Clinical trial NCT02516553
Conditions: Neoplasms NUT Carcinoma
Keywords: NUT midline carcinoma
Sponsor: Boehringer Ingelheim
Start date: 2015-07-08; Completion date: 2021-11-23
Enrollment: 174 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study is open to adults with different types of advanced cancer (solid tumours). The study is also open to patients with diffuse large B-cell lymphoma in whom previous treatment was not successful. In some countries, adolescents who are at least 15 years old and who are diagnosed with NUT carcinoma can also participate. No standard treatment exists for this rare and aggressive form of cancer.

The purpose of this study is to find out the highest dose of BI 894999 that people can tolerate.

BI 894999 is tested for the first time in humans. Participants take tablets once daily. The study also tests whether participants can tolerate BI 894999 better when taken continuously or with breaks in between.

Participants can stay in the study as long as they benefit from the treatment and can tolerate it.

The doctors also regularly check the general health of the participants.

Detailed description:

Arms: arm 1: Once daily continuous oral intake in 3-week cycles. arm 2: Once daily continuous oral intake in 3-week cycles. arm 3: Once daily continuous oral intake in 3-week cycles. arm 4: Once daily continuous oral intake in 3-week cycles. arm 5: Once daily continuous oral intake in 3-week cycles. arm 6: Once daily continuous oral intake in 3-week cycles. arm 7: Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. arm 8: Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. arm 9: Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. arm 10: Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days. arm 11: Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days. arm 12: Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days. arm 13: Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. arm 14: Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. arm 15: Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. arm 16: Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days. arm 17: Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days. arm 18: Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. arm 19: Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. arm 20: Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. arm 21: Once daily intermittent oral intake with two weeks on treatment followed by one week off in 3-week cycles. arm 22: Once daily loading dose on Day 1 followed by six days daily intake of maintenance dose, followed by one week off, repeated every two weeks in cycles of 28 days.
Interventions: intervention 1: BI 894999
Intervention descriptions: intervention 1: film-coated tablets

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c03063854-14
EudraCT No.:
2015-001111-12
BI Trial No.:
1367.1
BI Investigational 
Product(s):
BI 894999
Title:
An open label, Phase Ia/Ib dose finding study with BI 894999 
orally administered once a day in patients with advanced 
malignancies with repeated administration in patients with clinical 
benefit
Brief Title:
BI 894999 first in human dose finding study in advanced 
malignancies
Clinical Phase:
Phase Ia/Ib
Trial Clinical 
Monitor:
Phone:
Fax: 
Coordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol based on global amendment 
11)
Version and Date:
Version: 12.0
Date: 24 Jun 2020
Page 1 of 206
Proprietary confidential information.
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product: NA
Name of active ingredient:
BI 894999
Protocol date:
30 Mar 2015
Trial number:
1367.1
Revision date:
24 Jun 2020
Title of trial:
An open label, Phase Ia/Ib dose finding study with BI 894999 orally administered 
once a day in patients with advanced malignancies, with repeated administration in 
patients with clinical benefit
Coordinating
Investigator:
Phone: 
Fax: 
Trial site(s):
Multi-centre trial in 1 up to 10 countries
Clinical phase:
Phase Ia/Ib
Objective(s):
Dose escalation part (Phase Ia)
To investigate the maximum tolerated dose (MTD) through dose limiting toxicities 
(DLTs), safety and tolerability, pharmacokinetics, f
 biomarker and 
efficacy of BI 894999 monotherapy in patients with advanced and/or metastatic solid 
tumours in three different schedules (Schedule A with continuous dosing, Schedule B 
with two weeks on treatment and one week off in 3-week cycles, Schedule C with a 
loading dose on Day 1 followed by a maintenance dose on the six next days and a 
week off, repeated every two weeks in 4-week cycles) and provide safety data in 
terms of drug-related adverse events (AEs) for the recommendation of the dose and 
schedule of treatment for the expansion Phase Ib of this trial (between Schedules A 
and B) and for further trials in the development of BI 894999 (between Schedules B 
and C).
To determine the MTD in patients with diffuse large B-cell lymphoma (DLBCL) 
once the MTD has been determined for both schedules A and B in patients with solid 
tumours, (Schedule B was selected based on Schedule A and B data according to the 
Data Monitoring Committee (DMC) recommendation). The MTD will also be 
determined for Schedule C in DLBCL patients. Once both MTDs for Schedule B and 
Schedule C are determined for DLBCL, the DMC will recommend the best schedule 
and dose to be used for the extension of MTD cohort in DLBCL patients.
Expansion part (Phase Ib)
To further collect safety information, PK and anti-tumour activity at the 
recommended dose and schedule in patients with solid tumours to confirm the RP2D


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001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
Name of company:
Boehringer Ingelheim 
Name of finished product: NA
Name of active ingredient:
BI 894999
Protocol date:
30 Mar 2015
Trial number:
1367.1
Revision date:
24 Jun 2020
and schedule.
Methodology:
Uncontrolled, open label, dose escalation followed by an expansion cohort phase
No. of patients: 
Up to approximately 204
total entered:
Dose escalation part (Phase Ia): approximately 104 patients
-
a number of 40 patients (actual number was 40) for determination of MTD 
in both Schedules A and B in solid tumours, 
-
an extension of MTD cohort in solid tumours with 6 patients (actual number 
was 7) with the selected schedule by DMC (which was Schedule B) in order 
to have 12 patients treated at MTD and evaluable for DLT,
-
approximately 12 patients (actual number was 16) to determine the MTD in 
Schedule C in solid tumours patients
-
7 additional patients to confirm the MTD in Schedule C in solid tumours 
patients in order to have 12 patients treated at MTD
-
approximately 12 patients (actual number was 14) to determine the MTD
with Schedule B in the DLBCL cohort 
-
approximately 12 patients to determine the MTD with Schedule C in the 
DLBCL cohort
-
6 up to 8 additional patients in the extension of MTD in the DLBCL cohort
with Schedule B or Schedule C, according to the DMC recommendation on 
the best schedule between B and C
Expansion part (Phase Ib): approximately 80 up to 100 patients
-
9 to 20 for each of the three types of solid tumour in the expansion part with 
Schedule B according to the decision taken by the DMC: SCLC, mCRPC 
and CRC
37 patients were recruited in the three cohorts.
Cohorts of colorectal cancer (CRC), small cell lung cancer (SCLC)and 
metastatic castrate resistant prostate cancer (mCRPC) were closed for futility 
after 9 evaluable patients per RECIST 1.1 or Prostate Cancer Clinical Trials 
Working Group 3 (PCWG3)
-
20 patients for the NUT carcinoma (NC) cohort were recruited with 
Schedule B. Up to 40 patients to be recruited with Schedule C which was 
opened after the DMC decision to open the NC cohort with Schedule C and 
to close the NC cohort with Schedule B
each treatment:
Up to 204
Diagnosis :
Patients with a confirmed diagnosis of an advanced and/or metastatic solid tumour or 
relapsed/refractory DLBCL


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Name of company:
Boehringer Ingelheim 
Name of finished product: NA
Name of active ingredient:
BI 894999
Protocol date:
30 Mar 2015
Trial number:
1367.1
Revision date:
24 Jun 2020
Main criteria
for inclusion:
In the dose escalation phase: adult patients with a confirmed diagnosis of advanced, 
unresectable and/or metastatic malignant solid tumour or relapsed/refractory DLBCL, 
and who have failed conventional treatment or for whom no therapy of proven 
efficacy exists or who are not amenable to standard therapies.
In the expansion phase: recruitment is restricted to the following solid tumours types: 
SCLC, mCRPC, CRC and NC.
Age ≥ legal adult age in the given country (except for NC, where patients ≥ 15 years 
of age at the time of consent may be included in countries where allowed).
Test product(s):
BI 894999
dose:
Starting dose was 0.2 mg once per day for the very first patient of the trial, treated in 
Schedule A
mode of 
administration:
Once daily oral intake, in three different schedules:
-
Schedule A: continuous dosing schedule, repeated every 3 weeks
-
Schedule B: two weeks on treatment, one week off treatment, repeated every 
3 weeks
-
Schedule C: loading dose on Day 1 followed by a maintenance dose on the 
six next days and a week off, repeated every two weeks in 4-week cycles
Comparator products:
NA
dose:
NA
mode of 
administration:
NA
Duration of treatment:
One treatment cycle consists of 21 days in Schedules A and B and of 28 days in 
Schedule C. Minimum of one treatment cycle, continued until disease progression or 
intolerability of the trial drug.
Endpoints
Dose escalation part (Phase Ia) in patients with solid tumours and in patients 
with DLBCL:
Primary:
-
Number of patients experiencing DLT graded according to the common 
terminology criteria for adverse events (CTCAE) v. 4.03, observed in the
first cycle (3 weeks for Schedules A and B, 4 weeks for Schedule C) in 
order to meet the objective of assessment of the MTD of BI 894999 for each 
schedule in patients with solid tumours and for Schedules B and C in the 
DLBCL cohort
Secondary:
-
Cmax and AUC0-24 after single and Cmax,ss and AUCτ,ss after multiple dose of 


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Name of company:
Boehringer Ingelheim 
Name of finished product: NA
Name of active ingredient:
BI 894999
Protocol date:
30 Mar 2015
Trial number:
1367.1
Revision date:
24 Jun 2020
BI 894999, as measured during the first cycle (3 weeks for Schedules A and 
B, 4 weeks for Schedule C)
-
Number of patients experiencing DLTs from start of treatment until end of 
treatment (in all cycles) as assessed approximately every 3 weeks for 
Schedules A and B, 4 weeks for Schedule C after Cycle 2, for each schedule 
in patients with solid tumours and for Schedules B and C in the DLBCL 
cohort
-
Objective Response (Complete Response (CR) and Partial Response (PR)) 
according to RECIST version 1.1 as assessed by the investigator throughout 
the entire treatment period for each schedule in patients with solid tumours 
and according to RECIL 2017 for the Schedules B and C in the DLBCL 
cohort (a minor response is not included as a PR for RECIL 2017 
evaluation)
Expansion part (Phase Ib) in patients with solid tumours:
Primary:
-
Number of patients experiencing DLTs from start of treatment until end of 
treatment (in all cycles) as assessed approximately every 3 weeks for 
Schedule B (at the end of each new cycle) in order to determine the 
recommended Phase II dose with the schedule selected at the end of Phase 
Ia, schedules A and B part. Schedule B was selected. 
If the DMC decides that the safety profile of Schedule C is better than Schedule B in 
Phase Ia solid tumours, the following endpoint will be assessed:
-
Number of NC patients in the Schedule C cohort experiencing DLTs from 
start of treatment until end of treatment (in all cycles) as assessed every 4 
weeks.
For the NC cohort, a comparison of safety profile will be performed at the 
end of the trial, if applicable, in order to determine the recommended Phase 
II schedule and dose
Secondary:
-
Cmax and AUC0-24 after single and Cmax,ss and AUCτ,ss after multiple dose of 
BI 894999, observed in the first 3 weeks for Schedule B (first cycle) or in 
the first 4 weeks for Schedule C NC cohort (first cycle)
-
Objective response (CR, PR) as assessed by the investigator with a tumour
assessment by RECIST 1.1 every 2 cycles (6 weeks if no delays for 
Schedule B, 8 weeks for the NC cohort with Schedule C) during the entire
treatment period. For mCRPC patients with non-measurable disease by 
RECIST 1.1, the assessment will be performed by bone scan plus prostate 
specific antigen (PSA) percentage change at the same time-points as bone 


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Name of company:
Boehringer Ingelheim 
Name of finished product: NA
Name of active ingredient:
BI 894999
Protocol date:
30 Mar 2015
Trial number:
1367.1
Revision date:
24 Jun 2020
scan every 4 cycles (12 weeks if no delays for Schedule B), as described by 
the PCWG3
-
Progression-free Survival (PFS) with tumour assessment every 2 cycles (6 
weeks if no delays for Schedule B, 8 weeks for the NC cohort with Schedule 
C) during the treatment period and until progression or death is reported
(radiological PFS with tumour assessment by bone scan every four cycles 
for mCRPC patients with non-measurable disease by RECIST 1.1)
-
Best overall response with an evaluation of approximately every 2 cycles (6 
weeks if no delays for Schedule B, 8 weeks for the NC cohort with Schedule 
C) during the entire treatment period (every four cycles for mCRPC patients 
with non-measurable disease by RECIST 1.1)
-
In mCRPC patients: PSA response – defined as a decline in PSA value ≥
50% with an evaluation every cycle during the entire treatment period
-
Overall survival (OS) for the NC patients 
Safety criteria:
Adverse events (AE) according to CTCAE v. 4.03, incidence of DLTs, determination 
of MTD, laboratory evaluations, vital signs, electrocardiograms (ECG), left 
ventricular ejection fraction (LVEF).
Statistical methods:
For the primary endpoint in the Phase Ia part of this study, a Bayesian logistic 
regression model (BLRM) with overdose control will be fitted to binary toxicity 
outcomes. The estimate of parameters will be updated as data are accumulated using 
the BLRM. At the end of the Phase Ia part for Schedules A and B, the toxicity 
probability at each dose level was calculated to determine the MTD. The analysis of 
the primary endpoint of the Phase Ia part happened once the last entered patient with 
solid tumour from Schedules A and B reached Day 22 of the first cycle and was 
evaluable for DLT occurrence or not in the first cycle.
Results of the primary endpoint of the Phase Ia part in patients with solid tumours for 
Schedule C and for DLBCL patients in Schedules B and C are planned to be reported
with final analysis of the trial.
For the primary endpoint in the Phase Ib part of this study, the number of patients 
with DLT during the entire treatment period will be summarized by cohorts. The 
analysis of the primary endpoint of the Phase Ib part will happen together with the 
final analysis when the last ongoing patient will have reached 4 cycles of trial 
treatment or stopped trial treatment and will have performed the end of residual effect 
period (EOR) visit, at least 30 days after last trial drug intake, whatever occurs first.
An updated report will then be written once the last ongoing patients will have 
reached the end of trial.
Exploratory analyses and descriptive statistics will be used for secondary endpoints 


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Name of company:
Boehringer Ingelheim 
Name of finished product: NA
Name of active ingredient:
BI 894999
Protocol date:
30 Mar 2015
Trial number:
1367.1
Revision date:
24 Jun 2020
of toxicity, pharmacokinetics (PK) parameters, and efficacy. 
 
 
 
 
 
For the Phase Ib part, a 2-stage Bayesian hierarchical model approach will be 
implemented with an interim futility assessment conducted when approximate 9 
patients are enrolled and treated in each of the SCLC, mCRPC and CRC patients’ 
cohorts. If no objective response is observed in the 9 first patients evaluable for 
efficacy in a cohort with Schedule B, then this cohort will be closed for the stage 2 of 
the phase Ib part. For the response endpoints (i.e. objective response, disease control) 
in the Phase Ib part, a Bayesian hierarchical modelling approach with a scale 
parameter for the inter-cohort variability will be used. The prior for the inter-cohort 
variability will be chosen as half-normal with a scale parameter of 100. Thereby the 
shrinkage estimators allowing borrowing information from different patient cohorts
will be considered (response data from the MTD expansion cohort of DLBCL will 
also be considered in the Bayesian hierarchical model). Additionally descriptive 
statistics of these endpoints for the specific cohorts will be provided.


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FLOW CHART FIRST TREATMENT CYCLE IN SCHEDULE A*
Study Periods
Screen
Treatment Cycle 1
EOT1
FU2
Visit
Screen
1
2
3
4
53
EOT 
FU 
Day
(day range)
-28 
- 1
1
2
34
8
(± 
1)
12
(± 
1)
14
15
22
First = 
EOR
+30 (+7)
after EOT
Informed Consents5
x
Demographics
x
Medical History
x
In- /Exclusion Criteria
x
x
Physical Examination 
x22
x22
x22
x6
Height
x
Body weight
x
x
x
x
ECOG performance score
x
x
x
x
Pregnancy test
x7
x
12-lead-ECG
x8
x8
x8
x8
x8
x8
x8
x8
x6
LVEF9
x
x23
x6
Dispensing of BI 894999
x
Intake of BI 894999
x10
x10
x10
x10
x10
x10
x10
x10
Compliance check
x
x
x
x
x
Completion of diary card11
x--- ---- ---- ----- ----- ----- ----- ----x
Vital Signs
x
x12
x
x
x
x
x12
x
x
x
Safety lab parameters
x13
x13
x13
x
x13
x
x13
x6
Tumour markers14
x
Urine examination15
x
x
x
x
x
x
Pharmacokinetics (plasma)
x16
x16
x16
x16
x16
x16 x16
Pharmacokinetics (urine) 17
x17
x17
x17
x17
Adverse Events
x
x
x
x
x
x
x
x
x
x
x18
Concomitant Therapy
x
x
x
x
x
x
x
x
x
x
x18
CT and/or MRI – PET/CT for DLBCL19
x19
x19
x6
Bone marrow in DLBCL if PET/CT neg.
x19
Bone scan in mCRPC
x
Tumour assessment19
x
x19
x6
Tumour biopsy for exploratory 
 
analysis20
x20
x20
Mandatory DNA blood20
x20
 
Optional bio-banking sample
x
Termination of study medication
x
Patient’s status (alive/PD/dead)
x


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* Schedule A Flow Chart not updated in this version of the protocol except for the body weight cross at follow-up 
visit, which was missing in error, since no new patients will be included in this schedule at the time of creation 
of protocol version 9.0
1 end of treatment (EOT) investigations which have to be performed at the EOT visit (as soon as possible when a 
patient discontinues treatment)
2 FU= follow up visits until progression, lost to follow up, treatment with another anti-cancer drug or end of the 
whole trial as specified in Section 8.6. The first follow-up visit is the End of Residual Effect Period visit (EOR) 
which must happen at the earliest 30 days after the end of treatment (see Section 6.2.3.2)
3 visit 5 of Cycle 1 may correspond to visit 1 of Cycle 2 if an additional cycle is indicated
4 patients recruited for the food interaction cohorts must have one PK sampling on Day 3 (approximately 24h after 
BI 894999 intake on Day 2). See Appendix 10.2 for further details
5 the informed consent consist of 2 forms:
-
a main informed consent for participation to the trial including a separate sub-section for participation to 
the food interaction sub-study and 
-
a separate informed consent for biomarkers analyses: 
o
mandatory blood samples for pharmacogenomics, 
o
optional bio-banking sample for pharmacogenomics 
o
tumour biopsies for pharmacogenomics biomarkers analyses

optional in escalation part until MTD in patients with solid tumours and in DLBCL 
cohort

optional in MTD extension part in patients with solid tumours and in DLBCL cohort

mandatory in Phase Ib expansion in patients with solid tumours (at screening and in 
cycle 1 at steady state)
o
optional consent for sending of archival tissue for genomic analysis in case of objective 
response or if patient is benefiting from treatment
o
optional consent for a fresh tumour biopsy in patients who have an objective response or are 
benefiting from treatment
o
mandatory consent for an additional 2-3 mL EDTA Blood DNA tube at the time of objective 
response or when a patient is benefiting from treatment, if consent is given for archival/fresh 
tumour biopsy
o
mandatory consent for sampling of an additional 2-3 mL EDTA Blood DNA tube at the time of 
the fresh tumour biopsy at steady state in cycle 1 for patients who consented to have two fresh 
tumour biopsies in first cycle
6 optional, to perform if needed to follow-up on adverse events (AE) present/ongoing at previous visit or if not 
performed at the EOT visit
7 a serum or urine beta human chorionic gonadotrophin (βHCG) pregnancy test must be performed within 7 days 
prior to first treatment in women of childbearing potential
8 At screening, on Days 1-2 and 14-15: pre-dose and at approximately 2h, 4h, 8h, 24h post-dose, as well as on 
Days 8 and 22 of Cycle 1 and at EOT. For each ECG, digitalized triplicate acquisition using dedicated 
equipment for central reading by clinical research organization (CRO). The ECGS are to be performed before 
the blood sampling when at same time-point as blood sampling (see 5.4.2)
9 by echocardiography or MUGA scan, but each time by the same method
10 intake of BI 894999 done at the clinical site on Days 1, 2, 8, 12, 14, 15 and 22 and by the patient anywhere else 
on the other days
11 the diary card must be completed every day of intake in Cycle 1
12 vital signs (blood pressure, pulse and body temperature): on days 1 and 14: pre-dose, and approximately 4h, 8h 
post-dose. On all other visit days, once at any time during the visit day
13 including coagulation parameters (aPTT, PT expressed in sec and international normalized ratio (INR)) only to 
be performed at screening, on Day 1 pre-dose, on Day 2 and pre-dose on the day of tumour biopsy when 
applicable and at EOT
14 only in patients with tumour types where there is a clinically relevant tumour marker which is already used in 
routine clinical practice for tumour restaging (on Day 1 of every cycle). Prostate specific antigen (PSA)
mandatory for mCRPC patients
15 urine examination by dipstick for pH, glucose, erythrocytes, leukocytes, protein, nitrite. If pathological findings, 
further evaluation (see Section 5.3.3)
16 intensive PK blood sampling will be performed in Cycle 1, as summarized in Appendix 10.2


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For the food interaction cohorts, same PK time points as for other patients with in addition on Day 2: 0:30min, 
1h, 2h, 3h, 4h, 6h, 8h 24h (Days 2 and 15) post-dose and on Day 3: 24h post-dose of Day 2 (see 10.2.2).
Pre-dose sampling will be conducted at Days 8 and 12 just before drug administration of the dose
17 one blank urine will be collected prior to the BI 894999 intake on visit 1 and visit 4 (at least two 2 mL aliquots). 
In addition urine will be collected as summarized in Appendix 10.2
18 all AEs and concomitant medication must be collected until 30 days (until EOR) after the last BI 894999 intake. 
After EOR, for subsequent FU visits, only SAEs/AESIs which are considered study drug related need to be 
collected as well as their related treatment
19 according to RECIST 1.1 guidelines for patients with solid tumours (including mCRPC patients who have
measurable disease). Imaging and assessment are required every 2 cycles (meaning every 6 weeks if no delays in 
cycles but as close as possible to the end of the second of the two cycles of treatment if there was a delay). 
For mCRPC patients, in addition to the CT/MRI every 2 cycles, a bone scan has to be performed at screening 
and then every 4 cycles (every 12 weeks if no delays in cycles) with a PSA evaluation at the same time-points as 
the bone scan. 
According to RECIL 2017 guidelines for DLBCL patients, a fluorodeoxyglucose positron emission-tomography 
(FDG-PET coupled to a computed tomography (CT) scan (or MRI if CT not possible but each time, same 
method) must be performed at screening, at the end of Cycle 2 (at 6 weeks if no delays in cycles), at the end of 
Cycle 4 (week 12) and then every 4 cycles. In patients with negative FDG-PET uptake in the bone marrow at 
screening, a bone marrow aspirate and biopsy need to be performed in order to rule out bone marrow 
involvement. 
EOT/FU imaging and assessment are optional if previous examination was performed in the past 4 weeks
20optional for patients in the escalation phase including the patients in the extension of MTD cohort who agree to 
tumour biopsy, and mandatory for patients in the solid tumour expansion Phase Ib, a tumour biopsy for 
biomarker analysis (see 5.5.1.2) must be performed at baseline and between Day 11 and Day 14 of Cycle 1: the 
biopsy may only be performed if the platelet count is above 50 000/mm3 (coagulation must be checked on the 
day of the biopsy). For those patients having a tumour biopsy at steady state, a mandatory 2-3 mL EDTA DNA 
blood sample must be taken at the same time as the tumour biopsy, at steady state. In Phase Ib, for mCRPC 
patients with only bone metastases and for NC patients, tumour biopsies are not requested.
21 HEXIM1 (or other genes related to the mechanism of action (MOA) gene expression will be analysed in whole 
blood as summarized in Appendix 10.2
22 In DLBCL patients, the physical examination will include a tumour evaluation (largest palpable lymph node per 
area, measured in two dimensions if one diameter at least is > 1cm, evaluation of spleen and liver enlargement 
by measuring the cm below costal margin and two dimensional evaluation of any other palpable tumour 
manifestation).
23 to be performed if not done in the past 6 weeks and if possible, according to the patient’s  condition at the time 
of EOT


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FLOW CHART: SECOND AND FURTHER TREATMENT CYCLES IN 
SCHEDULE A**
Study Periods
Treatment Cycles
EOT1
FU2
Visit
C2V1 C2V2
C2V33
CxV1
CxV23
EOT 
FU 
Day
(day range)
1
15
(-4+2)
22
1
15
(-4+2)*
22
First = 
EOR +30 
(+7) after 
EOT
Eligibility for re-treatment
x
x
Physical Examination
x8
x8
x4-8
x5
Body weight
x
x
x4
x
ECOG performance score
x
x
x4
x
Pregnancy test
x
x
x4
12-lead-ECG
x6-14
x14
x14
x6-14
x14
x14
x14
x5-14
LVEF15
x15
x16
x5
Dispensing of BI 894999
x
x
Intake of BI 894999
x7
------- ---------
x7
-------
x7
Compliance check
x
x
x
Vital Signs
x
x
x
x
x
x
Safety lab parameters
x18
x
x
x18
x17
x17
x18
x5
Tumour markers
x19
x19
Urine examination
x
x
x
Pharmacokinetics
x9
Adverse Events
x
x
x
x
x
x
x
x10
Concomitant Therapy
x11
x
x
x
x
x
x
x10
CT and/or MRI -  PET/CT in DLBCL12
x12
x12
x12
x12
Bone Marrow in DLBCL when CR12
x12
x12
Bone scan in mCRPC
x12
Tumour assessment12
x12
x12
x12
x12
Optional archival tumour tissue 
x13
Optional fresh tumour biopsy 
x13
Mandatory DNA blood13
x13
Termination of study medication
x
Patient’s status (alive/PD/dead)
x
*this intermediate visit during a cycle becomes optional starting from C5 onwards if there are no concerns 
regarding cardiac safety of the patient (normal or stable CK, troponin, ECG, LVEF)
**Schedule A Flow Chart not updated in this version of the protocol except for the body weight cross at follow-up 
visit, which was missing in error, since no new patients will be included in this schedule at the time of creation 
of protocol version 9.0
1 end of treatment; investigations which have to be performed at the EOT visit (as soon as possible when a patient 
discontinues treatment)
2 FU= follow up visit until progression, lost to follow up, treatment with another anti-cancer drug or end of the 
whole trial as specified in Section 8.6. The first follow-up visit is the End of Residual Effect Period visit (EOR) 
which must happen at the earliest 30 days after the end of treatment (see Section 6.2.3.2)


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3 last visit of a cycle may correspond to visit 1 of next Cycle if an additional cycle is indicated
4 data from the last visit of the previous cycle (Day 22) may be used in case examinations were done within the 
past two weeks
5 optional, to perform if needed to follow-up on AEs present/ongoing at previous visit or if not performed at the 
EOT visit
6 ECG must be repeated pre-dose on C2V1 (or CxV1) if C2V1 (or CxV1) happens on a different day than C1V5
(or last visit of previous cycle)
7 the first dose of the cycle is administered on site, all other doses are taken by the patient outside the clinical site
8 In DLBCL patients, the physical examination will include a tumour evaluation (largest palpable lymph node per 
area, measured in two dimensions if one diameter at least is > 1cm, evaluation of spleen and liver enlargement 
by measuring the cm below costal margin and two dimensional evaluation of any other palpable tumour 
manifestation)
9At any time, only in case of drug related Grade 3 or Grade 4 toxicity, every effort must be made to collect a PK 
sample; date and time of the sample and of the most recent drug intake (before PK sample) need to be recorded 
for such samples
10 all AEs and concomitant medication must be collected until 30 days (until EOR) after the last BI 894999 intake. 
After EOR, for subsequent FU visits, only SAEs/AESIs which are considered study drug related need to be 
collected as well as their related treatment
11 update only
12 according to RECIST 1.1 guidelines for patients with solid tumours (including mCRPC patients who have a
measurable disease). Imaging and assessment are required every 2 cycles (meaning every 6 weeks if no delays in 
cycles but as close as possible to the end of the second of the two cycles of treatment if there was a delay). EOT/ 
FU imaging and assessment are optional if previous exam was performed in the past 4 weeks. The choice of 
computed tomography (CT) and/or magnetic resonance imaging (MRI) is left to the investigator’s judgement but 
the method must remain the same for all evaluations. If the patient did not end the trial treatment due to 
progressive disease (PD), the tumour assessments during follow-ups will be according to standard of care for the 
site/country. 
For mCRPC patients, in addition to the CT/MRI every 2 cycles, a bone scan has to be performed at screening 
and then every 4 cycles (every 12 weeks if no delays in cycles) with a PSA evaluation at the same time-points as 
the bone scan.
According to RECIL 2017 guidelines for DLBCL patients, a FDG-PET coupled to a CT scan (or MRI if CT not 
possible but each time, same method) must be performed at screening, at the end of Cycle 2 (at 6 weeks if no 
delays in cycles), at the end of Cycle 4 (week 12) and then every 4 cycles. In case a complete response is 
observed, a BM aspirate and biopsy have to be performed for confirmation of CR
13 If a patient has an objective response or is benefiting from the treatment and he/she agreed beforehand for 
   sending of archival tumour tissue or/and for a fresh tumour biopsy (if deemed safe and feasible by the 
   investigator) for gene analysis, 2-3 mL EDTA DNA blood tube at any time during response
14 For each ECG, digitalized triplicate acquisition using dedicated equipment for central reading by clinical 
research organization (CRO). The ECGS are to be performed before the blood sampling when at same time-
point as blood sampling (see 5.4.2)
15 to be performed at the end of Cycle 2 by echocardiography or MUGA scan, by the same method as at baseline
16 to be performed if not done in the past 6 weeks and if possible, according to the patient’s  condition at the time 
of EOT
17 measurements of CK and troponin and any other parameter deemed necessary to be controlled by the 
investigator
18 including measurements of coagulation parameters: aPTT, PT expressed in seconds and INR
19 PSA mandatory for mCRPC patients


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FLOW CHART FIRST TREATMENT CYCLE IN SCHEDULE B
Study Periods
Screen
Treatment Cycle 1
EOT1
FU2
Visit
Screen
1
2
3
4
53 EOT 
FU 
Day
(day range)
-28 - 1
1
2
34
8
(± 1)
12
(± 
1)
14
15
18
(± 
1)
22
FU1 = 
EOR
+30 
(+7) 
after 
EOT
Informed Consents5
x
Demographics
x
Medical History
x
In- /Exclusion Criteria
x
x
Physical Examination 
x
x
x
x6
Height
x
Body weight
x
x
x
x
ECOG performance score
x
x
x
x
Pregnancy test
x7
x
12-lead-ECG
x
x8
x8
x8
x8
x8
x8
x8
x6
LVEF9
x
x22
x6
Dispensing of BI 894999
x
Intake of BI 894999
x10
x10
x10
x10
x10
x10
Compliance check
x
x
x
x
Completion of diary card11
x--- ---- ----
----
----- ----x
Vital Signs
x
x12
x
x
x
x
x12
x
x
x
x
Safety lab parameters
x13-13b x13-
13a
x13
x13
x13-
13a
x13
x13
x6
Tumour markers14
x
Urine examination15
x
x
x
x
x
x
Pharmacokinetics (plasma)
x16
x16
x16
x16
x16
x16
x16
x16
Pharmacokinetics (urine)
x17
x17
x17
x17
Adverse Events
x
x
x
x
x
x
x
x
x
x
x
x18
Concomitant Therapy
x
x
x
x
x
x
x
x
x
x
x
x18
CT and/or MRI-PET/CT in DLBCL19
x19
x19
x6
Bone scan in mCRPC
x
Tumour assessment19
x
x19
x6
Tumour biopsy for exploratory biomarker 
analysis20-a-b
x20-a
x20-a-
b
Mandatory DNA blood20-a-b
x
x
 gene expression in whole blood
x21
x21
x21
x21
x21
Optional bio-banking sample
x
Termination of study medication
x
Overall clinical benefit assessment by 
Investigator for NC patients
x
Patient’s status (alive/PD/dead)
x23


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1 end of treatment (EOT) investigations which have to be performed at the EOT visit (as soon as possible when a 
patient discontinues treatment)
2 FU= follow up visits until progression, lost to follow up, treatment with another anti-cancer drug or end of the 
whole trial as specified in Section 8.6. The first follow-up visit is the End of Residual Effect Period visit (EOR) 
which must happen at the earliest 30 days after the end of treatment (see Section 6.2.3.2)
3 visit 5 of Cycle 1 may correspond to visit 1 of Cycle 2 if an additional cycle is indicated
4 patients recruited for the food interaction cohorts must have one PK sampling on Day 3 (approximately 24h after 
BI 894999 intake on Day 2). See Appendix 10.2 for further details
5 the informed consent consist of 2 forms (or different sections, depending on the countries): 
-
a main informed consent for participation to the trial including a separate sub-section for participation to 
the food interaction sub-study and 
-
a separate informed consent for biomarkers analyses: 
o
mandatory blood samples for pharmacogenomics, 
o
optional bio-banking sample for pharmacogenomics 
o
tumour biopsies for pharmacogenomics biomarkers analyses

optional in escalation part until MTD in patients with solid tumours and in DLBCL 
cohort

optional in MTD extension part in patients with solid tumours and in DLBCL cohort

mandatory in Phase Ib expansion at Screening and in Cycle 1 at steady state in patients 
with solid tumours For patients with NC, and mCRPC with only bone lesions, the 
biopsies are not requested (remain optional for NC) as well as for patients with 
therapeutic INR because of treatment with a vitamin K antagonist or a novel oral 
anticoagulant. The on treatment biopsy may remain optional if no easily accessible 
lesions are available. The screening biopsy may be replaced by sending of archival 
tumour tissue from a biopsy taken from the latest relapse and not older than 6 months.
o
optional consent for sending of archival tissue for genomic analysis in case of objective 
response or if patient is benefiting from treatment
o
optional consent for a fresh tumour biopsy in patients who have an objective response or are 
benefiting from treatment
o
mandatory consent for an additional 2-3 mL EDTA Blood DNA tube whenever tumour tissue is 
sent (from fresh tumour biopsy or archival tumour tissue) 
For the NC indication, when patients are aged between 15 and <18 years, they will have to sign an assent form 
for the main part of the trial as well as for the biomarker part while parents (both or one according to national 
regulation) or the legal guardian must sign both consent forms.
6 optional, to perform if needed to follow-up on adverse events (AE) present/ongoing at previous visit or if not 
performed at the EOT visit
7 a serum or urine beta human chorionic gonadotrophin (βHCG) pregnancy test must be performed within 7 days 
prior to first treatment in women of childbearing potential
8 at screening, on Days 1-2 and 14-15: pre-dose and at approximately 2h, 4h, 8h, 24h post-dose, as well as on Days
8 and 22 of Cycle 1, and at EOT, at any time of the visit when not on an intensive PK day. For each ECG,
digitalized triplicate acquisition using dedicated equipment for central reading by clinical research organization 
(CRO). The ECGS are to be performed before the blood sampling when at same time-point as blood sampling 
(see 5.4.2)
9 by echocardiography or MUGA scan, but each time by the same method
10 intake of BI 894999 done at the clinical site on Days 1, 2, 8, 12, 14, and by the patient anywhere else on the 
other days (between Day 1 and Day 14). The patient may take the medication before arriving at the clinical site 
on the day of biopsy at steady state in Cycle 1 if performed on a different day then Day 8 but must clearly note 
the exact hour of intake 
11 the diary card must be completed every day of intake in Cycle 1
12 vital signs (blood pressure, pulse and body temperature): on days 1 and 14: pre-dose, and approximately 4h, 8h 
post-dose. On all other visit days, once at any time during the visit day


