point with a 
concentration above the quantification limit. All other BLQ/NOP 
values of the profile will be ignored. If the predose concentration is 
less than or equal to 5% of Css value in that subject, the subject’s 
data without any adjustments can be included in all 
pharmacokinetic measurements and calculations (i.e. the predose 
value will not be changed to zero). If the predose value is greater 
than 5% of Css, the subject should be dropped from all statistical 
evaluations. The individual pharmacokinetic parameters can be 
calculated and listed separately.
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of up to 50 subjects in this trial. The 
planned sample size is not based on a power calculation.


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10.2 FLOW CHART PHARMACOKINETIK ASSESSMENTS
BLOOD SAMPLING TIMES FOR PHARMACOKINETICS
Triple ECG for QTc assessment for previous expansion was deleted.
Rationale for change
BI 836909 has been out-licenced to AMGEN. Development of the 
solution for subcutaneous injection of BI 836909 will not be 
pursued by Amgen and therefore Arm B has been cancelled and 
therefore all part B related parts of the protocol have been deleted. 
The same is true for the expansion cohort for the continuous 
infusion with . BI 836909. Efficacy as well as safety of BI 836909 
will be tested within a newly designed study and therefore the 
previous expansion cohort was cancelled and all the expansion 
cohort related parts of the protocol have been deleted, but additional 
6 patients will be treated at MTD or recommended dose for the 
confirmation of MTD and safety. 
Also follow up visits beyond the REP visit have been cancelled and 
the respective parts of the protocol have been deleted because 
efficacy will be tested within a phase II study.
Additional cohorts have been included because no DLTs occurred 
up to now and more cohorts to detect MTD may be needed. The 
corresponding parts of the protocol have been updated accordingly.
For safety reason 
5.1.1 Endpoints efficacy 
The analysis of supportive care requirements (percentage […]) was 
cancelled due to small size of the amended study. 


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Date of CTP revision
07 Jun 2017
EudraCT number
2014-004896-22
BI Trial number
1351.1
BI Investigational 
Product(s)
BI 863909
Title of protocol
An open label, phase I, dose escalation study to characterize 
the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of intravenous  doses of BI 836909 in 
relapsed and/or refractory multiple myeloma patients
To be implemented only 
after approval of the 
IRB/IEC/Competent 
Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified 
of change with request 
for approval
Can be implemented 
without IRB/IEC/ 
Competent Authority 
approval as changes 
involve logistical or 
administrative aspects 
only
Sections to be changed
1. Synopsis, Titel page and Methodology 
2. Footnote 8 of Flow chart: BI 836909 
CONTINUOUS INTRAVENOUS INFUSION
4. Section 3.1; Table 3.1:1 and foot notes
5. Section 4.1.4; Table 4.1.4:1 and footnotes
6. Section 5.1.2.1
7. Section 5.6.1.1
8. Section 6.2.3; Table 6.2.3:1
9. Section 6.2.4; Table 6.2.4:2
10. Section 6.2.5.1; Table 6.2.5.1:1


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Description of change
1.
The following on the Titel page:
Trial Clinical Monitor:
Was changed to 
Trial Clinical Monitor:
The following for Methodology within synopsis
……
The following dose cohorts will be tested within the above-
mentioned dose range:
• 3.2, 6.5, 13, 25, 50, 100, 200 and 400 µg/day and higher 
doses if MTD has not yet been established. Additional and 
intermediate dose cohorts will be entered if determined by 
the safety committee.
Was changed to:
…..
The following dose cohorts will be tested within the above-
mentioned dose range:
3.2, 6.5, 13, 25, 50, 100, 200, 400 and 800 µg/day. 
Intermediate dose cohorts with 50% increments of 
previous dose will be entered if determined by the safety 
committee. 
2.
Flow Chart: CONTINUOUS INTRAVENOUS 
INFUSION
The following was added to foot note 8
Percentage (%) of plasma cells in bone marrow should be 
assessed locally according to institutional standards and 
documented in eCRF.


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Number of global 
amendment
3
4.   Section 3.1; Table 3.1:1and foot notes
the following:
Dose 
level
Dose µg/d
Patients per 
cohort
Approximate 
increment to next 
dose
1
0.2
1
2x
2
0.4
1
2x
3
0.8
1
2x
4
1.6
1
2x
5
3.2
3 (+3)
2x
6
6.5
3 (+3)
2x
7
13
3 (+3)
2x
8
25
3 (+3)
2x
9
50
3 (+3)
2x 
10
100
3 (+3)
2x 
11
200
3 (+3)
2x
12
400*
3 (+3)
2x
*further doses will be tested in case that MTD could not be 
confirmed at a dose level of 400 µg/day. Intermediate dose 
cohorts will be entered if determined by the safety 
committee, for example, in case that the dose cohort 400 
µg/day exceeds MTD (> 1 patient out of 6 with DLT) and 
no DLT is observed on 200 µg/day consider 300 µg/day,
was changed to:
Dose 
level
Dose 
µg/d
Patients per 
cohort
Approximate 
increment to 
next dose
1
0.2
1
2x
2
0.4
1
2x
3
0.8
1
2x
4
1.6
1
2x
5
3.2
3 (+3)
2x
6
6.5
3 (+3)
2x
7
13
3 (+3)
2x
8
25
3 (+3)
2x
9
50
3 (+3)
2x 
10
100*
3 (+3)
2x 