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13 When a blood glucose test is performed, the investigator must indicate whether the patient was in fasting 
condition at the time of the blood sampling, meaning the sample is taken after an overnight fasting. Safety lab 
parameters including coagulation parameters (aPTT, PT expressed in sec and INR) only to be performed at 
screening, on Day 1 pre-dose, on Day 2, Day 8, pre-dose on the day of tumour biopsy when applicable (if on a 
different day then Day 8), on Day 14 and at EOT. Each time a safety lab is foreseen per protocol, troponin hs 
test must be performed (T hs or I hs but always the same test for a given patient).
13a In the first 20 patients to be entered in phase Ib after approval of protocol version 7.0, coagulation factors II, V, 
VII and IX will be measured on C1D1 pre-dose, on C1D14 pre-dose and on C2V1D1 pre-dose. 
13b Hep B DNA test, Hep C RNA test and HIV infection detection by an established HIV diagnostic assay 
performed at screening (results within 4 weeks before screening are acceptable) .
14 only in patients with tumour types where there is a clinically relevant tumour marker which is already used in 
routine clinical practice for tumour restaging (on Day 1 of every cycle). PSA mandatory for mCRPC patients
15 urine examination by dipstick for pH, glucose, erythrocytes, leukocytes, protein, nitrite. If pathological findings, 
further evaluation (see Section 5.3.3)
16 intensive PK blood sampling will be performed in Cycle 1, as summarized in Appendix 10.2
For the food interaction cohorts, same PK time points as for other patients with in addition on Day 2: 0:30min, 
1h, 2h, 3h, 4h, 6h, 8h 24h (Days 2) post-dose and on Day 3: 24h post-dose of Day 2 (see 10.2.2)
Pre-dose sampling will be conducted at Days 8 and 12 just before drug administration of the dose
A PK sample will also be taken at the time of the visit on Day 18
17one blank urine will be collected prior to the BI 894999 intake on visit 1 and visit 4 (at least two 2 mL aliquots). 
In addition urine will be collected as summarized in Appendix 10.2
18 all AEs and concomitant medication must be collected until 30 days (until EOR) after the last BI 894999 intake. 
After EOR, for subsequent FU visits, only SAEs/AESIs which are considered study drug related need to be 
collected as well as their related treatment
19according to RECIST 1.1 guidelines for patients with solid tumours (including mCRPC patients who have a
measurable disease). Imaging and assessment are required every 2 cycles (meaning every 6 weeks if no delays in 
cycles but as close as possible to the end of the second of the two cycles of treatment if there was a delay). 
EOT/FU imaging and assessment are optional if previous examination was performed in the past 6 weeks
For mCRPC patients, in addition to the CT/MRI every 2 cycles, a bone scan has to be performed at screening 
and then every 4 cycles (every 12 weeks if no delays in cycles) with a PSA evaluation at the same time-points as 
the bone scan.
According to RECIL 2017 guidelines for DLBCL patients, a FDG-PET/CT scan (or MRI if CT not possible but 
each time same method) must be performed at screening, at the end of Cycle 2 (at 6 weeks if no delays in 
cycles), at the end of Cycle 4 (week 12) and then every 4 cycles. EOT/ FU imaging and assessment are optional 
if previous exam was performed in the past 6 weeks
20aoptional for patients in the escalation phase including the patients in the extension of MTD cohort who agree to 
tumour biopsy and mandatory for patients in the expansion Phase Ib, a tumour biopsy for biomarker analysis 
(see 5.5.1.2) must be performed at baseline and between Day 8 and Day 11 (4-8hrs after drug intake) of Cycle 1: 
the biopsy may only be performed if the platelet count is above 50 000/mm3 without support from a transfusion
and coagulation parameters (aPTT, PT in sec and INR) are within normal limits on the day of the biopsy. The 
baseline biopsy may be replaced by the sending of archival tumour tissue from a biopsy performed at the latest 
progression and not older than 6 months. For those patients having a tumour biopsy or sending of archival 
tumour tissue, a mandatory 2-3 mL EDTA DNA blood sample must be taken once, at any time, being it at 
screening or with steady state biopsy. In Phase Ib, for mCRPC patients with only bone metastases and for NC
patients, tumour biopsies are not requested (remain optional) as well as for patients with therapeutic INR 
because of treatment with a vitamin K antagonist or a novel oral anticoagulant. The on treatment biopsy may 
remain optional if no easily accessible lesions are available
20bif abnormal coagulation parameters and/or a platelet count below 50 000/mm3 prevent tumour biopsies between 
Day 8 and Day 11 of Cycle 1 in 5 or more of the 20 first patients of Phase Ib in solid tumours, the window for 
tumour biopsy will be moved ahead between Day 3 and Day 8 (4-8hrs after drug intake) in the further entered 
patients. Where a fresh biopsy is taken for the baseline sample the subsequent on-treatment biopsy should be 
taken, where feasible, from the same lesion (not to be considered as a target lesion)
 (or other genes related to MOA) gene expression will be analysed in whole blood as summarized in 
Appendix 10.2
22 to be done if not performed within the previous 6 weeks and if possible, according to the patient’s condition at 
the time of EOT


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23 for NC patients recruited in Phase Ib after approval of protocol version 11.0, the patient’s survival status will 
continue to be collected until death, lost to follow-up or until 12 months after the end of trial, even if the patient 
progressed according to RECIST 1.1 or started with another anti-cancer treatment, according to patient’s 
informed consent


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FLOW CHART: SECOND AND FURTHER TREATMENT CYCLES IN 
SCHEDULE B
Study Periods
Treatment Cycles
EOT1
FU2
Visit
C2V1
C2V2
C2V33
CxV1
CxV23
EOT 
FU 
Day
(day range)
1
2
15
(-4+2)
22
1
15
(-4+2)*
22
First = 
EOR 
+30 (+7) 
after 
EOT
Eligibility for re-treatment
x
x
Physical Examination 
x
x
x4
x5
Body weight
x
x
x4
x
ECOG performance score
x
x
x4
x
Pregnancy test
x
x
x4
12-lead-ECG
x6-18
x18
x18
x6-18
x18
x18
x18
x5-18
LVEF
x15
x16
x5
Dispensing of BI 894999
x
x
Intake of BI 894999 from Day 1 till 
Day 14 of a cycle
x7
x7
x7
Compliance check
x
x
x
Vital Signs
x
x
x
x
x
x
x
Safety lab parameters
x19-
19a
x19
x19
x19
x17-19
x17-19
x19
x5
Tumour markers
x20
x20
Urine examination
x
x
x
Pharmacokinetics
x8
x8
x9
Adverse Events
x
x
x
x
x
x
x
x
x10
Concomitant Therapy
x11
x
x
x
x
x
x
x
x10
CT and/or MRI – PET/CT in DLBCL12
x12
x12
x12
x12
Bone scan in mCRPC
x12
Tumour assessment12
x12
x12
x12
x12
1 gene expression in whole 
blood13
x13
x13
Optional archival tumour tissue: 
x14
Optional fresh tumour biopsy 
x14
Mandatory DNA blood14
x14
Termination of study medication
x
Overall clinical benefit assessment by 
Investigator for NC patients
x
Patient’s status (alive/PD/dead)
x21
*this intermediate visit during a cycle becomes optional starting from C5 onwards if there are no concerns 
regarding cardiac safety of the patient (normal or stable CPK, troponin, ECG, LVEF)


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1 end of treatment; investigations which have to be performed at the EOT visit (as soon as possible when a patient 
discontinues treatment)
2 FU= follow up visit until progression, lost to follow up, treatment with another anti-cancer drug or end of the 
whole trial as specified in Section 8.6. The first follow-up visit is the End of Residual Effect Period visit (EOR) 
which must happen at the earliest 30 days after the end of treatment (see Section 6.2.3.2)
3 last visit of a cycle may correspond to visit 1 of next Cycle if an additional cycle is indicated
4 data from the last visit of the previous cycle (Day 22) may be used in case examinations were done within the 
past two weeks
5 optional, to perform if needed to follow-up on AEs present/ongoing at previous visit or if not performed at the 
EOT visit
6 ECG must be repeated pre-dose on C2V1 (or CxV1) if C2V1 (or CxV1) happens on a different day than C1V5
(or last visit of previous cycle)
7 the first (and second for C2) doses of the cycle are administered on site, all other doses are taken by the patient 
outside the clinical site
8 PK blood sampling before intake of BI 894999, only in Cycle 2 Days 1-2 (see Appendix 10.2) 
9At any time, only in case of drug related Grade 3 or Grade 4 toxicity, every effort must be made to collect a PK 
sample; date and time of the sample and of the most recent drug intake (before PK sample) need to be recorded 
for such samples
10 all AEs and concomitant medication must be collected until 30 days (until EOR) after the last BI 894999 intake. 
After EOR, for subsequent FU visits, only SAEs/AESIs which are considered study drug related need to be 
collected as well as their related treatment
11 update only
12 according to RECIST 1.1 guidelines for patients with solid tumours (including mCRPC patients who have a 
measurable disease). Imaging and assessment are required every 2 cycles (meaning every 6 weeks if no delays in 
cycles but as close as possible to the end of the second of the two cycles of treatment if there was a delay). EOT/ 
FU imaging and assessment are optional if previous exam was performed in the past 6 weeks. The choice of 
computed tomography (CT) and/or magnetic resonance imaging (MRI) is left to the investigator’s judgement but 
the method must remain the same for all evaluations. If the patient did not end the trial treatment due to 
progressive disease (PD), the tumour assessments during follow-ups will be according to standard of care for the 
site/country. 
For mCRPC patients, in addition to the CT/MRI every 2 cycles, a bone scan has to be performed at screening 
and then every 4 cycles (every 12 weeks if no delays in cycles) with a PSA evaluation at the same time-points as 
the bone scan.
According to RECIL 2017 guidelines for DLBCL patients, a FDG-PET/CT scan (or MRI if CT not possible but 
each time same method) must be performed at screening, at the end of Cycle 2 (at 6 weeks if no delays in 
cycles), at the end of Cycle 4 (week 12) and then every 4 cycles with interpretation according to RECIL 2017
guidelines. EOT/ FU imaging and assessment are optional if previous exam was performed in the past 6 weeks
13 Gene expression will be analysed in whole blood which must be collected as summarized in Appendix 10.2
14 If a patient has an objective response or is benefiting from the treatment and he/she agreed beforehand for 
sending of archival tumour tissue or/and for a fresh tumour biopsy (if deemed safe and feasible by the 
investigator) for gene analysis, 2-3 mL EDTA DNA blood tube at any time (if not yet done before)
15 to be performed by echocardiography or MUGA scan, by the same method as at baseline
16 to be performed if not done in the past 6 weeks and if possible, according to the patient’s  condition at the time 
of EOT
17 measurements of CK and troponin and any other parameter deemed necessary to be controlled by the 
investigator
18 For each ECG, digitalized triplicate acquisition using dedicated equipment for central reading by clinical 
research organization (CRO). The ECGS are to be performed before the blood sampling when at same time-
point as blood sampling (see 5.4.2)
19 When a blood glucose test is performed, the investigator must indicate whether the patient was in fasting 
condition at the time of the blood sampling, meaning the sample is taken after an overnight fasting. Safety lab 
parameters including measurements of coagulation parameters: aPTT, PT expressed in seconds and INR. Each 
time a safety lab is foreseen per protocol, troponin hs test must be performed (T hs or I hs but always the same 
test for a given patient).Coagulation parameters will be evaluated on V1 and V2 of Cycles 2, 3 and 4 and on V1 from 
Cycle 5 onwards.


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19a In the first 20 patients to be entered in phase Ib after approval of protocol version 7.0, coagulation factors II, V, 
VII and IX will be measured on C1D1 pre-dose, on C1D14 pre-dose and on C2V1D1 pre-dose. 
20 PSA mandatory for mCRPC patients
21 for NC patients recruited in Phase Ib after approval of protocol version 11.0, the patient’s survival status will 
continue to be collected until death, lost to follow-up or until 12 months after the end of trial, even if the patient 
progressed according to RECIST 1.1 or started with another anti-cancer treatment, according to patient’s 
informed consent


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FLOW CHART FIRST TREATMENT CYCLE IN SCHEDULE C FOR 
SOLID TUMOUR PATIENTS IN PHASE IA
Study Periods
Screen
Treatment Cycle 1
EOT1
FU2
Visit
Screen
1
2
3
4
53
EOT 
FU 
Day
(day range)
-28 - 1
1
2
8
15
21
22
29
FU1 = EOR
+30 (+7) after 
EOT
Informed Consents4
x
Demographics
x
Medical History
x
In- /Exclusion Criteria
x
x
Physical Examination 
x
x
x
x5
Height
x
Body weight
x
x
x
x
ECOG performance score
x
x
x
x
Pregnancy test
x6
x
12-lead-ECG
x7
x7
x7
x7
x7
x7
x7
x7
x7
x5
LVEF8
x
x20
x5
Dispensing of BI 894999
x
Intake of BI 894999
x9
x9
x9
x9
Compliance check
x
x
x
Completion of diary card10
x---
---x
x---- ----x
Vital Signs
x
x11
x
x
x
x11
x
x
x
Safety lab parameters 
x12-12a x12
x12
x12
x12
x12
x12
x12
x5
Tumour markers13
x
Urine examination14
x
x
x
x
x
Pharmacokinetics (plasma)
x15
x15
x15
x15
x15
x15
Adverse Events
x
x
x
x
x
x
x
x
x
x16
Concomitant Therapy
x
x
x
x
x
x
x
x
x
x16
CT and/or MRI - 17
x17
x17
x5
Tumour assessment17
x
x17
x5
Tumour biopsy for exploratory biomarker 
analysis18-a-b
x189-a
x18-
a-b
Mandatory DNA blood18-a-b
x18-a-b
x18-
a-b
 gene expression in whole blood19
x19
x19
x19
x19
Optional bio-banking sample
x
Termination of study medication
x
Patient’s status (alive/PD/dead)
x
1 end of treatment (EOT) investigations which have to be performed at the EOT visit (as soon as possible when a 
patient discontinues treatment)


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2 FU= follow up visits until progression, lost to follow up, treatment with another anti-cancer drug or end of the 
whole trial as specified in Section 8.6. The first follow-up visit is the End of Residual Effect Period visit (EOR) 
which must happen at the earliest 30 days after the end of treatment (see Section 6.2.3.2)
3 Visit 5 of Cycle 1 may correspond to Visit 1 of Cycle 2 if an additional cycle is indicated
4 the informed consent consist of 2 forms (or different sections, depending on the countries): 
-
a main informed consent for participation to the trial 
-
a separate informed consent for biomarkers analyses: 
o
mandatory blood samples for pharmacogenomics, 
o
optional bio-banking sample for pharmacogenomics 
o
optional tumour biopsies for pharmacogenomics biomarkers analyses
o
optional consent for sending of archival tissue for genomic analysis in case of objective 
response or if patient is benefiting from treatment
o
optional consent for a fresh tumour biopsy in patients who have an objective response or are 
benefiting from treatment
o
mandatory consent for an additional 2-3 mL EDTA Blood DNA tube, if consent is given for 
archival/fresh tumour biopsy
5 optional, to perform if needed to follow-up on adverse events (AE) present/ongoing at previous visit or if not 
performed at the EOT visit
6 a serum or urine beta human chorionic gonadotrophin (βHCG) pregnancy test must be performed within 7 days 
prior to first treatment in women of childbearing potential
7 at Screening, on Days 1-2 and 21-22: pre-dose and at approximately 2h, 4h, 8h, 24h post-dose, on Days 8 and 15, 
as well as on Day 29 of Cycle 1, and at EOT, at any time of the visit when not on an intensive PK day. For each 
ECG, digitalized triplicate acquisition, using dedicated equipment for central reading by clinical research 
organization (CRO). The ECGS are to be performed before the blood sampling when at same time-point as 
blood sampling (see Section 5.4.2)
8 by echocardiography or MUGA scan, but each time by the same method
9 intake of BI 894999 done at the clinical site on Days 1, 2, 15 and on Day 21, and by the patient anywhere else on 
the other days (between Day 3 and Day 7 and between Day 16 and Day 20). On the day of biopsy, if not 
performed on Day 21, the patient may take the medication before arriving at the clinical site but must note the 
exact hour of intake
10 the diary card must be completed every day of intake in Cycle 1
11 vital signs (blood pressure, pulse and body temperature): on Days 1 and 21: pre-dose, and approximately 4h, 8h 
post-dose. On all other visit days, once at any time during the visit day
12 When a blood glucose test is performed, the investigator must indicate whether the patient was in fasting 
condition at the time of the blood sampling, meaning the sample is taken after an overnight fasting. Safety lab 
parameters including coagulation parameters (aPTT, PT expressed in sec and INR) only to be performed at 
screening, on Day 1 pre-dose, on Day 2, Day 8, Day 21, pre-dose and on the day of tumour biopsy when 
applicable (if on a different day then Day 21), and at EOT. Each time a safety lab is foreseen per protocol, 
troponin hs test must be performed (T hs or I hs but always the same test for a given patient).
12a Hep B DNA test, Hep C RNA test and HIV infection detection by an established HIV diagnostic assay 
performed at screening (results within 4 weeks before screening are acceptable) 
13 only in patients with tumour types where there is a clinically relevant tumour marker which is already used in 
routine clinical practice for tumour restaging (on Day 1 of every cycle) 
14 urine examination by dipstick for pH, glucose, erythrocytes, leukocytes, protein, nitrite. If pathological findings, 
further evaluation (see Section 5.3.3)
15 intensive PK blood sampling will be performed in Cycle 1, as summarized in Appendix 10.2. 
A PK sample will also be taken at the time of the visit on Day 8 and on Day 29
16 all AEs and concomitant medication must be collected until 30 days (until EOR) after the last BI 894999 intake. 
After EOR, for subsequent FU visits, only SAEs/AESIs which are considered study drug related need to be 
collected as well as their related treatment
17according to RECIST 1.1 guidelines for patients with solid tumours. Imaging and assessment are required every 
2 cycles (meaning every 8 weeks if no delays in cycles but as close as possible to the end of the second of the 
two cycles of treatment if there was a delay). EOT/FU imaging and assessment are optional if previous 
examination was performed in the past 6 weeks


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18aoptional for patients in the escalation phase including the patients in the extension of MTD cohort, who agree to 
tumour biopsy, a tumour biopsy for biomarker analysis (see Section 5.5.1.2) may be performed at baseline and 
between Day 18 and Day 21 (4-8h after drug intake) of Cycle 1: the biopsy may only be performed if the platelet 
count is above 50 000/mm3 without support from a transfusion and coagulation parameters (aPTT, PT in sec and 
INR) are within normal limits on the day of the biopsy. For those patients having a tumour biopsy or sending of 
archival tumour tissue, a mandatory 2-3 mL EDTA DNA blood sample must be taken once, being it at screening 
or when steady state tumour biopsy is taken. 
18bWhere a fresh biopsy is taken for the baseline sample the subsequent on-treatment biopsy should be taken, 
where feasible, from the same lesion (not to be considered as a target lesion)
 
 (or other genes related to MOA) gene expression will be analysed in whole blood as summarized in 
Appendix 10.2
20 to be done if not performed within the previous 6 weeks and if possible, according to the patient’s  condition at 
the time of EOT


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FLOW CHART: SECOND AND FURTHER TREATMENT CYCLES IN 
SCHEDULE C FOR SOLID TUMOUR PATIENTS IN PHASE IA
Study Periods
Treatment Cycles
EOT1
FU2
Visit
C2V1
C2V2
C2V33
CxV1
CxV23
EOT 
FU 
Day
(day range)
1
15
29
1
15
29
First = 
EOR +30 
(+7) after 
EOT
Eligibility for re-treatment
x
x
Physical Examination 
x
x
x4
x5
Body weight
x
x
x4
x
ECOG performance score
x
x
x4
x
Pregnancy test
x
x
x4
12-lead-ECG
x6-16
x16
x16
x6-16
x16
x16
x16
x5-16
LVEF
x13
x14
x5
Dispensing of BI 894999
x
x
Intake of BI 894999 
x7
x7
x7
x7
Compliance check
x
x
x
Vital Signs
x
x
x
x
x
x
x
Safety lab parameters
x17
x17
x17
x17
x15-17
x15-17
x17
x5
Tumour markers
x
x
Urine examination
x
x
x
Pharmacokinetics
x8
Adverse Events
x
x
x
x
x
x
x
x9
Concomitant Therapy
x10
x
x
x
x
x
x
x9
CT and/or MRI11
x11
x11
x11
x11
Tumour assessment11
x11
x11
x11
x11
Optional archival tumour tissue: 
x12
Optional fresh tumour biopsy 
x12
Mandatory DNA blood12
x12
Termination of study medication
x
Patient’s status (alive/PD/dead)
x
1 end of treatment; investigations which have to be performed at the EOT visit (as soon as possible when a patient 
discontinues treatment)
2 FU= follow up visit until progression, lost to follow up, treatment with another anti-cancer drug or end of the 
whole trial as specified in Section 8.6. The first follow-up visit is the End of Residual Effect Period visit (EOR) 
which must happen at the earliest 30 days after the end of treatment (see Section 6.2.3.2)
3 last visit of a cycle may correspond to visit 1 of next Cycle if an additional cycle is indicated
4 data from the last visit of the previous cycle (Day 29) may be used in case examinations were done within the 
past two weeks
5 optional, to perform if needed to follow-up on AEs present/ongoing at previous visit or if not performed at the
  EOT visit


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6 ECG must be repeated pre-dose on C2V1 (or CxV1) if C2V1 (or CxV1) happens on a different day than C1V5 
(or last visit of previous cycle)
7 from Day 1 till Day 7 and from Day 15 till Day 21 of a cycle with a loading dose on Days 1 and 15. The doses 
of Day 1 and Day 15 of the cycle are administered on site, all other doses are taken by the patient outside the 
clinical site
8  at any time, only in case of drug related Grade 3 or Grade 4 toxicity, every effort must be made to collect a PK 
sample; date and time of the sample and of the most recent drug intake (before PK sample) need to be recorded 
for such samples
9  all AEs and concomitant medication must be collected until 30 days (until EOR) after the last BI 894999 intake. 
After EOR, for subsequent FU visits, only SAEs/AESIs which are considered study drug related need to be 
collected as well as their related treatment
10 update only
11 according to RECIST 1.1 guidelines for patients with solid. Imaging and assessment are required every 2 cycles 
(meaning every 8 weeks if no delays in cycles but as close as possible to the end of the second of the two cycles 
of treatment if there was a delay). EOT/ FU imaging and assessment are optional if previous exam was 
performed in the past 6 weeks. The choice of computed tomography (CT) and/or magnetic resonance imaging 
(MRI) is left to the investigator’s judgement but the method must remain the same for all evaluations. If the 
patient did not end the trial treatment due to progressive disease (PD), the tumour assessments during follow-ups 
will be according to standard of care for the site/country
12 If a patient has an objective response or is benefiting from the treatment and he/she agreed beforehand for 
sending of archival tumour tissue or/and for a fresh tumour biopsy (if deemed safe and feasible by the 
investigator) for gene analysis, 2-3 mL EDTA DNA blood tube at any time, if not yet done before
13 to be performed by echocardiography or MUGA scan, by the same method as at baseline
14 to be performed if not done in the past 6 weeks and if possible, according to the patient’s  condition at the time 
of EOT
15 measurements of CK and troponin and any other parameter deemed necessary to be controlled by the 
investigator
16 For each ECG, digitalized triplicate acquisition using dedicated equipment for central reading by clinical 
research organization (CRO). The ECGS are to be performed before the blood sampling when at same time-
point as blood sampling (see Section 5.4.2)
17 When a blood glucose test is performed, the investigator must indicate whether the patient was in fasting 
condition at the time of the blood sampling, meaning the sample is taken after an overnight fasting. Safety lab 
parameters including measurements of coagulation parameters: aPTT, PT expressed in seconds and INR. Each 
time a safety lab is foreseen per protocol, troponin hs test must be performed (T hs or I hs but always the same 
test for a given patient).
Coagulation parameters will be evaluated only on V1 of each cycle.


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FLOW CHART FIRST TREATMENT CYCLE IN SCHEDULE C FOR 
DLBCL PATIENTS IN PHASE IA AND NC PATIENTS IN PHASE IB
Study Periods
Screen
Treatment Cycle 1
EOT1
FU2
Visit
Screen
1
2*
3
4
53
EOT 
FU 
Day
(day range)
-28 - 1
1
8
15
21
22
29
FU1 = EOR
+30 (+7) after 
EOT
Informed Consents4
x
Demographics
x
Medical History
x
In- /Exclusion Criteria
x
x
Physical Examination 
x
x
x
x5
Height
x
Body weight
x
x
x
x
ECOG performance score
x
x
x
x
Pregnancy test
x6
x
12-lead-ECG
x7
x7
x7
x7
x7
x7
x7
x7
x5
LVEF8
x
x20
x5
Dispensing of BI 894999
x
Intake of BI 894999
x9
x9
x9
Compliance check
x
x
x
Completion of diary card10
x---
x---- ----x
Vital Signs
x
x11
x
x
x11
x
x
x
Safety lab parameters 
x12-12a
x12
x12
x12
x12
x12
x12
x5
Urine examination13
x
x
x
x
Pharmacokinetics (plasma)
x14
x14
x14
x14
Adverse Events
x
x
x
x
x
x
x
x
x15
Concomitant Therapy
x
x
x
x
x
x
x
x
x15
CT and/or MRI - PET/CT in DLBCL16
x16
x16
x5
Tumour assessment16
x
x16
x5
Tumour biopsy for exploratory biomarker 
analysis17-a-b
x17-a
x17-
a-b
Mandatory DNA blood17-a-b
x17-a-b
x17-
a-b
1 gene expression in whole blood18
x18
x18
x18
Optional bio-banking sample
x
Termination of study medication
x
Overall clinical benefit assessment by 
Investigator for NC patients
x
Patient’s status (alive/PD/dead)
x19


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* Examinations of visit on Day 8 may be performed locally, close to the patient’s home, with all tests done as 
foreseen per protocol and a phone call visit with the Investigator happens to evaluate the patient’s safety, if the 
patient is unable to travel frequently to the site and if allowed by local country regulations
1 end of treatment (EOT) investigations which have to be performed at the EOT visit (as soon as possible when a 
patient discontinues treatment)
2 FU= follow up visits until progression, lost to follow up, treatment with another anti-cancer drug or end of the 
whole trial as specified in Section 8.6. The first follow-up visit is the End of Residual Effect Period visit (EOR) 
which must happen at the earliest 30 days after the end of treatment (see Section 6.2.3.2)
3 Visit 5 of Cycle 1 may correspond to Visit 1 of Cycle 2 if an additional cycle is indicated
4 the informed consent consist of 2 forms (or different sections, depending on the countries): 
-
a main informed consent for participation to the trial 
-
a separate informed consent for biomarkers analyses: 
o
mandatory blood samples for pharmacogenomics, 
o
optional bio-banking sample for pharmacogenomics 
o
optional tumour biopsies for pharmacogenomics biomarkers analyses
o
optional consent for sending of archival tissue for genomic analysis in case of objective 
response or if patient is benefiting from treatment
o
optional consent for a fresh tumour biopsy in patients who have an objective response or are 
benefiting from treatment
o
mandatory consent for an additional 2-3 mL EDTA Blood DNA tube, if consent is given for 
archival/fresh tumour biopsy
For the NC indication, when patients are aged between 15 years and legal adult age, they will have to sign an 
assent form for the main part of the trial as well as for the biomarker part while parents (both or one according to 
national regulation) or the legal guardian must sign both consent forms.
5 optional, to perform if needed to follow-up on adverse events (AE) present/ongoing at previous visit or if not 
performed at the EOT visit
6 a serum or urine beta human chorionic gonadotrophin (βHCG) pregnancy test must be performed within 7 days 
prior to first treatment in women of childbearing potential
7 at Screening, on Day 1 pre-dose and at approximately 2h and 4h post-dose and on Days 21-22: pre-dose and at 
approximately 2h, 4h, 8h, 24h post-dose, on Days 8 and 15, as well as on Day 29 of Cycle 1, and at EOT, at any 
time of the visit when not on an intensive PK day. For each ECG, as far as possible, digitalized triplicate 
acquisition, using dedicated equipment for central reading by clinical research organization (CRO). The ECGS 
are to be performed before the blood sampling when at same time-point as blood sampling (see Section 5.4.2). If 
on Day 8, the patient has the assessments performed locally, the ECG will not be performed on the central 
reading ECG device and the ECG tracing must be sent to the site which will send it to the Central Reading 
laboratory for evaluation. 
8 by echocardiography or MUGA scan, but each time by the same method
9 intake of BI 894999 done at the clinical site on Days 1, 15 and on Day 21, and by the patient anywhere else on 
the other days (between Day 3 and Day 7 and between Day 16 and Day 20). On the day of biopsy (optional) if 
not performed on Day 21, the patient may take the medication before arriving at the clinical site but must note 
the exact hour of intake
10 the diary card must be completed every day of intake in Cycle 1
11 vital signs (blood pressure, pulse and body temperature): on Days 1 and 21: pre-dose, and approximately 4h, 8h 
post-dose. On all other visit days, once at any time during the visit day
12 When a blood glucose test is performed, the investigator must indicate whether the patient was in fasting 
condition at the time of the blood sampling, meaning the sample is taken after an overnight fasting. Safety lab 
parameters including coagulation parameters (aPTT, PT expressed in sec and INR) only to be performed at 
screening, on Day 1 pre-dose, on Day 8, Day 21, pre-dose and on the day of tumour biopsy when applicable (if 
on a different day then Day 21), and at EOT. Each time a safety lab is foreseen per protocol, troponin hs test 
must be performed (T hs or I hs but always the same test for a given patient).
12a Hep B DNA test, Hep C RNA test and HIV infection detection by an established HIV diagnostic assay 
performed at screening (results within 4 weeks before screening are acceptable) 
13 urine examination by dipstick for pH, glucose, erythrocytes, leukocytes, protein, nitrite. If pathological findings, 
further evaluation (see Section 5.3.3)
14 intensive PK blood sampling will be performed in Cycle 1, as summarized in Appendix 10.2. 


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15 all AEs and concomitant medication must be collected until 30 days (until EOR) after the last BI 894999 intake. 
After EOR, for subsequent FU visits, only SAEs/AESIs which are considered study drug related need to be 
collected as well as their related treatment
16according to RECIST 1.1 guidelines for patients with solid tumours. Imaging and assessment are required every 
2 cycles (meaning every 8 weeks if no delays in cycles but as close as possible to the end of the second of the 
two cycles of treatment if there was a delay). EOT/FU imaging and assessment are optional if previous 
examination was performed in the past 6 weeks
According to RECIL 2017 guidelines for DLBCL patients, a FDG-PET/CT scan (or MRI if CT not possible but 
each time same method) must be performed at screening, at the end of Cycle 2 (at 8 weeks if no delays in 
cycles), at the end of Cycle 4 (week 16) and then every 4 cycles. EOT/ FU imaging and assessment are optional 
if previous exam was performed in the past 6 weeks
17a optional for DLBCL patients in the escalation phase including the patients in the extension of MTD cohort and 
optional for NC patients in Phase Ib, who agree to tumour biopsy, a tumour biopsy for biomarker analysis (see 
Section 5.5.1.2) may be performed at baseline and between Day 18 and Day 21 (4-8h after drug intake) of Cycle 
1: the biopsy may only be performed if the platelet count is above 50 000/mm3 without support from a 
transfusion and coagulation parameters (aPTT, PT in sec and INR) are within normal limits on the day of the 
biopsy. For those patients having a tumour biopsy or sending of archival tumour tissue, a mandatory 2-3 mL 
EDTA DNA blood sample must be taken once, being it at screening or when steady state tumour biopsy is taken. 
17b Where a fresh biopsy is taken for the baseline sample the subsequent on-treatment biopsy should be taken, 
where feasible, from the same lesion (not to be considered as a target lesion)
 (or other genes related to MOA) gene expression will be analysed in whole blood as summarized in 
Appendix 10.2
19 only for NC patients recruited in Phase Ib after approval of protocol version 11.0, the patient’s survival status 
will continue to be collected until death, lost to follow-up or until 12 months after the end of trial, even if the 
patient progressed according to RECIST 1.1 or started with another anti-cancer treatment, according to patient’s 
informed consent
20 to be done if not performed within the previous 6 weeks and if possible, according to the patient’s condition at 
the time of EOT


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FLOW CHART: SECOND AND FURTHER TREATMENT CYCLES IN 
SCHEDULE C FOR DLBCL PATIENTS IN PHASE IA AND NC 
PATIENTS IN PHASE IB
Study Periods
Treatment Cycles
EOT1
FU2
Visit
C2V1
C2V2* C2V33
CxV1
CxV23
EOT 
FU 
Day
(day range)
1
15
29
1**
15*
29
First = 
EOR +30 
(+7) after 
EOT
Eligibility for re-treatment
x
x
Physical Examination 
x
x
x4
x5
Body weight
x
x
x4
x
ECOG performance score
x
x
x4
x
Pregnancy test
x
x
x4
12-lead-ECG
x6-16
x16
x16
x6-16
x16
x16
x16
x5-16
LVEF
x13
x14
x5
Dispensing of BI 894999
x
x
Intake of BI 894999 
x7
x7
x7
x7
Compliance check
x
x
x
Vital Signs
x
x
x
x
x
x
x
Safety lab parameters
x17
x17
x17
x17
x15-17
x15-17
x17
x5
Tumour markers
x
x
Urine examination
x
x
x
Pharmacokinetics
x8
Adverse Events
x
x
x
x
x
x
x
x9
Concomitant Therapy
x10
x
x
x
x
x
x
x9
CT and/or MRI - PET/CT in DLBCL11
x11
x11
x11
x11
Tumour assessment11
x11
x11
x11
x11
Optional archival tumour tissue: 
x12
Optional fresh tumour biopsy 
x12
Mandatory DNA blood12
x12
Termination of study medication
x
Overall clinical benefit assessment by 
Investigator for NC patients
x
Patient’s status (alive/PD/dead)
x18
* Examinations of visit on Day 15 may be performed locally, close to the patient’s home, with all tests done as 
foreseen per protocol and a phone call visit with the Investigator happens to evaluate the patient’s safety, if the 
patient is unable to travel frequently to the site and if allowed per local country regulations
** The Day 1 visit of even cycles, from Cycle 6 onwards may also be performed locally, close to the patient’s 
home with all tests done as foreseen per protocol and a phone call visit with the Investigator happens to evaluate 
the patient’s safety, if the patient is unable to travel frequently to the site. It means that a drug dispensation may 
happen for two consecutive cycles on Day 1 of uneven cycles starting from C5 onwards, after discussion with 
the Sponsor and if deemed safe by the Investigator


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1 end of treatment; investigations which have to be performed at the EOT visit (as soon as possible when a patient 
discontinues treatment)
2 FU= follow up visit until progression, lost to follow up, treatment with another anti-cancer drug or end of the 
whole trial as specified in Section 8.6. The first follow-up visit is the End of Residual Effect Period visit (EOR) 
which must happen at the earliest 30 days after the end of treatment (see Section 6.2.3.2)
3 last visit of a cycle may correspond to visit 1 of next Cycle if an additional cycle is indicated
4 data from the last visit of the previous cycle (Day 29) may be used in case examinations were done within the 
past two weeks
5 optional, to perform if needed to follow-up on AEs present/ongoing at previous visit or if not performed at the
  EOT visit
6 ECG must be repeated pre-dose on C2V1 (or CxV1) if C2V1 (or CxV1) happens on a different day than C1V5 
(or last visit of previous cycle)
7 from Day 1 till Day 7 and from Day 15 till Day 21 of a cycle with a loading dose on Days 1 and 15. The doses 
of Day 1 and Day 15 of the cycle are administered on site if applicable (when the patient has an on site visit), all 
other doses are taken by the patient outside the clinical site
8  at any time, only in case of drug related Grade 3 or Grade 4 toxicity, every effort must be made to collect a PK 
sample; date and time of the sample and of the most recent drug intake (before PK sample) need to be recorded 
for such samples
9  all AEs and concomitant medication must be collected until 30 days (until EOR) after the last BI 894999 intake. 
After EOR, for subsequent FU visits, only SAEs/AESIs which are considered study drug related need to be 
collected as well as their related treatment
10 update only
11 according to RECIST 1.1 guidelines for patients with solid. Imaging and assessment are required every 2 cycles 
(meaning every 8 weeks if no delays in cycles but as close as possible to the end of the second of the two cycles 
of treatment if there was a delay). EOT/ FU imaging and assessment are optional if previous exam was 
performed in the past 6 weeks. The choice of computed tomography (CT) and/or magnetic resonance imaging 
(MRI) is left to the investigator’s judgement but the method must remain the same for all evaluations. If the 
patient did not end the trial treatment due to progressive disease (PD), the tumour assessments during follow-ups 
will be according to standard of care for the site/country
According to RECIL 2017 guidelines for DLBCL patients, a FDG-PET/CT scan (or MRI if CT not possible but 
each time same method) must be performed at screening, at the end of Cycle 2 (at 8 weeks if no delays in 
cycles), at the end of Cycle 4 (week 16) and then every 4 cycles. EOT/ FU imaging and assessment are optional 
if previous exam was performed in the past 6 weeks
12 If a patient has an objective response or is benefiting from the treatment and he/she agreed beforehand for 
sending of archival tumour tissue or/and for a fresh tumour biopsy (if deemed safe and feasible by the 
investigator) for gene analysis, 2-3 mL EDTA DNA blood tube at any time, if not yet done before 
13 to be performed by echocardiography or MUGA scan, by the same method as at baseline
14 to be performed if not done in the past 6 weeks and if possible, according to the patient’s  condition at the time 
of EOT
15 measurements of CK and troponin and any other parameter deemed necessary to be controlled by the 
investigator
16 For each ECG, as far as possible, digitalized triplicate acquisition using dedicated equipment for central reading 
by clinical research organization (CRO). The ECGS are to be performed before the blood sampling when at 
same time-point as blood sampling (see Section 5.4.2). When the assessments are performed locally, the ECG 
will not be performed on the central reading ECG device and the ECG tracing must be sent to the site which will 
send it to the Central Reading laboratory for evaluation. 
17 When a blood glucose test is performed, the investigator must indicate whether the patient was in fasting 
condition at the time of the blood sampling, meaning the sample is taken after an overnight fasting. Safety lab 
parameters including measurements of coagulation parameters: aPTT, PT expressed in seconds and INR. Each 
time a safety lab is foreseen per protocol, troponin hs test must be performed (T hs or I hs but always the same 
test for a given patient).
Coagulation parameters will be evaluated only on V1 of each cycle.
18 only for NC patients recruited in Phase Ib after approval of protocol version 11.0 or 12.0 (depending on the 
country), the patient’s survival status will continue to be collected until death, lost to follow-up or until 12 
months after the end of trial, even if the patient progressed according to RECIST 1.1 or started with another anti-
cancer treatment, according to patient’s informed consent