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Number of global 
amendment
3
11
200*
3 (+3)
2x
12
400*
3 (+3)
2x
13
800*
3 (+3)
2x
*Intermediate dose cohorts with up to 50% increment 
versus the previous cohort will be entered if determined by 
the safety committee,in case that the dose of a cohort  
exceeds MTD (> 1 patient out of 6 with DLT) and the 
previous cohort is well tolerated. 
For example:
- 75µg/day in case a dose of 100µg/day exceeds MTD
150µg/day in case a dose of 200µg/day exceeds MTD
- 300µg/day in case a dose of 400µg/day exceeds MTD
- 600µg/day in case a dose of 800µg/day exceeds MTD
The above-mentioned intermediate dose cohorts will follow 
the 3 (+3) design.
5.    Section 4.1.4; Table 4.1.4:1 and footnotes
The following:
……
Table 4.1.4: 1
Dose escalation scheme
Dose 
µg/day
Patients 
per 
cohort
Observation time of ongoing 
patients before enrolment/entry 
of next patient/cohort
0.2
1
2 weeks, then enrol next cohort
0.4
1
As in previous cohort
0.8
1
As in previous cohort
1.6
1
As in previous cohort
3.2
3 (+3)
1 week for first patient, then 
enter next two patients; 
additional patients should not 
start treatment before the 
previous patient has been 
treated for 48 hours in order to 
monitor initial transient 
toxicities due to cytokine 
release syndrome. All 3 must 
have completed 4 weeks before 
enrolling next cohort
6.5
3 (+3)
As in previous cohort
13
3 (+3)
As in previous cohort
25
3 (+3)
As in previous cohort
50
3 (+3)
As in previous cohort


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3
100
3 (+3)
As in previous cohort
200
3 (+3)
As in previous cohort
400….*
3 (+3)
As in previous cohort
*further and intermediate dose cohorts may be added
was changed to:
Table 4.1.4: 1
Dose escalation scheme
Dose 
µg/day
Patients 
per 
cohort
Observation time of ongoing 
patients before 
enrolment/entry of next 
patient/cohort
0.2
1
2 weeks, then enrol next 
cohort
0.4
1
As in previous cohort
0.8
1
As in previous cohort
1.6
1
As in previous cohort
3.2
3 (+3)
1 week for first patient, then 
enter next two patients; 
additional patients should not 
start treatment before the 
previous patient has been 
treated for 48 hours in order to 
monitor initial transient 
toxicities due to cytokine 
release syndrome. All 3 must 
have completed 4 weeks 
before enrolling next cohort
6.5
3 (+3)
As in previous cohort
13
3 (+3)
As in previous cohort
25
3 (+3)
As in previous cohort
50
3 (+3)
As in previous cohort
100
3 (+3)
As in previous cohort
200
3 (+3)
As in previous cohort
400
3 (+3)
As in previous cohort
800
3 (+3)
As in previous cohort
*Intermediate dose cohorts may be added based on decision of the safety 
committee (see table 3.1:1) and will follow the above-mentioned rules. 
6.    Section 5.1.2.1
The following 


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…………..
The following laboratory parameters must be evaluated to 
assess response of treatment:
•Multiple myeloma (MM) cells in bone marrow
Analysis of myeloma cells in bone marrow will be 
conducted using a diagnostic FACS panel including 
markers for CD45, CD38, CD19, CD138, CD56 and 
kappa/lambda chains. Scheduled sampling time points will 
be as follows (see flow charts): within 14 days before day 1 
cycle 1or in cycle 1, day 1 before start of treatment, when 
M protein/FLC becomes undetectable during treatment, on 
day 29 of cycle 3 and at EOT.  The analysis will be 
performed centrally.
…………
Was changed to:
….
The following laboratory parameters must be evaluated to 
assess response of treatment:
•Multiple myeloma (MM) cells in bone marrow
Analysis of myeloma cells in bone marrow will be 
conducted using a diagnostic FACS panel including 
markers for CD45, CD38, CD19, CD138, CD56 and 
kappa/lambda chains. Scheduled sampling time points will 
be as follows (see flow charts): within 14 days before day 1 
cycle 1or in cycle 1, day 1 before start of treatment, when 
M protein/FLC becomes undetectable during treatment, on 
day 29 of cycle 3 and at EOT.  The analysis will be 
performed centrally.
Percentage (%) of plasma cells in bone marrow should 
be assessed locally according to institutional standards 
and documented in eCRF at each timepoint.
….
7.  Section 5.6.1.1
The following:
…….
Was changed to:


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8.    Section 6.2.3
The following:
………
Bone marrow
aspirate for disease 
assessment and 
DNA banking of 
bone marrow
(Section 5.6.1)
Karyotyping: recent analysis will be 
accepted if performed within 3 months 
prior to start of study medication in 
case that no therapy has been given 
between assessment of karyotyping 
and study medication; otherwise, a 
baseline karyotype should be 
performed at screening; subsequent 
karyotyping could be performed in 
subsequent marrow samples.
The following assessments will be 
performed (see Flow charts): 

MM cells in bone marrow

BCMA expression by 
myeloma cells in bone marrow
Obtain bone marrow biopsy if aspirate
could not be obtained (punctio sicca).
One sample of bone marrow will be 
provided for DNA banking.


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amendment
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Disease assessment:
Clinical/MRI and
blood/urine
(Section 5.6.1)
Evaluation of multiple myeloma 
according to IMWG (2006)
Clinical: if patient has clinical
symptoms of Multiple
Myeloma, they should be recorded as 
baseline conditions.
Total body MRI should be performed; 
results from routine assessments 
(MRI) for multiple myeloma are 
accepted if performed no later than 28 
days before start of treatment.
Biomarkers in blood and urine 
according to specific Flow chart for 
biomarkers:
Adverse events
(Section 5.2.2)
Occurrence of AEs since signing the 
Informed Consent Form will be 
documented. For patients who become 
screen failures, if an AE occurs during 
this period, the patient should be 
followed until the PI determines the 
patient is a screen failure.
Concomitant 
therapies
(Section 4.2)
All concomitant therapies (including 
transfusions and anti- infectives) at 
trial entry and/or during screening will 
be recorded in the eCRF.
Was changed to:


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Bone marrow
aspirate for disease 
assessment and 
DNA banking of 
bone marrow
(Section 5.6.1)
Karyotyping: recent analysis will be 
accepted if performed within 3 months 
prior to start of study medication in case 
that no therapy has been given between 
assessment of karyotyping and study 
medication; otherwise, a baseline 
karyotype should be performed at 
screening; subsequent karyotyping 
could be performed in subsequent 
marrow samples.
The following assessments will be 
performed (see Flow charts): 

MM cells in bone marrow; 
percentage (%) of plasma cells 
in bone marrow should be
assessed locally according to 
institutional standards and 
documented in eCRF.

BCMA expression by myeloma 
cells in bone marrow
Obtain bone marrow biopsy if aspirate
could not be obtained (punctio sicca).
One sample of bone marrow will be 
provided for DNA banking.


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Disease
assessment:
Clinical/MRI and
blood/urine
(Section 5.6.1)
Evaluation of multiple myeloma 
according to IMWG (2006)
Clinical: if patient has clinical
symptoms of Multiple
Myeloma, they should be recorded as 
baseline conditions.
Total body MRI should be performed; 
results from routine assessments (MRI) 
for multiple myeloma are accepted if 
performed no later than 28 days before 
start of treatment.
Adverse events
(Section 5.2.2)
Occurrence of AEs since signing the 
Informed Consent Form will be 
documented. For patients who become 
screen failures, if an AE occurs during 
this period, the patient should be 
followed until the PI determines the 
patient is a screen failure.
Concomitant 
therapies
(Section 4.2)
All concomitant therapies (including 
transfusions and anti- infectives) at trial 
entry and/or during screening will be 
recorded in the eCRF.


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9.    Section 6.2.4, table 6.2.4.2:2
……
Table 6.2.4.2: 2     Cycle 2 – 5 (or further cycles): Visit 2 - 4
Physical
examination
(Section 5.2.6.2)
A general physical examination will be
performed, preferably by the same
investigator through the study to enable
comparability. This includes blood 
pressure, heart rate and temperature.
Weight
(Section 5.2.6.2)
Weight is measured; preferably, the
same weight scale should be used 
throughout the study to ensure
consistency of data collected.
ECG/PK samples
(Section 5.5 and 
5.2.5)
For PK sampling, see separate Flow 
chart and Section 5.5. A 12-lead ECG 
will be done at the start of each cycle.
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation
parameters and urinalysis (dipstick).
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant
therapies
(Section 4.2)
Any new or any change in concomitant
therapies since the last visit, will be
recorded in the eCRF.


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Disease
assessment:
clinical and blood 
and urine markers
(Section 5.6.1)
Clinical: if patient has any new clinical
symptoms of
multiple myeloma, these should be
recorded in the “disease
assessment” page and as an AE when 
applicable (see Section 5.2.2.1).
Bone Marrow
Bone marrow aspirate will be done on 
day 29 of cycle 3:
The following assessments will be 
performed:

MM cells in bone marrow

BCMA expression by myeloma 
cells in bone marrow

MRD (in case M protein/FLC 
becomes undetectable)
Obtain bone marrow biopsy if aspirate 
could not be obtained (punctio sicca).
One sample of bone marrow will be 
provided for DNA banking.
…..
Was changed to:
….. 


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Physical
examination
(Section 5.2.6.2)
A general physical examination will be
performed, preferably by the same
investigator through the study to enable
comparability. This includes blood 
pressure, heart rate and temperature.
Weight
(Section 5.2.6.2)
Weight is measured; preferably, the same
weight scale should be used throughout
the study to ensure consistency of data
collected.
ECG/PK samples
(Section 5.5 and 
5.2.5)
For PK sampling, see separate Flow 
chart and Section 5.5. A 12-lead ECG 
will be done at the start of each cycle.
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation
parameters and urinalysis (dipstick).
Adverse events
(Section 5.2.2)
Occurrence of AEs since last visit.
Concomitant
therapies
(Section 4.2)
Any new or any change in concomitant
therapies since the last visit, will be
recorded in the eCRF.


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Disease
assessment:
clinical and blood 
and urine markers
(Section 5.6.1)
Clinical: if patient has any new clinical
symptoms of
multiple myeloma, these should be
recorded in the “disease
assessment” page and as an AE when 
applicable (see Section 5.2.2.1).
Bone Marrow
Bone marrow aspirate will be done on 
day 29 of cycle 3:
The following assessments will be 
performed:

MM cells in bone marrow; 
percentage (%) of plasma cells in bone 
marrow should be assessed locally 
according to institutional standards and 
documented in eCRF.

BCMA expression by myeloma cells 
in bone marrow

MRD (in case M protein/FLC 
becomes undetectable)
Obtain bone marrow biopsy if aspirate 
could not be obtained (punctio sicca).
One sample of bone marrow will be 
provided for DNA banking.


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Number of global 
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10. Section 6.2.5.1
The following:
Table 6.2.5.1:1 Visit at the end of Treatment (EOT)
ECG
(Section 5.2.5)
Resting 12-lead ECG (digital)
Physical
examination
(Section 5.2.6.2)
A general physical examination as well as 
an orientated neurological examination will
be performed, preferably by the same
investigator throughout the study to 
enable comparability. This includes 
Weight
(Section 5.2.6.2)
Weight is measured; preferably, the same
weight scale should be used throughout
the study to ensure consistency of data
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation
parameters, and urinalysis (dipstick).
Disease
assessment:
clinical and
blood/MRI
(Section 5.5.1)
Clinical: if patient has any new clinical 
symptoms of
multiple myeloma, these should be 
recorded in the “disease assessment” 
page and as an AE when applicable (see 
Section 5.2.2.1).
Total body MRA should be performed.


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Bone Marrow 
aspirate
(Section 5.6.1)
The following assessments will be 
performed:

MM cells in bone marrow; 
percentage (%) of plasma cells in bone 
marrow should be assessed locally 
according to institutional standards and 
documented in eCRF.