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART FIRST TREATMENT CYCLE IN SCHEDULE A*...............................8
FLOW CHART: SECOND AND FURTHER TREATMENT CYCLES IN 
SCHEDULE A**.................................................................................................11
FLOW CHART FIRST TREATMENT CYCLE IN SCHEDULE B ...............................13
FLOW CHART: SECOND AND FURTHER TREATMENT CYCLES IN 
SCHEDULE B.....................................................................................................17
FLOW CHART FIRST TREATMENT CYCLE IN SCHEDULE C FOR SOLID 
TUMOUR PATIENTS IN PHASE IA ..............................................................20
FLOW CHART: SECOND AND FURTHER TREATMENT CYCLES IN 
SCHEDULE C FOR SOLID TUMOUR PATIENTS IN PHASE IA ............23
FLOW CHART FIRST TREATMENT CYCLE IN SCHEDULE C FOR DLBCL 
PATIENTS IN PHASE IA AND NC PATIENTS IN PHASE IB...................25
FLOW CHART: SECOND AND FURTHER TREATMENT CYCLES IN 
SCHEDULE C FOR DLBCL PATIENTS IN PHASE IA AND NC 
PATIENTS IN PHASE IB..................................................................................28
TABLE OF CONTENTS ......................................................................................................30
ABBREVIATIONS................................................................................................................35
1.
INTRODUCTION...............................................................................................38
MEDICAL BACKGROUND.............................................................................38
1.1
Non Clinical Pharmacology................................................................................38
1.2.1
Pharmacokinetics and product metabolism in pre-clinical.............................40
1.2.2
Toxicology............................................................................................................40
1.2.3
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....44
RATIONALE FOR PERFORMING THE TRIAL.........................................44
2.1
TRIAL OBJECTIVES........................................................................................44
2.2
BENEFIT - RISK ASSESSMENT.....................................................................45
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................49
OVERALL TRIAL DESIGN AND PLAN .......................................................49
3.1
Administrative structure of the trial .................................................................56
3.1.1


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DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................59
SELECTION OF TRIAL POPULATION .......................................................59
3.3
Main diagnosis for trial entry ............................................................................59
3.3.1
Inclusion criteria .................................................................................................60
3.3.2
In patients with solid tumours...............................................................................60
3.3.2.1
In patients with DLBCL........................................................................................62
3.3.2.2
Exclusion criteria ................................................................................................63
3.3.3
In patients with solid tumours...............................................................................63
3.3.3.1
In patients with DLBCL........................................................................................64
3.3.3.2
Removal of patients from therapy or assessments...........................................65
3.3.4
Removal of individual patients .............................................................................65
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................66
3.3.4.2
4.
TREATMENTS...................................................................................................67
TREATMENTS TO BE ADMINISTERED.....................................................67
4.1
Identity of BI investigational product(s)...........................................................67
4.1.1
Method of assigning patients to treatment groups...........................................67
4.1.2
Selection of doses in the trial..............................................................................68
4.1.3
4.1.3.1
First cycle of administration of BI 894999 ...........................................................68
4.1.3.2
Additional cycles of BI 894999 ............................................................................69
Drug assignment and administration of doses for each patient......................70
4.1.4
Cycle 1 ..................................................................................................................70
4.1.4.1
Further Cycles.......................................................................................................71
4.1.4.2
Dose interruptions and reductions.........................................................................72
4.1.4.3
4.1.4.3.1
Dose interruptions.................................................................................................72
4.1.4.3.2
Dose reductions.....................................................................................................73
Blinding and procedures for unblinding...........................................................73
4.1.5
Blinding.................................................................................................................73
4.1.5.1
Unblinding and breaking the code ........................................................................73
4.1.5.2
Packaging, labelling, and re-supply...................................................................74
4.1.6
Storage conditions...............................................................................................74
4.1.7
Drug accountability.............................................................................................74
4.1.8
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................75
Rescue medication, emergency procedures, and additional treatment(s) .....75
4.2.1
Restrictions ..........................................................................................................76
4.2.2
Restrictions regarding concomitant treatment ......................................................76
4.2.2.1
Restrictions on diet and life style..........................................................................77
4.2.2.2
Restrictions regarding women of childbearing potential ......................................77
4.2.2.3
TREATMENT COMPLIANCE........................................................................78
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................79
TRIAL ENDPOINTS..........................................................................................79
5.1
Primary Endpoint(s)...........................................................................................79
5.1.1
Phase Ia .................................................................................................................79
5.1.1.1
Phase Ib.................................................................................................................79
5.1.1.2


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Secondary Endpoint(s) .......................................................................................79
5.1.2
ASSESSMENT OF EFFICACY........................................................................81
5.2
Tumour assessment.............................................................................................81
5.2.1
ASSESSMENT OF SAFETY.............................................................................82
5.3
Physical examination ..........................................................................................82
5.3.1
Physical examination, height, body weight, performance status..........................82
5.3.1.1
Vital Signs............................................................................................................83
5.3.2
Safety laboratory parameters ............................................................................83
5.3.3
Electrocardiogram ..............................................................................................84
5.3.4
Other safety parameters.....................................................................................85
5.3.5
Left ventricular ejection fraction...........................................................................85
5.3.5.1
Assessment of adverse events.............................................................................86
5.3.6
Definitions of AEs ................................................................................................86
5.3.6.1
Adverse event collection and reporting.............................................................89
5.3.7
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................91
Assessment of Pharmacokinetics.......................................................................91
5.4.1
Methods of sample collection .............................................................................91
5.4.2
Plasma sampling for BI 894999 pharmacokinetics...............................................91
5.4.2.1
Urine sampling and analysis for pharmacokinetics ..............................................92
5.4.2.2
OTHER ASSESSMENTS...................................................................................97
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................97
5.7
6.
INVESTIGATIONAL PLAN.............................................................................98
VISIT SCHEDULE.............................................................................................98
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................99
6.2
Screening period................................................................................................100
6.2.1
Treatment period(s)..........................................................................................101
6.2.2
Follow Up Period and Trial Completion.........................................................101
6.2.3
End of treatment (EOT) visit ..............................................................................101
6.2.3.1
Follow-up visits...................................................................................................102
6.2.3.2
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE....................................................................................................................103


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STATISTICAL DESIGN - MODEL...............................................................103
7.1
NULL AND ALTERNATIVE HYPOTHESES .............................................108
7.2
PLANNED ANALYSES...................................................................................108
7.3
Primary endpoint analyses...............................................................................109
7.3.1
Secondary endpoint analyses ...........................................................................109
7.3.2
Safety analyses...................................................................................................113
7.3.4
Pharmacokinetic analyses ................................................................................113
7.3.5
INTERIM ANALYSES ....................................................................................114
7.4
HANDLING OF MISSING DATA .................................................................115
7.5
Plasma concentration - time profiles...............................................................115
7.5.1
Pharmacokinetic parameters...........................................................................115
7.5.2
RANDOMISATION .........................................................................................116
7.6
DETERMINATION OF SAMPLE SIZE .......................................................116
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS......118
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT .........................................................................................................118
DATA QUALITY ASSURANCE ....................................................................119
8.2
RECORDS.........................................................................................................119
8.3
Source documents .............................................................................................119
8.3.1
Direct access to source data and documents...................................................120
8.3.2
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
8.4
EVENTS.............................................................................................................120
Listedness...........................................................................................................120
8.4.1
Expedited reporting to health authorities and IRB / IEC.............................120
8.4.2
STATEMENT OF CONFIDENTIALITY......................................................120
8.5
END OF TRIAL................................................................................................120
8.6
9.
REFERENCES..................................................................................................122
PUBLISHED REFERENCES..........................................................................122
9.1
UNPUBLISHED REFERENCES....................................................................124
9.2
10.
APPENDICES...................................................................................................126
PHARMACOKINETIC ANALYSES.............................................................126
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) AND 
10.2
BIOMARKER BLOOD SAMPLING.............................................................129
Blood and urine sampling schedule.................................................................129
10.2.1
Details of procedures for food interaction cohorts ........................................133
10.2.2
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
10.3
AND DATA SCENARIOS ...............................................................................139
Model Performance and Data Scenarios for Schedules A and B .................139
10.3.1
Statistical Appendix for Schedule C................................................................144
10.3.2
VISIT SCHEDULE...........................................................................................153
10.4


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For Cycle 1.........................................................................................................153
10.4.1
For Cycle 2.........................................................................................................153
10.4.2
For next cycles in all Schedules........................................................................154
10.4.3
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ...............155
10.5
Screening period for all Schedules ..................................................................155
10.5.1
Treatment period ..............................................................................................155
10.5.2
Cycle 1 ................................................................................................................155
10.5.2.1
Further Cycles.....................................................................................................161
10.5.2.2
End of Treatment (EOT) visit..........................................................................163
10.5.3
Follow-up (FU) visit ..........................................................................................163
10.5.4
CLINICALLY RELEVANT CYP1A2, CYP2C8, CYP3A4 
10.6
SUBSTRATES: .................................................................................................165
RECIL 2017 RESPONSE CRITERIA AND DEAUVILLE SCORE...........167
10.7
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................168
GLOBAL AMENDMENT 1 ............................................................................168
11.1
GLOBAL AMENDMENT 2 ............................................................................171
11.2
GLOBAL AMENDMENT 3 ............................................................................177
11.3
GLOBAL AMENDMENT 4 ............................................................................179
11.4
GLOBAL AMENDMENT 5 ............................................................................181
11.5
GLOBAL AMENDMENT 6 ............................................................................185
11.6
GLOBAL AMENDMENT 7 ............................................................................189
11.7
GLOBAL AMENDMENT 8 ............................................................................193
11.8
GLOBAL AMENDMENT 9 ............................................................................195
11.9
GLOBAL AMENDMENT 10 ..........................................................................198
11.10
GLOBAL AMENDMENT 11 ..........................................................................202
11.11


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ABBREVIATIONS
ABC
Activated B-cell
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine amino Transferase
AML
Acute Myeloid Leukaemia
ANOVA
Analysis of variance
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate amino Transferase
AUC
Area under the Curve
BET
Bromodomain and Extraterminal domain
βHCG
Beta Human Chorionic Gonadotrophin
BHM
Bayesian Hierarchical Model
BI
Boehringer Ingelheim
BLQ
Below the Limit of Quantification
BLRM
Bayesian Logistic Regression Model
BP
Blood pressure
CA
Competent Authority
CK
Creatine phosphokinase
CML
Local Clinical Monitor 
COO
Cell of Origin
CPT
Cell Preparation Tube
CR
Complete Response
CRA
Clinical Research Associate
CRC
Colorectal Cancer
CRF
Case Report Form
CRO
Clinical Research Organization
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450 enzymes
DEDP
Drug Exposure During Pregnancy
DEL
Double Expressor Lymphoma 
DHL
Double Hit Lymphoma
DILI
Drug Induced Liver Injury
DLBCL
Diffuse Large B-cell Lymphoma
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EGFR
Epidermal Growth Factor Receptor
EOR
End Of Residual effect period


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EOT
End Of Treatment 
EWOC
Escalation With Overdose Control
FDG
Fluorodeoxyglucose 
FMO
Flavin-containing monooxygenases 
FU
Follow-Up
GCB
Germinal Centre B-cell
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GM-CSF
Granulocyte Macrophage Colony Stimulating Factor
Hep B
Hepatitis B
Hep C
Hepatitis C
hexamethylene bis-acetamide inducible 1 [ Homo sapiens (human) ]
HIV
Human Immunodeficiency Virus
hs
Highly sensitive
IB
Investigator’s Brochure
ICF
Informed Consent Form
IEC
Independent Ethics Committee
INR
International Normalized Ratio
i.p.
Intra-peritoneally
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
Kd
Dissociation Constant
LC-MSMS
Liquid Chromatography coupled to tandem Mass Spectrometry
LDH
Lactic Dehydrogenase
LHRH
Luteinizing Hormone-Releasing Hormone
LPLVPE
Last Patient Last Visit Primary Endpoint
LVEF
Left Ventricular Ejection Fraction
MAP
Meta-analytic Predictive
MASCC
Multinational Association of Supportive Care in Cancer
mCRPC
Metastatic Castration Resistant Prostate Cancer
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Drug Regulatory Activities
MM
Multiple Myeloma
MOA
Mechanism of Action
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated Acquisition scan
MYC
Myelocytomatosis oncogene
NC
NUT Carcinoma
NCI
National Cancer Institute from the USA
NHL
Non-Hodgkin Lymphoma
NOA
Not Analysed
NOAEL
No Observed Adverse Effect Level
NOP
No Peak detectable


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NOR
No valid Result
NOS
No Sample
OR
Objective Response
OS
Overall Survival
PBMC
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PDX
Patient Derived Xenograft
PET
Positron Emission Tomography
PFS
Progression Free Survival
PGx
Pharmacogenomics
PI
Principal Investigator
PK
Pharmacokinetics
PR
Partial Response
PSA
Prostate Specific Antigen
PT
Prothrombin Time
RAS
Rat Sarcoma Virus
RBC
Red Blood Cell count
RDC
Remote Data Capture
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
SCLC
Small Cell Lung Cancer
SD
Stable Disease
SOP
Standard Operating Procedure
STD
Severely Toxic Dose
TBA
Trial Bio-analyst
TCM
Trial Clinical Monitor
TCPK
Trial Pharmacokineticist
TGI
Tumour Growth Inhibition
TLS
Tumour Lysis Syndrome
TME
Translational Medicine Expert
TMF
Trial Master File
TMM
Team Member Medicine
TNM
Tumour, (lymph) Node, Metastasis 
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TSTAT
Trial Statistician
ULN
Upper Limit of Normal
UV
Ultraviolet
WBC
White Blood Cell count


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
The high medical need for new drugs in cancer therapy remains unchanged as still most 
patients with locally advanced or metastatic cancers will eventually die from the disease. The 
demographic development will lead to further increase in cancer incidence and the unmet need 
for therapy.
Several drugs targeting epigenetic modifiers have been successfully developed, including 
inhibitors of enzymatic “writers” such as DNA methyltransferases, and inhibitors of enzymatic 
“erasers” such as histone deacetylases. Modulation of the epigenetic regulators known as 
“readers” has recently emerged as a therapeutic strategy. One bromodomain-containing family 
is the BET family comprising BRD2, BRD3, BRD4 and BRDT. BET is important in regulating 
transcription, epigenetic memory and cell growth.
The bromodomain and extraterminal (BET) protein BRD4 recruits transcriptional regulatory 
complexes to acetylated chromatin, therefore facilitating the transcription of genes in areas of 
“open” chromatin. Pharmacological inhibition of BET proteins shows therapeutic activity in a 
variety of different pathologies, particularly in cancer models. These effects have been 
attributed to downstream target genes, whose expression is particularly sensitive to BET 
inhibition. 
BI 894999 is an inhibitor of the BET family. The preclinical efficacy and safety profile of BI 
894999 is expected to translate into a benefit for cancer patients. This study will investigate the 
safety and maximum tolerated dose of BI 894999, a BET inhibitor, administered orally to 
patients with various advanced or metastatic cancers. 
Non Clinical Pharmacology
1.2.1
Molecular potency and selectivity of BI 894999
Biochemical assays were conducted to assess the inhibitory potency of BI 894999 on the 
protein-protein interaction of acetylated lysine and the bromodomains BRD4 BD1 and BRD4 
BD2. BI 894999 inhibited the binding of bromodomain BRD4 BD1 to acetylated Histone with 
an IC50 of 5 ± 3 nM, of BRD4 BD2 to with an IC50 of 41 ± 30 nM.
In the BROMOscan selectivity screen, BI 894999 affected only bromodomains of the BET 
family (BRD2, 3, 4, T) with a constant of dissociation (Kd) of 0.49 to 1.6 nM, all the other 23 
bromodomains tested showed at least 200 fold selectivity vs. BRD4 BD1. In a broader 
biochemical screen (from the 
, 71 binding assays and 25 enzymatic assays) 
out of all the test targets, only one receptor, the benzodiazepine receptor BZD, showed 51 % 
inhibition of control specific binding at a test concentration of 1 µM.


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Overall, the BET inhibitor BI 894999 shows a very good selectivity profile.
Cellular Activity
The cellular potency of BI 894999 was determined in cell proliferation assays. A panel 
consisting of >50 acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), 
multiple myeloma (MM), chronic myelogenous leukaemia (CML), DLBCL (ABC and GCB-
type), and T-cell lymphoma (TCL) cell lines was tested. All cell lines except the CML line 
K562, showed an EC50 <100 nM, with most of the cell lines displaying single digit nM EC50 
values. 
For solid cancer types including SCLC, mCRPC, NC, head and neck squamous cell carcinoma, 
neuroblastoma, medulloblastoma and glioblastoma multiforme, cell line data showed 
proliferation inhibitory activity of BI 894999 (c03016865-02). Proliferation inhibitory activity 
with BI 894999 was also recently noted in CRC cell lines in vitro (new data on file, not yet 
reported).
In vivo efficacy of BI 894999
The in vivo efficacy of BI 894999 was assessed in disseminated and subcutaneously engrafted 
xenograft models.
In lymphoma studies, the subcutaneously engrafted xenograft model TMD8 is the established 
routine model for DLBCL (ABC type) in C.B-17scid mice. Treatment with BI 894999 was 
started at a tumour size of about 70 – 100 mm3. Compound was administered at daily oral 
doses of 12 mg/kg. Monotherapy of BI 894999 resulted in tumour growth inhibition (TGI) at
day 20 (sacrifice of vehicle control group due to tumour size) of 89 % compared to control. 
Rituximab was administered intra-peritoneally (i.p.) at 1 mg/kg q3 or 4 d and resulted in TGI 
of 77 %. Combination of BI 894999 and rituximab resulted in TGI of 92 %.
In a second TMD8 xenograft experiment, BI 894999 treatment was combined with ibrutinib.
In this experiment BI 894999 was dosed at 8 mg/kg (daily, per os) and ibrutinib at 12 mg/kg 
(daily, i.p.). In this experiment, BI 894999 as monotherapy was dosed below the MTD but still 
resulted in TGI of 64 %. Ibrutinib dosed at the MTD resulted in TGI of 45 %. Combination of 
both resulted in TGI of 110% with tumour regression in 6/7 animals.
Anti-tumour activity of BI 894999 was demonstrated in patient-derived xenograft (PDX) 
models for SCLC in NCR-nude or NMRI-nude mice. Mice were treated at the MTD (which is 
different depending on the mouse strain). Three of the 12 models tested were highly sensitive 
to BI 894999 with TGIs between 80% and 105% and tumour regressions, whereas the other 
nine models show TGIs between 7% and 68%. The search for a patient selection biomarker for 
SCLC is ongoing.
Anti-tumour activity of BI 894999 was also demonstrated in a prostate carcinoma xenograft 
model (MDA-PCA-2B). Mice were treated with 5 mg/kg enzalutamide once daily or with 12 
mg/kg BI 894999 once daily, with a dose reduction to 8 mg/kg on Day 12. Median tumour 
volume was compared with the median tumour volume in control mice. BI 894999 treatment 
resulted in TGI of 98%.


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In the ongoing clinical study 1367.1 two responses have been documented in patients with 
solid tumour so far: a partial response in a patient with small bowel adenocarcinoma (treated 
with Schedule A) that lasted until the end of Cycle 12 and a partial response in a patient with 
oesophageal squamous cell carcinoma (treated with Schedule B) that lasted until the end of 
Cycle 6.
In summary, BI 894999 is a potent and selective BET inhibitor that showed in vitro and in vivo 
activity in hematological malignancies and solid tumours.
Pharmacokinetics and product metabolism in pre-clinical
1.2.2
The in vitro metabolism of [14C] labelled BI 894999 was investigated by the use of human liver 
microsomes and cytosol, expressed cytochrome P450 (CYP) enzymes and flavin-containing 
monooxygenases (FMO) enzymes and human hepatocytes. Based on incubations with human 
hepatocytes and with liver microsomes at low concentrations of BI 894999 (10 µM) the 
contribution to hepatic oxidative metabolism of the single enzymes was estimated to 
approximately 50 to 60% for CYP 3A4 and to approximately 40 to 50% for FMO3 
(n00240842-01)
CYP enzyme induction in human hepatocytes
The in vitro induction of CYP enzymes by BI 894999 was investigated by incubations with 
human hepatocytes (n00244406). Based on the results of these incubations, BI 894999 caused 
enzyme induction on the messenger ribonucleic acid (mRNA) level in human hepatocytes of 
CYP1A2, 2C8 and 3A4. 
According to current most conservative cut-off criteria from the FDA (P12-05791) and EMA
(P14-08681) Drug-drug interaction guidelines, BI 894999 is likely a CYP inducer if Cmax total 
exceeds 0.83 nM (CYP3A4), 0.14 nM (CYP2C8) or 1.38 nM (CYP1A2).
Estimated efficacious human dose
A human clearance of 7.9 mL/min/kg was predicted based on simple allometry. A human 
volume of distribution at steady state of 4.9 L/kg was predicted based on mean of animal data. 
This resulted in a predicted human disposition mean residence time and effective half-life of 
10.5 h and 7 h, respectively.
The human therapeutic dose is predicted based on effective plasma concentration in the mouse 
xenograft model. Assuming similar potency of BI 894999 in humans and the mouse model, and 
taking into account similar protein binding between both species; this translates into a 
therapeutic dose of 45 mg (free base) once daily to achieve an anticipated effective plasma 
concentration above 35 nM for 6h in humans (n00240650-01).
Toxicology
1.2.3
The toxicity profile for BI 894999 has been assessed in a 2-week exploratory study in rats, a 2-
week dose range-finding study in dogs and 4-week toxicity studies in both species. In rats, a no 
observed adverse effect level (NOAEL) was achieved with 0.075 mg/kg. In dogs, there was no 
free dose down to a level of 0.0125 mg/kg. The nonclinical safety package, which also includes 


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safety pharmacology and immuno-toxicology endpoints, supports the administration of BI 
894999 to humans. 
The primary target organs of toxicities were the lymphoid and hematopoietic system (decreases 
in white blood cell count, monocytes, lymphocytes and platelet counts), the digestive tract (oral 
mucositis, degeneration, erosion and ulcers), the liver (hepatocellular atrophy, changes in liver 
enzymes), the testes (germ cell degeneration and loss) and the kidneys. Inhibition of the BET 
proteins with BI 894999 showed a rather steep dose-adverse effect curve and a delayed onset of 
adverse effects.
The assessment of the photochemical properties of BI 894999 indicates a potential risk of 
photo-toxicity. Appropriate protective measures must be taken during outpatient trials.
No cardio-toxicity risk is expected based on pre-clinical toxicity data.
A safe starting dose was estimated in accordance with the General Guide for Starting Dose 
Selection for a Cytotoxic Agent in Cancer Patients (FDA/CDER) and based on the data of 4-
week toxicity studies in rats and dogs. Using the conversion factor of 6, the high dose of the rat 
study of 0.5 mg/kg (severely toxic dose for 10 % of rodents, STD10) was transformed to 3 
mg/m². The high dose of the dog study (non-severely toxic dose) was converted from 0.05 
mg/kg to 1 mg/m² using the conversion factor of 20. The dog was considered to be the most 
sensitive species. Following the recommended decision tree 1/6 of 1 mg/m² = 0.17 mg/m² is the 
safe starting dose for cancer patients, which corresponds to 0.0045 mg/kg (using the conversion 
factor of 37). Based on a patient body weight of 70 kg, the calculated starting dose would be 
0.31 mg/patient/day.  However, due to the availability of tablet dose strengths, the starting dose 
in this first-in-human Phase I trial will actually be 0.2 mg per patient per day for the very first 
patient included in the trial, in Schedule A.
In summary, based on preclinical safety pharmacology studies, side effects of BI 894999 in 
humans may include symptoms related to the lymphoid and hematopoietic system (decreases in 
white blood cell count, monocytes, lymphocytes and platelet counts), the digestive tract (oral 
mucositis, diarrhoea,), liver (liver enzymes), kidneys and blood glucose levels. Patients will 
therefore be monitored for these side effects. Based on current knowledge of BET inhibitors 
and non-clinical data obtained for BI 894999, effects on testes are anticipated.
 
 
 
 
 
 
 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Most patients with locally advanced or metastatic tumours will succumb to their disease. Thus, 
there is a substantial need for novel therapeutic strategies to improve the outcome for patients 
with advanced or metastatic malignancies. This is particularly true for patients with NC which 
is a very aggressive malignancy for which no standard of care has been established. As this rare 
disease is observed in adolescents and young adults (R18-2451), for this indication, the trial 
will allow inclusion of minor patients aged 15 years or more. 
Recently, preliminary data of the Phase I trials of other BET inhibitors have been reported and 
promising results were observed in patients with lymphoma particularly in DLBCL. In the 
Phase I trial of CPI-0610 in patients with relapsed/refractory lymphoma, objective responses 
were observed in 4 patients with lymphoma including 3 patients with DLBCL (R16-1012). In 
the Phase I trial of OTX015 in patients with advanced haematological malignancies, 3 patients 
in the DLBCL cohort experienced an objective response (R15-1329).
BI 894999 is a potent inhibitor of BET bromodomain and as such prevents the transcription of 
relevant, as yet unidentified genes and thereby blocks proliferation and induces apoptosis in 
cancer cells (data on file).
Based on the preclinical studies 
, the observed anti-tumour 
activity in preclinical studies of BI 894999 and in clinical studies of other BET inhibitors and 
safety profile of BI 894999, clinical testing of BI 894999 is warranted. The present study is the 
first-in-human study to determine the safety profile and the MTD of BI 894999 in cancer 
patients for whom no standard treatment options exist.
TRIAL OBJECTIVES
2.2
The main objective of the dose escalation part of the trial is to determine the MTD using a 
continuous dosing Schedule A , the MTD using an intermittent Schedule B (2 weeks on, one 
week off in 3-week cycles) and the MTD using an intermittent Schedule C (a loading dose on 
first day followed by a maintenance dose for the next six days and followed by one week off 
treatment, repeated every two weeks in 4-week cycles) in patients with solid tumours and 
provide safety data in terms of drug-related adverse events (AEs) for the recommendation of 
the dose and schedule of treatment for the expansion Phase Ib of this trial (between Schedules 
A and B) and for further trials in the development of BI 894999 (between Schedules B and C) 
(see Section 5.2). Once the MTD has been determined for both schedules A and B in patients 
with solid tumours, the MTD was determined as well in patients with diffuse large B-cell 
lymphoma (DLBCL), using the DMC recommended schedule for solid tumours which was 
Schedule B. The MTD will also be determined in patients with DLBCL using the Schedule C 
in order to recommend the dose and schedule for further trials in DLBCL in the development 
of BI 894999 (see Section 1.3).


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Secondary 
 objectives are the determination of the pharmacokinetic (PK) profile of 
BI 894999 after single and multiple dose (see Section 5.4),
 
) and assessment of anti-tumour activity (see Section 
5.2). 
In the expansion phase, the main objective lies upon collection of further safety information at 
the dose recommended by the data monitoring committee (DMC) for Phase Ib (2.5 mg in 
Schedule B was recommended based on Schedule A and B data) and with the Schedule 
(between B and C) and dose recommended by the DMC for the Phase Ib NC cohort. The 
secondary 
 objectives will be to increase the number of patients with solid tumours 
and with evaluable PK results at the recommended Phase Ib dose for Schedule B in the four 
types of tumours and for Schedule C in the NC cohort, and the same as in the dose escalation 
part for the assessment of anti-tumour activity.
 
 
 
BENEFIT - RISK ASSESSMENT
2.3
BI 894999 inhibits tumour growth and induces tumour regression in pre-clinical models. Based 
on pre-clinical results, the inhibitory effects on BET bromodomain may translate into a clinical 
benefit in cancer patients. Although the starting dose is not expected to be efficacious, the dose 
escalation scheme guided by a Bayesian two-parameter logistic regression model (BLRM) (de-
escalation of dose is possible in case of insufficient tolerability of a dose level) is designed to 
escalate the dose quickly into a dose range where efficacy may be seen while still minimizing 
the risk of undue tolerability issues. 
None of the doses tested in dogs were free of adverse effects. Based on these studies, the most 
relevant side effect of BI 894999 is expected to be a transient inhibition of proliferation of 
normal dividing cells in mucosal tissue and bone marrow. Inhibition of mucosal proliferation 
may lead to gastro-intestinal symptoms such as nausea, diarrhoea, mucositis, and/or abdominal 
pain. Patients in this study will be closely monitored for these side effects and supportive 
treatment will be given by the investigators if necessary. The side effects on bone marrow cells 
may lead to a temporary decrease of blood cells and platelets. These side effects are frequently 
seen in cancer patients treated with conventional cytotoxics or targeted therapies and can 
readily be monitored with regular blood tests. Supportive treatment for some of these effects is 
available. 
In addition to these effects, some changes in laboratory values were observed such as an 
increased level of glucose and a decrease of phosphate.
Specific procedures have been implemented to early detect these and other potential side 
effects and to allow their immediate supportive treatment and follow up. The sites will be 
experienced Phase I oncology sites with the appropriate clinical personnel available and access 
to emergency care units in case of need. The patients will also remain at the clinical site, under 
surveillance, for the first 24 hours after the very first administration.


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Preclinical studies with BI 894999 have also shown degeneration of germ cells in testes of 
dogs. This is the reason why male patients having a partner of childbearing potential must use 
condoms and ensure their partner is using a highly effective method of birth control during the 
trial and for at least three months after the end of the trial.
In the study of the effect on hERG-mediated potassium current, BI 894999 did not show any in 
vitro signal for a pro-arrhythmic risk based on prolongation of ventricular repolarisation. This 
was confirmed in studies in dogs and rats which did not show a negative effect on myocardial 
contractility or a pro-arrhythmic effect (c03016865-02). However, to confirm this absence of 
pro-arrhythmic effect in humans, in addition to normal clinical monitoring of the 
cardiovascular functions by measurement of pulse and blood pressure (BP), regular 
electrocardiogram (ECG) records will be performed for further characterisation and will be 
centrally analysed by a core lab. 
On 04 Oct 2016, the sponsor decided to put a temporary hold on further recruitment of patients 
in trial 1367.1. The measure was taken since review of patient data revealed some patients with 
increased troponin levels. A thorough review by cardiologists was initiated with regards to 
troponin levels, ECG, and clinical summaries of all enrolled patients. Evidence supporting a 
causal association between the increased laboratory troponin values and the administration of 
the trial medication could not be established. There were no corresponding clinically 
significant findings based on the reviewed ECGs and the clinical summaries of enrolled 
patients. The external review concluded that the cause of troponin elevation may be 
multifactorial in the trial patient population. In conclusion, the findings were considered to not 
preclude further clinical development. Consequently, patient recruitment was re-started.
Patients on study will be closely monitored and will undergo regular controls of CK and 
troponin highly sensitive (see Section 5.3.3), together with ECG evaluation.
Furthermore, every patient will undergo a mandatory echocardiography or multiple gated 
acquisition (MUGA) scan for left ventricular ejection fraction (LVEF) determination during 
screening and then at the end of Cycle 2 and at the end of treatment (if the patient’s condition 
at the time of end of treatment permits so). Cardiologic assessments (CK, troponin hs (T or I), 
ECG, echocardiography and any other examination as judged necessary) should be prompted 
by the investigator upon clinical indication at any time (see Section 4.1.4.3.1).
Other treatment-emergent AEs which were most frequently observed in this Phase I trial so far 
include: fatigue, thrombocytopenia, decreased appetite, dysgeusia, increased CK, diarrhoea, 
nausea and stomatitis. Neutropenia was also observed but it was less frequent than the above 
AEs.
Thrombocytopenia 
is 
considered 
an 
expected 
AE 
associated 
with 
BI 
894999. 
Thrombocytopenia (especially CTCAE grade 4) could be associated with an increased risk of 
bleeding and is therefore considered medically important.
Asymptomatic grade 1–2 factor VII decrease was noted in some patients treated with another 
BETi, OTX-015 in a Phase I study conducted in patients with lymphoma or multiple myeloma 
(R15-1329). Prolonged coagulation times have also been reported as treatment related adverse 
events in a Phase I study with the BET inhibitor INCB057643 (R18-1831) and in a Phase I 


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Study with the BET inhibitor GSK525762 (R18-2390). Monitoring of coagulation parameters 
in the 1367.1 study revealed that some patients present with mild prolongation of prothrombin 
time (PT) and increase in international normalized ratio (INR) on Day 14 of Cycle 1. 
Coagulation parameters will continue to be monitored during the study and will be evaluated 
before the performance of tumour biopsies. Tumour biopsies will only be performed if the 
platelet count is above 50 000/mm3 without the support of transfusion and coagulation 
parameters (aPTT, PT in sec and INR) are within normal limits on the day of the biopsy. It is 
possible that prolonged PT will occur concurrently with thrombocytopenia in a patient being 
treated with BI 894999. The coexistence of thrombocytopenia and coagulopathy could 
potentially increase the risk of bleeding events. In order to reduce the risk of bleeding events in 
patients with severe thrombocytopenia and prolonged coagulation times, mandatory 
prophylactic platelet transfusions need to be administered to all patients who present with a 
platelet count below 20 000/mm3. 
Based upon a non-clinical safety study in vitro, a potential risk of photo-toxicity /
photosensitization in vivo could not be excluded. Therefore, adequate precautions must be 
taken during treatment with BI 894999 (avoidance of prolonged ultraviolet (UV) exposure, use 
of broad spectrum sunscreen).
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and follow-
up of laboratory alterations of selected liver laboratory parameters to ensure patients’ safety 
(see also Section 5.3.6.1).
Based on its mode of action, BI 894999 is not expected to have a relevant impact on 
susceptibility to or on the course of an infection, however, in DLBCL patients, the 
susceptibility to a COVID-19 infection may be increased.
Patients in this trial may have an increased risk for severe illness from COVID-19. In case of 
an increased risk of COVID-19 infection, physical visits to the sites should be avoided where 
the investigator judges that this is the safest course of action. They should be replaced with 
remote visits, procedures and lab testing will be done remotely as far as possible (see Sections
4.1.4.2 and 6.1). These measures ensure the safety of the patients throughout the trial, maintain 
the integrity of the trial and will not affect the benefit-risk of BI 894999.
In case of a confirmed infection, trial treatment will be interrupted immediately and appropriate 
measures for monitoring, treatment and quarantine will be implemented. The patient may 
resume treatment following recovery from a COVID-19 infection if the patient is expected to 
derive clinical benefit, as agreed between the Investigator and Sponsor.
Trial procedures such as blood sampling, imaging with e.g. contrast media, tumour biopsies,
are part of standard of care in these advanced cancer patients but are performed at a higher 
frequency during this trial. The additional blood samplings increase the risk for anaemia which 
can be corrected by appropriate transfusion if necessary. The imaging performed every other 
cycle can bring additional long term radiation burden but these advanced patients are not 
expected to remain for very long periods in the study and it is the only way to detect early 
progression or early response to avoid unnecessary further treatment or a premature stop while 
the trial treatment would be beneficial to the patient.


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There is an added risk for pain, swelling, bleeding for those patients who will undergo tumour 
biopsies at screening and during the trial, under treatment. For this reason, biopsies will only be 
performed when deemed safe by the investigator, if the platelet count is at least 
50 000/mm3 without the support of transfusion and if coagulation parameters are within normal 
limits on the day of the biopsy.
Patients with advanced solid tumours, and relapsed/refractory DLBCL who have limited or no 
established treatment options may theoretically benefit from the treatment with BI 894999 
(tumour regression, disease stabilisation or improvement of tumour-related symptoms). The 
potential benefit of therapy with BI 894999 is expected to outweigh the treatment and 
procedures related risks.
For the NUT carcinoma patients of Phase Ib, enrolment of adolescents ≥15 years of age will be 
allowed. Indeed, the dose, safety and metabolism in adolescents of ≥15 years are expected to 
be similar to adults because body size is expected to be close to adults and organ maturation is 
expected to be completed. However, to confirm the hypothesis that safety is similar in 
adolescents and adults, a mandatory DMC meeting will take place after the first and after the 
second adolescent patient completes Cycle 1 to assess whether the adult dose is tolerable in 
adolescents. In this population the benefit is expected to outweigh the risks because there is no 
standard treatment available and BI 894999 is specifically targeting the NUT fusion that is 
characteristic for the disease.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
or
*dark boxes show completed steps at the time of protocol version 12.0
Figure 3.1: 1: Trial Design for Solid Tumours
DMC
decision to
proceeding 
to Phase Ib
with Sch. B 
MTD
DMC
DMC
DMC
Extension 
of MTD 
cohort 
with 
selected 
Schedule 
B in solid 
tumours
DMC
Schedule B intermittent intake in 
solid tumours 
(2 weeks-on, 1 week off in 3-
week cycles)
MTD
DMC
DMC
BLRM
BLRM
Schedule C intermittent intake in solid tumours 
(Day1 loading dose + 6 days intake of maintenance 
dose - 1 week off, repeated every 2 weeks in 4 
week-cycles) 
(started with protocol version 10.0)
MTD
BLRM
results of 
modelling on 
toxicity versus 
PK
loading of 5 
mg, mainte-
nance of 2,5 
mg
Solid Tumours
Schedule A continuous intake in 
solid tumours*
mCRPC
SCLC 
CRC
NC
DMC
DMC will meet at least every 3 
months + after end of C1 of first and 
of second adolescent patient in NC
NC with Sch. C     
with Schedule B 
Phase Ia dose finding
Phase Ib expansion
DMC
decision to
proceeding 
to Phase Ib
with Sch. C 
in NC cohort 
Extension 
of MTD 
cohort 


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*dark boxes show completed steps at the time of protocol version 12.0
** DMC made the decision on MTD in Sch. B after protocol version 11.0 approval and before start of Sch. C dose finding part
Figure 3.1: 2: Trial Design for DLBCL
The trial is designed as an open label, uncontrolled study and had a dose escalation Phase Ia to 
determine the MTD in solid tumours in two different schedules, Schedule A with continuous 
dosing once daily in 3-week cycles and Schedule B with once daily dosing for 2 weeks 
followed by one week off treatment in 3-week cycles with an extended cohort at MTD in the 
selected schedule B) as decided by the DMC in December 2017, based on the safety, 
pharmacokinetic and pharmacodynamics data available from all patients treated by that stage. 
This is then followed by an expansion Phase Ib in selected solid tumour indications with the 
chosen dose (2.5 mg) and schedule (Schedule B) as decided by the DMC in April 2018. The 
DMC also confirmed the decision on which types of tumours to include in this expansion phase
(DMC meeting of September 2017). During the Phase Ia, once the MTD has been determined 
in both Schedules A and B in solid tumours, testing of the chosen Schedule by the DMC (i.e.
Schedule B) in patients with DLBCL commenced to determine the MTD of BI 894999 with 
Schedule B in patients with DLBCL. The starting dose was one dose lower than the MTD dose 
in patients with solid tumours.
The dose escalation part using Schedule B in patients with solid tumours happened in parallel 
with the dose escalation part of Schedule A and started at the highest dose level tested in 
Schedule A in solid tumours considered to be safe by the DMC. 
loading of 
4 mg, 
mainte-
nance of 2 
mg
MTD
DMC
DMC
Extension 
of MTD 
cohort in 
DLBCL 
with 
selected 
Schedule 
B or C at 
MTD dose
BLRM
MTD in 
solid 
tumours 
Sch. B 
minus one 
dose
DMC
MTD in 
Sch. B**
DMC selection of 
Sch. B after MTD 
determination in 
both Sch. A and 
Sch. B in solid 
tumours
BLRM
DMC
Schedule B
Schedule C
DMC
DLBCL in Phase Ia dose finding
DMC selection 
of Sch. B or C 
after MTD 
determination in 
both Sch. B and 
Sch.C 


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Further to the results from modelling of toxicity observed on thrombocytes and results of PK 
and pharmacodynamics, an additional dose escalation was performed with a Schedule C with 
the aim of finding an optimal dosing schedule (loading dose on Day 1 followed by 6 days of 
maintenance dose and one week off treatment, repeated every 2 weeks in 4-week cycles) in 
parallel with the dose finding part in DLBCL patients with Schedule B. The starting 
maintenance dose for Schedule C was the dose selected by the DMC for Schedule B in Phase 
Ib which is 2.5 mg with a double loading dose of 5 mg. In parallel, after approval of protocol 
version 11.0, the MTD will also be determined for Schedule C in patients with DLBCL, 
starting at one dose tier below the one used in solid tumours to start with Schedule C, both for 
the loading dose and for the maintenance dose, meaning with a loading dose of 4 mg and a 
maintenance dose of 2 mg. Once the MTD with both Schedules B and C in DLBCL patients 
have been determined, the DLBCL cohort will be extended at the MTD level of the schedule 
selected by the DMC to have the best toxicity profile, to include in total for the MTD cohort 
from 12 to 14 patients.
The dose escalation will be guided by a BLRM (see the different scenarios in Appendix 10.3) 
(de-escalation of dose is possible in case of insufficient tolerability of a dose level) (R04-0569),
and will be determined by the DMC which will evaluate and decide on the dose to be 
administered for the next cohort. An escalation with overdose control design will increase the 
chance of treating patients at efficacious doses while reducing the risk of overdosing.
Dose escalation Phase Ia of Schedule A in patients with solid tumour:
One patient was treated per dose cohort until a first drug-related AE of CTCAE grade ≥ 2 
occurred during the first treatment cycle (see description in Section 4.1.3.1). Thus, the next 
patient could only start the treatment at the next dose level once it was confirmed that the 
previous patient from the lower dose level did not experience a drug-related CTCAE grade ≥ 2 
AE during Cycle 1. 
In case no patient from the first cohort experienced a CTCAE ≥ grade 2 drug-related AE during 
Cycle 1, the dose could be increased from 0.2 mg to 1 mg in the second cohort. In case no 
patient from the second cohort experienced a CTCAE ≥ grade 2 drug-related AE during Cycle 
1, the dose could be increased from 1 mg to 5 mg in the third cohort. Afterwards, increments 
have followed the Bayesian model as explained in Appendix 10.3.
If a patient, in a single patient cohort, experienced a CTCAE grade ≥ 2 drug-related AE during 
Cycle 1 at any dose level, additional patients were to be entered in the same cohort and at least 
2 patients evaluable for dose limiting toxicity (DLT) in Cycle 1 were required per cohort, from 
that cohort onwards.
The second patient of a same cohort could only start his treatment after the first patient of the 
cohort had been observed for a period of 7 days of treatment and a second and a third patient 
could then be started at the same time.
In case only 2 patients were evaluable and neither had experienced a dose-limiting toxicity 
within the first cycle (21 days), then dose-escalation could occur based on these 2 patients. But, 
if one of these 2 patients experienced a DLT in the first cycle (21 days), a third patient had to 
be enrolled at the same dose level and be evaluable for DLT in the first cycle. 


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After all patients in a cohort had either experienced a DLT or had been observed for at least 
one cycle without a DLT (until Day 22 of Cycle 1), the BLRM was updated with the newly 
accumulated data. The overdose risk was then calculated for each dose, and escalation was
permitted to all doses, which fulfilled the Escalation with Overdose Control (EWOC) criterion 
and dose escalation rules according to Section 4.1.3. Decision on next step (dose escalation, de-
escalation or cohort extension) was made by the DMC, based on the collected safety data as 
well as other data (e.g., PK / pharmacodynamics data) when available.
If DLTs were observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort was stopped. The BLRM was re-run to confirm that the 
dose-level still fulfilled the EWOC criterion. The DMC decided whether the next patients were 
to be enrolled at the same dose level, or if they were to be enrolled to a lower dose level. Figure 
3.1: 3 shows how the decision of dose escalation was made.
Figure 3.1: 3: Escalation Decision – Combination of clinical and statistical expertise
Dose escalation Phase Ia and expansion Phase Ib of Schedule B in patients with solid tumour:
The starting dose for the dose escalation Phase Ia of Schedule B in patients with solid tumour 
was the highest dose level tested in Schedule A in solid tumours considered to be safe by the 
DMC. Dose escalation and de-escalation was guided by the BLRM from the beginning, i.e., no 
single patient cohorts were foreseen.
The DMC could recommend stopping the dose escalation phase after the criterion for MTD 
was fulfilled.
Once the MTD had been determined for both Schedules A and B in patients with solid 
tumours, the DMC made a recommendation on the recommended Schedule based on safety, 
PK and pharmacodynamics data available from all patients treated at this stage, and the MTD 
cohort of the chosen schedule which was Schedule B was further extended to enrol a total of 12 
patients with solid tumour at this dose level of 2.5 mg. 


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At doses deemed close to the MTD in Schedule A in patients with solid tumours (decision was
made by DMC on which cohort(s) the 
 study would happen) and at the MTD dose in 
patients with solid tumours, a minimum of 12 patients and up to 20 patients in total with solid 
tumours in either Schedule A or B participated to the determination of 
 on 
pharmacokinetics (see Section 10.2.2).
Once the MTD was determined for both Schedules A and B in solid tumours and the choice of 
the most appropriate Schedule was made (Schedule B), newly recruited patients in the 
extension of the MTD cohort could undergo optional tumour biopsies at screening and at 
steady state in Cycle 1.
In Phase Ib, the tumour biopsies at baseline and at steady state (between Day 8 and Day 11) 
under treatment in Cycle 1 were mandatory. The baseline biopsy could be replaced by sending 
of tumour archival tissue from the latest relapse if not older than 6 months. A 2-3 mL EDTA 
blood DNA sample was mandatory, once, at any time, for all patients undergoing a tumour 
biopsy or for whom archival tumour tissue is sent. 
For the biopsy to be allowed, platelet count and coagulation have to be checked prior to each 
biopsy and have to be adequate, meaning platelets of at least 50 000/mm 3 without the support 
of transfusion and coagulation parameters within normal limits.
Should the biopsy under study treatment, between Day 8 and Day 11 of Cycle 1 not be feasible 
in 5 out of the first 20 patients of Phase Ib in solid tumours because of abnormal coagulation 
parameters and/or a platelet count below 50 000/mm3, the timing of biopsy at steady state 
would be moved ahead, between Day 3 and Day 8 for the next patients.
The tumour biopsies in Phase Ib were however not requested for mCRPC patients with only 
bone lesions and for patients with therapeutic INR because of treatment with a vitamin K 
antagonist or a novel oral anticoagulant. Biopsies remained optional for NC patients. 
The on treatment biopsy could remain optional if no easily accessible lesions were available.
Dose escalation Phase Ia with Schedule C in patients with solid tumours:
The starting dose for the dose escalation Phase Ia of Schedule C in patients with solid tumour 
was the MTD determined for Schedule B, which is 2.5 mg with a loading dose of 5 mg. So the 
patients took 5 mg on Day 1 followed by 2.5 mg from Day 2 till Day 7, t hen a week off 
treatment and again a loading dose of 5 mg on Day 15 followed by a maintenance dose of 2.5 
mg from Day 16 till Day 21, then a week off treatment in 4-week cycles. Dose escalation and 
de-escalation for subsequent cohorts was guided by the BLRM for this schedule.
The DMC could recommend stopping the dose escalation phase after the criterion for MTD 
was fulfilled (see Section 7.1).
Once the MTD has been determined for Schedule C in patients with solid tumours, the MTD 
cohort will be further extended to enrol a total of 12 patients with solid tumour at this dose 
level. 
Dose escalation Phase Ia of selected schedule (B) in patients with DLBCL:
Once the MTD was determined for both Schedules A and B in solid tumours and the choice of 
the most appropriate Schedule was made (Schedule B), the dose escalation started with this 
Schedule (B) in patients with DLBCL.


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The starting dose for the dose escalation in patients with DLBCL (2 mg) was one dose level 
below the MTD of the selected schedule (B) in patients with solid tumour and the dose 
escalation and de-escalation was guided by the BLRM from the beginning, i.e., no single 
patient cohorts were foreseen. 
Dose escalation Phase Ia of Schedule C in patients with DLBCL:
After MTD determination for Schedule B in DLBCL patients, a dose escalation was started 
with Schedule C in patients with DLBCL.
The doses to use in the first cohort for the dose escalation Phase Ia of Schedule C in patients 
with DLBCL were, both for the loading and the maintenance dose, one dose tier below the 
doses used for the first cohort with Schedule C in patients with solid tumours. So the patients 
take 4 mg on Day 1 followed by 2 mg from Day 2 till Day 7, then a week off treatment and 
again a loading dose of 4 mg on Day 15 followed by a maintenance dose of 2 mg from Day 16 
till Day 21, then a week off treatment in 4-week cycles. Dose escalation and de-escalation for 
subsequent cohorts will be guided by the BLRM for this schedule.
Once the MTD will be determined in both Schedules B and C in patients with DLBCL, the 
DMC will make a recommendation on the schedule to be selected between B and C to further 
expand the MTD cohort in DLBCL in 6 to 8 additional patients.
In addition, patients (with solid tumour or DLBCL) who are responding to treatment or who 
are benefiting from treatment, may undergo optional fresh tumour biopsy (platelet count and 
coagulation must be checked prior to each biopsy and must be adequate, see above) and may 
provide optional consent for analysis of their archival tumour sample. In these patients who 
provide consent for a fresh tumour biopsy and/or analysis of their archival tumour sample, a 2-
3 mL EDTA blood DNA sample is mandatory.
The observation period for DLT is 21 days of the first cycle only (to be assessed at Day 22) ) in 
Schedules A and B. For Schedule C, the observation period for DLT is 28 days of the first 
cycle (to be assessed on Day 29).
However, confirmation of the recommended dose for the Phase Ib expansion part was made by 
the DMC, based on all available safety, PK and pharmacodynamics data at all treatment cycles, 
at the time of decision in April 2017. The DMC in addition made recommendation on the types
of solid tumours that were chosen for the Phase Ib part, based on anti-tumour signals that 
appeared from data collected during the escalation part, together with additional pre-clinical 
data available at the time of the end of the escalation phase.
The expansion Phase Ib with Schedule B recruited a minimum of 9 evaluable patients (for PK 
and response by RECIST at the end of Cycle 2 or by bone scan and PSA at the end of Cycle 4 
in mCRPC patients with non-measurable disease by RECIST 1.1) and a maximum of 20 
evaluable patients with measurable (or non-measurable per RECIST 1.1 for mCRPC patients) 
and progressive disease, per type of tumours selected by the DMC: SCLC, mCRPC, CRC and 
NC. For the NC cohort, since this is a rare disease, the number of patients was not pre-defined 
but tended to include up to a maximum of 40 patients. 
Once the MTD for Schedule C was determined in Phase Ia in patients with solid tumours, the 
DMC recommended the best schedule between B or C to further recruit patients in the NC 


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cohort. As Schedule C was selected, a Schedule C NC cohort was opened to recruitment for up 
to a maximum of 40 patients while the NC cohort with Schedule B was closed to recruitment.
This expansion phase will further evaluate the safety including re-evaluation of the 
recommended Phase II dose and the selected schedule (B or C), efficacy, pharmacokinetic and 
biomarker profile of BI 894999 in patients with the chosen specific types of tumours. The 
DMC will have regular meetings (at least once every 3 months) to evaluate the safety of the 
patients in Phase Ib and confirm the safety of the selected dose in the specific patients’ 
population. In addition, the DMC will have meetings after the first and after the second 
adolescent patient with NC finishes the first cycle to assess whether the adult dose is tolerable 
in adolescents.
Patients will be kept at the institution, based on convenience for the patient and the 
investigator’s decision of patient’s need for safety surveillance, for the first administration of 
study medication, for a period of 24h from C1D1 until C1D2 (at investigator’s discretion, can
be limited to a period of 4h on Day 1 in DLBCL and NC patients recruited after approval of 
protocol version 12.0) and for 48h in the 
 cohort until drug administration of 
C1Day3. Patients will be kept at the institution for a period of 24h, from C1D14 until last PK 
sample of Day 15 for Schedules A and B (24h post-dose of Day 14 dose in Schedule A or 32h 
post-dose of Day 14 in Schedule B), based on convenience for the patient and investigator’s 
decision. For Schedule C, this will be on C1D21 until last PK sample of Day 22. However, all 
other visits from first cycle and all visits from subsequent cycles will be performed in an 
outpatient setting except if medically or operationally justified, at the discretion of the 
investigator. During treatment, the investigator will determine the safety parameters, record the 
AEs and perform additional investigations as outlined in the Flow Chart.
A clinical disease assessment will be performed after every treatment cycle and a tumour 
response assessment by imaging every other cycle for all patients with solid tumours. The type 
of imaging (computed tomography (CT) scan or magnetic resonance imaging (MRI), with or 
without contrast media) is left to the decision of the investigator but must be the same all over 
the trial period and must allow for evaluation according to RECIST 1.1. Assessment of 
response will be performed at the investigator’s site and will be sufficient for the decision 
whether the patient will continue therapy according to the criteria specified in Section 4.1.4. In 
mCRPC patients without a measurable disease via RECIST 1.1, the response assessment had to
be performed on bone scan every 12 weeks coupled with PSA level at the same time-point as 
imaging. In patients with DLBCL, the response assessment will be performed by imaging via 
FDG-PET/CT scan after end of Cycle 2, of Cycle 4 and every four cycles thereafter.
Patients with a clinical benefit after a cycle of BI 894999 (absence of disease progression
(except for NC patients for whom the investigator judges that there is clinical benefit and for 
whom no other treatment option is available) and good treatment tolerance) and who have 
recovered from any clinically or haematologically relevant drug-related AE of grade 3 or 4 (to 
grade 1 or less or to baseline grade, except grade 2 peripheral sensory neuropathy as well as 
anaemia, lymphopenia), as judged by the investigator, are eligible for a further treatment cycle. 
Intra-patient dose escalation will not be allowed as well as switch from one schedule to 
another. Patients included in the escalation phase are not eligible to enter the expansion phase.


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Patients experiencing DLT or any drug related significant AE necessitating a dose reduction 
according to investigator’s judgement are eligible for further treatment cycles with BI 894999
at one dose tier below in the same schedule, as soon as recovery from drug related toxicities 
allows further treatment. For Schedule C, this means a decrease of the loading dose in steps of 
1 mg and of the maintenance dose in steps of 0.5 (e. g., for the first cohort, the loading dose 
would be reduced from 5 mg to 4 mg, from 4 mg to 3 mg, from 3 mg to 2 mg while the 
maintenance dose would be decreased from 2.5 mg to 2 mg, from 2 mg to 1.5 mg, from 1.5 mg 
to 1 mg). Once a dose reduction occurred, the patient must continue at the reduced dose and 
may not be re-escalated later on. A patient may decrease the dose each time as necessary 
during the trial to the next lower dose level tested (or as explained above for Schedule C)
because of DLT occurrence but not below a dose of 1 mg (maintenance dose in Schedule C).
Patients eligible for a further (repeat) treatment cycle will not start before 22 days after the start 
of the previous cycle for Schedules A and B, not before 29 days after the start of previous cycle 
for Schedule C. 
If a patient has to be discontinued from the trial treatment, the end of treatment (EOT) visit 
with all necessary assessments as described in Sections 6.2.3 and 10.5.3 must be performed as 
soon as possible once the decision is taken. Follow-up visits will be performed after the EOT 
visit until progression of disease, death, treatment with any other anti-tumour therapy, lost to 
follow-up (every attempt must be made to avoid this option, e.g. by phone contact with the 
patient or relatives) or until the end of the trial. For the NC patients, the vital status will
continue to be collected until death, loss to follow-up, withdrawal of consent to be further 
followed-up or until 12 months after the end of the whole trial, to be able to determine the 
overall survival in this population, according to their informed consent. Ongoing AEs must also 
be followed up until resolution or until the investigator deems it is no longer necessary to 
follow them up. The first follow-up visit which is the end of residual effect period (EOR) visit 
must be performed 30 days (+7 days) after the EOT and subsequent follow-ups, if applicable, 
at 12 weeks intervals or earlier if appropriate. Follow-up visits may also be performed by 
telephone interview in case the patient is unable to visit the investigator.
The trial will end when the last ongoing patient has completed the EOT visit and the EOR visit.
Administrative structure of the trial
3.1.1
Boehringer Ingelheim (BI) is the sponsor of this trial and it was planned to start the trial in 2 
centres specialized in the treatment of advanced cancers and experienced in Phase I studies in 
oncology, in one country. More centres from the same country and from additional countries 
were initiated. However, Schedule C escalation part in patients with solid tumours only 
happens in the participating sites in Belgium.
A Coordinating Investigator was nominated by BI from one of the trial participating 
investigators and is responsible to coordinate investigators at different centres participating in 
this multicentre trial. Tasks and responsibilities, including the final signature of the clinical trial 
report (CTR), are defined in a contract. Relevant documentation on the participating (Principal) 
Investigators and other important participants, including their curricula vitae, are filed in the 
trial master file (TMF).


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BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating all required 
activities, in order to 
-
manage the trial in accordance with applicable regulations and internal standard 
operation procedures (SOPs),
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
order the materials as needed for the trial, 
-
ensure appropriate training and information of local clinical monitors (CMLs), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
A DMC was appointed for Phase Ia to evaluate DLTs, overall safety and other available data 
(e.g. PK data) and confirm dose escalation steps in the three Schedules A, B and C in patients 
with solid tumours. Once the MTD was determined for both Schedules A and B in solid 
tumours, the DMC recommended a Schedule to use in the MTD extension cohort in patients 
with solid tumours as well as for determination of MTD in patients with DLBCL. Schedule B 
was selected. After decision in protocol version 11.0 to also test Schedule C for MTD 
determination in DLBCL patients, once MTD will be determined for both Schedules B and C 
in this patient population, the DMC will recommend a Schedule to use in the MTD extension 
cohort in patients with DLBCL.
The DMC also evaluated all available data to confirm the proceeding to Phase Ib expansion, 
the recommended Phase Ib dose (2.5 mg) and schedule (Schedule B) in patients with solid 
tumours as well as the decision for the types of tumours in this expansion Phase Ib. 
Once the MTD was determined for Schedule C in solid tumours patients, the DMC made the
recommendation for continuing the recruitment in the NC cohort of Phase Ib with Schedule C. 
The recruitment to the NC cohort with Schedule B was closed.
Members of this DMC are the Principal Investigators (PIs) of the participating trial sites, the 
Team Member Medicine (TMM), the TCM, the trial statistician (TSTAT), the Trial 
Pharmacokineticist (TCPK) and the Translational Medicine Expert (TME) or their delegates. 
The extended membership is described in the DMC charter.
During DMC meetings, the information on the overdose risk are presented by the BI trial team. 
Additional information, such as lower grade AEs, PK (when available), pharmacodynamics
biomarkers (when available), individual patient profiles and other relevant information such as 
the outcome events of progressive disease not reported as (S)AEs are also presented. Based on 
this information, the members of the DMC reach a joint decision on the next dose level to be 
investigated. This dose level may be above, below or identical to the currently investigated 
dose level. The DMC also recommends the size for the next cohort (minimum one, maximum 
six patients per cohort, until MTD where up to 12 patients will be included, for the chosen 
Schedule between A and B, which was Schedule B, for Schedule C in patients with solid 
tumours and in patients with DLBCL). The final decision on the next cohort size is however 
made by a mutual decision between the TMM and the Coordinating Investigator.
 
 


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Minimum needed data for dose escalation decision is detailed in a DMC charter that is filed in 
the TMF. Minutes of the DMC meetings and recommendations are documented and archived 
by the TCM in the TMF.
During Phase Ib, the DMC will also regularly review the safety and efficacy data of patients 
entered in the specific cohorts. In the NC cohort, the DMC will specifically evaluate safety data 
of the first cycle in the first and second adolescent included in the cohort to assess whether the 
adult dose is tolerable in adolescents. 
Once the primary endpoint of the Phase Ia was reached in patients with solid tumours for both 
Schedules A and B and the MTD was confirmed in the extension cohort with the most 
appropriate schedule in these patients (Schedule B was selected), the Phase Ib started and a 
Phase Ia safety analysis report was prepared based on the Phase Ia data for Schedules A and B 
in patients with solid tumours. A summary of safety and efficacy endpoints and determination 
of the recommended Phase Ib dose and schedule was included in the Phase Ia safety analysis 
report. The Phase Ia report is made available for all investigators who participate in the Phase 
Ib. This report is also sent to regulatory agencies. It will be the basis, together with the 
Schedule C results in patients with solid tumours, for publication of Phase Ia results of patients 
with solid tumours by the Coordinating Investigator.
The safety laboratory investigations are performed at the investigator’s site (see 5.3.3), as well 
as ECGs. In addition, all ECGs are analysed by a central laboratory (in case of clinically 
relevant abnormalities, the investigator will be notified by email and/or fax by the central 
laboratory).
Analyses of pharmacokinetics samples are performed by BI. 
 
 
Further details on CROs for samples handling, shipments and analyses are given in the 
ISF/laboratory manual.
The trial drug is directly forwarded by Boehringer Ingelheim or via a distributing CRO to the 
investigator’s pharmacy where it will be stored according to storing requirements as described 
in the pharmacy manual. The pharmacist (or investigator directly to the patient, where legally 
authorised) will deliver the necessary amount for an individual patient to the investigator upon 
his/her request, according to the procedure described in the pharmacy manual or the local site 
procedure.
Data Management and Statistical Evaluation is done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
This is an open label, uncontrolled, first-in-human trial of the BET inhibitor BI 894999 in 
patients with advanced solid tumours and in a cohort of patients with DLBCL, following a dose 
escalation trial design, based on BLRM with overdose control. 
The starting treatment schedule was a continuous daily dosing in 3-week cycles. An additional 
intermittent dosing schedule with 2 weeks on and one week off treatment in 3-week cycles 
(Schedule B) was investigated in parallel, starting at the highest dose investigated in Schedule 
A in solid tumours which was considered to be safe by the DMC.
Once the MTD of both Schedules A and B in solid tumours was determined, the DLBCL 
cohort started using the MTD of the selected schedule (B) determined in the solid tumour 
cohort of this Schedule minus one dose level as the starting dose. This MTD determination in 
DLBCL was started in parallel with the MTD extension cohort in patients with solid tumours 
with the selected schedule (B). After MTD was confirmed for Schedule B in the patients with 
solid tumours, recruitment was opened to Phase Ib expansion cohorts in SCLC, mCRPC, CRC 
and NC patients with selected Schedule B. These cohorts are closed to recruitment at the time 
of protocol version 12.0 and only the cohort of NC patients with Schedule C is ongoing in the 
Phase Ib expansion.
The MTD will also be determined with Schedule C in DLBCL patients. Once the MTD of both 
Schedules B and C in DLBCL will be determined, the MTD cohort in DLBCL patients will be 
further extended using the selected schedule (B or C) to have a total of 12 to 14 DLBCL 
patients treated at the MTD of the selected schedule.
In parallel to MTD determination in DLBCL for both Schedules B and C, a Schedule C was
tested in patients with solid tumours to determine the MTD in this schedule and then the MTD 
cohort will be further extended to up to 12 patients.
An escalation with overdose control design will increase the chance of treating patients at 
efficacious doses while reducing the risk of overdosing. This design is based on practical 
experience and is a preferable algorithmic method due to its superior ability to identify the dose 
with the desired toxicity rate and its allocation to a greater proportion of patients to doses at or 
close to that dose (R13-4802, R13-4804, R13-4805).
SELECTION OF TRIAL POPULATION
3.3
A log of all patients enrolled into the trial (i.e. who have signed informed consent) is
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
Main diagnosis for trial entry
3.3.1
Patients with advanced, unresectable and/or metastatic solid tumours, who have failed 
conventional treatment or for whom no therapy of proven efficacy exists, or who are not 
amenable to standard therapies are eligible for the escalation part (Phase Ia) of this trial. 


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For patients in the DLBCL cohort, eligible patients are patients with histologically confirmed 
DLBCL, for whom there are limited or no standard treatment options available.
Fresh tumour biopsies at screening and under treatment, between Day 8 and Day 11 of the first 
cycle are mandatory for patients with solid tumours treated in the expansion Phase Ib with 
Schedule B. The fresh tumour biopsies at screening may be replaced by sending of archival 
tumour tissue provided that it was taken from the most recent relapse and not older than 6 
months. The on treatment biopsy may remain optional if no easily accessible lesions are 
available. 
Tumour biopsies are however not requested for mCRPC patients with only bone metastases
and for patients with therapeutic INR because of treatment with a vitamin K antagonist or a 
novel oral anticoagulant. The tumour biopsies remain optional for NC patients and for patients 
with solid tumours or DLBCL treated in the Phase Ia, including the MTD extension cohorts.
The platelet count and coagulation must be checked prior to each biopsy and must be adequate
with platelets of at least 50 000/mm3 without the support of transfusion and normal coagulation 
parameters. Should the biopsy under treatment with Schedule B, between Day 8 and Day 11 of 
Cycle 1 not be feasible in 5 of the first 20 patients of Phase Ib (see 3.1), the timing of biopsy 
under treatment in Cycle 1 will be moved ahead, between Day 3 and Day 8 for the next 
patients. 
Patients in the expansion part (Phase Ib) must in addition to the Phase Ia criteria for solid 
tumours, have progressive disease within the last 6 months and have one of the four types of 
solid tumours selected for the expansion cohorts. The tumours that are investigated in the four 
expansion cohorts of Phase Ib are SCLC, mCRPC, CRC and NC out of which only the NC 
cohort with Schedule C is ongoing at the time of protocol version 12.0.
Patients who are responding to treatment or who are benefiting from treatment may provide 
optional consent to undergo a fresh tumour biopsy (platelet count and coagulation must be 
checked prior to the biopsy and must be adequate, see above) at the time of response and also 
provide optional consent for their archival tumour sample to be analysed. If they give consent 
for these to be done, a sample of 2-3 mL EDTA blood DNA tube is mandatory.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
Inclusion criteria
3.3.2
In patients with solid tumours
3.3.2.1
1.
Patients with a histologically or cytologically confirmed diagnosis of an advanced 
unresectable and/or metastatic, malignant solid tumour, who have failed conventional 
treatment or for whom no therapy of proven efficacy exists, or who are not amenable to 
standard therapies
2.
Age ≥ legal age to be adult for the given country at the time of signature of the informed 
consent. For NC patients, age 15 years or older at the time of signature of the informed 
consent ( in Germany and South Korea, only legally adult patients may be included)
3.
Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score 0 or 1 at the 
time of screening. A score of 2 is allowed for NUT carcinoma patients


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4.
Recovery of therapy-related toxicities from previous chemotherapy, tyrosine kinase 
inhibitors, hormone therapy, immunotherapy, antibodies, vaccine therapy, or radiotherapy 
to CTCAE ≤ grade 1 (with the exception of alopecia, peripheral sensory neuropathy grade 
2)
5.
Life expectancy of at least 12 weeks after the start of the treatment according to the 
investigator’s judgement
6.
Male or female patients. Women of childbearing potential* must be ready and able to use 
highly effective methods of birth control per ICH M3(R2) that result in a low failure rate 
of less than 1% per year when used consistently and correctly. A list of contraception 
methods meeting these criteria is provided in the patient information. For women of 
childbearing potential using a contraceptive pill, an additional barrier method is necessary 
due to the potential CYP3A4 inducing effect of BI894999. Male patients having a partner 
of childbearing potential must use condoms and ensure their partner is using a highly 
effective method of birth control as described above, during the trial and for at least three 
months after the end of the trial treatment
* Any female who has experienced menarche and does not meet the criteria for "women not of childbearing potential" as 
described below.
Women not of childbearing potential are defined as: women who are postmenopausal (12 months with no menses 
without an alternative medical cause) or who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
7.
Written informed consent consistent with ICH-GCP and local legislation. For adolescent 
NC patients aged 15 years to adult legal age written assent of the patient and written 
informed consent of the parents (both or one according to national regulation) or legal 
guardian of the adolescent 
8.
Written informed consent for tumour biopsies in the escalation phase Ia
a.
Optional for those patients until extension of the MTD cohort,
b.
Optional for the patients in the extension of MTD cohort at the same time points as 
described below for the expansion phase. For these patients in the extension of the 
MTD cohort, if they have an accessible lesion for biopsy, they will be offered optional 
consent for tumour biopsies
In addition, all patients included in the expansion Phase Ib must: 
9.
Have been diagnosed with one of the four types of tumours selected:
       a.   small cell lung cancer (SCLC) 
       b.  metastatic castrate resistant prostate cancer (mCRPC)
       c.  colorectal cancer (CRC)
       d.   NUT carcinoma (NC) (for which the “midline” origin is not a
     prerequisite)
10. Have failed conventional treatments or who are not amenable to standard therapies (per 
criterion 1) that specifically include for: 
a.   SCLC: a platinum-based therapy (previous treatment with topotecan is not mandatory)
b.
mCRPC: a hormonal agent (abiraterone, enzalutamide, or apalutamide) and a taxane
     (docetaxel or cabazitaxel)
c. CRC: fluoropyrimidine, oxaliplatin and irinotecan, bevacizumab for patients eligible
           to this treatment and an anti-epidermal growth factor receptor (EGFR) in RAS (Rat
             Sarcoma Virus) wild type metastatic CRC.
11. Have measurable disease (radiated lesions and lesions used for biopsy do not qualify as 
target lesions), according to RECIST 1.1 (R09-0262) (for NC patients only non-


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measurable disease is acceptable); or according to PCWG3 (R17-3377) for the mCRPC 
cohort (see point 5 of inclusion criteria below, specific to mCRPC patients)
12. Have progressive disease within the last 6 months, according to RECIST 1.1 (R09-0262)
or according to PCWG3 (R17-3377) for the mCRPC cohort (see point 5 of inclusion 
criteria below, specific to mCRPC patients). NC patients do not need to show progression 
per RECIST 1.1 (for example, if newly diagnosed).
13. Have a tumour lesion accessible for biopsies (pre- and at steady state under treatment in 
Cycle 1, ideally from the same anatomic lesion) (except for mCRPC patients having only 
bone metastases or for patients with therapeutic INR because of treatment with a vitamin 
K antagonist or a novel oral anticoagulant. Biopsies are optional for NC patients
14. Give written informed consent for two tumour biopsies, one at screening and one after start 
of treatment, between Day 8 and Day 11 of Cycle 1 (or between day 3 and day 8 if the day 
of biopsy in Cycle 1 needs to be moved as explained in Section 3.1) (when applicable)
In addition, all patients in the mCRPC expansion cohort of Phase Ib must have:
15. Histologically or cytologically confirmed adenocarcinoma of the prostate
16. Radiographic evidence of metastatic prostate cancer (stage M1 or D2). Distant metastases 
evaluable by bone scan, CT scan, or MRI within 28 days before the start of study 
treatment.
17. PSA ≥ 5 ng/mL (if no measurable disease by RECIST 1.1)
18. Prior surgical or chemical castration with a serum testosterone of <50 ng/dL (< 1.7 
nmol/L) by luteinizing hormone releasing level hormone (LHRH) agonist or antagonist, or 
by abiraterone or by enzalutamide or apalutamide. If the actual method of castration is 
LHRH agonist or antagonist, the patient must be willing to continue the use of LHRH 
agonist or antagonist during protocol treatment.
19. Progressive disease defined as at least one of the following:
       a.   Progressive measurable disease: using conventional solid tumour criteria RECIST 1.1
       b.   Bone scan progression: at least two new lesions on bone scan plus a rising PSA as
             described in point c below
       c.   Increasing PSA level: at least two consecutive rising PSA values over a reference value
             (PSA no.1) taken at least 1 week apart. A third PSA (PSA no. 3) is required to be >
            than PSA no. 2; if not, a fourth PSA (PSA no. 4) is required to be > to PSA no. 2
In patients with DLBCL
3.3.2.2
1.
Patients with histologically confirmed DLBCL who have failed 2 or more lines of systemic 
therapy including an anti-CD-20 therapy and an anthracycline or who are not amenable to 
standard therapies but have an indication for therapy as per investigator’s judgement. 
Standard therapies may also include but are not limited to CAR-T cells therapy, depending 
on approved therapies in the country where the patient is treated
2.
Age 18 years or older at the time of signature of the informed consent
3.
ECOG Performance Status 0, 1 or 2 at the time of screening
4.
Measurable disease (radiated lesions do not qualify as target lesions) according to RECIL 
2017 (R17-3378) on the CT scan part of the FDG/PET-CT scan
5.
Recovery of therapy-related toxicities from previous anti-lymphoma therapy to CTCAE ≤ 
grade 1 (with the exception of alopecia, peripheral sensory neuropathy grade 2) 
6.
Life expectancy of ≥12 weeks according to the investigator’s judgement


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7.
Male or female patients. Women of childbearing potential* must be ready and able to use 
highly effective methods of birth control per ICH M3(R2) that result in a low failure rate 
of less than 1% per year when used consistently and correctly. A list of contraception 
methods meeting these criteria is provided in the patient information. For women of 
childbearing potential using a contraceptive pill, an additional barrier method is necessary 
due to the potential CYP3A4 inducing effect of BI894999. Male patients having a partner 
of childbearing potential must use condoms and ensure their partner is using a highly 
effective method of birth control as described above, during the trial and for at least three 
months after the end of the trial treatment
* Any female who has experienced menarche and does not meet the criteria for "women not of childbearing potential" as 
described below.
Women not of childbearing potential are defined as: women who are postmenopausal (12 months with no menses 
without an alternative medical cause) or who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
8.
Written informed consent which is consistent with ICH-GCP guidelines and local
Legislation
9.
Written informed consent for tumour biopsies (optional)
Exclusion criteria
3.3.3
In patients with solid tumours
3.3.3.1
1.
Inability to swallow tablets
2.
Additional other serious illness, concomitant non-oncological disease (e.g. active 
infectious disease including an active infection with SARS-CoV-2 confirmed by a PCR 
test or had one in the prior 6 weeks or active hepatitis (Hep) B infection as defined by
positive Hep B DNA test, active Hep C infection as defined by positive Hep C RNA test 
and human immunodeficiency virus (HIV) infection (positive result in established HIV 
diagnostic assay), or ongoing toxicity from prior therapies considered by the investigator 
to potentially compromise patient’s safety in this trial
3.
History or presence of cardiovascular abnormalities deemed clinically relevant by the 
investigator such as uncontrolled hypertension, congestive heart failure NYHA 
classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction 
within 6 months prior to study entry. LVEF less than 50% at baseline
4.
Clinical evidence of symptomatic progressive brain or leptomeningeal disease during the 
last 28 days before the start of treatment with BI 894999
5.
Second malignancy currently requiring another anti-cancer therapy
6.
Absolute neutrophil count less than 1500/mm3
7.
Platelet count less than 100 000/mm3
8.
Bilirubin greater than 1.5 mg/dL (>26 µmol/L, SI unit equivalent) (except known Gilbert’s 
syndrome (accepted up to 2 mg/dL or up to 34.2 µmol/L in this case)
9.
Aspartate amino transferase (AST) and/or alanine amino transferase (ALT) greater than 
2.5 times the upper limit of normal (in the presence of liver metastases, greater than five 
times the upper limit of normal)
10. Serum creatinine greater than 1.5 mg/dL (>132 µmol/L, SI unit equivalent)
11. Women who are breastfeeding, pregnant or who plan to become pregnant while in the trial
12. Previous treatment with a BET inhibitor. Previous treatment with a BET inhibitor is 
however allowed for NC patients