BCMA expression by myeloma cells 
in bone marrow

MRD (in case M protein/FLC 
becomes undetectable)
Obtain bone marrow biopsy if aspirate 
could not be obtained (punctio sicca).
One sample of bone marrow will be 
provided for DNA banking.
…
Was changed to:
ECG
(Section 5.2.5)
Resting 12-lead ECG (digital)
Physical
examination
(Section 5.2.6.2)
A general physical examination as well as 
an orientated neurological examination will
be performed, preferably by the same
investigator throughout the study to 
enable comparability. This includes 
Weight
(Section 5.2.6.2)
Weight is measured; preferably, the same
weight scale should be used throughout
the study to ensure consistency of data
Safety laboratory
(Section 5.2.4)
Haematology, biochemistry, coagulation
parameters, and urinalysis (dipstick).


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Number of global 
amendment
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Disease
assessment:
clinical and
blood/MRI
(Section 5.5.1)
Clinical: if patient has any new clinical 
symptoms of
multiple myeloma, these should be 
recorded in the “disease assessment” 
page and as an AE when applicable (see 
Section 5.2.2.1).
Total body MRA should be performed.
Bone Marrow 
aspirate
(Section 5.6.1)
The following assessments will be 
performed:

MM cells in bone marrow; 
percentage (%) of plasma cells in bone 
marrow should be assessed locally 
according to institutional standards and 
documented in eCRF.

BCMA expression by myeloma cells 
in bone marrow

MRD (in case M protein/FLC 
becomes undetectable)
Obtain bone marrow biopsy if aspirate 
could not be obtained (punctio sicca).
One sample of bone marrow will be 
provided for DNA banking.
Rationale for change
1. Change in responsibility
2. Request of the Germany authority PEI to define the 
highest dose as well as the intermediate doses
3. Correlation between soluable BCMA and free drug; 
it is important to know the sBCMA levels before 
start of treatment; therefore one additional sampling 
of sBCMA has been implemented
4. Necessity of documentation of % of plasma cells in 
bone marrow for response assessment. 


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Number of global 
amendment
4
Date of CTP revision
26 Nov 2018
EudraCT number
2014-004896-22
BI Trial number
1351.1
BI Investigational 
Product(s)
BI 863909
Title of protocol
An open label, phase I, dose escalation study to characterize 
the safety, tolerability, pharmacokinetics, and 
pharmacodynamics of intravenous  doses of BI 836909 in 
relapsed and/or refractory multiple myeloma patients
To be implemented only 
after approval of the 
IRB/IEC/Competent 
Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified 
of change with request 
for approval
Can be implemented 
without IRB/IEC/ 
Competent Authority 
approval as changes 
involve logistical or 
administrative aspects 
only
Sections to be changed
1. Titel page 
2. Flow Chart, Section 3.1, Section 6.2.5.3
3. Section 2.3
4. Section 4.1.4.1.4
5. Section 4.2.1.2.3
6. Appendix 10.1


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Number of global 
amendment
4
Description of change
1. The following on the Titel page:
Trial Clinical Monitor
Was changed to 
Clinical Trial Leader
2.
FlowChart, Section 3.1 Overall trial design and plan, 
Section 6.2.5.3 Extended follow up
Wording was introduced to allow for extended follow up 
for responders:
In case of ongoing clinical benefit, patients can be followed 
up to collect data for duration of response. Follow-up visits 
for responders will be at 3, 6 and 12 months after EOT if a 
patient did not progress, started a new anti-cancer 
treatment, died, or withdrew informed consent and will 
assess related SAEs and AESIs.
3.
2.3 Benefit-Risk Assessment
The following was added:
Cytokine release can be associated with clinical 
symptoms such as fever, chills, nausea, vomiting, 
hypotension, dyspnoea, tachypnea, headache, 
tachycardia, rash, and/or hypoxia. 
4.
4.1.4.1.4 Handling of infusion-related reactions or 
cytokine release syndromes
Recommendations for CRS management were modified 
and Table 4.1.4.1.4: 1 Grading and management of 
cytokine release syndrome was added.
5.
4.2.1.2.3 Infections
The following was added:
Prophylactic antibiotics, antifungal and antivirals are 
allowed and should be given according to institutional 
standards. Pneumocystis prophylaxis should also be given 
according to institutional standards. For patients who are 
considered to have an increased risk for herpes infections, 
the prophylaxis is mandatory unless medically 
contraindicated. Subjects who may experience neutropenia 
for 7 days or longer are at a high risk for infectious 
complications. As appropriate, these subjects will be 
administered prophylactic antibacterial, antifungal, and 
antiviral medications. These subjects will be monitored for 
early signs of breakthrough infections after the initiation of 
antibacterial therapy to prompt additional evaluation and 