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13. Treatment with other investigational drugs or participation in another clinical 
interventional trial within the past four weeks (past two weeks for NC patients) or within 
five times the half-life of the previous investigational drug, whichever is the shorter, before 
start of therapy or concomitant with this trial
14. Systemic anti-cancer therapy within four weeks (past two weeks for NC patients) or five 
times the half-life of the drug, whichever is shorter. Radiotherapy given for curative intent
within the past four weeks before start of therapy or concomitantly with this trial. These 
restrictions do not apply to LHRH agonists or antagonists, steroids (given at a stable dose 
in the last four weeks) used for palliative intent, bisphosphonates, denosumab and to 
palliative radiotherapy (no wash out required)
15. Patients unable to comply with the protocol
16. Patients who are actively abusing alcohol or drugs. Since no alcohol or drug testing is 
required per protocol, it is at the investigator’s discretion to determine abuse.
In patients with DLBCL
3.3.3.2
1.
Patient is eligible for curative salvage high dose therapy followed by stem cell transplant.
2.
Primary central nervous system (CNS) lymphoma or known CNS involvement
3.
Prior allogeneic bone marrow or stem cell transplant
4.
Second malignancy currently requiring another anti-cancer therapy
5.
High-dose therapy with stem cell support <3 months prior to visit 1
6.
Inability to swallow tablets
7.
AST or ALT >2.5 x upper limit of normal (CTCAE grade 2 or higher)
8.
Total bilirubin >1.5 x upper limit of normal (CTCAE grade 2 or higher)
9.
Absolute neutrophil count <1.0 x 109/L (without growth factor support)
10. Platelets <100 x 109/L (without transfusions)
11. Serum creatinine 1.5 mg/dL (132 µmol/L) 
12. Significant concurrent medical disease or condition which according to the investigator’s 
judgement would either compromise patient safety or interfere with the evaluation of the 
safety of the test drug, e.g. LVEF less than 50% at baseline, symptomatic congestive heart 
failure, unstable angina pectoris, myocardial infarction within 6 months prior to study 
entry, cardiac arrhythmia requiring therapy with the exception of extra systoles or minor 
conduction abnormalities
13. Chronic or ongoing infection requiring treatment at the time of enrolment or within the 
previous two weeks, e.g. active infectious disease including an active infection with 
SARS-CoV-2 confirmed by a PCR test or one in the previous 6 weeks or active Hep B 
infection as defined by positive Hep B DNA test, active Hep C infection as defined by 
positive Hep C RNA test and HIV infection (positive result in established HIV diagnostic 
assay)
14. Women who are breastfeeding, pregnant or who plan to become pregnant while in the trial 
15. Patients who are actively abusing alcohol or drugs. Since no alcohol or drug testing is 
required per protocol, it is at the investigator’s discretion to determine abuse.
16. Previous treatment with a BET inhibitor
17. Treatment with other investigational drugs or participation in another clinical 
interventional trial within the past two weeks or within five times the half-life of the 
previous investigational drug, whichever is the shorter, before start of therapy or 
concomitant with this trial


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18. Systemic anti-DLBCL therapy within the past two weeks or five times the half-life of the 
drug, whichever is shorter (palliative radiotherapy and agents used for palliative reasons 
for example steroids and bisphosphonates, are allowed)
19. Patients unable to comply with the protocol 
Removal of patients from therapy or assessments
3.3.4
Removal of individual patients
3.3.4.1
A patient has to be withdrawn from the treatment and/or the trial if:

The patient withdraws consent for study treatment or study participation, without the need 
to justify the decision

The patient is no longer able to participate (e.g. severe AEs, surgery, disease progression, 
concomitant diagnoses, concomitant therapies or administrative reasons, occurrence of a 
second cancer). The investigator may also stop the patient’s participation, if the patient is 
no longer able to attend the visits e.g. due to worsening of disease. For NUT carcinoma, 
patients are allowed to continue the trial treatment after progression as long as, based on the 
investigator’s judgement, they have a clinical benefit to continue and there are no further 
treatment options available

If eligibility criteria are violated in such a way that it might put the patient at risk if they 
continue on the trial treatment or the patient fails to comply with the protocol (e.g. non -
compliance to study visits, to study treatment)

The patient experiences a COVID-19 infection confirmed by a PCR test and the 
Investigator judges that the benefit-risk balance is not in favour of resuming treatment with 
BI 894999 after recovery from the infection
For all patients the reason for withdrawal (e.g. AEs) must be recorded in the electronic Case 
Report Form (eCRF). These data will be included in the trial database and reported.
As soon as a patient is withdrawn from the trial and 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 in Section 6.2.3.
After withdrawal, the patient will further receive the available treatment for his condition at 
investigator’s discretion.
Patients withdrawn for another reason than DLT or patients who miss more than one visit 
during their first treatment cycle will be replaced. Patients who miss one visit may be replaced 
after discussion between the sponsor and the investigator if the information that needed to be 
collected during this visit is not available and makes the patient non-evaluable for 
pharmacokinetics analyses or safety parameters (including evaluation for DLT).
Patients who take incomplete doses or miss two doses or more of BI 894999 during their first 
treatment cycle for other reasons than toxicity will be replaced.
Patients who come off study due to DLT will not be replaced.
If a patient should become pregnant during the trial, the treatment with BI 894999 must 
immediately be stopped. The patient will be followed up until delivery or termination of 


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pregnancy (see Section 5.3.7). The data of the patient will be collected and reported in the CTR 
until last patient last visit and any events occurring thereafter will be reported in BI drug safety 
database.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim, after consultation with DMC, reserves the right to discontinue the trial 
overall or at a particular trial site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-risk-
assessment that could significantly affect the continuation of the trial. In such case the 
patient will be withdrawn from treatment and discontinued from trial. Further treatment 
will be based on investigator’s judgment
3. Violation of good clinical practice (GCP), the clinical trial protocol (CTP), or the contract 
disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
Identity of BI investigational product(s)
4.1.1
Table 4.1.1: 1
Test product
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
 
 
 
 
 
 
 
 
Method of assigning patients to treatment groups
4.1.2
The first part of the study is an open label, dose escalation Phase Ia study. Patients with solid 
tumours will enter treatment according to the next available slot determined via an Interactive 
Response Technology (IRT) system, at the time they are enrolled, being it for Schedule A, for 
Schedule B or for Schedule C. The DLBCL cohort of selected schedule (B) was only opened to 
DLBCL patients once the MTD had been determined for both Schedules A and B in patients 
with solid tumours and the recommended Schedule had been determined by the DMC
(Schedule B). Starting from protocol version 11.0 onwards, DLBCL patients will enter 
Schedule C for MTD determination after MTD has been determined for Schedule B. After 
DLBCL Schedule C dose escalation is complete, the DMC will then recommend the Schedule 
to further use for the extension of the DLBCL MTD cohort. 
For Schedule C dose finding in patients with solid tumours, only a limited number of sites in 
Belgium will recruit patients (e.g., the two initial sites in Belgium at the start of schedule C, 
with the possibility to extend to additional Belgian sites, as needed) and for these sites, Phase 


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Ia inclusion will have privilege over Phase Ib, should a patient be eligible for any of the two 
parts of the study.
In the second part (Phase Ib), patients were treated with the schedule and dose determined by
the DMC based on the safety, pharmacokinetic and biomarker results from the Phase Ia part in 
solid tumours, which was Schedule B. Furthermore, only patients with one of the four types of 
solid tumours were enrolled to Part Ib. Once MTD was determined for Schedule C in solid 
tumours patients of Phase Ia, and the DMC recommended Schedule C as selected schedule for 
further recruitment of patients in the NC cohort, the NC cohort with Schedule B was closed and 
a NC cohort with Schedule C opened for up to a maximum of 40 patients.
At the end of the screening period or during the first visit of Cycle 1, once the patient’s 
eligibility is confirmed but before any drug administration, the dose and the bottles of treatment 
are assigned via IRT. To facilitate the use of the IRT, the investigator receives all necessary 
instructions in the ISF.
Selection of doses in the trial
4.1.3
4.1.3.1
First cycle of administration of BI 894999
Table 4.1.3.1: 1
Treatment schedule
Treatment at start 
of the study: 
Schedule A
The starting schedule was continuous daily 
intake in cycles of 21 days 
Treatment 
alternative which
started in parallel 
to Schedule A
Schedule B
continuous daily intake for 14 days followed by
one week off treatment in cycles of 21 days
Treatment 
alternative which
started in parallel 
to Schedule B in 
DLBCL and to 
Phase Ib
Schedule C
Once daily loading dose on Day 1 followed by 
six days daily intake of maintenance dose, 
followed by one week off, repeated every two 
weeks in cycles of 28 days
A starting dose of 0.2 mg once per day was determined to be the safe starting dose in humans
(see Section 1.2.2) with Schedule A. 
Initially, only 1 patient was entered into each cohort, until the observation of a drug-related 
AE CTCAE ≥ grade 2 during Cycle 1 (21 days), for the AEs listed below only:

Clinical: all AEs except alopecia, inadequately treated nausea, vomiting or diarrhoea, 
fatigue if there is only one CTCAE grade of difference between the baseline condition and 
the worsening of fatigue.

Laboratory parameters: 


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
Haematology: neutropenia, leukopenia, thrombocytopenia

Biochemistry: increased liver function tests (AST, ALT, bilirubin and alkaline 
phosphatase), increased creatinine.
Once a patient experienced such a drug related AE, the single patient cohort was expanded to a 
total of 3 patients. This cohort and all subsequent dose cohorts were then to be treated 
according to a BLRM.
For any dose-escalation cohort after a drug related CTCAE ≥ grade 2 (as listed above) during 
Cycle 1 was observed, at least 3 patients were required, but two out of those patients must be 
evaluable patients (DLT evaluation in 21 days of first cycle for Schedules A and B, in 28 days 
of first cycle for Schedule C) to make the decision on the dose for the next patients/cohort. The 
DMC will also recommend the size for the next cohort up to six patients. However, the final 
decision on the next cohort size will be made by a mutual decision between the TMM and the 
Coordinating Investigator. 
After all patients in a cohort have either experienced a DLT or have been observed for 21 days
in the first cycle without experiencing a DLT (28 days in the first cycle for Schedule C), the 
BLRM will be updated with the newly accumulated data and the overdose risk will be 
calculated. Based on the model and on additional information (e.g. patient profiles, PK, 
pharmacodynamics biomarkers) when available at the time of decision, the members of the 
DMC will reach a joint decision on the next dose level to be investigated.
For each new dose tier, the second patient may only be included from day 8 onwards in the first 
cycle of the first patient. If no serious drug-related AE (serious adverse event (SAE)) occurs in 
the first patient, the next patients within the same cohort may be simultaneously included. The 
decision regarding the magnitude of the dose escalation/de-escalation steps will only be taken 
by the DMC, considering toxicity data from each patient cohort.
During the expansion phase, a patient who experiences a DLT will undergo dose de-escalation 
in the same way as patients treated in the dose escalation phase but the occurrence of a DLT 
will not lead to a change in MTD. However any DLTs occurring in the expansion Phase Ib will 
be considered in the evaluation of the recommended Phase II dose and schedule. In the NC
population of the expansion phase, the DMC will have meetings after the first and after the 
second adolescent patient finishes the first cycle to assess whether the adult dose is tolerable in 
adolescents.
4.1.3.2
Additional cycles of BI 894999
Patients who tolerate the trial drug and experience at least disease stabilisation or an 
improvement of disease-related symptoms according to the investigator’s judgement may 
continue treatment. The dose of BI 894999 administered in further cycles must be the same as 
the dose administered in the previous cycle, unless the patient experienced dose limiting 
toxicity or any drug related significant AE necessitating a dose reduction according to 
investigator’s judgement (see Section 4.1.4). 


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Drug assignment and administration of doses for each patient
4.1.4
At the first visit of each cycle, the patient will receive the necessary amount of medication 
bottles from the applicable strength(s) to cover for the cycle period. The treatment numbers of 
the bottles will be assigned via the IRT system (see Section 4.1.2). If slots were available to 
patients with solid tumours at the same time in Schedules A and B, patients were allocated in 
priority to Schedule A in order to determine MTD. If slots were available at the same time in 
Schedule C and in the expansion Phase Ib in one of the sites participating in recruitment for 
Schedule C in patients with solid tumours, patients were allocated in priority to Schedule C in 
order to determine MTD. For DLBCL slots, patients are included in Schedule C since MTD 
has been determined for Schedule B.
The trial drug administration will happen at the clinical site on the days of visits or outside the 
clinical site on the other days, in the morning of each day, at approximately the same hour of 
the day if possible (e.g. 1h before breakfast, except for the 
 cohort), according to the 
schedule (see Flow Chart). 
Patients experiencing emesis may not take a replacement dose. 
If a patient forgets to take a dose, he/she may not take it if more than 3 hours elapsed after the 
normal hour for intake. He/she will then simply take the next dose at the planned time. The 
patient will be instructed to never take two doses to make up for the forgotten dose as BI 
894999 must not be taken more than once a day under any circumstances.
During the COVID-19 pandemic, physical visits to the sites may need to be restricted to ensure 
patient’s safety. Based on a thorough assessment of the benefits and risks, the investigator may 
still decide to continue the trial treatment and trial medication may be shipped to the patient’s 
home if acceptable according to local law and regulations. This will also be applicable in the 
post-pandemic context, after approval of protocol version 12.0 (for more details see Sections
6.1 and 10.5).
Cycle 1 
4.1.4.1
The trial drug administration should be started in the morning of the first treatment day. The 
assigned dose for a patient, according to the dose tier and treatment schedule will be 
administered at the investigational site on the morning of Day 1, after an overnight fast and 1 
hour before breakfast (with exclusion of the patients participating to the food interaction sub-
study, see Section 10.2.2), and the tablets must be swallowed with at least 250 mL water. On 
Day 2, while the patient is still kept at the institution, the dose is given after the PK sample and 
whole blood sample for 
 gene expression at 24h post-dose have been taken (not 
applicable anymore for NC patients and DLBCL patients after protocol version 12.0 approval 
where the visit of Day 2 is cancelled). 
The next doses will be taken by the patient outside of the clinical site up to day 7 (except third 
dose for the 
 cohort, see Appendix 10.2.2). 
On the mornings of Day 8 and Day 12 for Schedules A and B, the patient came to the 
investigational site with his/her medication bottle(s) without having taken his/her morning dose
and he/she received his/her dose after the necessary visit procedures happened, including PK 
sample before the drug was administered (see Appendix 10.2). 
For Schedules A and B, on Day 14 and Day 15 (not on Day 15 in Schedule B), the dose was
given at the investigational site after the PK sample and whole blood samples for HEXIM1 
gene expression pre-dose and at 24h post-dose had been taken. In Schedule B, the medication 


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bottle(s) were returned to the site on Day 14. For Schedule C, on Day 15 and on Day 21, the 
dose is given at the investigational site, on Day 21 after the PK sample and whole blood 
samples for HEXIM1 gene expression pre-dose have been taken.
The other doses of the cycle will be taken by the patient outside of the clinical site. 
On all days when there is no safety lab sampling to be taken which includes fasting blood 
glucose, the patient should however have an overnight fast before the drug intake and should 
not eat until one hour after drug intake. Medication should not be taken together with a meal.
On Day 22 in Schedule A, the patient returned the medication bottle(s) from Cycle 1 to the 
investigational site. For the three Schedules, he/she will receive his/her dose of the first day of 
next cycle, if applicable, from the bottle(s) of the second cycle, after the necessary visit 
procedures happened.
The exact time of trial medication intake on the investigational site must be recorded in the 
eCRF as this information is crucial for proper evaluation of pharmacokinetics and other data. 
Tumour biopsy (where applicable) must be performed in Cycle 1, between Days 8 and 11 
(between Day 3 and Day 8 if not feasible between Day 8 and Day 11 (see 3.1) for patients in 
Schedule A or B, between Days 18 and 21 for patients in Schedule C), 4h to 8 h after the daily 
dose of BI 894999 has been taken.
The patient will record the date and time of each medication intake during the first cycle in a 
diary to help with the compliance check. 
Each time the patient comes to the trial site for a visit (up to Day 14 in Schedule B, up to Day 
21 in Schedule C) he/she will bring his/her medication bottles and patient diary card (in first
cycle) and a compliance check must be performed. Discrepancies between the number of 
tablets remaining and the number of tablets the patient should have taken must be documented 
and explained, whenever possible (see 4.3). 
During the first cycle, the patient may interrupt treatment (not including the one week 
scheduled treatment break in Schedule B or the two times one week treatment break in 
Schedule C) only in case of a DLT (see 5.3.6.1) or at the end of the evaluation period of 21 
days (28 days in Schedule C) for recovery of another drug-related AE of CTCAE grade 3 or 4.
Further Cycles
4.1.4.2
For all subsequent cycles, the medication intake will happen outside of the clinical site except 
on the first day of each cycle (first two days for Cycle 2 in Schedule B, Days 1 and 15 in 
Schedule C) when it has to be administered at the trial site following an assessment by the 
investigational team, and he/she will have to return all the received medication bottles at the 
end of cycle visit.
Starting from protocol version 12.0 onwards, for NC and DLBCL patients, if the patient is 
unable to travel frequently to the site and if deemed safe by the investigator, the investigator 
may instead organize for the patient to have examinations of visit on Day 15 of any Cycle after 
Cycle 1 performed locally, close to the patient’s home, if allowed by local country regulations. 
The investigator must ensure that the persons and facilities executing the local tests are 
adequately qualified for performing those tests. The investigator will then have, as a minimum,
a phone call visit with the patient to evaluate the patient’s safety based on 
 conversation with 
the patient and the results from the local tests. In this case, the patient will take his medication 
at home on Day 15 of the cycle.


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The Day 1 tests of even cycles, from Cycle 6 onwards may also be performed locally, close to 
the patient’s home with a phone call visit with the site investigator to evaluate the patient’s
safety, if the patient is unable to travel frequently to the site. It means that a drug dispensation 
may happen for two consecutive cycles on Day 1 of uneven cycles starting from C5 onwards, 
after discussion with the Sponsor, and if deemed safe by the Investigator. Alternatively, if 
applicable by the local regulation in the given country, a direct shipment from the site to the 
patient may happen, but in this case, via a courier approved by the Sponsor and aware of the 
procedure set-up by the Sponsor to ensure the correct conditions of the shipment.
In parallel to Schedule A an alternative Schedule B was started at the same dose tier at which 
the highest safe continuous daily dosing in 3-week cycles was investigated, according to DMC 
decision. An additional Schedule C was tested in patients with solid tumours, in parallel to 
Schedule B dose finding in DLBCL patients, starting with the recommended phase Ib dose of 
2.5 mg as maintenance dose from Day 2 to Day 7 and from Day 16 to Day 21 and a loa ding 
dose of 5 mg on Day 1 and Day 15, in 4-week cycles.
As the MTD was determined for DLBCL patients in Schedule B, the Schedule C is also being
tested in patients with DLBCL, starting with a loading dose of 4 mg and a maintenance dose of 
2 mg in the first cohort.
For a patient to be eligible for treatment with further cycles, the following criteria must be met:

Absence of disease progression (except for NC patients deriving clinical benefit and for 
whom no other treatment option is available)

Acceptable tolerability: patients experiencing DLT are eligible for further treatment cycles 
with BI 894999 at one dose tier below as soon as recovery from drug related toxicities 
allows further treatment. This means for Schedule C, a reduction of the loading dose in 
steps of 1 mg and a reduction of the maintenance dose in steps of 0.5 mg (e. g., for the first 
cohort, the loading dose would be reduced from 5 mg to 4 mg, from 4 mg to 3 mg, from 3 
mg to 2 mg while the maintenance dose would be decreased from 2.5 mg to 2 mg, from 2 
mg to 1.5 mg, from 1.5 mg to 1 mg).
Patients eligible for a further (repeat) treatment cycle will not start before day 22 after start of 
the previous cycle (Day 29 for Schedule C). 
Before the start of each next cycle, any remaining medication from the previous cycle must be 
collected. If the patient is eligible for a further cycle of treatment, new bottle(s) must be 
dispensed.
Dose interruptions and reductions
4.1.4.3
4.1.4.3.1
Dose interruptions
Dosing will be interrupted for any patient that experiences a dose limiting toxicity as defined in 
5.3.6.1.
Patients may continue therapy at a reduced dose of BI 894999 only after recovery from the 
DLT to at least CTCAE grade 1 or baseline level (except peripheral sensory neuropathy,
anaemia or lymphopenia where treatment continuation is allowed at CTCAE grade 2). 
At the end of the 21 day cycle, for Schedules A and B or 28 day cycle for Schedule C, dosing 
may be interrupted (i.e. start of next cycle postponed) at investigators discretion for recovery of 
other drug-related AEs of CTCAE grade 3 or 4 that do not qualify for DLT.


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AEs of increased troponin
A CTCAE grade 3 troponin increase that is considered to be drug related qualifies for DLT 
according to 5.3.6.1 and will lead to an immediate dose interruption and additional cardiac 
investigations (e.g., review by a cardiologist, CK/CKMB, ECG, echocardiography) must be
performed as soon as possible to determine whether there is evidence of relevant 
cardiotoxicity. Only in case these investigations rule out new or emerging cardiotoxicity, the 
patient can resume treatment with BI 894999 upon recovery of the troponin increase to a grade 
1 or baseline and at a reduced dose according to the DLT rules (see 4.1.4.3.2). Intensified 
cardiac monitoring will be performed in these cases by evaluation of LVEF before the re-start 
of treatment and every 2 cycles thereafter to detect any new impaired wall motility or an 
indisputable drop of LVEF (percentage points reduction of ≥10 from baseline value or drop of 
LVEF below 50%, corresponding to a CTCAE grade 2) which would lead to drug 
discontinuation. 
AE of COVID-19 infection
In case of COVID-19 infection confirmed by a PCR test, the treatment with BI 894999 should 
be interrupted until recovery. The patient may resume treatment following recovery if the 
patient is expected to derive clinical benefit, as agreed between the Investigator and the 
Sponsor.
4.1.4.3.2
Dose reductions
If an AE is a DLT, the dose of BI 894999 must be reduced and treatment can continue only 
after sufficient recovery as explained in Section 4.1.4.3.1.  
In case of DLT, the new dose of BI 894999 will be the one used at the previous dose tier of one 
of the treatment schedules used in the study (e.g., dose reductions from 2.5 mg to 2 mg, from 2 
mg to 1.5 mg, from 1.5 mg to 1 mg). For Schedule C this applies to the loading dose which will 
be decreased in steps of 1 mg while the maintenance dose will be decreased in steps of 0.5 mg.
If an AE is not a DLT, the dose of BI 894999 should be kept the same and treatment can 
continue only after sufficient recovery as explained in Section 4.1.4.3.1. The BI 894999 dose 
may be reduced as a result of non-DLT AEs if deemed safer for the patient by the investigator.
For patients delaying the subsequent cycle by more than 14 days because of a drug related AE, 
treatment should be continued at a reduced dose.
Once a dose reduction occurred, the patient must continue at the reduced dose and cannot be 
re-escalated later on. 
Blinding and procedures for unblinding
4.1.5
Blinding
4.1.5.1
Not applicable in this open-label trial. 
Unblinding and breaking the code
4.1.5.2
Not applicable.


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Packaging, labelling, and re-supply
4.1.6
For details of packaging and the description of the label, refer to the ISF.
BI 894999 will be supplied as film coated tablets. 
 
 
 
Bottles are labelled according to local regulations and include the following as a minimum;

Study number (1367.1)

Product name (BI 894999)

Contents of the bottle (30 tablets/bottle)

Tablet strength

Batch number

Medication number

Use-by date

Storage information

Instructions for use

Sponsor name and address

A statement that the medication is for clinical trial use 

A caution statement that the medication has to be kept out of the reach and the view of 
children.
The necessary bottles of medication are to be dispensed on day 1 of each cycle, regardless of 
the number of tablets remaining in the bottle(s) from the previous cycle which is collected on 
day 1 of each next cycle. In the event that dose reduction is necessary, the patient will return to 
the clinic and new medication will be dispensed, at the new dose level.
Storage conditions
4.1.7
Drug supplies are to be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A temperature 
log must be maintained for documentation 
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.”
Drug accountability
4.1.8
The pharmacist (or the investigator where legally authorized) will receive the investigational 
drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by an Institutional Review Board (IRB) / an independent 
ethics committee (IEC), 

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,


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
Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the Principal Investigator where applicable

Availability of FDA Form 1572 (for US sites) 
Investigational drugs are not allowed to be used outside the context of this protocol. They must 
not be forwarded to other investigators or clinics. Patients should be instructed to return unused 
investigational drug. 
The pharmacist (or the investigator where legally authorized) must maintain records of the 
product’s delivery to the trial site, the inventory at the site, the use by each patient, and the 
return to the Sponsor or warehouse / drug distribution centre or alternative disposal of unused 
products. If applicable, the sponsor or warehouse / drug distribution centre will maintain 
records of the disposal. 
These records must include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
pharmacist (or the investigator where legally authorized) must 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 or 
appointed CRO or alternative disposition, the pharmacist (or the investigator where legally 
authorized) must verify that all unused or partially used drug supplies have been returned by 
the clinical trial patient and that no remaining supplies are in the Investigator’s possession.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
Rescue medication, emergency procedures, and additional treatment(s)
4.2.1
Rescue medication to reverse the action of BI 894999 is not available.
Potential adverse reactions of BI 894999 have to be treated symptomatically.
In patients with DLBCL who are at risk of developing Tumour Lysis Syndrome (TLS), it is up 
to the investigator’s discretion what monitoring and precautionary measures are to be taken (for 
example, hydration, administration of allopurinol or rasburicase) in these patients. In the event 
that a patient develops TLS, he/she should be treated according to the institutional or standard 
guidelines and the TLS reported as an AE.
Concomitant therapy must be recorded in the eCRF, during the screening and treatment period, 
starting at the date of signature of informed consent, and ending at the end of the residual effect 
period (REP), 30 days after the last study drug intake (see Section 5.3.7). For parenteral 
nutrition during the trial, the components need not to be specified in detail. It should just be 
indicated as ‘parenteral nutrition’. 
After the REP, only concomitant therapy indicated for treatment of a related AE has to be 
reported. The start of a new anti-cancer treatment will be documented in the eCRF on the 
patient’s status page of the follow-up visit.


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During the first cycle, the use of growth factors for treatment of evident haemato-toxicity is not 
allowed except under life-threatening circumstances in patients with solid tumours (allowed for 
DLBCL patients). After the first cycle, the use of haematologic growth factors (e.g. 
granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating 
factor (GM-CSF), erythropoietin, platelet-stimulating agents, pegylated G-CSF) in case of 
haematological toxicity of the experimental compound BI 894999 will be considered and 
discussed within the team if required. If this is the case, it has to be recorded in the eCRF 
including duration and dose of the treatment. 
If any diarrhoea is experienced (CTCAE grade ≥2), the patient must be treated with 
antidiarrheal treatment according to the local standard (for example loperamide two 2 mg 
tablets taken immediately, followed by one 2 mg tablet with every loose bowel movement, up 
to a maximum daily dose of 8 tablets (16 mg)).
In the event of diarrhoea, patients must be advised to avoid lactose-containing products or any 
foods known to aggravate diarrhoea.
Oral hydration is essential regardless of severity; appropriate rehydration (1.5 L/m2/day plus 
equivalent of actual fluid loss) and electrolyte replacement has to be ensured in the event of 
CTCAE grade 2 and grade 3 AEs.
In case of nausea and/or vomiting, the patient must be treated according to the local standard 
or according to the recommendations given in the Consensus Statement of the Anti-emetic 
Subcommittee of the Multinational Association of Supportive Care in cancer (MASCC): 
Prevention of chemotherapy- and radiotherapy-induced emesis: results of the Perugia 
Consensus Conference (R06-0986).
Symptomatic drug treatments of adverse reactions or tumour-associated symptoms are allowed, 
including the use of LHRH agonists or antagonists, steroids (given at the lowest possible dose 
and for the shortest possible duration to keep interference with response evaluation at the 
minimum, if introduced during the study treatment period), bisphosphonates and denosumab. 
It is possible that some patients treated with BI 894999 will experience concurrent severe 
thrombocytopenia and changes in coagulation lab assays. The coexistence of thrombocytopenia 
and changed coagulation lab results potentially increases the risk of bleeding events. In order to 
reduce the risk of bleeding events in patients with severe thrombocytopenia and prolonged 
coagulation times, mandatory prophylactic platelet transfusions need to be administered to all 
patients who present with a platelet count below 20 000/mm3.
Restrictions
4.2.2
Restrictions regarding concomitant treatment
4.2.2.1
Additional systemic anti-cancer therapies or curative radiotherapy is not allowed during the 
study. 
For symptom control, palliative radiotherapy is permitted for any lesion in the dose escalation 
part of the study, except during the first cycle if it is considered by the investigator and the 
TMM that it could interfere with the DLT evaluation for MTD determination. In the expansion 
phase (Part Ib), palliative radiotherapy is only allowed to non-target lesions, following 
discussion with the TCM, provided that the reason for radiotherapy does not reflect PD and 
does not interfere with response assessment (for NUT carcinoma patients, palliative 
radiotherapy to target lesions or to lesions that indicate PD is allowed for patients that are 


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deriving clinical benefit from the study treatment as confirmed by the investigator). Lesions 
that have been exposed to radiotherapy are no longer evaluable, and may not be included in the 
assessment of the non-target lesions (or target lesions for NC patients) and the overall 
assessment. These lesions may also not be used anymore for the study biopsy. Unless in 
emergency situations, the TCM should be contacted prior to the administration of palliative 
radiotherapy in the expansion phase.
During the first cycle, the use of growth factors for prevention or treatment of evident haemato-
toxicity is not allowed in patients with solid tumours (allowed for DLBCL patients) except 
under life-threatening circumstances (see Section 4.2.1).
Because of the non-clinical (in vitro) finding of the potential CYP inducing effect of BI 894999 
on CYP3A4, CYP 2C8 and CYP 1A2 , there is a risk that BI 894999 might reduce the plasma 
concentrations of some concurrent medications which are substrates of CYP3A4, CYP2C8 and 
CYP1A2, for example oral contraceptive pills, potentially resulting in a reduction in their 
effectiveness. There, the investigators should be aware of this when concomitant medications 
which are substrates of these CYP enzymes are given to the patient, with attention to a 
potential decrease of efficacy of the concomitant medication (a list of medications considered 
clinically relevant substrates of CYP 1A2, CYP 2C8 and CYP 3A4 is given in in Appendix 
10.6).
Restrictions on diet and life style
4.2.2.2
The usual restrictions on diet and life style which were already applicable for a given patient 
before entry into the study, according to his/her medical condition, have to be continued.
During treatment with BI 894999, all study patients will be advised to avoid sun exposure or 
artificial UVA/UVB radiation in solaria or tanning booths. If exposure to sunlight cannot be 
avoided, protective clothing and broad spectrum (UVA/UVB) sunscreens must be used. After 
discontinuation of BI 894999 treatment, all protective measures must be continued for at least 1 
week.
Restrictions regarding women of childbearing potential 
4.2.2.3
Women of childbearing potential must be ready and able to use highly effective methods of 
birth control per ICH M3(R2) that result in a low failure rate of less than 1% per year when 
used consistently and correctly, and this during the trial and for at least six months after the end 
of the trial treatment (see Section 3.3.2 and explanation given in the informed consent 
information form for more information on highly effective methods of birth control). Women 
of childbearing potential taking a contraceptive pill as birth control method must use an 
additional barrier method for the entire duration of the study treatment intake and for up to one 
month after the end of the study treatment intake.
Male patients with partners of childbearing potential need to use condoms and ensure their 
partner is using an additional highly effective method of birth control, during the trial and until 
at least three months after the end of the trial treatment.


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TREATMENT COMPLIANCE
4.3
Patients are requested to bring all remaining trial medication including empty package material 
with them when attending visits. Based on tablet counts, treatment compliance will be 
calculated as the number of tablets taken, divided by the number of doses which should have 
been taken according to the scheduled period, multiplied by 100. Compliance will be verified 
by the on-site monitor authorised by the Sponsor.
Treatment compliance (%) =
Number of tablets from each strength actually taken 100
Number of tablets from each strength which should have 
been taken
If the number of tablets taken is not between 80-100%, site staff will explain to the patient the 
importance of treatment compliance.


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5.
VARIABLES AND THEIR ASSESSMENT 
Safety data will be collected and evaluated routinely on an ongoing basis.
TRIAL ENDPOINTS
5.1
Primary Endpoint(s)
5.1.1
Phase Ia
5.1.1.1
The primary endpoint for the Phase Ia part of the study is the number of patients with DLT (see 
Section 5.3.6.1 for definition of DLT) observed during the first treatment cycle (the first 21 
days for Schedules A and B, the first 28 days for Schedule C), which will be assessed for dose 
escalation in order to meet the objective of the determination of the MTD of BI 894999 for 
each schedule in patients with solid tumours and for the Schedules B and C in the DLBCL 
cohort.
Phase Ib
5.1.1.2
For the Phase Ib part of this study, the primary endpoint is the number of patients with DLTs
observed during the entire treatment period (as assessed approximately every 3 weeks, at the 
end of each new cycle after Cycle 2, every 4 weeks for Schedule C in the NC cohort if this 
cohort is opened to recruitment) for patients who are enrolled in one of the four pre-selected 
types of cancer in the Phase Ib part and are treated at the Phase Ib dose and schedule 
recommended by the DMC as determined from the Phase Ia part and ongoing safety data 
collected during Phase Ib.
All DLTs occurring during the entire treatment period will be considered for the evaluation of 
the recommended Phase II dose and schedule of BI 894999 and the recommended dose and 
schedule will be re-evaluated based on BLRM and other data collected from Phase Ib.
Secondary Endpoint(s)
5.1.2
Secondary endpoints are:
For Phase Ia

the number of patients with DLTs (see Section 5.3.6.1 for definition of DLT) observed 
during all treatment cycles for each of the schedules (A, B and C) in patients with solid 
tumours and for the Schedules B and C in the DLBCL cohort
All DLTs occurring during the entire treatment period for Schedules A and B will be 
considered for the evaluation of the recommended Phase Ib dose of BI 894999.
All DLTs occurring during the first or repeated treatment cycles will be reported as significant 
AEs, as if an SAE (see Section 5.3.6.1).


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For both Phases Ia and Ib:

PK parameters after single dose and at steady state (C max, AUC0-24, Cmax,ss and AUCτ,ss, ), 
measured during the first cycle (the first 3 weeks for Schedules A and B, the first 4 weeks 
for Schedule C) 

Objective response (OR), defined as CR or PR with tumour assessment during treatment 
period for each schedule (see 5.2.1). For DLBCL patients, a minor response according to 
RECIL 2017 is not part of an objective response
For Phase Ib:

Progression-free survival (PFS) defined from date of start of BI 894999 to the date of 
objective disease progression or death, whichever is earlier, with tumour assessment every 
2 cycles (every 6 weeks for Schedule B if no delays or as close as possible to the end of the 
second of the two cycles of treatment if there was a delay) during treatment period
Or 
Radiological PFS with tumour assessment by bone scan every four cycles for mCRPC 
patients with non-measurable disease by RECIST 1.1

Best overall response, with tumour assessment according to Section 5.2.1, depending on the 
type of solid tumour, during treatment period

PSA response in patients with mCRPC (see 5.2.1)

Overall survival in patients with NC. This will be for patients in the trial after approval of 
protocol version 11.0 and who gave consent to this collection. The overall survival status 
will continue until 12 months after the end of trial as defined in Section 8.6.


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ASSESSMENT OF EFFICACY
5.2
Tumour assessment
5.2.1
The tumour response will be evaluated:

using the RECIST 1.1 (R09-0262), with tumour assessment every 2 cycles (every 6 
weeks if no delays for Schedules A and B, every 8 weeks for Schedule C or as close as 
possible to the end of the second of the two cycles of treatment if there was a delay) 
during treatment period for each schedule in all patients with solid tumours 

using PCWG3 (R17-3377) recommendation every 4 cycles (12 weeks if no delays or as 
close as possible to the end of the second of the four cycles of treatment if there was a 
delay) based on bone scan coupled with PSA percentage change at the same time-points 
as bone scan for mCRPC patients without measurable disease according to RECIST 1.1 
in Phase Ib

using RECIL 2017 (R17-3378) (see Appendix 10.7) based on FDG-PET/CT scans for 
selected schedule (A or B) in the DLBCL cohort every 2 cycles during first four cycles, 
then every four cycles. The assessment of overall response rate in DLBCL will only 
include patients who achieve a partial or a complete response
The assessment by the investigator and/or the local radiologist will be the basis for 
continuation or discontinuation of the trial in an individual patient (in addition to safety). 
The baseline scan(s) (CTscan, bone scan, FDG-PET/CT scans, and/or MRI according to 
investigator’s decision) from screening must have been performed within six weeks prior to 
treatment with the trial drug and the investigator will record results of assessment in the 
patient’s medical records and in the eCRF before the start of treatment according to the 
assessment method: 
-
According to RECIST 1.1, the target (five target lesions in total and maximum two per 
organ) and non-target lesions at baseline. 
-
According to RECIL 2017, target (up to three target lesions in total) and non-target 
lesions at baseline.


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-
According to PCWG3: on bone scan, 2 new lesions are considered as progressive 
disease. 
The same method of assessment and the same technique must be used to characterise each 
reported lesion at baseline and during treatment. Lesions in previously irradiated areas may not 
be considered measurable or evaluable at baseline unless the lesions occurred after irradiation. 
A tumour lesion used for biopsy is not to be considered as a target lesion. 
Tumour response assessment will be performed every two cycles (every 4 cycles after Cycle 4 
in DLBCL patients, every 4 cycles for bone scan in mCRPC patients) and at the EOT visit (if 
not performed within the last 6 weeks).
PSA evaluation in mCRPC patients:

A PSA response is defined as a decline in PSA value ≥50% from baseline (which is 
confirmed by a second value 3 to 4 weeks apart)

A PSA progression is a 25% or greater increase in PSA, and an absolute increase of 2 
ng/mL or more from the nadir and which is confirmed by a second value 3 or more weeks 
later
A rising PSA corresponding to the definition of disease progression (see definition above) is 
not a reason on its own to stop with the trial treatment in mCRPC patients otherwise benefitting 
from the treatment but is considered as PD if concomitant with 2 new bone lesions on bone 
scan or PD according to RECIST 1.1 or clinical evidence of PD.
If the patient stops with the trial medication intake for another reason than PD, the tumour 
assessment according to RECIST, RECIL or PCWG3 will be performed according to standard 
of care until the last follow-up needed according to protocol (progression, death, lost to follow-
up, end of the trial).
For the NC patients, the overall clinical benefit assessment per Investigator’s judgement will be 
based on the following points:

response (CR, PR or SD, mixed response)

symptom relief such as pain, breathing problems, other improvements (Investigator to 
specify)

other reason for considering the clinical benefit (Investigator to specify)
ASSESSMENT OF SAFETY
5.3
Physical examination
5.3.1
Physical examination, height, body weight, performance status
5.3.1.1
Physical examination will be performed at screening, on visit 1 of each cycle prior to study 
medication intake and at the EOT visit. 
Physical examination will include e.g. measurement of height and of body weight and the 
evaluation of the ECOG performance score. Height will be documented only once during 
screening. Weight will be measured during screening, on visit 1 day 1 of each cycle, at the 


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EOT visit and at FU. The ECOG score will be assessed during screening, on visit 1 day 1 of 
each cycle, and at the EOT and FU visits. 
For DLBCL patients, a tumour size determination (by palpation) will be performed at 
screening and at the first visit day of each cycle. For the lymph nodes, only the largest lymph 
node per area will be assessed in two dimensions (if greater than 1 cm in any diameter, which 
can be physically assessed). The spleen and liver enlargement will be expressed in cm below 
the costal margin. Any other tumour manifestation will also be evaluated in two dimensions.
Vital Signs
5.3.2
Vital signs (blood pressure, body temperature and pulse rate after 2 minutes supine rest) will be 
recorded at the screening visit, at every visit of the treatment cycles and at the EOT visit. In 
addition, during the first cycle, vital signs will be measured more frequently on PK sampling 
days (see Flow Chart).
Safety laboratory parameters
5.3.3
Blood (venous) samples will be collected at the times indicated in the Flow Chart and analysed 
by the site’s local safety laboratory.
Laboratory tests will include the following safety lab parameters:

Haematology
Red blood cell count (RBC), haemoglobin, haematocrit, mean corpuscular volume (MCV), 
white blood cell count (WBC) and differential expressed in absolute values, platelets

Biochemistry
Fasting glucose (after overnight fast), sodium, potassium, calcium, phosphate, urea, creatinine, 
AST, ALT, alkaline phosphatase, lactate dehydrogenase (LDH), bilirubin, total protein, 
albumin, uric acid, creatine phosphokinase (CK) and highly sensitive (hs) troponin (T or I, 
according to the laboratory assay used at a given site, but always with the same method for a 
given patient) must be performed and the findings documented.
In case of significant troponin hs increase, further investigations according to standard clinical 
practice should be undertaken by the investigator as deemed appropriate (see Section 
4.1.4.3.1).
Monitoring for TLS includes the following tests:

uric acid, creatinine

sodium, potassium, calcium, phosphate

lactate dehydrogenase (LDH)

Coagulation parameters
Prothrombin time (PT) (expressed in seconds and in international normalized ratio (INR)) and 
activated partial thromboplastin time (aPTT); at screening, in Cycle 1: on day 1 before the first 


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dose of BI 894999, on day 2, on day 8, on pre-dose on the day of tumour biopsy when 
applicable and on day 14, on the first day of every next cycle and on day 15 of Cycles 2, 3 and 
4 and at EOT. In addition, activity of factors II, V, VII and IX will be measured in the first 20 
patients of the Phase Ib in Cycle 1 on Day 1 before first dose of BI 894999 and on Day 14 as 
well as on Cycle 2 Day 1 pre-dose. 
In patients with out of range coagulation lab results (PT, aPTT) in the routine safety laboratory 
assessments, additional coagulation investigations should be performed as appropriate and 
guided by the specific lab findings (such as analysis of single coagulation factor activity and 
mixing studies to distinguish factor deficiencies from inhibitors) in order to investigate the 
underlying reasons for the prolongation of coagulation times.

Virology, only at screening (starting from protocol version 9.0 onwards)

Hep B DNA test, 

Hep C RNA test 

HIV test with an established HIV diagnostic assay
Tests results obtained within 4 weeks of screening are acceptable and must be negative for 
inclusion of the patient in the trial.

Urine 
Urine (pH, glucose, erythrocytes, leukocytes, protein, nitrite) will be analysed by dipstick 
(semi-quantitative measurements) during the screening visit, at visit 1 Days 1 and 2, at visits 4 
and 5 of initial treatment cycle, at visit 1 of repeated treatment cycles and at the EOT visit. In 
case of pathological findings, further evaluation must be performed and the findings 
documented.

Pregnancy test
Beta human chorionic gonadotrophin (β-HCG) pregnancy test in urine or serum will be 
performed for women of childbearing potential at screening, within 7 days prior to first study 
treatment and before the start of each repeated cycle as well as at the EOT visit.
These parameters will be assessed as specified in the Flow Chart. In case of toxicity, adequate 
and more frequent blood sampling is at the discretion of the investigator. In the event of grade 
4 neutropenia or grade 4 thrombocytopenia, blood will be examined at least twice weekly after 
the first occurrence of the grade 4 until return to a lower grade and then further followed at the 
discretion of the investigator.
In case where laboratory investigations have been performed more than 72h prior to the first 
study treatment intake, the results of new laboratory investigations performed within 72h
before the first treatment administration must be available and confirm eligibility.
Electrocardiogram
5.3.4
In Cycle 1, standard 12-lead resting (after at least 5 minutes rest in the supine position) ECGs
matched with PK samples will be performed according to the Flow Chart and in the Appendix
10.2, as much as possible in triplicate. At screening and in patients eligible for repeated cycles 
of treatment, standard (triplicate) 12-lead resting digitalized ECGs must be done according to 


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the Flow Chart (before the intake of BI 894999 at the start of a new cycle) and whenever the 
investigator deems it necessary. An ECG will also be performed at the EOT visit and at the 
follow-up visit (optional if performed at the EOT visit and no drug related abnormalities were 
detected in on-study ECGs).
In case of drug related ECG changes, additional ECG monitoring will be performed in the 
respective and later cycles of treatment, as deemed necessary by the investigator.
All ECGs have to be digitally recorded, if possible in triplicates, within a period of maximum 3 
minutes, using dedicated equipment provided by the CRO and sent electronically to the CRO.
When the ECG time point is concomitant with a blood sampling (or any other procedure), the 
ECG must always be performed prior to the blood sampling (or other procedure) to allow the 
recording in reproducible resting conditions. Detailed instructions for correct ECG recording 
are provided in the ISF.
If for a visit, the patient has the assessments performed locally and not on the clinical site, the 
ECG will not be performed on the central reading ECG device and the ECG tracing must be 
sent to the site which will send it to the Central Reading laboratory for evaluation. 
The recordings will be checked for pathological results (to be recorded as AEs) by the 
investigator. In addition a centralised evaluation of all 12-lead ECGs will be performed by the 
CRO for all ECGs sent to them. This analysis will include the determination of RR-intervals, 
PR-intervals, QRS-intervals, QT-intervals. The CRO is also in charge of a safety over read of 
ECGs (one ECG out of every series of three) which will be done by a board -certified 
cardiologist. In case of clinical abnormalities detected by the cardiologist, the report will be 
provided to the investigator via email or fax by the central reading laboratory and will be 
reported as an AE by the investigator if not already spontaneously reported. 
To allow for a heart rate correction of QT intervals the QT intervals will be matched to the 
preceding RR intervals using at least QTcF (Fridericia’s formula QTcF = QT * RR-1/3) and 
QTcB (Bazett’s formula QTcB = QT * RR-1/2 ).
When preliminary PK results are available (e.g. at the end of the escalation phase), ECG 
recording time points may be adjusted, or new time points may be added according to the 
pharmacokinetic profile of BI 894999.
Other safety parameters
5.3.5
Left ventricular ejection fraction
5.3.5.1
Due to the cardiac findings seen in some patients in this first in human trial as described in 
Section 2.3, the decision has been taken to add an echocardiography or MUGA scan at 
screening and then at the end of Cycle 2 and at EOT (if not performed within the last 6 weeks 
before and if the patient’s health status allows), in order to assess the LVEF. Additional 
measures must be performed in case a grade 3 troponin increase is seen (see Section 4.1.4.3.1).
The same method of measurement (echocardiography or MUGA scan) should be used 
throughout the study.


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Echocardiography should be performed according to the standard guidelines of the American 
Society of Echocardiography (ASE) (R16-5269).
Assessment of adverse events
5.3.6
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.
An AE can therefore be any 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 SAE is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Life-threatening in this context refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death if 
more severe.
Every new occurrence of cancer of new histology must be reported as a serious event 
regardless of the duration between discontinuation of the study drug and the occurrence of the 
cancer.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be considered 
to be “serious” even though they may not have met the criteria of an SAE as given above.
The latest list of “Always Serious AEs” can be found in the remote data capture 
(RDC)/electronic data capture (EDC) system. These events must always be reported as SAEs 
as described in section 5.3.6.1.
Adverse events of special interest (AESIs)


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The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same timeframe 
that applies to SAE, see Section 5.3.7.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
For patients with normal hepatic function at baseline

an elevation of AST and/or ALT >3 fold the Upper Limit of Normal (ULN) combined with 
an elevation of total bilirubin >2 fold ULN measured in the same blood draw sample, 
and/or

marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
For patients with abnormal hepatic function at baseline (e.g., due to primary liver cancer or 
hepatic metastases)

an elevation of AST and/or ALT ≥5 fold ULN combined with an elevation of bilirubin ≥2 
fold ULN measured in the same blood draw sample. 
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “Drug Induced Liver Injury (DILI)
checklist” provided via the RDC-system/EDC-system. Lab values meeting the hepatic injury 
definition must always be reported as an AESI. Exemption does not apply.
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 has to make sure these parameters are analysed, 
if necessary in an unscheduled blood test. Should the results meet the criteria of hepatic injury 
alert, the procedures described in the DILI checklist must be followed.
Any DLT:
The following drug related AEs will qualify as a dose limiting toxicity: 
For solid tumours patients:

Any CTCAE grade ≥3 non haematological toxicity considered related to trial medication
with the following exceptions:

inadequately treated nausea, vomiting or diarrhoea. For fatigue, if present at baseline, 
there must be an increase of 2 grades, 

electrolytes abnormalities that can be corrected within 72 hours with adequate treatment 
(in case it occurs, a control should be performed at 72h to determine the 72h duration of 
the grade 3)

Any hematologic AE related to the trial medication defined as follows:

CTCAE grade ≥4 neutropenia lasting ≥ 7 days (in case it occurs, a control haematology 
test must be performed at least twice weekly until improvement to a lower grade) 
and/or complicated by infection, or


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
CTCAE grade≥4 thrombocytopenia (in case it occurs, a control haematology test must 
be performed at least twice weekly until improvement to a lower grade), or

CTCAE grade≥ 3 thrombocytopenia coupled with grade ≥ 2 of bleeding, or

Febrile neutropenia CTCAE grade 3 (ANC<1000/mm3 and fever ≥ 38.5°C) or higher, 

Any other drug-related AE preventing the patient from taking his treatment according to 
the given schedule (defined as more than 2 consecutive doses missed during the 21 days of 
intake of the Cycle for Schedule A or 14 days of intake for Schedule B or during the two 
times one week of intake of Schedule C or a treatment break between cycles > 14-days in 
addition to the one week off foreseen in Schedules B and C).
For DLBCL patients:

Any CTCAE grade ≥3 non haematological toxicity considered related to trial medication 
with the following exceptions:

inadequately treated nausea, vomiting or diarrhoea. For fatigue, if present at baseline, 
there must be an increase of 2 grades), 

electrolytes abnormalities that can be corrected within 72 hours with adequate treatment 
(in case it occurs, a control should be performed at 72h to determine the 72h duration of 
the grade 3)

Any hematologic AE related to the trial medication defined as follows:

CTCAE grade ≥4 neutropenia lasting ≥ 7 days (in case it occurs, a control haematology 
test must be performed at least twice weekly until improvement to a lower grade) 
and/or complicated by infection, or

CTCAE grade ≥ 4 thrombocytopenia (in case it occurs, a control haematology test must 
be performed at least twice weekly until improvement to a lower grade), or

CTCAE grade≥ 3 thrombocytopenia coupled with grade ≥ 2 of bleeding, or

Febrile neutropenia CTCAE grade 3 (ANC<1000/mm3 and fever ≥ 38.5°C) or higher 
which does not resolve within 48 hours with appropriate treatment (antibiotics, 
antifungal, antiviral agents and growth factors), 

Any other drug-related AE preventing the patient from taking his treatment according to 
the given schedule (defined as more than 2 consecutive doses missed during the 14 days of 
intake in Schedule B which is selected, or treatment break between cycles > 14-days in 
addition to the one week off foreseen in Schedule B).
For definition of DLT, it is essential that patients are sufficiently treated according to 
supportive care standards (see 4.2.1). Patients with treatable AEs (nausea, vomiting, and 
diarrhoea) that are not sufficiently treated do not qualify for DLT and need to be 
replaced, if this occurs in Cycle 1.
AESIs are to be reported in an expedited manner similar to SAEs, even if they do not meet any 
of the seriousness criteria – for details please see 5.3.7.
Severity of AEs
The severity of the AE must be classified and recorded in the eCRF according to CTCAE
version 4.03 in the eCRF (R10-4848).


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Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
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.
Adverse event collection and reporting
5.3.7
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patients’ files
The following must be collected and documented on the appropriate eCRF by the Investigator:
-
From signing the informed consent onwards through the REP, until the end of the REP:
- all AEs (non-serious and serious) and all AESIs.
-
After the end of the REP until individual patient’s end of trial:
- all related SAEs and all related AESIs.
After the individual patient’s end of trial, the investigator does not need to actively monitor the 
patient for AEs but must only report relevant SAEs and relevant AESIs of which the 
investigator may become aware of.
IC = informed consent
End of treatment = last dose of BI 894999
REP = residual effect period of 30 days
End of trial = individual patient’s end of trial = last visit mandated per protocol which is the first follow-up if the patient 
stopped study treatment because of PD or the follow-up at which PD is observed or the decision is taken to start with the 
next line of cancer treatment or the last ongoing patient has reached the first follow-up at the end of the REP
Figure 5.3.7: 1: Type of AE collection according to trial period


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The REP is defined as 30 days after the last trial medication intake. All AEs which occurred 
through the treatment phase and throughout the REP will be considered as on treatment please 
see Section 7.3.4. Events which occurred after the REP will be considered as post treatment 
events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, by completing and sending the BI SAE form immediately (within 24 
hours ) to the Sponsor’s unique entry point (country specific contact details will be provided in 
the ISF). The same timeline applies if follow-up information becomes available. In specific 
occasions the Investigator could inform the Sponsor upfront via telephone. This does not 
replace the requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator must provide the 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 must determine 
the causal relationship to the trial medication.
The following must also be recorded as an (S)AE in the eCRF and SAE form (if applicable):

Worsening of the underlying disease (if not part of the exemption as described below) or 
other pre-existing conditions

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after trial completion must be followed up until they 
have resolved, have been sufficiently characterized, or no further information can be obtained.
Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (country-specific 
contact details will be provided in the ISF). The Pregnancy Monitoring Form for Clinical Trials 
(Part A) must 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
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is 


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to be completed. If there is an SAE and/or AESI associated with the pregnancy then the SAE
and/or AESI has to be reported on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
Exemptions to SAE Reporting
Progressive disease (PD) in oncology trials is a study endpoint for analysis of efficacy. PD is 
exempted from reporting as a (S)AE. Progression of the subject's underlying malignancy will 
be recorded in the appropriate pages of the eCRF as part of efficacy data collection. Death due 
to PD is to be recorded on the appropriate eCRF page and not on a SAE form.
Examples of exempted events of PD are:

Progression of underlying malignancy (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.
When there is evidence suggesting a causal relationship between the study drug and the event 
of progression of the underlying disease, the event must be reported as (S)AE in the eCRF and 
on a SAE form (if applicable).
The study is monitored by a DMC in order to review data on a regular basis.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
Assessment of Pharmacokinetics
5.4.1
Standard pharmacokinetic parameters of BI 894999 as listed under secondary 
 
endpoints will be determined from plasma 
 analyses after a single oral dose and after 
repeated dosing, at steady state along with descriptive statistics. 
 
 
.
At any time, only in case of drug related grade 3 or grade 4 toxicity, every effort must be made 
to collect a plasma PK sample; date and time of the sample and of the most recent drug intake 
(before PK sample) need to be recorded for such samples.
Methods of sample collection
5.4.2
Plasma sampling for BI 894999 pharmacokinetics
5.4.2.1
For quantification of BI 894999 plasma concentrations, up to 102 mL blood will be taken from 
a forearm vein in an EDTA anticoagulant blood drawing tube at the time points specified in the 
Flow Chart and in Appendix 10.2. 


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Every attempt must be made to adhere to the time points for the sampling. For the quality of 
pharmacokinetic analysis, however, the actual times of drug intake and blood sampling as well 
as of dose administration are crucial. Therefore, exact and actual clock time of BI 894999 
intake and blood samplings have to be recorded in the eCRF. 
A total of two plasma aliquots will be generated (with about 0.7 mL plasma in each aliquot) 
from each blood sample. The first aliquot will be used primarily for PK bio-analysis of BI
894999 plasma concentrations, the second aliquot will serve as a back-up sample. The plasma 
samples (including PK back-up samples) must be stored at about -20°C or below at the clinical 
site until shipment on dry ice to the bio-analytical laboratory. There, they will also be stored at
about -20°C or below until analysis (see Section 5.4.3).
Details on sample collection, preparation of plasma aliquots, handling, storage and shipment 
are provided in the ISF/laboratory manual.
Urine sampling and analysis for pharmacokinetics
5.4.2.2
A blank urine sample will be collected prior to the first drug administration and two 4 mL 
aliquots retained to check for analytical interference. A protocol start time of -2:00 and a stop 
time of -2:00 will be used for database setup. All urine voided during the sampling intervals 
described in Appendix 10.2 will be collected in containers. Patients have to empty their bladder 
at the end of each sampling interval. The urine weight/volume (weight will be set equal to 
volume, i.e. 1 kg = 1 L, without correction for specific gravity of urine) for each collection 
interval will be documented (the weight of the empty and filled container needs to be 
documented) and two 4 mL aliquots will be stored for bio-analytical measurement. In order to 
prevent adsorption of BI 894999 it might be necessary to add an additive to the container prior 
to start of urine collection. The procedure and details will be given in the ISF/laboratory 
manual.
Until shipment on dry ice to the bio-analytical laboratory, the urine samples will be stored at 
about -20°C or below at the clinical site and in the same conditions at BI until analysis.
The urine sampling for PK will not happen anymore for the patients recruited under protocol 
version 12.0 onwards.


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OTHER ASSESSMENTS
5.6
Not applicable.
APPROPRIATENESS OF MEASUREMENTS
5.7
The endpoints chosen for this study are generally recognized methods of assessing safety and 
efficacy in oncology studies.
AEs will be graded according to the National Cancer Institute (NCI) CTC AE criteria version 
4.03 (R10-4848).
The tumour response will be evaluated by means of the RECIST 1.1 (R09-0262), RECIL 2017 
(R17-3378) and PCWG3 (R17-3377) that are well established and scientifically accepted 
or/and by means of the appropriate tumour marker, depending on the type of cancer.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
The study consists of two parts, a dose escalation part (Phase Ia) to determine the MTD in three 
different Schedules (Schedule A of continuous dosing, Schedule B with an intermittent dosing 
of 2 weeks on treatment followed by one week break in 3-week cycles, and, starting from 
protocol version 10.0 onwards, Schedule C with a once daily loading dose on Day 1 followed 
by 6 days daily intake of a maintenance dose then one week off treatment, repeated every two 
weeks in 4-week cycles) in patients with solid tumours. The best schedule of administration of 
BI 894999 in patients with solid tumours was determined between Schedules A and B. The 
schedule shown to have a more favourable safety, pharmacokinetics and biomarker profile was 
Schedule B which was chosen to be further investigated in an extension of MTD cohort in 
patients with solid tumours, to determine the MTD in a DLBCL cohort with extension of this 
cohort at MTD and in the expansion phase (Phase Ib). In addition, the 
 on the 
pharmacokinetics of BI 894999 was also investigated in some of the patients from the Phase Ia 
part (around and at MTD), starting in Schedule A and continuing in Schedule B in order to 
obtain results for at least 12 patients and up to 20 patients. Once MTD was determined for 
Schedule B in DLBCL patients, MTD will be determined as well with Schedule C in DLBCL 
patients. Thereafter, the DMC will recommend the best schedule of administration of BI 
894999 between Schedules B and C in patients with DLBCL. The schedule shown to have a 
more favourable safety, pharmacokinetics and biomarker profile will be chosen to be further 
investigated in an extension of MTD cohort in patients with DLBCL.
The second part (Phase Ib) is an expansion phase to further evaluate safety, efficacy and 
pharmacokinetics profile of BI 894999 in patients with selected types of solid tumours (SCLC, 
mCRPC, CRC or NC), as well as biomarker values as a result of treatment with BI 894999
with the selected schedule from Phase Ia, between Schedules A and B, which was B. Once the 
MTD from Schedule C from Phase Ia was known for patients with solid tumours, the DMC 
recommended the schedule shown to have a more favourable safety, pharmacokinetics and 
biomarker profile between B and C. Schedule C was selected, NC cohort with Schedule B was
closed to recruitment and NC cohort with Schedule C was opened..
Patients meeting the inclusion and exclusion criteria for the part they are participating in and 
who have given their written informed consent, are eligible for participation in the study.
Patients will visit the clinical site at the time points specified in the Flow Chart for the 
appropriate Schedule of dosing they are entering (see also Appendix 10.4 for a complete list). 
In situations where a patient is unable or unwilling to attend a clinic visit, the Investigator must 
assess the benefit-risk balance for the individual patient and may decide to perform a visit 
remotely if this is in the best interest of the patient and if agreed with the Sponsor, provided 
that it is allowed by local country regulations and the investigator ensures that the local 
facilities are adequately qualified to perform the tests required per protocol for the given visit.
If a patient misses a scheduled visit, and the patient reports to the investigator between the 
missed visit and the next scheduled visit, the missed visit must be done with the actual date and 
the reason must be given for the delayed visit. 
For the biopsies and PK sampling procedures of Cycle 1, the patient must however still be 
under treatment and not in a treatment break period to perform the evaluations foreseen during 


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the missed visit. The next visit must then take place at the scheduled time after the first 
administration of the trial drug in the respective treatment cycle.
Once the decision for any reason is taken for a patient to stop the treatment with BI 894999, an 
EOT visit must occur as soon as possible.
After the EOT visit, the patient must undergo a follow-up evaluation during an EOR visit (or at 
least a phone contact if a visit is not possible), 30 days (+ 7 days) after the last BI 894999 
intake. 
If the patient was not discontinued because of withdrawal of consent, disease progression,
treatment with another anti-cancer drug, loss to follow-up or because of the end of the trial, 
he/she must continue to undergo follow-up visits every 12 weeks until disease progression, lost 
to follow-up, treatment with another anti-cancer therapy or end of the trial. For NC patients, the 
survival status will be collected for all patients until death, lost to follow-up or until 12 months 
after the end of the trial, according to their consent, after approval of protocol version 11.0.
The study will be conducted according to the principles of Good Clinical Practice (GCP).
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
The procedures required at each study visit in both phases are presented in the appropriate 
study Flow Charts for the Schedule of this protocol and are detailed per visit in Appendix 10.4.
Listed below are the key procedures required:

PK samples during Cycle 1 at Visits 1, 2, 3 and 4 in Schedule A or during Cycles 1-2 in 
Schedule B or during Cycle 1 at Visits 1, 2, , 4 and 5 in Schedule C (not anymore at Visits
2 and 3 for NC and DLBCL patients starting from protocol version 12.0)

Registration of all AEs occurring after the Informed Consent Form (ICF) has been signed 
and until the end of the REP

Baseline and on treatment, in Cycle 1 for the three Schedules and in Cycle 2 for Schedule B
whole blood biomarkers assessments and tumour biopsies biomarkers assessments (only 
when opted for in the escalation phase and in the expansion phase)

Tumour assessment (based on CT and/or MRI scan according to RECIST 1.1 in patients 
with solid tumours including mCRPC patients with measurable disease according to 
RECIST 1.1, or based on FDG-PET/CT scans according to RECIL 2017 (R17-3378) in 
DLBCL patients or based on bone scan and PSA level according to PCWG3 (R17-3377) in 
mCRPC patients of Phase Ib without measurable disease according to RECIST 1.1) must 
be performed once every 2 cycles (meaning every 6 weeks for Schedules A and B, every 8 
weeks for Schedule C, if no delays in cycles but as close as possible to end of the second of 
the two cycles of treatment if there was a delay), in DLBCL every 2 cycles until Cycle 4, 
every 4 Cycles thereafter, every 4 cycles in mCRPC patients) after start of BI 894999.

LVEF assessment at screening, at the end of Cycle 2 during the treatment period as well as 
at the EOT if not performed within the last 6 weeks before and if the patient’s health status 
allows.


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Screening period
6.2.1
Screening Period
The screening period may run over a period of 28 days (period within the trial and before the 
very first intake of BI 894999). For the detailed description of the tests to be performed during 
this period, please refer to Appendix 10.5.1.
Baseline Conditions
Demographics (sex, birth date, race and ethnicity where allowed), information on smoking and 
alcohol history, and baseline conditions will be collected during the screening visit.
Medical History:
History of cancer will also be obtained. 
For solid tumours, the type of cancer, the date of the first histological diagnosis (month and 
year may be sufficient), and the primary tumour site will be reported on the eCRF. The 
differentiation grade (not specified, undifferentiated, poorly differentiated, moderately 
differentiated, well differentiated) obtained at the time of diagnosis and the location of 
metastatic sites as well as the stage according to the tumour, (lymph) node, metastasis (TNM) 
classification will be provided as obtained at diagnosis and at study screening. Previous 
surgeries will be reported. For NUT carcinoma patients entered into the trial, the methodology 
implemented to diagnose NC, the NUT fusion partner, and the threshold for a positive NC will 
be recorded in the eCRF.
For DLBCL, the date of first histological diagnosis (month and year may be sufficient), the 
staging according to revised Ann Arbor staging system as proposed by Cheson et al ( R14-
3387), (see Table 6.2.1: 1 the immunohistochemical cell of origin (COO) information, the 
double-hit lymphoma (DHL) or the double expressor lymphoma (DEL) status should be 
documented.


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Table 6.2.1: 1 Revised Ann Arbor staging (R14-3387)
Previously administered chemotherapy, tyrosine kinase inhibitors treatment, vaccine-therapy, 
antibodies therapy, immune-therapy, and hormone-therapy will be reported including start and 
end dates (month and year may be sufficient), as well as whether therapy was given as neo -
adjuvant, adjuvant, curative or palliative therapy.
Concomitant therapies
Relevant concomitant diagnoses and/or therapies present at study entry and/or during screening 
and relevant to the patient’s safety during the study as judged by the investigator w ill be 
recorded in the eCRF.
Treatment period(s)
6.2.2
Please refer to Appendix 10.5.2 for a detailed description of each visit during the treatment 
period.
Follow Up Period and Trial Completion
6.2.3
End of treatment (EOT) visit
6.2.3.1
The EOT visit will be performed after permanent discontinuation of trial medication for any 
reason, as soon as possible but no later than 7 days 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. 
The assessments of the EOT visit will then be performed instead of the next planned visit. For 
NC patients, overall clinical benefit based on investigator’s judgement will also be recorded
(see Section 5.2.1).
Revised Staging System for Primary Nodal Lymphomas
Stage                        Involvement                         Extranodal (E) Status
Limited
I                One node or a group of adjacent     Single extranodal lesions 
nodes                                                without nodal
involvement
II               Two or more nodal groups on the    Stage I or II by nodal
same side of the diaphragm            extent with limited
contiguous extranodal
involvement
II bulky*             II as above with “bulky” disease      Not applicable
Advanced
III              Nodes on both sides of the              Not applicable 
diaphragm; nodes above the
diaphragm with spleen 
involvement
IV             Additional noncontiguous                  Not applicable 
extralymphatic involvement
NOTE. Extent of disease is determined by positron emission tomography–
computed tomography for avid lymphomas and computed tomography for
nonavid histologies. Tonsils, Waldeyer’s ring, and spleen are considered 
nodal tissue.
*Whether
stage
II
bulky disease is
treated
as limited
or
advanced
diseasemay be determined by histology and a number of prognostic
factors


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If the patient finishes active treatment without having progressive disease, tumour 
assessment/imaging must be performed at the time of treatment discontinuation, unless it has 
been done within the past 6 weeks. If active treatment is stopped due to progressive disease, 
then imaging must be performed at the point in time when progression is first noted 
irrespective of when the most recent imaging was done.
Follow-up visits
6.2.3.2
The REP is defined in Section 5.3.7. The first follow-up visit corresponds to the End of REP 
(EOR) visit and may not be performed earlier than 30 days after permanent discontinuation of 
the trial medication. The information collected at this visit must include all new AEs that 
occurred after EOT and a follow-up of AEs ongoing at EOT.
Additional follow-up visits after the EOR visit will only be performed for patients who did not 
progress on treatment, once every 12 weeks (at least by telephone) until disease progression, 
introduction of a new anti-cancer treatment, death, loss to follow-up or end of the whole trial as 
specified in Section 8.6.
A patient will be considered as having completed the study if he/she discontinues because of 
disease progression and has performed the EOR visit 30 days after EOT or was lost to follow-
up or withdrew consent for further evaluation at the EOT visit. If the patient discontinues for 
any other reason, he/she will be considered as withdrawn.
For NC patients, after approval of protocol version 11.0, the overall survival status will be 
collected, according to patient’s consent, until death, loss to follow-up, withdrawal of consent 
to be further followed-up or until 12 months after the end of the whole trial.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a Phase I, open-label, dose-escalation trial to determine the MTD for three Schedules of 
BI 894999 in patients with solid tumour and for Schedule B and Schedule C in the DLBCL 
cohort and also to assess the safety profile, PK/pharmacodymamics biomarkers, and anti-
cancer activities of BI 894999.
Phase Ia:
The objective of the Phase Ia is to determine the MTD, defined as the highest dose with less 
than 25% risk of the true DLT rate being above 33%, separately for three Schedules of BI 
894999 in patients with solid tumour and for the Schedules B and C in the DLBCL cohort. 
Dose escalation and determination of MTD for Schedule A and Schedule B will be guided by a 
Bayesian 2-parameter logistic regression model with overdose control (R13-4803; R13-4806). 
Dose escalation and MTD determination for Schedule C will be guided by a Bayesian 5-
parameter logistic regression model with overdose control (R15-4233), which is described in 
statistical appendix section 10.3.2. These designs have been shown to be superior regarding the 
precision of MTD determination compared to 3+3 designs.
The Bayesian 2-parameter logistic regression model (BLRM) is formulated as follows:
logit(p(d)) = log(α) + β x log(d/d*),
where logit(p) = log(p/(1-p)). 
p(d) represents the probability of having a DLT in the first cycle at dose d, d* = 80 mg is the 
reference dose, allowing for the interpretation of α as the odds of a DLT at dose d*, and θ = 
(log(α), log(β)) with α, β > 0 is the parameter vector of the model.
Since a Bayesian approach is applied, a prior distribution π(θ) for the unknown parameter 
vector θ needs to be specified. This prior distribution used in the BLRM for the dose escalation 
of Schedule A will be specified as a mixture of three multivariate normal distributions, i.e.
π(θ) = φ1π1(θ) + φ2π2(θ) + φ3π3(θ)
with 
φi, i = 1, 2, 3 the prior mixture weights (φ1+ φ2+ φ3 = 1)
and 
πi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, with








2
22
,
22
,
11
,
22
,
11
,
2
11
,
i
i
i
i
i
i
i
i
i










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Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
Initial prior derivation
For the current study of Schedule A dose escalation, no relevant information in the form of 
human data is available, since no study in a comparable population has been conducted. 
Therefore, the three mixture components were established as follows:
1. A weakly informative prior was derived to reflect a priori assumption that the median DLT 
rate at the starting dose of 0.2 mg would equal 1%, and the median DLT rate at 80 mg 
would equal 40%. This yields μ1 = (-0.402, -0.350). The standard deviations were set such 
that large uncertainty about the parameter means is reflected, and the correlation was set to 
0, thus yielding σ1,11 = 2, σ1,22  = 1 and ρ1 = 0, respectively. The prior weight φ1 for the first 
component was chosen as 0.9.
2. A high-toxicity weakly informative prior was derived to reflect the case that the compound 
would be much more toxic than expected. For this prior component, it was assumed that the 
median DLT rate at the starting dose of 0.2 mg would equal 10%, and the median DLT rate
at 80 mg would equal 60%. These assumptions yield μ2 = (0.409, -0.826). The standard 
deviations and correlations were set identical to the weakly informative prior, i.e. σ 2,11 = 2, 
σ2,22  = 1 and ρ2 = 0, respectively. The prior weight φ2 for the second component was 
chosen as 0.05.
3. A low-toxicity weakly informative prior was derived to reflect the case that the compound 
would be much less toxic than expected. For this prior component, it was assumed that the 
median DLT rate at the starting dose of 0.2 mg would equal 0.1%, and the median DLT
rate 80 mg would equal 5%. These assumptions yield μ3 = (-2.936, -0.413). The standard 
deviations and correlations were set to σ3,11 = 5, σ3,22  = 0.01, therefore almost fixing the 
slope parameter to its mean. The correlation was set to 0, i.e. ρ3 = 0. The prior weight φ3 for 
the third component was chosen as 0.05.
A summary of the prior distribution used in the BLRM for Schedule A dose escalation is 
provided in Table 7.1:1. Additionally, the prior probabilities of DLT at different doses, as well 
as the corresponding probability of under-, targeted and overdosing, are shown in Table 7.1: 2. 
Graphically, the prior medians with accompanying 95% credible intervals are shown in Figure 
7.1: 3. As can be seen from both the Table and the Figure, the prior medians of the DLT 
probabilities are in-line with the prior medians derived from the weakly informative prior, and 
the uncertainty around the medians is large, showing the low amount of information this prior 
provides. This is also supported by the prior sample size, i.e. the information contained in the 
prior. This is approximately equal to 1.22 patients, i.e. less than or around half of the weight 
the first cohort in the study will have.
Table 7.1: 1 Summary of prior distribution
Prior Component
Mixture Weight
Mean vector
SD vector
Correlation
1: Weakly inf.
0.900
(-0.402, -0.350)
(2.000, 
1.000)
0.000
2: High Tox
0.050
(0.409, -0.826)
(2.000, 
1.000)
0.000
3: Low Tox
0.050
(-2.936,  -0.413)
(5.000, 
0.010)
0.000


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Table 7.1: 2
Prior probabilities of DLT at selected doses
Dose
Probability of true DLT rate in
Quantiles
[0–0.16)
[0.16–0.33)
[0.33–1]
Mean
SD
2.5%
50%
97.5%
0.2
0.815
0.073
0.112
0.102
0.203
<0.000
0.007
0.793
0.5
0.784
0.083
0.134
0.119
0.218
<0.000
0.012
0.830
1.0
0.755
0.090
0.155
0.136
0.231
<0.000
0.020
0.855
2.5
0.704
0.108
0.188
0.164
0.249
<0.000
0.036
0.885
5
0.659
0.117
0.224
0.191
0.263
<0.000
0.058
0.904
10
0.597
0.134
0.269
0.226
0.278
<0.000
0.092
0.924
20
0.513
0.156
0.331
0.273
0.293
<0.000
0.150
0.941
40
0.407
0.171
0.422
0.339
0.306
0.001
0.243
0.958
80
0.280
0.165
0.555
0.435
0.317
0.005
0.395
0.974
120
0.219
0.148
0.633
0.499
0.324
0.007
0.502
0.986
Doses printed in bold face meet the overdose criterion (P (overdose) < 0.25)


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Figure 7.1: 3
Prior medians and 95% credible intervals
The priors may be updated once the trial has started in case new data that can be used will be 
available. After the initial prior derivation the five different BLRM models used for the dose 
finding of Schedule A in patients with solid tumour, of Schedule B in patients with solid 
tumour, of Schedule C in patients with solid tumour, of Schedule B in patients with DLBCL, 
and of Schedule C in patients with DLBCL will be handled separately.
For Schedule A and Schedule B, the MTD may be considered reached if the following criteria 
are fulfilled (for Schedule C, see Section 10.3.2)
1. At least 1 DLT on the trial and either
2. At least 6 patients have been treated at the MTD and the posterior probability of the true 
DLT rate in the target interval (16%-33%) is above 50% for Schedule A dose escalation / > 


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60% for Schedule B dose escalation in solid tumour and the DLBCL dose escalation (due 
to the fact that an updated prior based on observed safety data from Schedule A dose
escalation is used for the Schedule B dose escalation in solid tumour and DLBCL dose 
escalation), OR
3. At least 12 patients in each schedule in solid tumours and in Schedule B in the DLBCL 
indication with 6 patients having been treated at MTD for each MTD determination.
Statistical model assessment
The model was assessed using two different metrics:
1. Hypothetical data scenarios: for various potential data constellations as they could occur in 
the actual trial, the maximal next doses as allowed by the model and by the 100% 
escalation limit are investigated. Data scenarios thus provide a way to assess the “on-study” 
behaviour of the model.
2. Simulated operating characteristics: these illustrate for different assumed true dose-toxicity 
relationships, how often a correct dose would be declared as MTD by the model. They are a 
way to assess the “long-run” behaviour of the model.
In summary, the model showed very good behaviour as assessed by these metrics. More details 
can be found in Section 10.3. The simulations for scenarios and operating characteristics were 
produced using R version 3.0.3.
With the addition of Schedule B and Schedule C in patients with solid tumour and Schedule B
and Schedule C in the DLBCL cohort after the start of Schedule A in patients with solid 
tumour, the initial priors used in the Bayesian logistic regression model were updated based on 
the cumulatively observed data. For Schedule C, loading dosing and maintenance dosing will 
be treated as a combination of BI 894999. The initial priors for maintenance dosing are updated 
based on the observed data from Schedule A and B in patients with solid tumour. More details 
can be found in Section 10.3 and TSAP.
Phase Ib:
The expansion Phase Ib will recruit a minimum of 9 patients and a maximum of 20 patients
with measurable disease according to RECIST 1.1 (mCRPC patients with no measurable-
disease are eligible according to PCWG3 criteria (see 3.3.2.1) to the dose and Schedule 
recommended by the DMC for Phase Ib part (based on MTD) per type of tumour (SCLC, 
mCRPC or CRC) selected by the DMC. For NC patients, up to 40 patients will be recruited 
with Schedule B and/or with Schedule C. 
Five patient cohorts are considered in the Phase Ib part of this study. To effectively use the 
information from these 5 patients’ cohorts in the assessment of the efficacy of BI 894999, a 2-
stage Bayesian hierarchical model (BHM) approach, which assumes full exchangeability of 
model parameters and allows borrowing information across patients’ cohorts, will be used to 
analyse the response rate endpoints (i.e. objective response rate, disease control rate). The 
BHM has 2 main components: a data model and a parameter model. The data model is a 
binomial sampling model
rj | nj ~ Binomial (πj, nj), j = 1, 2, 3, 4, 5


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where nj and rj are the number of patients and the corresponding number of patients with 
response in each patient cohort. The parameter model for the exchangeable log-odds 
parameters θj = log(πj / (1 - πj)) is specified as
θj | μ, τ ~ N(μ, τ2), j = 1, 2, 3, 4, 5
where μ denotes the “overall” mean and τ determines the inter-cohort heterogeneity. A non-
informative (improper) uniform prior is used for the main parameter μ. For the inter-cohort 
heterogeneity parameter τ, a half-normal prior with scale parameter 100 is used which is a very 
conservative assumption regarding between-cohort variability and hence leads to only little 
borrowing of data across patient cohorts because there is little prior information on the strength 
of the correlation between the treatment effects across the 5 cohorts.
In stage 1 of the Phase Ib part, approximately 9 patients will be enrolled and treated in each of 
the SCLC, mCRPC and CRC cohorts. If no objective response is observed out of the 
approximate 9 patients in a patient cohort, this cohort will be closed for stage 2 recruitment.
Analysis of stage 1 may be performed for each cohort separately. At the end of stage 2 of the 
Phase Ib part, the BHM approach will be used to estimate the shrinkage estimator of θj for each 
patient cohort and the response data from the DLBCL MTD extension cohort will also be 
considered in the shrinkage estimator of θj. Since the full exchangeability assumption may not 
hold for the BHM, the exchangeability-non exchangeability (R17-3435) approach will also be 
applied as a sensitivity analysis of the response rate endpoints in the Phase Ib part.
NULL AND ALTERNATIVE HYPOTHESES
7.2
No formal hypothesis testing is planned in this trial. This is an exploratory Phase Ia/Ib study 
with the main objective of dose escalation and MTD determination (for Phase Ia part) and 
safety and efficacy evaluation (for Phase Ib part). All analyses in this trial are descriptive and 
exploratory by nature.
PLANNED ANALYSES
7.3
Only one analysis population will be considered for efficacy and safety analyses: the treated 
set. The treated set (TS) will consist of all patients who were treated with any dose of BI 
894999. Patients will be analysed under the actual treatment received on Day 1.
The PK set includes all subjects in the TS who provide at least one observation for at least one 
PK endpoint without important protocol violations relevant to the evaluation of PK.
The primary analysis will be based on the treated set population excluding patients that have to 
be replaced for analysis of the MTD, see Section 3.3.4.1 for further details.
No per protocol population will be used for analyses; however important protocol violations 
will be identified and listed.