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BI Trial No.: 1351.1
Doc. No.: c02587386-05
Trial Protocol
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Number of global 
amendment
4
possible therapy modification. 
Infections should be treated according to local 
guidelines/standards. 
Patients who develop fever >38.3°C or a sustained 
temperature of >38°C ≥1 h will be hospitalised, undergo the 
following diagnostic work-up and started on empirical 
treatment with broad spectrum i.v. antibiotics according to 
institutional standards:
-
Blood cultures from central line and peripheral veins 
-
Urine culture 
-
CT-Thorax low dose 
-
Respiratory virus by pharyngeal wash (Parainfluenza 1-
4, Influenza A + B, Adenovirus, Metapneumovirus, 
Echovirus, Rhinovirus, Bocavirus, Coronavirus, 
Entrovirus und RSV by multiplex PCR) 
Subjects with active systemic infections requiring IV 
antibiotics, antivirals, or antifungals should not be dosed 
with BI 836909 until infection has resolved and if being 
treated with an anti-infectious therapy, the course of such 
therapy should have been completed. 
Patients requiring interruption of treatment for >14 days due 
to active infection will be permanently discontinued.
6.
10.1 International Myeloma Working Group (IMWG) 
uniform resonse criteria for multiple myeloma
The following was added:
SD – Not meeting criteria for CR, VGPR, PR, or 
progressive disease
Rationale for change
1.
Change in nomenclature
2.
Collection of data for long-term responders
3.
Request of the French authority ANSM to add 
additional clinical signs and symptoms as described in 
CTCAE v5 in order to enhance investigators’ awareness 
for occurrence of CRS clinical events. However, the 
grading of CRS will continue to be based on CTCAE v4 
until completion of the trial.
4.
Request of the French authority ANSM to add risk 
minimization measures and detailed procedures in case 
of suspicion of CRS.
5.
Correction/completion of IMWG criteria.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02587386
5.0
clinical-trial-protocol-revision-04
An open label, phase I, dose escalation study to characterize the safety, tolerability,
pharmacokinetics, and pharmacodynamics of intravenous doses of BI 836909 in
relapsed and/or refractory multiple myeloma patients
Author-Clinical Trial Leader
26 Nov 2018 10:38 CET
Approval-Therapeutic Area 
26 Nov 2018 10:47 CET
Approval-Translational Medicine
Expert
26 Nov 2018 10:52 CET
Approval-Translational Medicine
Expert
26 Nov 2018 11:00 CET
Approval-Biostatistics
26 Nov 2018 14:46 CET
Author-Trial Clinical
Pharmacokineticist
26 Nov 2018 21:49 CET
Approval-Team Member Medicine
27 Nov 2018 10:42 CET
Verification-Paper Signature
Completion
29 Nov 2018 07:17 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02587386
5.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c17409411-02
BI Trial No.:
1351.1
Title:
An open label, phase I, dose escalation study to characterize the 
safety, tolerability, pharmacokinetics, and pharmacodynamics of 
intravenous doses of BI 836909 in relapsed and/or refractory 
multiple myeloma patients
Including revised Protocol Amendment c02587386-04
Investigational
Product:
BI 836909
Responsible trial 
statistician:
  Phone:
  Fax:
Date of statistical 
analysis plan:
07 Sep., 2018 SIGNED
Version:
Revised
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reserved.
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.6.1
Safety data and other data .................................................................................16
6.6.2
AE dates and times..............................................................................................16
6.6.3
Missing plasma concentrations and pharmacokinetic parameters................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................17
7.
PLANNED ANALYSIS......................................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................19
7.3
TREATMENT COMPLIANCE........................................................................19
7.4
PRIMARY ENDPOINTS...................................................................................19
7.5
SECONDARY ENDPOINTS.............................................................................19
7.5.1
Key secondary endpoint .....................................................................................19
7.5.2
Other Secondary endpoints................................................................................19
7.7
EXTENT OF EXPOSURE.................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................21


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7.8.2
Laboratory data ..................................................................................................22
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................23
8.
REFERENCES....................................................................................................24
10.
HISTORY TABLE..............................................................................................26


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LIST OF TABLES
Table 6.1: 1 
Treatment labels for use in CTR ......................................................................12
Table 6.1: 2
Definition of treatment periods ........................................................................13
Table 6.2: 1
Important protocol deviations ..........................................................................14
Table 6.3: 1
Subject sets analysed........................................................................................16
Table 10: 1
History table .....................................................................................................26


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the tSAP
Term
Definition / description
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BCMA
B-cell maturation antigen
BI
Boehringer Ingelheim
BRPM
Blinded Report Planning Meeting
CR
Complete response
CRS
Cytokine release syndrome
CTC
Common Terminology Criteria  
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DLT
Dose limiting toxicity
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DOR
Duration of response
ECG
Electrocardiography
ECOG
Eastern Cooperative Oncology Group
ICH
International Conference on Harmonisation
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IMWG
International Myeloma Working Group
i.v.
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
MRD
Minimal residual disease
MTD
Maximum tolerated dose
PD
Progressive disease


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Term
Definition / description
PFS
Progression free survival
PK
Pharmacokinetics
PR
Partial response
PT
Preferred term
PD
Protocol deviation
Q1
Lower quartile
Q3
Upper quartile
RPM
Report planning meeting
SC
Safety committee
sCR
Stringent complete response
SOC
System organ class
TSAP
Trial statistical analysis plan
VGPR
Very good partial response


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3.
INTRODUCTION
As per ICH E9 [1], the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
SAS® Version 9.4 or newer version will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary objective is to assess the safety of BI 836909 in humans and to determine the 
maximum tolerated dose (MTD). The primary endpoints are the following:
•
MTD of BI 836909: MTD is defined as the highest dose of the dose level tested where 
≤ 1 patient out of 6 develops dose limiting toxicity (DLT)
•
Number of patients with DLTs
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
5.2.2
Secondary endpoints

Objective response rate (percentage of patients with stringent complete response 
(sCR), complete response (CR), partial response (PR) and very good partial response 
(VGPR))

Duration of response (DOR)

Minimal residual disease (MRD)

Duration of MRD response

Progression-free survival (PFS)
      Secondary pharmacokinetic endpoint is:

Serum concentration at steady state (Css) for c.i.v.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Patients are administered BI 836909 as a continuous 4-week infusion followed by a 2-week 
break for 5 cycles or until progression, unacceptable adverse events or other reason 
necessitating withdrawal. In case of ongoing clinical benefit a maximum of 5 additional 
treatment cycles can be given.
Figure 6.1:1
Overall study design
For all analyses, statistics will be tabulated by treatment dose group (see Table 6.1: 1).


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Table 6.1: 1 
Treatment labels for use in the CTR
Treatment label
Short label
BI 836909, 0.2 μg/d, c.i.v.[1]
0.2 μg/d civ
BI 836909, 0.4 μg/d, c.i.v. [1]
0.4 μg/d civ
BI 836909, 0.8 μg/d, c.i.v. [1]
0.8 μg/d civ
BI 836909, 1.6 μg/d, c.i.v. [1]
1.6 μg/d civ
BI 836909, 3.2 μg/d, c.i.v.
3.2 μg/d civ
BI 836909, 6.5 μg/d, c.i.v.
6.5 μg/d civ
BI 836909, 13 μg/d, c.i.v.
13 μg/d civ
BI 836909, 25 μg/d, c.i.v.
25 μg/d civ
BI 836909, 50 μg/d, c.i.v.
50 μg/d civ
BI 836909, 100 μg/d, c.i.v.
100 μg/d civ
BI 836909, 200 μg/d, c.i.v.
200 μg/d civ
BI 836909, 400 μg/d, c.i.v.
400 μg/d civ
BI 836909, 800 μg/d, c.i.v.[2]
800 μg/d civ
[1] The 1st four treatment label (0.2 – 1.6 µg/d) may be combined into one column for selected displays.
[2] Further doses will be tested in case that MTD could not be confirmed at a dose level of 800 μg/day. 
Intermediate doses cohorts will be entered if determined by the safety committee, for example, in case that the 
dose cohort 400 μg/day exceeds MTD (>1 patients out of 6 with DLT) and no DLT is observed on 200 μg/day, 
300 μg/day might be considered.
The purpose of the definition below is to describe the different study interval in this trial.
The treatment periods of the study are:

Screening period:
The screening period starts from the date of informed consent and ends at the date of 
the first administration of study drug.

Treatment period:


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Treatment period starts from the date of the first administration of study drug and 
ends at the date of the last administration of study drug. 

Residual effect period:
Residual effect period starts from the date of the last administration of study drug + 1, 
and ends at the date of the last administration of study drug + 30 days .

Follow-up period;
The Follow-up period starts from the last administration of study drug + 30 days. 
Please see Table 6.1:2 below, for a definition of treatment periods. The purpose of the 
definitions below is to describe the treatment periods in this trial.  
Table 6.1: 2
Definition of treatment periods
Analyzing Treatment 
Period
Start Date 
Start Time
End Date
Screening
Date of informed consent
Date of the first 
administration of 
BI 836909
Treatment
Date of the first 
administration of BI 836909 
Time of the first 
administration of BI 
836909 
Date of the last 
administration of 
BI 836909 
Residual effect period
Date of the last 
administration of BI 836909  
+ 1 day
Date of the last 
administration of 
BI 836909  + 30
day
Post-treatment 
Date of the last 
administration of BI 836909  
+ 31 day
Not applicable
For safety analyses, adverse events (AEs) will be classified to one of the following time 
periods: “Screening”, “Treatment”, or “Post-treatment”. Section 5.2.2 of the protocol 
specifies that all AE reported within 30 days of the last trial medication will be considered on 
treatment. Detailed rule for assigning AEs to these time periods are listed below:

If the date of informed consent ≤ AE onset date < date of first administration of BI 
836909, then the AE is assigned to “Screening”;

If date of first administration of BI 836909 ≤ AE onset date ≤ date of last 
administration of BI 836909 + 30 days, then the AE is assigned to “Treatment”;

If AE onset date > date of last administration of BI 836909 + 30 days, then the AE is 
assigned to “Post-treatment”.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation (PD) is important if it affects the rights or safety of the study patients, or 
if it can potentially influence the primary outcome measurements in a non-negligible way.  
Patients with important PDs that could potentially impact the evaluation of the primary 
endpoints will be excluded (Refer to Section 6.3 Table 6.3:1).
A list of important PDs is given in Table 6.2: 1 below.  Important PDs will be reviewed at 
Medical Quality Review Meetings (MQRMs) conducted periodically during the trial.  A list 
of protocol deviations will be discussed at the Blinded Report Planning Meeting (BRPM). 
If the data show other important PDs, this table will be supplemented accordingly at MQRMs 
or RPMs or through team review of the manual PD log.  The decision whether a patient will 
be excluded from the analysis will be made at the final BRPM prior to DBL.
Table 6.2: 1
Important protocol deviations
Category
/ Code
Description
Requirements
Excluded 
from
A
Entrance criteria not met
A1
Inclusion criteria not met
A1.1
Disease severity for MM not met
Inclusion criteria (IN) 1 or 3 not met.
None
A1.2
Disease measurability not met
IN 2
None
A1.3
Requirements on ECOG status, age, 
ability to adhere to study visit schedule 
not met 
IN 5 or 6 not met
None
A2
Exclusion criteria met
A2.1
Certain prior or current disease 
conditions.
Exclusion criteria (EX) 1, 2, 3, 23, 24 
or 25 met
None
A2.2
Last anticancer or investigational 
treatment, transplantation
EX 4, 6, 7 or 21 met
None
A2.3
Pregnancy / breast feeding / 
contraception related
EX 17, 18 or 19 met
None
A2.4
Clinical relevant concurrent medical 
disease, infections or conditions
EX 9, 10, 11, 12, 13,14, 15 or 16 met
None
A2.5
Hypersensitivity to investigational drug
EX 22 met
None
B
Informed consent
B1
Informed consent not available/not done
Informed consent date missing
All
B2
Informed consent too late
Informed consent date was after 
Screening Visit date
None
B3
Outdated informed consent signed
e.g., Outdated version of informed 
consent with major change
None
C
Trial medication and randomisation
C1
Incorrect trial medication taken
Medication kit assigned not 
matching IVRS assignment
None


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Table 6.2: 1 (continued)
Important protocol deviations
Category
/ Code
Description
Requirements
Excluded 
from
C2
Non-compliance with BI 836909
Any patients with non-compliance 
issues as defined in Section 5.4.2 or 
other issue related such as 
manipulation of bump by patients.
None
C3
Improper preparation or administration 
of BI 836909 for IV infusion 
Create listing, decision at MQRM / 
RPM, see CTP Section 4.1.4 for drug 
preparations and mandatory pre-
medications. Check comment in the 
eCRF. 
None
D
Concomitant medication
D2
Prohibited medication use concomitantly 
with study medication
•
Chronic oral use of NSAIDs
•
Chronic systemic use of 
corticosteroids
•
Quinidine
•
Cytotoxic/myelosuppressive
, immunologic drugs or 
radiation therapy
None
F
Other category
F1
Other trial specific
Other protocol deviations deemed to 
be IPD from manual PD log, e.g., 
multiple procedures not performed 
correctly.
None
Note: Missing visits, evaluations, and tests will be considered missing data, not protocol deviations. All final 
decisions as to whether any deviation is relevant will be taken at the RPM.
6.3
SUBJECT SETS ANALYSED
All entered subjects who received trial medication will be included in the safety analysis and 
in the pharmacokinetic analysis set depending on the availability of measurement values and 
on their adherence to the CTP. The criteria for inclusion into these populations are defined as 
follows:
Populations: Please see below for the specified populations.
Treated set (TS): all patients who were administered study medication. This set of 
patients is used for all analyses except for analysis of PK data.
MTD evaluation set (MTDS): all patients in the TS who were not replaced for the MTD 
determination. Rules for replacement of patients were defined in CTP, Section 4.1.4.5. In 
addition safety committee will decide the replacement of patients.
PK Analysis Set (PKS): all evaluable patients in the treated set which provide at least 
one evaluable observation for at least one PK endpoint.