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Primary endpoint analyses
7.3.1
In order to determine the MTD, the occurrence of DLTs in the first cycle will be assessed on an 
individual patient level in Phase Ia part. The MTD will be determined as described in
Section7.1 for Schedules A and B in patients with solid tumour and in Section 10.3.2 for 
Schedule C. The description for MTD determination for Schedule B and Schedule C in the 
DLBCL cohort can be found in Section 7.1.
Based on the data observed in the trial, other models might be considered either additionally or 
replacing the primary model. For feasibility or other reasons, a different dose might be 
considered as the recommended dose for Phase Ib.
The number of patients with DLTs that occurred during the first treatment cycle (first 21 days
for Schedules A and B, first 28 days for Schedule C) in Phase Ia part and during the entire 
treatment period in Phase Ib part of this study will be summarized separately. For Phase Ia part 
of this study, the number of patients with DLTs during the first cycle will be summarized by 
dose level for each schedule (A, B and C) in solid tumour and for Schedule B and Schedule C
in the DLBCL cohort. For the Phase Ib part of this study, the number of patients with DLTs 
during entire treatment period will be summarized by different cohorts and the BLRM will be 
rerun to re-evaluate the MTD together with all relevant data collected in Phase Ib.
Secondary endpoint analyses
7.3.2
Descriptive analyses will be conducted for secondary endpoints.
Number of DLTs
The number of DLTs occurred during the entire treatment period in Phase Ia part of this study 
will be summarized by dose level for each schedule (A, B and C) in solid tumour and for 
Schedule B and Schedule C in the DLBCL cohort.
Secondary efficacy analyses
Objective response and best overall response assessed by the investigator according to RECIST 
version 1.1 for solid tumour in each schedule, or using RECIL 2017 for the DLBCL patients or 
via bone scan in combination with PSA evaluation, as well as the PSA responder rate will be 
analysed descriptively for each schedule in solid tumour and for Schedule B and Schedule C in 
the DLBCL cohorts. The number of patients with objective response and with best overall 
response will be summarized separately for the Phase Ia part and the Phase Ib part. For the 
Phase Ia part, frequency distribution and descriptive statistics will be provided by dose level for 
each schedule in solid tumour and for Schedule B and Schedule C in the DLBCL cohorts. For 
the Phase Ib part, a Bayesian hierarchical modelling approach will be used to derive the 
shrinkage estimators of the response rate endpoints of each patient cohort together with the 
95% credible interval. The MTD extension cohort of the DLBCL cohort will also be 
considered in the BHM of the shrinkage estimators of the response rate endpoints. In addition, 
the frequency distribution and descriptive statistics will also be provided for each patient 
cohort. A sensitivity analysis using the EXNEX method may also be conducted to account for 
non-exchangeability of the response rates across patient cohorts.


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For PFS to be assessed for the Phase Ib part of this study, if a patient did not die or progress 
until the last visit in the study, this patient will be censored at the last time point known to be 
alive and progression-free. Kaplan-Meier method will be used to analyse PFS.
For patients with ‘event’ as an outcome for PFS:
• PFS [days] = date of outcome – date of the first treatment administration + 1.
For patients with ‘censored’ as an outcome for PFS:
• PFS (censored) [days] = date of outcome – date of the first treatment administration + 1.
For NC patients, overall survival is a secondary endpoint, defined as the time from the first 
treatment administration to the date of death. OS will be analysed descriptively by Kaplan-
Meier method.
For patients with ‘event’ as an outcome for overall survival:
• Overall survival [days] = date of death – date of the first treatment administration + 1.
For patients with ‘censored’ as an outcome for overall survival:
•Overall survival (censored) [days] = date of outcome – date of the first treatment 
administration + 1.
 
 
 
 
 
 
 
 
 
 
 
 
 


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Details of analysis of PK endpoints and other efficacy endpoints will be provided in the TSAP.


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Safety analyses
7.3.4
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. Standard BI summary tables and listings will be produced. All AEs with an onset 
between start of treatment and end of the REP, a period of 30 days after the last dose of trial
medication, will be assigned to the treatment period for evaluation under the treatment received 
on Day 1. The actual treatment at AE onset will be displayed in subject data listings.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between start of treatment and end of the residual effect period will be 
considered ‘treatment-emergent’. The residual effect period is defined as 30 days after the last 
trial medication intake. AEs that start before first drug intake and deteriorate under treatment 
will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class and 
preferred term after coding according to the current version of the MedDRA.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will be 
done via comparison of laboratory data to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listi ngs. 
Treatment groups will be compared descriptively with regard to distribution parameters as well 
as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, baseline, 
during the course of the trial and at the end-of-trial evaluation will be assessed with regard to 
possible changes compared to findings before start of treatment.
Pharmacokinetic analyses
7.3.5
For pharmacokinetic analysis and displays, concentrations will be used in the same format as 
reported in the bio-analytical report. Only concentrations within the validated concentration 
range and actual sampling times will be used for the calculation of pharmacokinetic 
parameters. For derivation of pharmacokinetic parameters see Appendix 10.1.
Non-compartmental pharmacokinetic analyses of the plasma concentration-time data will be 
performed using a validated software program (WinNonlin®Phoenix, current version) and for 
this purpose the actual sampling time for pre-dose samples will be set to zero.
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the 
drug plasma concentration-time tables. For the presentation of the mean profiles, the arithmetic 
and geometric mean and the planned blood sampling times will be used. If the actual sampl ing 


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time deviates significantly from the planned time, the corresponding plasma concentration will 
be excluded from the calculation of descriptive statistics.
 
 
 
 
 
 
 
 
 
 
 
INTERIM ANALYSES
7.4
Interim safety evaluations will be performed as considered necessary. In particular safety 
evaluations will be performed after each dose cohort by the DMC consisting of the 
investigators and representatives of the sponsor (refer to Section 3.1.1). Based on this, the 
DMC will recommend the next dose level as well as the corresponding cohort size. DMC 
meeting minutes and outputs provided for these DMC meetings will be documented and 
archived in the TMF.
In the Phase Ib part of this study, an interim futility assessment will be conducted after 
approximate 9 patients are enrolled and evaluable for tumour response evaluation by imaging 
in each of the SCLC, mCRPC and CRC patients’ cohorts. If no objective response is observed 
in any of the patients in a cohort, this patient cohort will be closed for further enrolment. These 
futility assessments may be performed separately for each cohort.
 
Unblinded preliminary exploratoryPK analysis of BI 894999 and pharmacodynamics analyses 
will be performed each time it will be deemed necessary by the trial team and DMC to 
investigate the PK and pharmacodynamics characteristics of BI 894999.


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The TCPK will receive the bio-analytical results to be able to perform the exploratory PK 
analysis from the Trial Bio-analyst (TBA).
 
 
 
 
Once the primary endpoint of the Phase Ia was reached in patients with solid tumours for both 
schedules A and B, and the MTD was confirmed in the extension cohort with the selected
schedule (B) in these patients, a Phase Ia report was prepared based on the Phase Ia data for 
patients with solid tumours in Schedules A and B. For this purpose, a database snapshot was
performed. A summary of safety and efficacy endpoints and determination of the 
recommended Phase Ib dose and schedule was included in the Phase Ia report. The Phase Ia 
report is made available for all investigators who participate in the Phase Ib. Once MTD in 
Schedule C will be determined and confirmed in the extension cohort, the report for Schedules 
A and B in solid tumours together with the results for Schedule C will be the basis for 
publication by the Coordinating Investigator. Prior to initiation of Phase Ib, relevant data from 
the Phase Ia part for Schedules A and B will also be sent to regulatory agencies in the countries 
where Phase Ia Schedules A and B took place and where Phase Ib will take place.
HANDLING OF MISSING DATA
7.5
Missing baseline laboratory values will be imputed by the respective values from the screening 
visit. No other imputations will be performed on missing data and every effort will be made to 
obtain complete information on all AEs with particular emphasis on potential DLT and to 
follow-up the patients for efficacy data.
Plasma concentration - time profiles
7.5.1
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).
Pharmacokinetic parameters
7.5.2
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 pre-
dose concentration is less than or equal to 5% of Cmax value in that subject, the subject’s data 


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without any adjustments can be included in all pharmacokinetic measurements and calculations 
(i.e. the pre-dose value will not be changed to zero). If the pre-dose value is greater than 5% of 
Cmax, the subject should be dropped from all statistical evaluations. The individual 
pharmacokinetic parameters can be calculated and listed separately. Every effort will be made 
to include all concentration data in an analysis. If not possible, a case to case decision is 
required whether the value should only be excluded from half-life estimation or the complete 
analysis. 
• If a concentration is only excluded from half-life determination, it will be used for all other 
calculations (e.g. descriptive statistics) and for graphical presentation.
• If a concentration value is excluded from all calculations, it will not be presented graphically 
or used for the calculation of descriptive statistics and parameter determination. However the 
excluded concentration itself will be listed in the clinical trial report associated with an 
appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not be 
recorded or will be missing for a certain time point, the planned time will generally be used for 
this time point instead. Pharmacokinetic parameters which cannot be determined will be 
identified by "not calculated”.
RANDOMISATION
7.6
Patients will be assigned, not randomised, into escalating dose cohorts by order of admission 
into the trial. Doses will be assigned based on the decision made by the DMC (see Section
7.3.4).
DETERMINATION OF SAMPLE SIZE
7.7
About 104 patients are expected for the Phase Ia dose escalation part:
-
47 patients were included for both Schedules A and B in patients with solid tumours
including a total of 12 patients in the MTD cohort of solid tumours for the selected 
schedule between A and B (B) (refer to Table 10.3.1: 3)
-
approximately 34 patients in the DLBCL cohort:14 patients were included to determine 
the MTD in Schedule B, 12 patients are expected to be necessary to determine the MTD 
in Schedule C and 6 up to 8 patients to confirm the MTD in the schedule selected by the 
DMC (B or C). 
-
Approximately 23 patients for Schedule C in patients with solid tumours (16 were 
necessary for MTD determination and an addition of 7 patients to confirm the MTD)
Fewer or more patients might be needed for the Phase Ia part based on the recommendation of 
the DMC and the criteria specified (see Section 7.1). 
 
 
About 80 up to100 patients are expected for the Phase Ib expansion part: 
Additional minimum 9 evaluable patients will be included in the Phase Ib expansion phase for 
each type of solid tumour (SCLC, mCRPC or CRC). If at least 1 out of 9 evaluable patients in a 


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given cohort has an objective response, the cohort would be further extended up to 20 patients. 
The 3 cohorts recruited respectively 12, 11 and 14 patients to reach the minimum of 9 
evaluable patients. The cohorts of CRC, mCRPC and SCLC didn’t pass the futility. 20 patients
with NC were recruited in Schedule B. Since 
Schedule C was selected after MTD 
determination of Schedule C in phase Ia solid tumour patientsas recommended by DMC, the 
NC cohort with Schedule B was closed and the NC cohort with Schedule C is recruiting up to 
40 patients.
Different homogeneous scenarios and heterogeneous scenarios are
considered in the 
simulations to assess the frequentist operating characteristics of the BHM approach for the 
Phase Ib part of the study. The simulation results as shown in Table 7.7: 1 below show that, 
with the proposed maximum cohort size of 20 patients and an interim futility assessment after 9 
patients in each patient cohort in the SCLC, CRPC and CRC cohorts, the BHM approach has 
high probability of making the correct decision under a wide range of scenarios of both 
complete exchangeability assumption and some “nugget” scenarios.
Table 7.7: 1
Operating characteristics of the Bayesian Hierarchical Modelling 
approach used in the Phase Ib part of this study under different 
scenarios
Scenario (objective 
response rate (%) in 
each patient cohort)
Probability of shrinkage 
estimator of the objective 
response rate ≥20% in at 
least one cohort
Probability of shrinkage 
estimator of the objective 
response rate ≥20% in 
each cohort 
Average 
total 
sample 
size
30 / 30 / 30
0.99
0.92 / 0.94 / 0.94
59
25 / 25 / 25
0.94
0.74 / 0.74 / 0.80
58
10 / 10 / 10
0.16
0.09 / 0.08 / 0.07
47
5 / 5 / 5
0.04
0.02 / 0.02 / 0
38
10 / 10 / 30
0.81
0.24 / 0.22 / 0.74
51
5 / 5 / 30
0.84
0.07 / 0.08 / 0.83
45
10 / 30 / 30
0.97
0.50 / 0.89 / 0.89
55
5 / 30 / 30
0.98
0.57 / 0.86 / 0.89
52
20 patients in each cohort with interim futility assessment after 9 patients in each cohort. Number of simulations = 
100
Therefore, a total sample size of approximately 196 patients is expected for this study.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down in 
the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for 
GCP and relevant BI Standard Operating Procedures (SOPs), the EU regulation 536/2014 and 
the US FDA regulations.
For each US site / investigator incorporated under a US IND, the US IND requirements outlined in 
the US Code of Federal Regulations must also be met and a Form FDA 1572 needs to be filled in.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of the 
protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of this 
trial are described in the Investigator contract. The abbreviated safety interim report written at 
the end of the Phase Ia for Schedules A and B in patients with solid tumours together with the 
results of primary endpoint in Schedule C in patients with solid tumours may be the basis for a 
publication. However, concerning all the trial results including the Phase Ib results, they may 
not be published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).”
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / 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 from the patient’s parents (both or one, based on national regulation) or from the legal 
guardian if the patient is not legally adult according to ICH / GCP and to the regulatory and legal 
requirements of the participating country. For a minor patient, in addition to the parents or legal 
guardian informed consent, the minor patient must also sign an informed assent. 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.
For patients < legal age to be adult: If only mother or father (or one legal guardian) has sole 
legal custody, this needs to be confirmed with signature and date on the informed consent by 
the person with legal custody. Both documents (consent and assent) outline the participant’s 
rights to decline to participate or to withdraw from the study at any time. Consenting/assenting 


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is a dynamic and continuous process that should be maintained during the trial. At each new 
treatment course the site staff should briefly discuss with legal representative for a minor 
patient and with the patient him/herself the main aspects of the trial, focusing in particular on 
any new information that might affect their willingness to continue the participation in the trial. 
The site staff is recommended to document this process in the medical records.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the Investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
RECORDS
8.3
eCRF for individual patients will be provided by the Sponsor. For drug accountability, refer to 
Section 4.1.8.
Source documents
8.3.1
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, all data need to be derived from source documents, e.g.:

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

AEs and outcome events (onset date (mandatory), and end date (if available))

SAEs (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)

Originals or copies of imaging diagnostics

ECG results (original or copies of printouts)

Completion of Patient’s Participation in the trial

Prior to allocation of a patient to a treatment into a clinical trial, there must be documented 
evidence in the source data (e.g., medical records) that the trial participant meets all 
inclusion criteria and does not meet any exclusion criteria. The absence of records (either 
medical records or testing conducted specific for a protocol) to support inclusion/exclusion 
criteria does not make the patient eligible for the clinical trial.


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Technical information collected on PK sampling days (such as i.e. PK sampling times, weight 
of containers for urine PK, repeated vital signs linked with PK) may be collected on specific 
paper PK logs which will be considered as source data for related entries in eCRF and are 
considered part of the ISF.
Direct access to source data and documents
8.3.2
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review and 
regulatory inspection, providing direct access to all related source data / documents. eCRF and 
all source documents, including progress notes and copies of laboratory and medical test results 
must be available at all times for review by the Sponsor’s clinical trial monitor, auditor and 
inspection by health authorities (e.g. FDA). The CRA / on site monitor and auditor may review 
all eCRF, and written informed consents. The accuracy of the data will be verified by 
reviewing the documents described in Section 8.3.1.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
Listedness
8.4.1
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular AE is "listed", i.e. is a known adverse reaction of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For BI 894999, this is the current version of the Investigator’s Brochure (c03016865-02). 
The current version of this reference document is provided in the ISF. No AEs are classified as 
listed for trial design, or invasive procedures.
Expedited reporting to health authorities and IRB / IEC
8.4.2
Expedited reporting of SAEs, e.g. suspected unexpected serious adverse reactions (SUSAR) to 
health authorities and IRB / IEC, will be done according to local regulatory requirements. BI is 
responsible to fulfil their legal regulatory reporting obligations and in accordance to the 
requirements defined in this protocol.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate medical 
personnel responsible for the patient’s welfare. Data generated as a result of the trial need to be 
available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IEC and the regulatory authorities.
END OF TRIAL
8.6
The end of the trial is defined as the time when the last ongoing patient in the trial will have 
undergone the EOT visit and the EOR visit.


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The IRB / 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.
The last patient last visit primary endpoint (LPLV PE) is defined as the date when the last 
patient with solid tumour of the dose escalation Phase Ia from Schedules A and B has reached 
the end of 21 days in Cycle 1 and is evaluable for DLTs.
Overall survival status collection for NC patients will end 12 months after the end of trial.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P12-05791
U.S. Department of Health and Human Services Food and Drug Administration 
Center for Drug Evaluation and Research (CDER). Guidance for industry: drug 
interaction studies - study design, data analysis, implications for dosing, and 
labeling recommendations (draft guidance, February 2012) (this guidance 
document 
is 
being 
distributed 
for 
comment 
purposes 
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Website:fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guida nces/ucm292362.pdf (access 
date: 14 May 2012) ; U.S.Department of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER) 2012.
P14-08681
European Medicines Agency (EMA). Committee for Human Medicinal Products 
(CHMP): guideline on the investigation of drug interactions, final (21 June 
2012, CPMP/EWP/560/95/Rev. 1 Corr.) (this guideline replaces guideline 
CPMP/EWP/560/95). Website: ema.europa.eu/docs/en GB/
document_library/Scientific_guideline/2012/0 7/WC500129606.pdf (access 
date: 4 June 2014) ; London: European Medicines Agency (EMA) 2012.
R01-0787
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am 
J Clin Oncol 1982; 5: 649-655.
R04-0569
Kang SH, Ahn CW. An investigation of the traditional algorithm-based designs 
for phase 1 cancer clinical trials. Drug Inf J 2002. 36:865-873.
R06-0986
Antiemetic Subcommittee of the Multinational Association of Supportive Care 
in Cancer (MASCC). Prevention of chemotherapy- and radiotherapy-induced 
emesis: results of the 2004 Perugia International Antiemetic Consensus 
Conference. Ann Oncol 2006; 17(1): 20-28.
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al. 
New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). Eur J Cancer 2009; 45: 228-247.
R10-4848
Common terminology criteria for adverse events (CTCAE) Version 4.0 
published: May 28, 2009 (v4.03: June 14, 2010). Website: 
evs.nci.nih.gov/ftp1/ctcae_4.03.2010-06-14_quickreference_8.5x11.pdf


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R13-4802
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a 
comparison of trial designs. Cancer Chemother Pharmacol 2013. 71:1107-1114.
R13-4803
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian 
approach to phase I cancer trials. Stat Med 2008. 27:2420-2439. 
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Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. 
Translation of innovative designs into phase I trials. J Clin Oncol 2007. 
25(31):4982-4986.
R13-4805
Tourneau C le, Gan HK, Razak ARA, Paoletti X. Efficiency of new dose 
escalation designs in dose-finding phase I trials of molecularly targeted agents. 
Plos One 2012. 7(12):e51039.
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Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose 
escalation with overdose control. Stat Med 1998. 17:1103-1120.
R14-3387 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister 
TA. Recommendations for initial evaluation, staging, and response assessment 
of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 32, (2014).
R15-1329 
Stathis A, et al. Results of a first-in-man phase I trial assessing OTX015, an 
orally available BET-bromodomain (BRD) inhibitor, in advanced hematologic 
malignancies. EORTC-NCI-AACR Annual Meeting, 2014. Abstract 5LBA.
R15-4233
Zhao W, Yang H, editors. Statistical methods in drug combination studies. 
(CRC Biostatistics Series) Boca Raton: CRC Press (2015) 
R16-1012
Abramson J, et al. BET Inhibitor CPI-0610 is well tolerated and induces 
responses in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma:
preliminary analysis of an ongoing Phase 1 study. Blood  2015; 126 (23):1491.
R16-1148
NCCN clinical practice guidelines in oncology (NCCN Guidelines): non-
Hodgkin's lymphomas (version 2.2016). 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (access date: 
14 March 2016) ; National Comprehensive Cancer Network (NCCN) 2016.
R16-5269
Nagueh SF, et al. Recommendations for the Evaluation of Left Ventricular 
Diastolic Function by Echocardiography: An Update from the American Society 
of Echocardiography and the European Association of Cardiovascular Imaging. 
J Am Soc Echocardiogr 2016; 29: 277-314.


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R17-3376
Barrington SF, et al. Concordance between four European centres of PET 
reporting criteria designed for use in multicentre trials in Hodgkin lymphoma. 
Eur J Nucl Med Mol Imaging (2010) 37:1824–1833
R17-3377
Scher HI, et al. Trial Design and Objectives for Castration-Resistant Prostate 
Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials 
Working Group 3. J Clin Oncol 34: 1402-1418, 2016.
R17-3378
Younes A, et al. International Working Group consensus response evaluation 
criteria in lymphoma (RECIL 2017). Annals of Oncology 28: 1436-1447, 2017.
R17-3435
Neuenschwander B, et al. Robust exchangeability designs for early phase 
clinical trials with multiple strata. Pharmaceut. Statis. 2015, 15 123-134
R18-1831
Forero-Torres A, et al. Preliminary results from an ongoing Phase1/2 study of 
INCB057643, a bromodomain and extraterminal protein inhibitor, in patients 
with advanced malignancies. ASH17 BET 57643 poster_KL20_FINAL.pdf
R18-2390
Dawson MA, Stein E, Huntley B, et al. A Phase I Study of GSK525762, a 
selective bromodomain (BRD) and extra-terminal protein (BET) inhibitor: 
results of part 1 of Phase I/II open-label single-agent study in patients with acute 
myeloid leukemia (AML). 59th Conference of the American Society of 
Hematology (ASH), Atlanta, 9 - 12 Dec 2017 (Poster) 2017.
R18-2451
Giridhar P, et al. Patterns of care and impact of prognostic factors in the 
outcome of NUT midline carcinoma: a systematic review and individual patient 
data analysis of 119 cases. European Archives of Oto-Rhino-Laryngology 
(2018) 275:815–821
R19-0148
Meille C, et al. PKPD modeling of preclinical anti-tumor activity translates to 
first-in-human phase I study of MDM2 inhibitor HDM201. Annual Meeting of 
the Population Approach Group in Europe, 2018, Abstract 8633
UNPUBLISHED REFERENCES
9.2
c03016865-02
 Investigator’s Brochure: BI 894999. Project 1367.P1, Version 2, 6 
April 2016.
n00240842-01
, Investigations on the in vitro 
metabolism of [14C]BI 894999 and assessment of the human cytochrome 
P450 enzymes that are involved.


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n00240650-01
, Prediction of BI 894999 Pharmacokinetics and
Therapeutic Dose in human.
n00241936 
 Effects of the BRD4 (BET) inhibitor BI 894999 on the 
proliferation of human lymphoma cell lines. 08 Apr 2015.
n00244406
 BI 894999: In vitro cytochrome P450 enzyme induction in 
primary human hepatocytes.


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10.
APPENDICES
PHARMACOKINETIC ANALYSES
10.1
Concentrations will be used for calculations in the format that is reported in the bio-analytical 
report. The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. For the calculation of pharmacokinetic parameters, 
only concentrations within the validated concentration range will be used. The actual sampling 
times will be used. For pre-dose samples, the actual sampling time will be set to zero. Non-
compartmental pharmacokinetic parameters will be determined using WinNonlin or another 
validated program.
Analyte plasma concentrations will be plotted graphically versus time for all subjects as listed 
in the analyte plasma concentration-time tables.  For the presentation of the mean profiles, the 
arithmetic/geometric mean and the planned blood sampling times will be used. 
In the following, the derivation of parameters that are determined after the first dose as single 
dose parameters and after the last dose of cycle 1as steady state parameters are described 
together, whereby (ss) denotes the steady state parameters. The derivation of parameters is no t 
affected by the attainment of steady state.
Cmax
Individual Cmax
values will be directly determined from the plasma 
concentration time profiles of each subject. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUC: The area under the curve will be calculated using the linear up/log down algorithm. If an 
analyte concentration is equal to or higher than the preceding concentration, the linear 
trapezoidal method will be used. If the analyte concentration is smaller than the preceding 
concentration, the logarithmic method will be used.
Linear trapezoidal rule (t2 > t1 and Ct2 Ct1):
The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed by:



t2
t1
1
2
t2
-
t1
C
C
t
t
0.5
AUC





Logarithmic trapezoid rule (t2 > t1 and Ct2 < Ct1):


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The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed by:





t1
t2
t1
t2
1
2
t2
t1
/C
C
ln
C
C
t
t
AUC







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gMean, gCV: The geometric mean (gMean) and coefficient of variation, gCV (given in %), 
will be calculated by the formulae:

)
ln(x
exp
)
ln(x
exp
gMean
i
n
1
i
i
n
1









1
))
Var(ln(x
exp
100
gCV(%)
i



where


2
n
1
i
i
i
i
)
ln(x
)
ln(x
1
n
1
))
Var(ln(x







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TIME SCHEDULE FOR PHARMACOKINETIC (PK) AND BIOMARKER
10.2
BLOOD SAMPLING
Blood and urine sampling schedule
10.2.1
Table 10.2.1: 1
Time schedule for PK blood and urine samplings and HEXIM1 
biomarker blood sampling during treatment Cycle 1 in Schedule A 
(except for food interaction cohorts)
Blood
Urine
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for 
PK
Whole Blood 
for 
HEXIM1gen
e expression
Urine for PK
1
1
1
Just before drug 
administration
-0:05
x
x
x
BI 
894999 
administration
0:00
0:30
0:30
x
1:00
1:00
x
2:00
2:00
x
x
3:00
3:00
x
4:00
4:00
x
x
6:00
6:00
x
8:00
8:00
x
x
2
Just before drug 
administration
23:55
x
x
BI 
894999 
administration
24:00
2
8 
Just before drug 
administration
167:55
x
BI 
894999 
administration
168:00
3
12 
Just before drug 
administration
263:55
x
BI 
894999 
administration
264:00
4
14
Just before drug 
administration
311:55
x
x
x
BI 
894999 
administration
312:00
0:30
312:30
x
1:00
313:00
x
2:00
314:00
x
x
3:00
315:00
x
4:00
316:00
x
x
6:00
318:00
x
8:00
320:00
x
x


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Table 10.2.1: 1
Time schedule for PK blood and urine samplings and HEXIM1 
biomarker blood sampling during treatment Cycle 1 in Schedule A 
(except for food interaction cohorts) (continued)
Blood
Urine
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for 
PK
Whole Blood 
for HEXIM1 
gene 
expression
Urine for PK
1
4
15
Just before drug 
administration
335:55
x
x
BI 
894999 
administration
336:00
Table 10.2.1: 2
Time schedule for PK blood and urine samplings and HEXIM1
biomarker blood sampling during treatment Cycles 1-2 in Schedule B 
(except for food interaction cohorts)
Blood
Urine
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for 
PK
Whole Blood 
for HEXIM1 
gene 
expression
Urine for PK
1
1
1
Just before drug 
administration
-0:05
x
x
x
BI 
894999 
administration
0:00
0:30
0:30
x
1:00
1:00
x
2:00
2:00
x
x
3:00
3:00
x
4:00
4:00
x
x
6:00
6:00
x
8:00
8:00
x
x
2
Just before drug 
administration
23:55
x
x
BI 
894999 
administration
24:00
2
8 
Just before drug 
administration
167:55
x
BI 
894999 
administration
168:00
3
12 
Just before drug 
administration
263:55
x


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Table 10.2.1: 2
Time schedule for PK blood and urine samplings and HEXIM1 
biomarker blood sampling during treatment Cycles 1-2 in Schedule B 
(except for food interaction cohorts) (continued)
Blood
Urine
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for 
PK
Whole Blood 
for HEXIM1 
gene 
expression
Urine for PK
1
3
12
BI 
894999 
administration
264:00
4
14
Just before drug 
administration
311:55
x
x
x
BI 
894999 
administration
312:00
0:30
312:30
x
1:00
313:00
x
2:00
314:00
x
x
3:00
315:00
x
4:00
316:00
x
x
6:00
318:00
x
8:00
320:00
x
x
15
24:00
336:00
x
x
26:00
338:00
x
28:00
340:00
x
32:00
344:00
x
18
At time of visit
408:00
x
x
2
1
1
Just before drug 
administration
-0:05
x
x
BI 
894999 
administration
0:00
2:00
2:00
x
x
4:00
4:00
x
x
8:00
8:00
x
x
2
Just before drug 
administration
23:55
x
x
BI 
894999 
administration
24:00


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Table 10.2.1: 3
Time schedule for PK blood and urine samplings and HEXIM1 
biomarker blood sampling during treatment Cycle 1 in Schedule C for 
patients with solid tumours in Phase Ia
Blood
Urine
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for 
PK
Whole Blood 
for HEXIM1 
gene 
expression
Urine for PK*
1
1
1
Just before drug 
administration
-0:05
x
x
x
BI 
894999 
administration
0:00
0:30
0:30
x
1:00
1:00
x
2:00
2:00
x
x
3:00
3:00
x
4:00
4:00
x
x
6:00
6:00
x
8:00
8:00
x
x
2
Just before drug 
administration
23:55
x
x
BI 
894999 
administration
24:00
2
8 
At time of visit
168:00
x
4
21
Just before drug 
administration
479:55
x
x
x
BI 
894999 
administration
480:00
0:30
480:30
x
1:00
481:00
x
2:00
482:00
x
x
3:00
483:00
x
4:00
484:00
x
x
6:00
486:00
x
8:00
488:00
x
x
22
24:00
504:00
x
x
26:00
506:00
x
28:00
508:00
x
32:00
512:00
x
x
5
29
At time of visit
672:00
x
*starting from protocol version 12.0, no urine collection anymore for PK


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Table 10.2.1: 4
Time schedule for PK blood samplings and HEXIM1 biomarker blood 
sampling during treatment Cycle 1 in Schedule C for DLBCL and NC 
patients starting from protocol version 12.0
Blood
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for PK
Whole Blood for 
HEXIM1 
gene 
expression
1
1
1
Just before drug 
administration
-0:05
x
x
BI 
894999 
administration
0:00
2:00
2:00
x
3:00
3:00
x
4:00
4:00
x
x
4
21
Just before drug 
administration
479:55
x
x
BI 
894999 
administration
480:00
0:30
480:30
x
1:00
481:00
x
2:00
482:00
x
3:00
483:00
x
4:00
484:00
x
x
6:00
486:00
x
8:00
488:00
x
22
24:00
504:00
x
x
5
29
At time of visit
672:00
x
Details of procedures for food interaction cohorts
10.2.2


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Table 10.2.2: 1
Time schedule for PK blood and urine samplings and HEXIM1 
biomarker blood sampling during treatment Cycle 1 in Schedule A (for 
food interaction cohorts)
Blood
Urine 
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for 
PK
Whole 
Blood 
for 
HEXIM1gene 
expression
Urine for PK
1
1
1
-0:30: Breakfast1 -0:30
Just before drug 
administration
-0:05
x
x
x
BI 
894999 
administration
0:00
0:30
0:30
x
1:00
1:00
x
2:00
2:00
x
x
2:05: Snack2
2:05
3:00
3:00
x
4:00
4:00
x
x
6:00
6:00
x
8:00
8:00
x
x
2
23:30: Breakfast2 23:30
Just before drug 
administration
23:55
x
x
BI 
894999 
administration
24:00
0:30
24:30
x
1:00
25:00
x
2:00
26:00
x
2:05: Snack2
26:05
3:00
27:00
x
4:00
28:00
x
4:05: Snack2
28:05
6:00
30:00
x
8:00
32:00
x
3 
Just before drug 
administration
47:55
x
BI 
894999 
administration
48:00
2
8 
Just before drug 
administration
167:55
x
BI 
894999 
administration
168:00
3
12 
Just before drug 
administration
263:55
x
BI 
894999 
administration
264:00


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Table 10.2.2: 1
Time schedule for PK blood and urine samplings and HEXIM1 
biomarker blood sampling during treatment Cycle 1 in Schedule A (for 
food interaction cohorts) (continued)
Blood
Urine
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for 
PK
Whole 
Blood 
for 
HEXIM1gene 
expression
Urine for PK
1
4
14
Just before drug 
administration
311:55
x
x
x
BI 
894999 
administration
312:00
0:30
312:30
x
1:00
313:00
x
2:00
314:00
x
x
3:00
315:00
x
4:00
316:00
x
x
6:00
318:00
x
8:00
320:00
x
x
15
Just before drug 
administration
335:55
x
x
BI 
894999 
administration
336:00
1 Only for patients who are under fasted conditions on Day 2 of Visit 1
2 Only for patients who are under fasted conditions on Day 1 of Visit 1, snack or meal after at least 2 hours fasted after intake 
of study medication
Table 10.2.2: 2
Time schedule for PK blood and urine samplings and HEXIM1 
biomarker blood sampling during treatment Cycles 1-2 in Schedule B 
(for food interaction cohorts)
Blood
Urine 
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for 
PK
Whole 
Blood 
for 
HEXIM1 
gene 
expression
Urine for PK
1
1
1
-0:30: Breakfast1 -0:30
Just before drug 
administration
-0:05
x
x
x
BI 
894999 
administration
0:00
0:30
0:30
x
1:00
1:00
x
2:00
2:00
x
x
2:05: Snack2
2:05
3:00
3:00
x