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The TS will be used for all efficacy and safety analyses. In addition, the MTDS represent the 
populated used for MTD determination. The primary analyses of DLTs during 1st cycle will 
be based upon the MTDS. PK analyses will be based on the PKS. Refer to Protocol Section 
7.3.5 on handling PK endpoints. 
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
Treated 
set
MTDS
PKS
Primary and key secondary
endpoints 
X
primary 
analysis
Other secondary and further 
endpoints 
X
Safety endpoints 
X
Demographic/baseline 
endpoints
X
PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Safety data and other data
In general, missing data will not be imputed and all reasonable efforts will be taken during 
the study conduct to obtain such data. Only observed values will be analysed. Data of 
subjects who withdrew after the screening examination or were not treated will be only listed.
6.6.2
AE dates and times
Missing or incomplete AE dates will be imputed according to BI standards (see DM&SM 
“Handling of missing and incomplete AE dates”). [3]
6.6.3
Missing plasma concentrations and pharmacokinetic parameters
Missing data and outliers of PK data are handled according to BI standards (see “Standards 
and processes for analyses performed within Clinical Pharmacokinetics/Pharmacodynamics”) 
[2].


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
In general, baseline values will be the measurements taken most recently prior to the first 
administration of study drug. If this value is not available, the measurement at screening visit 
will be used. If the lab is repeated at screening, then the last one should be used. 
For efficacy analyses, baseline is defined as the pre-treatment observation at C1V1. If C1V1 
is missing, then Screening will be used for baseline. 
Visit will be labelled according to the flow chart in the protocol: Study day will be calculated 
relative to the date of the first administration of study drug. The day prior to first 
administration of study drug will be ‘Day -1’ and the day of first administration of study drug 
will be ‘Day 1’; therefore ‘Day 0’ will not be used.
Clinical disease status will be assessed at screening and at the start of each new cycle (e.g., 
before Cycle 2, 3, 4 and 5, etc.) as well as EOT.
While nominal times listed in this section should be adhered to as closely as possible, the 
actual sampling times will be recorded and used for determination of pharmacokinetic 
parameters.


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7.
PLANNED ANALYSIS
For all the analyses in this open label phase I trial, patients will be included in the dose 
cohorts they were originally assigned to.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. The category “missing” will be displayed where applicable (i.e., 
if and only if there are actually missing values in the data). 
For in-text tables, the set of summary statistics is: N (number of patients with non-missing 
values), mean, standard deviation (SD), median, Q1 (lower quartile), Q3 (upper quartile), 
depending on the data. 
For end-of-text tables, the set of summary statistics is: N/Mean/SD/Q1/Median/Q3. For 
appendix tables, the set of summary statistics is: N/Mean/SD/Min/Q1/Median/Q3/Max.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Demographic and 
baseline characteristics collected and to be presented include

Gender  (Male/Female)

Age [years]

Race (as defined in the eCRF)

Body height [cm]

Body weight [kg]

Body mass index at baseline [kg/m2] 

Body surface area at baseline [m2]

Smoking status (as defined in the eCRF)

Alcohol status (as defined in the eCRF)

ECOG performance score (0/1/2)

Baseline cytogenetics

Time since first diagnosis [months]

ISS stage at screening (I/II/III)

Site of tumor manifestation at screening (Bone/CNS/Soft tissue plasmacytoma/Other)

Number of bony lesions (None/<10/≥10)

Sum of longest diameters of plasmacytomas if present [mm]


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
7.3
TREATMENT COMPLIANCE
Non-compliance is defined by any patients who are administered study medication less than 
14 days in any cycle (excluding those who discontinued per protocol, e.g., due to AE, or PD). 
Number of non-compliant patients will be summarized by descriptive statistics.
7.4
PRIMARY ENDPOINTS
In order to identify the MTD, the number of patients with DLTs during Cycle 1 at each dose 
level will be displayed descriptively by dose level with the lowest 4 doses pooled. In 
addition, the number of patients with DLTs during any treatment course will be analysed.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Other Secondary endpoints
Objective response rate (ORR)
Objective response rate is defined as the percentage of patients achieving a sCR, CR, PR and 
VGPR as evaluated by the investigator according to the response criteria of the International 
Myeloma Working Group. The objective response rate will be presented as the proportion of 
responders, with the exact 95% Clopper-Pearson confidence intervals. The best response 
(sCR > CR > PR > VGPR) across all assessment will be used and presented.
Duration of response (DOR)
For patients with objective response, the duration of response is calculated from the time of 
first recorded achievement of a response until documented progression or death. DOR will be 
summarized descriptively by quartiles if applicable. 
Minimal residual disease (MRD) response
MRD response is defined as <1 tumour cell within 104 normal cells in bone marrow using 
FACS analysis. MRD response rate will be calculated as the proportion of patients achieving 
MRD response with the exact 95% Clopper-Pearson confidence interval.
Duration of MRD response
For patients with MRD response, the duration of MRD response is calculated from the time 
of first recorded achievement of a MRD response until documented progression or death. 
Duration of MRD response will be summarized descriptively by quartiles if applicable. 


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Progression free survival (PFS)
PFS is defined as the time from first treatment with BI 836909 until disease progression or 
death. For patients who did not have any event (e.g., alive without progression), their PFS 
will be censored at date of last documented disease assessment. For patients without any 
events and no disease assessment performed post-baseline, their PFS will be censored at the 
date of treatment start. PFS will be summarized descriptively by quartiles with 95% 
confidence interval calculated from Kaplan-Meier estimate.
Pharmacokinetic analyses
The secondary pharmacokinetic endpoints Css, 
 
will be descriptively explored,
 
 
Refer to CTP Section 5.5.1 for pharmacokinetic parameters to be calculated. The derivation 
of the parameters will be according to BI’s standard operating procedures. Pharmacokinetic 
analyses of the plasma concentration-time data will be performed using a validated software 
program (Phoenix Winnonlin, version 6.3). The analysis of standard PK parameters is 
performed according to BI standards (see “Standards and processes for analyses performed 
within Clinical Pharmacokinetics/Pharmacodynamics”) [2].
7.7
EXTENT OF EXPOSURE
Extent of exposure will be summarized descriptively by total treatment time (days and 
number of courses), number of cycles initiated, average number of days of infusion per cycle, 
number of cycles with at least 14 days of infusion will be calculated; off-drug periods due to 
non-compliance or toxicity prior to permanent discontinuation will be included as treatment 
time. Standard descriptive summaries, by treatment group, of these data will be provided for 
the treated set. 


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set (TS). In addition, DLT occurred 
during course 1 will be tabulated based on the MTD evaluation set (MTDS).
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of subjects with AEs and NOT on the number 
of AEs.
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:
•
All AE attributes are identical (LLT, intensity, action taken, therapy required, seriousness, 
reason for seriousness, relationship, outcome, AE of special interest)
•
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).
For further details on summarization of AE data, please refer to [3, 4].
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till last drug 
intake + residual effect period will be assigned to the treatment. All adverse events occurring 
before first drug intake will be assigned to ‘screening’ and all adverse events occurring after 
the residual effect period will be assigned to ‘post-treatment’ (for listings only). For details 
on the treatment definition, see Section 6.1.
According to ICH E3 [5], AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious adverse events leading to treatment discontinuation or non-serious 
AEs leading to dose reduction.
An overall summary of adverse events will be presented. This summary will include the first 
6 categories from the list below and AEs by highest intensity graded according to CTCAE 
(version 4.03).
The frequency of subjects with adverse events will be summarised by treatment, primary 
system organ class and preferred term (mention MedDRA levels to be displayed in the 
tables).
Separate tables will be provided for patients with each of the following AE categories:

All AEs,

DLTs (Course 1 only1),

DLTs (All courses),

AEs leading to dose reduction,


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
AEs leading to treatment discontinuation,

Serious AEs,

Drug related AEs,

Drug related serious AEs,

CTCAE Grade 3 or higher AEs,

AEs leading to death,
[1]: Course 1 defined by from start of treatment to start of Cycle 2 or the last dose administration of 
BI 836909 during Cycle 1 + 30 days, whichever occurs earlier.
Separate tables will be provided for subjects with other significant adverse events according 
to ICH E3 [5], for subjects with adverse events of special interest (only if defined) and for 
subjects with serious adverse events.
The system organ classes will be sorted alphabetically, preferred terms will be sorted by 
frequency (within system organ class).
Additional AE tables will be produced for adverse events of special interest (AESIs):

Infusion-related reactions (CTCAE grade 3 or higher),

Cytokine release syndromes (CTCAE grade 3 or higher),

Tumour lysis syndrome,

CNS adverse events (CTCAE grade 2 or higher),

DLT,

Hepatic injury (defined in CTP Section 5.2.2.1).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards “Handling, Display and Analysis of Laboratory Data” [6]. The following analyses 
will be presented for all applicable laboratory parameters:

Descriptive statistics,

Frequency of patients with transitions in CTCAE grade from baseline to worst and 
last values during treatment,

Frequency of patients with possible clinically significant abnormalities.


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CTCAE version 4.03 grades will be applied to laboratory parameters using the current BI 
oncology standard [6]. Possible clinically significant abnormalities are defined as CTCAE 
grade of 2 or greater, with an increase of at least one grade from baseline.
Baseline is defined by the last available measurement before study drug administration. In 
cases of repeated measurements performed for the same visit the last observation will be used 
for tabulations.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
ECGs were collected with an adverse event recorded if the readout was associated with any 
clinical finding. 


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8.
REFERENCES
1. CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2. 001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
3. 001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
4. 001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
5. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version
6. 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
18-MAY-2017
None
This is the final TSAP 
Revised
07-SEP-2018
Title 
page
4
6.1
6.2
7.8.1
Delete “subcutaneous dose” from the 
title since that part is not included in the 
study any more. 
Change of responsible trial statistician.
The cut-off date for interim analysis and 
the interim last patient out (LPO) have 
been adjusted. 
The analysis content for the interim 
CTR has also been modified.
Update the overall study design scheme 
since part B and the long-term follow up 
is deleted from the study design.
Add one more row for the dose level of 
“800 μg/d, c.i.v” into Table 6.1:1.
Wording for the definition of “Residual 
effect period” has been updated to avoid 
confusion.
Change the terminology of ‘protocol 
violation’ to ‘protocol deviation’ per 
latest SOP 001-MCS-40-413.
Delete “or SC injection” from the 
description for the C3 category of iPD
and delete two duplicated rows for C2 
and C3 types of iPD in Table 6.2:1. 
Revise the definition of “Other 
significant AEs” based on the discussion 
during BRPM on July 24, 2018.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17409411
2.0
8-01-tsap
An open label, phase I, dose escalation study to characterize the safety,
Approval-Medical Writer
10 Sep 2018 16:03 CEST
Approval-Clinical Trial Leader
10 Sep 2018 16:13 CEST
Author-Trial Statistician
10 Sep 2018 20:28 CEST
Author-Trial Clinical
Pharmacokineticist
11 Sep 2018 16:15 CEST
Approval-Project Statistician
12 Sep 2018 21:40 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c17409411
2.0