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Table 10.2.2: 2
Time schedule for PK blood and urine samplings and HEXIM1 
biomarker blood sampling during treatment Cycles 1-2 in Schedule B 
(for food interaction cohorts) (continued)
Blood
Urine 
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for 
PK
Whole Blood for 
HEXIM1 
gene 
expression
Urine for PK
1
1
1
4:00
4:00
x
x
6:00
6:00
x
8:00
8:00
x
x
2
23:30: Breakfast2 23:30
Just before drug 
administration
23:55
x
x
BI 
894999 
administration
24:00
0:30
24:30
x
1:00
25:00
x
2:00
26:00
x
2:05: Snack2
26:05
3:00
27:00
x
4:00
28:00
x
6:00
30:00
x
8:00
32:00
x
3 
Just before drug 
administration
47:55
x
BI 
894999 
administration
48:00
2
8 
Just before drug 
administration
167:55
x
BI 
894999 
administration
168:00
3
12 
Just before drug 
administration
263:55
x
BI 
894999 
administration
264:00
4
14
Just before drug 
administration
311:55
x
x
x
BI 
894999 
administration
312:00
0:30
312:30
x
1:00
313:00
x
2:00
314:00
x
x
3:00
315:00
x
4:00
316:00
x
x
6:00
318:00
x
8:00
320:00
x
x
15
24:00
336:00
x
x


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Table 10.2.2: 2
Time schedule for PK blood and urine samplings and gene expression 
biomarker blood sampling during treatment Cycles 1-2 in Schedule B 
(for food interaction cohorts) (continued)
Blood
Urine 
Cycle
Visit Day
Time 
Point 
[hh:min]/event
CRF Time
planned
Plasma for 
PK
Whole Blood for 
HEXIM1 
gene 
expression
Urine for PK
1
4
15
26:00
338:00
x
28:00
340:00
x
32:00
344:00
x
18
At time of visit
408:00
x
x
2
1
1
Just before drug 
administration
-0:05
x
x
BI 
894999 
administration
0:00
2:00
2:00
x
x
4:00
4:00
x
x
8:00
8:00
x
x
2
Just before drug 
administration
23:55
x
x
BI 
894999 
administration
24:00
1 Only for patients who are under fasted conditions on Day 2 of Visit 1
2 Only for patients who are under fasted conditions on Day 1 of Visit 1. Snack or meal after at least 2 hours fasted after intake 
of study medication


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STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE AND 
10.3
DATA SCENARIOS
Model Performance and Data Scenarios for Schedules A and B
10.3.1
The model was assessed by two different metrics: hypothetical on-study data scenarios and 
long-run operating characteristics. The simulations for scenarios and operating characteristics 
were produced using R version 3.0.3.
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.3.1:1. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model. For each scenario, the 
probability of overdose for the current dose, the next optimal dose recommended by the model 
in terms of the probability of target dose, and the next maximal dose allowed by the model due 
to the bound of the overdose probability are shown. Furthermore the related probabilities of 
under-dosing, target dose, and overdosing for the next optimal dose are presented. The actual 
dose chosen for the next cohort, not shown in Table 10.3.1: 1, will be determined by the DMC 
after taking into consideration of the recommended dose from the model as well as other 
relevant data from this study.
For example, scenario 1 represents the case that no DLT is observed in the first patient at the 
starting dose of 0.2 mg. In this case, the next optimal dose, i.e. the dose with the highest 
probability of being in the target interval, is 40 mg. However since this dose has an overdose 
probability higher than 0.25, the next dose maximally allowed by the model is 20 mg. Similarly 
scenarios 2, 3, 5, 8, 9, 11, 12, 13 and 16 represent cases where no DLTs are observed. In 
scenario 4, one DLT is observed already in the patient at the second lowest dose level. There, 
the model recommends stopping the trial, because all pre-specified dose levels have high 
overdose probabilities. The same holds for scenario 7.
Finally, scenarios 14, 15, 17, and 19 illustrate cases where no DLTs are observed in the first 
patient cohorts and then DLTs occur in the higher dose levels. In scenarios 14 and 15, the 
model requires to re-enrol at 40 mg and at 80 mg, respectively. In both scenarios 17 and 19, 2 
DLTs occur which lead to a direct reaction of the model despite the fact that no DLTs were 
seen in the previous cohorts. It therefore recommends de-escalating to lower dose levels. These 
cases illustrate the adaptive behaviour of the model even in extreme situations.
Table 10.3.1: 1
Hypothetical data scenarios
Scenario
Dose 
(mg)
# 
DLT
# 
Pat
Current 
Dose: 
P(OD)
Next 
optimal 
dose
Maximum 
dose 
allowed
Next optimal dose
P(UD)
P(TD)
P(OD)
1
0.2
0
0.047
40
20
0.446
0.182
0.372**
2
0.2
0.5
0*
0
0.035
80
20
0.324
0.190
0.486**


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Table 10.3.1: 1
Hypothetical data scenarios (continued)
Scenario
Dose
(mg)
# 
DLT
# 
Pat
Current 
Dose: 
P(OD)
Next 
optimal 
dose
Maximum 
dose 
allowed
Next optimal dose
P(UD)
P(TD)
P(OD)
3
0.2
1.0
0
0
0.034
80
20
0.333
0.196
0.470**
4
0.2
0.5
0*
1
0.487
0.2
NA
0.352
0.249
0.399**
5
0.2
1.0
0
0
0.015
80
20
0.362
0.201
0.436**
6
0.2
1.0
0
1
0.248
2.5
1.0
0.315
0.313
0.372**
7
0.2
1.0
0
2
0.645
0.2
NA
0.265
0.325
0.410**
8
0.2
1.0
2.5
0
0
0
0.007
80
40
0.406
0.204
0.389**
9
0.2
1.0
5.0
0
0
0
0.056
80
20
0.368
0.200
0.432**
10
0.2
1.0
5.0
0
0
1
0.241
10
5.0
0.304
0.320
0.375**
11
0.2
1.0
2.5
5.0
0
0
0
0
0.004
80
40
0.446
0.195
0.360**
12
0.2
1.0
5.0
10
0
0
0
0
0.018
80
40
0.446
0.213
0.340**


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Table 10.3.1: 1
Hypothetical data scenarios (continued)
Scenario
Dose 
(mg)
# 
DLT
# 
Pat
Current 
Dose: 
P(OD)
Next 
optimal 
dose
Maximum 
dose 
allowed
Next optimal dose
P(UD)
P(TD)
P(OD)
13
0.2
1.0
5.0
10
20
0
0
0
0
0
0.012
80
40
0.529
0.206
0.265**
14
0.2
1.0
5.0
10
20
40
0
0
0
0
0
1
0.148
40
40
0.516
0.336
0.148
15
0.2
1.0
5.0
10
20
40
80
0
0
0
0
0
0
1
0.244
80
80
0.409
0.347
0.244
16
0.2
1.0
5.0
10
20
40
80
0
0
0
0
0
0
0
0.032
120
120
0.685
0.187
0.128
17
0.2
1.0
5.0
10
20
40
80
0
0
0
0
0
1
1
0.448
40
40
0.493
0.412
0.095


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Table 10.3.1: 1
Hypothetical data scenarios (continued)
Scenario
Dose 
(mg)
# 
DLT
# 
Pat
Current 
Dose: 
P(OD)
Next 
optimal 
dose
Maximum 
dose 
allowed
Next optimal dose
P(UD)
P(TD)
P(OD)
18
0.2
1.0
5.0
10
20
40
80
0
0
0
0
0
1
0
0.149
80
80
0.506
0.345
0.149
19
0.2
1.0
5.0
10
20
40
80
120
0
0
0
0
0
0
0
2
0.582
80
80
0.399
0.428
0.173
*non-DLT drug-related AE of CTCAE grade >=2
**Overdose-probability of the next optimal dose is too high (violates EWOC criterion), 
therefore the maximal allowed dose would be chosen as next dose by the model.
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model. Under an 
assumed true dose-toxicity curve, metrics such as the probability of recommending a dose with 
true DLT rate in the target interval can be approximated via simulation. Table 10.3.1: 2
describes 5 assumed true dose-toxicity scenarios which were used to assess the operating 
characteristics of the model. These scenarios reflect a wide range of possible cases. Scenario 1 
represents the DLT rates that are aligned with prior means per dose level. Scenarios 2 and 3 
reflect the extreme cases of very high and very low toxicity probabilities, respectively. 
Scenario 4 covers the case of a true dose-toxicity relationship that does not have a logistic 
form. Finally, scenario 5 reflects the possibility of having very low DLT rates at the lower dose 
levels and high DLT rates at the upper dose levels.


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Table 10.3.1: 2 Assumed true dose-toxicity scenarios
Scena
-rio
Dose (mg)
0.2
0.5
1.0
2.5
5.0
10
20
40
80
120
1: 
Prior
0.102
0.119
0.136
0.164
0.191
0.226
0.273
0.339
0.435
0.499
2: 
High 
Tox
0.100
0.199
0.305
0.314
0.387
0.456
0.498
0.527
0.600
0.723
3: Low 
Tox
0.001
0.005
0.009
0.013
0.028
0.041
0.050
0.057
0.060
0.160
4: 
Non-
Logis-
tic
0.020
0.050
0.065
0.080
0.130
0.210
0.280
0.320
0.380
0.410
5: 
Low-
High
0.001
0.005
0.009
0.013
0.314
0.387
0.456
0.498
0.527
0.600
Bold numbers indicate true DLT rates in the target interval [0.16, 0.33].
For each of these scenarios, 1000 trials were simulated. It was then assessed how often a dose 
was declared as MTD with true DLT rate in the under-, targeted or over-dose range. 
Furthermore, the average, minimum and maximum number of patients per trial and the average 
number of DLTs per trial are reported. Results are shown in Table 10.3.1: 3.
Table 10.3.1: 3 Simulated operating characteristics 
Scenario
% of trials declaring an MTD with true DLT rate in
# Patients
# DLT
underdose
target dose
overdose
STOPPED
Mean
(Min-Max)
Mean
(Min- Max)
1
8.5
54.5
4.6
32.4
17.25 (3-48)
2.99 (1-9)
2
2.6
47.9
11.3
38.2
13.96 (3-42)
3.40 (1-11)
3
38.2
61.4
0
0.4
33.59 (3-60)
1.68 (0-7)
4
23.1
67.4
3.1
6.4
24.70 (3-51)
3.49 (1-10)
5
10.5
52.7
25.3
11.5
20.14 (3-39)
4.92 (2-13)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
54.5% of the simulated trials declared a dose as MTD with true DLT rate in the targeted dose 
range. However, the starting dose 0.2 mg already has a DLT rate of 0.102. This contributes to 
the high percentage (32.4%) of all simulated trials for which the trial is stopped since none of 


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the doses is considered tolerable anymore. This is similar for scenario 2, where the DLT rate at 
the starting dose is 0.1, which leads to a high percentage of prematurely stopped trials (38.2%). 
But for a high-toxicity scenario, this is an expected situation.
Scenario 3 (low-toxicity scenario) shows, that even with small toxicity rates the model declares 
MTDs with true DLT rate in the targeted interval in a high percentage of trials (61.4%). 
Nevertheless, more patients are needed in this scenario. Since none of the pre-defined dose 
levels has a true DLT rate in the overdose range, only very few trials are stopped prematurely.
In both scenarios 4 and 5, more than 50% of the simulated trials declared a dose as MTD with 
true DLT rate in the targeted dose range.
The mean patient numbers range from 17.25 (scenario 1) to 33.59 (low-toxicity scenario) and 
the maximum number of patients in one trial was 60. Therefore the patient numbers are as 
expected and decrease when moving away from the low-toxicity scenario.
In summary, the considered data scenarios show a reasonable behaviour of the model and the 
operating characteristics demonstrate a good precision of MTD determination.
Since dose escalation for Schedule B is conducted after the dose escalation for Schedule A, the 
initial mixture prior used for Schedule A dose escalation will be updated using the observed 
safety data on Schedule A to derive a meta-analytic predictive (MAP) prior for the BLRM of 
Schedule B. Two MAP priors are derived with one using the observed DLT in each dose of 
Schedule A and the other one using the observed DLT and with the doses in Schedule A being 
increased by 1.5 times to derive a corresponding dose in Schedule B which gives the same total 
dose in each 21-day treatment cycle. These 2 MAP priors are used with equal weight in the 
updated mixture prior of the BLRM for Schedule B dose escalation in the assessment of new 
hypothetical data scenarios. The details of these simulation analyses will be provided in the 
minutes of the regular DMC meetings.
Observed data in both schedule dose escalations will be used to update the prior used in the 
BLRM for patients with DLBCL with the selected schedule.
Statistical Appendix for Schedule C
10.3.2
To determine the MTD for Schedule C in solid tumour, patients are entered sequentially into 
escalating dose cohorts. The dose escalation will be guided by a Bayesian 5-parameter logistic 
regression model with overdose control (R15-4233).
This logistic regression model is defined as follows. Let π1, d1 be the probability of having a 
DLT when giving dose d1 of BI 894999 maintenance dose as monotherapy, and π2, d2 the 
probability of having a DLT when giving dose d2 of the combination partner BI 894999 loading 
dose as monotherapy, respectively. A logistic regression is used to model the dose-toxicity 
relationship for each of these dosing approachs individually:
Maintenance dose:
logit(π1,d1) =log(α1) + β1log(d1/d1*)
Loading dose: logit(π2,d2) =log(α2) + β2log(d2/d2*)


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Here, the doses d1* = 4 mg and d2* = 5 mg represent the reference doses for maintenance dose 
and loading dose, respectively. 
In order to account for a potential positive (higher toxicity than expected under independence) 
interaction between maintenance dose and loading dose, a dose-dependent interaction term 
0<η<∞ is introduced in the model by the following definition: odds(π12,d1,d2) = odds(π0
12,d1,d2) 
exp(η d1/d1* d2/d2*)
and π12,d1,d2 is used in the likelihood
rd1,d2 ~ Binomial(nd1,d2,π12,d1,d2)
where rd1,d2 denotes the random variable describing the observed number of DLTs in nd1,d2
patients at the dose combination d1, d2.
Since a Bayesian approach is applied, prior distributions f for each of the parameter vectors 
θ1=(log(α1),log(β1)), θ2=(log(α2),log(β2)) and for the interaction term η need to be specified.
An informative prior is used for maintenance dose using historical information from schedule 
A and B with two transformation methods.
The prior distribution for θ1 will be specified as a mixture of two bivariate normal distributions, 
f(θ1) = a1f1(θ1) + a2f2(θ1)
with
ai, i = 1, 2 the prior mixture weights (a1+ a2 = 1)
and
fi(θ1) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where 
Σ = 
	
,
 , ,		
 , ,		
	
,		

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
A minimally informative prior is used for loading dose:
The prior distributions for θ2 will be specified as mixtures of three multivariate normal 
distributions, i.e.
а(θ2) = a1f1(θ2) + a2f2(θ2) + a3f3(θ2)
with
ai, i = 1, 2, 3 the prior mixture weights (a1+ a2+ a3 = 1)
and
fi(θ2) = MVN(μi, Σi),
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where 
Σ = 
	
,
 , ,		
 , ,		
	
,		

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.


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A weakly informative lognormal prior distribution will be used for η.
The estimated probability π12,d1,d2 of a DLT at each dose combination d1, d2 from the model 
will be summarized using the following intervals:
Under toxicity: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Overtoxicity: [0.33, 1.00]
The BLRM-recommended dose combination for the next cohort is the level with the highest 
posterior probability of the DLT rate falling in the target interval [0.16, 0.33) among the dose 
combinations fulfilling the EWOC principle. Per EWOC it should be unlikely (<25% posterior 
probability) that the DLT rate at the dose combination will exceed 0.33. However, the 
maximum allowable dose increment for the subsequent cohort will be no more than 100% for 
each drug.
The MTD may be considered reached if one of the following criteria is fulfilled:
1.
The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of the 
MTD is above 0.50, OR
2. At least 12 patients have been treated in the trial, of which at least 6 at the MTD.
Prior derivation:
To determine the maintenance dose prior distribution for θ1 and θ2, a meta-analytic predictive 
(MAP) approach will be used. Exact details on the derivation of the prior distributions and on 
the evaluation of the model using hypothetical data scenarios and operating characteristics are 
provided in the statistical appendix, a brief description is given here. 
The following steps were used to derive the prior distributions for all parameters:
1.
Maintenance dose θ1: 
Toxicity information on schedule C from schedule A and B in Phase Ia will be 
incorporated in Table 10.3.2: 1 with two transformation methods separately, which are 
equal total dose transformation and equal daily dose transformation during MTD 
evaluation period. The meta-analytic-predictive prior was derived using the historical 
toxicity information, allowing for substantial between-trial heterogeneity.
2.
Loading dose θ2: 
(1)
A low-toxicity weakly informative prior was derived reflecting the case that the 
compound would be much less toxic than expected. For this prior component, it 
was assumed that the median DLT rate at the starting dose of 2.5 mg would 
equal 0.001, and the median DLT rate at the anticipated MTD of 5 mg would 
equal 0.01. These assumptions yield μ31 = (-4.60, 1.20), i.e. basically a flat 
curve. The standard deviations and correlations were set to σ31,11 = 2, σ31,22 = 1, 
therefore almost fixing the slope parameter to its mean. The correlation was set 
to 0, i.e. ρ31 = 0. The prior weight a3,1 for the third component was chosen as 
0.8.


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(2)
A high-toxicity weakly informative prior was derived reflecting the case that the 
compound would be much more toxic than expected. For this prior component, 
it was assumed that the median DLT rate at the starting dose of 2.5 mg would 
equal 0.1, and the median DLT rate at the anticipated MTD of 5 mg would equal 
0.2. These assumptions yield μ12 = (-1.39, 0.16). The standard deviations and 
correlations were set identical to the weakly informative prior, i.e. σ21,11 = 2, 
σ21,22 = 1 and ρ21 = 0, respectively. The prior weight a2,1 for the second 
component was chosen as 0.1.
(3)
A weakly informative prior was derived reflecting the a priori assumption that 
the median DLT rate at the starting dose of 2.5 mg would equal 0.01, and the 
median DLT rate at the anticipated MTD of 5 mg would equal 0.1. This yields 
μ11 = (-2.20, 1.24). The standard deviations were set such that large uncertainty 
about the parameter means is reflected, and the correlation was set to 0, thus 
yielding σ11,11 = 2, σ11,22 = 1 and ρ11 = 0, respectively. The prior weight a1,1 for 
the first component was chosen as 0.1.
3.
Interaction term η: 
Based on the a priori assumption of positive interaction between the two compounds, a 
lognormal distribution with mean -2.30 and standard deviation 1 was chosen. At the 
starting dose combination, the corresponding 95% prior interval covers an up to 4 fold 
increase (or decrease) in the odds of a DLT over positive interaction.
Table 10.3.2: 1 Historical data for BI 894999 of Schedule A and Schedule B
Schedule
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of patients
Schedule A
0.2 mg
0/2
0.5 mg
0/2
1 mg
0/3
1.5 mg
0/6
  2 mg
3/6
5 mg
2/2
Schedule B
1.5 mg
1/5
2 mg
0/6
2.5 mg
2/13
A summary of the prior distributions is provided in Table 10.3.2: 2 and Table 10.3.2: 3. 
Additionally, the prior probabilities of DLTs at different dose combinations, as well as the 
corresponding probability of under-, targeted and overtoxicity, are shown in Table 10.3.2: 4. 
As can be seen from the tables, the prior medians of the DLT probabilities are in-line with the 


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prior medians derived from the weakly informative priors, and the uncertainty around the 
medians is large, showing the low amount of information these priors provide. This is also 
supported by the prior sample size, i.e. the information contained in the priors. This is 
approximately equal to 7.1 patients for the prior of the combination of loading dose and 
maintenance dose.
Table 10.3.2: 2 Prior distributions for loading dose
Prior Component
Mixture Weight
Mean Vector
SD Vector
Loading dose
1: Weakly inf.
0.100
(-2.197, 
1.241)
(2.000, 
1.000)
2: High Tox.
0.100
(-1.386, 
0.157)
(2.000, 
1.000)
3: Low Tox.
0.800
(-4.595, 
1.204)
(2.000, 
1.000)
Table 10.3.2: 3 Prior distributions for maintenance dose
Parameter
means, standard deviations, correlation
mixture weight
log(α2), log(β2): component 1
(-0.831, 1.045), (0.625, 0.611), 0.417
0.5
log(α2), log(β2): component 2
(-0.066, 0.957), (0.846, 0.589), 0.680
0.5
η
-2.30, 1, N/A
N/A
Table 10.3.2: 4 Prior probabilities of DLTs at selected doses
Mainten
ance
dose
Loadin
g dose
Probability of true DLT rate in 
Quantiles
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
2
1.5
0.75
0.204
0.046
0.12
0.113
0.004
0.092
0.409
2
2
0.733
0.214
0.053
0.126
0.12
0.004
0.095
0.444
2
2.5
0.717
0.222
0.061
0.132
0.126
0.005
0.099
0.476
2
3
0.7
0.229
0.071
0.139
0.133
0.006
0.103
0.515
2
3.5
0.679
0.239
0.083
0.146
0.141
0.007
0.108
0.56
2
4
0.654
0.249
0.098
0.156
0.149
0.008
0.114
0.607


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Table 10.3.2: 4 Prior probabilities of DLTs at selected doses: continued
Mainten
ance
dose
Loadin
g dose
Probability of true DLT rate in 
Quantiles
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
2
4.5
0.622
0.262
0.116
0.169
0.16
0.009
0.123
0.66
2
5
0.58
0.276
0.144
0.187
0.174
0.011
0.135
0.726
2
5.5
0.521
0.286
0.193
0.216
0.2
0.013
0.153
0.82
2
6
0.47
0.283
0.248
0.252
0.233
0.016
0.171
0.917
2.5
1.5
0.535
0.357
0.108
0.178
0.128
0.017
0.15
0.496
2.5
2
0.521
0.36
0.12
0.183
0.133
0.019
0.154
0.517
2.5
2.5
0.505
0.365
0.13
0.19
0.138
0.02
0.159
0.541
2.5
3
0.488
0.369
0.143
0.197
0.144
0.022
0.164
0.577
2.5
3.5
0.468
0.374
0.158
0.205
0.15
0.023
0.17
0.611
2.5
4
0.444
0.38
0.175
0.215
0.157
0.025
0.178
0.648
2.5
4.5
0.416
0.385
0.199
0.227
0.166
0.027
0.186
0.694
2.5
5
0.377
0.39
0.233
0.245
0.177
0.031
0.2
0.753
2.5
5.5
0.336
0.378
0.286
0.273
0.199
0.034
0.219
0.838
2.5
6
0.299
0.363
0.338
0.307
0.228
0.037
0.24
0.926
3
1.5
0.302
0.447
0.252
0.252
0.144
0.053
0.224
0.597
3
2
0.288
0.448
0.264
0.258
0.148
0.054
0.229
0.614
3
2.5
0.276
0.446
0.279
0.264
0.152
0.056
0.235
0.634
3
3
0.262
0.443
0.295
0.271
0.156
0.058
0.242
0.652
3
3.5
0.248
0.439
0.314
0.28
0.161
0.06
0.248
0.679
3
4
0.231
0.434
0.335
0.289
0.166
0.063
0.257
0.708
3
4.5
0.211
0.427
0.362
0.302
0.173
0.067
0.268
0.741
3
5
0.188
0.416
0.396
0.318
0.182
0.071
0.281
0.786
3
5.5
0.165
0.39
0.445
0.345
0.198
0.076
0.302
0.86
3
6
0.145
0.363
0.492
0.376
0.221
0.08
0.326
0.937
3.5
1.5
0.121
0.424
0.455
0.338
0.163
0.102
0.311
0.708
3.5
2
0.113
0.417
0.47
0.344
0.166
0.104
0.317
0.719
3.5
2.5
0.105
0.41
0.485
0.351
0.168
0.106
0.323
0.733
3.5
3
0.098
0.401
0.5
0.359
0.171
0.108
0.33
0.748
3.5
3.5
0.092
0.391
0.518
0.367
0.174
0.111
0.338
0.763
3.5
4
0.084
0.378
0.537
0.376
0.178
0.114
0.348
0.783


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Table 10.3.2: 4 Prior probabilities of DLTs at selected doses: continued
Mainten
ance
dose
Loadin
g dose
Probability of true DLT rate in 
Quantiles
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
3.5
4.5
0.075
0.364
0.561
0.388
0.182
0.118
0.36
0.806
3.5
5
0.065
0.343
0.591
0.404
0.188
0.123
0.376
0.836
3.5
5.5
0.055
0.315
0.63
0.428
0.199
0.128
0.398
0.885
3.5
6
0.048
0.285
0.668
0.456
0.215
0.133
0.423
0.947
4
1.5
0.045
0.306
0.649
0.427
0.184
0.138
0.404
0.82
4
2
0.041
0.297
0.662
0.434
0.185
0.14
0.412
0.827
4
2.5
0.038
0.288
0.674
0.44
0.187
0.143
0.419
0.835
4
3
0.035
0.277
0.688
0.448
0.188
0.146
0.427
0.844
4
3.5
0.032
0.265
0.703
0.456
0.19
0.149
0.436
0.851
4
4
0.03
0.252
0.718
0.465
0.192
0.153
0.446
0.862
4
4.5
0.027
0.237
0.736
0.476
0.194
0.157
0.458
0.874
4
5
0.023
0.22
0.757
0.49
0.197
0.165
0.473
0.889
4
5.5
0.018
0.197
0.784
0.511
0.203
0.172
0.496
0.92
4
6
0.016
0.178
0.806
0.536
0.213
0.18
0.521
0.96
Statistical model assessment
The model was assessed using hypothetical data scenarios and simulated operating 
characteristics. Hypothetical data scenarios are shown in Table 10.3.2: 5 reflecting potential 
on-study data constellations and related escalation as allowed by the model. Operating 
characteristics are assessed an assumed under assumed true dose-toxicity scenarios (Table 
10.3.2: 6), and the probability of recommending a dose with true DLT rate in the target interval 
can be approximated via simulation (Table 10.3.2: 7). More details are the same with model 
assessment for Schedule A and Schedule B which can be found in Section 10.3.1.
Table 10.3.2: 5
Hypothetical data scenarios
Sce
nari
o
Dose 
combina
tion 
(loading/
maintena
nce: mg)
# Patients / # 
DLT
Current 
Dose 
combinatio
n: P(OD)
Next 
recommen
ded dose 
combinati
on
Next optimal dose
P(UD)
P(TD)
P(OD)
1
5.0 / 2.5
 / 0
0.057
6.0 / 3.0
0.342      0.466
0.192


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Table 10.3.2: 5
Hypothetical data scenarios: continued
Sce
nari
o
Dose 
combina
tion 
(loading/
maintena
nce: mg)
# Patients / # 
DLT
Current 
Dose 
combinatio
n: P(OD)
Next 
recommen
ded dose 
combinati
on
Next optimal dose
P(UD)
P(TD)
P(OD)
2
5.0 / 2.5
6.0 / 3.0
 0
 1
0.223
6.0 / 3.0
0.244     0.534  
0.223
3
5.0 / 2.5
6.0 / 3.0
6.0 / 3.0
 0
 1
 1
0.249
6.0 / 3.0
0.178
0.573
0.249
4
5.0 / 2.5
6.0 / 3.0
 0
 2
0.453
5.0 / 2.5
0.313     0.522
0.164
5
5.0 / 2.5
 1
0.159
5.0 / 2.5
0.357     0.484  
0.159
6
5.0 / 2.5
5.0 / 2.5
 1
 0
0.067
6 / 3
0.211     0.542  
0.247
7
5.0 / 2.5
5.0 / 2.5
6.0 / 3.0
 1
 0
 1
0.256
5.0 / 2.5
0.450     0.487
0.063
8
5.0 / 2.5
5.0 / 2.5
 1
 1
0.178
5.0 / 2.5
0.263     0.559
0.178
Table 10.3.2: 6 Assumed true dose-toxicity scenarios
Scena-
rio
Loading dose (mg)/Maintenance dose (mg)
4.0/2.0
5.0/2.0
6.0/2.0
4.0/2.5
5.0/2.5
6.0/2.5
4.0/3.0
5.0/3.0
6.0/3.0
1: Prior
0.126
0.183
0.258
0.132
0.19
0.264
0.139
0.197
0.271
2: 
High 
Tox
0.24
0.27
0.31
0.265
0.29
0.33
0.289
0.33
0.36
3: 
Low 
Tox
0.007
0.013
0.017
0.012
0.016
0.020
0.015
0.019
0.160
4: 
Non-
Logis-tic
0.05
0.065
0.085
0.064
0.09
0.11
0.082
0.12
0.160
5: 
Low-
High
0.007
0.013
0.017
0.25
0.28
0.32
0.27
0.30
0.34


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Table 10.3.2: 7 Simulated operating characteristics 
Scenario
% of trials declaring an MTD with true DLT 
rate in
# Patients
# DLT
underdose
target 
dose
overdose
STOPPED
Mean
(Min-Max)
Mean
(Min- Max)
1
3.4
74.3
0
17.4
14.53 (3-18)
3.19 (0-8)
2
0
20.7
40.9
16.9
12.90 (3-18)
3.84 (1-9)
3
0.9
86.1
0
13
14.06 (12-18)
1.29 (0-5)
4
4.8
82.6
0
12.1
14.19 (3-18)
1.66 (0-7)
5
0
9.2
70.1
20.7
14.70 (12-18)
2.83 (0-8)


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VISIT SCHEDULE
10.4
For Cycle 1
10.4.1
Schedule A

Visit 1 is Day 1 of first intake of BI 894999 and Day 2 (Day 3 in addition if in the food 
effect cohort)

Visit 2 must be performed on day 8 plus or minus one day

Visit 3 must be performed on day 12 plus or minus one day

Visit 4 must be performed on Days 14 and 15

Visit 5 must be performed on Day 22, corresponding to Day 1 of the new cycle (if no delay 
in further cycle).
Schedule B

Visit 1 is Day 1 of first intake of BI 894999 and Day 2 (Day 3 in addition if in the 
 
cohort)

Visit 2 must be performed on day 8 plus or minus one day

Visit 3 must be performed on day 12 plus or minus one day

Visit 4 must be performed on Days 14 and 15 and on Day 18 plus or minus one day

Visit 5 must be performed on Day 22, corresponding to Day 1 of the new cycle (if no delay 
in further cycle)
Schedule C

Visit 1 is Day 1 of first intake of BI 894999 (loading dose) and Day 2 (maintenance dose)
(only Day 1 for DLBCL and NC patients after approval of protocol version 12.0)

Visit 2 must be performed on Day 8 

Visit 3 must be performed on Day 15 with second loading dose intake of the cycle

Visit 4 must be performed on Days 21 and 22 

Visit 5 must be performed on Day 29, corresponding to Day 1 of the new cycle (if no delay 
in further cycle)
For Cycle 2
10.4.2
Schedule A

Visit 1 is on the first day of intake of BI 894999 of the second cycle (which may 
correspond to last visit of first cycle)

Visit 2 will take place on Day 15 (- 4 + 2)

Visit 3 must be performed on Day 22, which may correspond to Day 1 of third cycle
Schedule B

Visit 1 is on the first day of intake of BI 894999 of the second cycle (which may 
correspond to last visit of first cycle) and on the second day

Visit 2 will take place on Day 15 (-4 + 2)

Visit 3 must be performed on Day 22, which may correspond to Day 1 of third cycle


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Schedule C

Visit 1 is on the first day of intake of BI 894999 (loading dose) of the second cycle (which 
may correspond to last visit of first cycle) 

Visit 2 will take place on Day 15 for second loading dose of the cycle

Visit 3 must be performed on Day 29, which may correspond to Day 1 of third cycle
For next cycles in all Schedules
10.4.3

Visit 1 is the first day of intake of BI 894999 of the next cycle and may correspond to last 
visit of previous cycle with returns on Day 15 (-4 +2 for Schedules A and B, no window 
allowed for Schedule C) for safety blood sampling and ECG. This visit may become 
optional starting from Cycle 5 onwards for Schedules A and B if there are no cardiac safety 
concerns as judged by the investigator from previous results. The visit will remain 
mandatory for all cycles in Schedule C

Visit 2 must be performed on Day 22 for Schedules A and B, on Day 29 for Schedule C, 
which may correspond to Day 1 of any new cycle.
Once the decision for any reason is taken for a patient to stop the treatment with BI 894999, an 
EOT visit must occur as soon as possible.
After the EOT visit, the patient must undergo a follow-up evaluation during a visit (or at least a 
phone contact if a visit is not possible), 30 days (+7) days after the last BI 894999 intake. 
If the patient was not discontinued because of withdrawal of consent, disease progression or 
treatment with another anti-cancer drug, he/she must continue to undergo follow-up visits 
every 12 weeks until progression, lost to follow-up, treatment with another anti-cancer therapy
or the end of the trial.


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DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
10.5
Screening period for all Schedules
10.5.1
The screening period may run over a period of 28 days (period within the trial and before the 
very first intake of BI 894999) and will include the following:

Informed consents

Demographics (sex, birth date (year)), race, ethnicity, alcohol and smoking history)

Medical history (oncologic history and any relevant non-oncologic history)

Occurrence of AEs since signature of the informed consent form

Concomitant therapy

Physical examination including body weight, height, vital signs and ECOG performance 
score. The physical examination will also include a tumour evaluation by palpation for the 
DLBCL patients

Resting 12-lead ECG

LVEF by MUGA scan or echocardiography

Safety laboratory parameters, including haematology with differential, biochemistry
including troponin hs, coagulation parameters, tumour markers if applicable (PSA 
mandatory for mCRPC patients), virology for Hep B, Hep C and HIV (from protocol 
version 9 onwards) and urinalysis

β-HCG serum or urine pregnancy test for women of childbearing potential (within 7 days 
before first treatment intake)

Baseline tumour assessment

with CT scan or MRI (if not performed within previous 6 weeks) in solid tumours 
including mCRPC patients 

with FDG-PET/CT (or MRI) scan for DLBCL patients (if not performed within 
previous 6 weeks

bone scan for mCRPC patients in Phase Ib (if not performed within previous 6 weeks)

Baseline tumour biopsy optional, for patients in the escalation part until MTD and for 
patients in the MTD extension cohort and mandatory for patients in the expansion Phase Ib 
(not requested for mCRPC patients presenting only with bone metastases or for patients 
with therapeutic INR because of treatment with a vitamin K antagonist or a novel oral 
anticoagulant, optional for NC patients) (platelet count and coagulation must be checked 
prior to each biopsy and must be adequate) (see 3.3.2 and 5.5). If archival tumour tissue 
sampled within 6 months of inclusion in this trial is available, archival tumour tissue may 
be used instead of a fresh biopsy

Mandatory 2-3 mL EDTA blood DNA sample for the patients who undergo a tumour 
biopsy or for whom archival tumour tissue is sent (sample to be collected only once during 
the trial, at any time)

Patient’s eligibility (inclusion and exclusion criteria)
Treatment period
10.5.2
Cycle 1
10.5.2.1
Visit 1 on Day 1 for all Schedules


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
Review of patient’s eligibility

Changes in concomitant therapy

Occurrence of AEs since last visit

Physical examination including body weight and ECOG performance score 

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position before the study drug intake and then according to the time points as 
specified in the Flow Chart

Digitalised 12-lead ECGs if possible in triplicate taken after at least 5 min rest in supine 
position before intake of BI 894999 and then at several time points (see 5.3.4 and Flow 
Chart)

Safety laboratory parameters if previous lab older than 72 hours, including haematology 
with differential, biochemistry (with CK and troponin hs) and coagulation parameters (plus 
factors II, V, VII and IX in 20 first patients of Phase Ib), and urinalysis via dipstick to 
confirm eligibility prior to trial drug intake

Plasma and urine PK samplings (see 5.4, Flow Chart and Appendix 10.2). No urine PK 
samplings from protocol version 12.0 onwards

Whole blood sampling for HEXIM1 (or other genes related to the MOA of BI 894999) 
gene expression before intake of BI 894999 and then at several time points (see 5.5, 
Appendix 10.2 and Flow Chart)

Optional blood sampling for DNA bio-banking (separate informed consent)
Whenever vital signs, digitalized ECGs and PK sampling must happen at the same time-point, 
vital signs will be taken first, then ECGs (which should be taken after 5 minutes resting after 
the vital signs are taken) and only afterwards, the PK samplings.

Breakfast a half hour before first dosing for the food interaction cohort only, for pati ents 
who are under fasted conditions on Day 2 of Visit 1 (see Appendix 10.2.2)

First oral intake of BI 894999 (loading dose in Schedule C)

Completion of a diary card indicating the intake of BI 894999 with date and hour.

Snack at least 2h post-dose for the food interaction cohort only, for patients who are under 
fasted conditions on Day 1 of Visit 1 (see Appendix 10.2.2)
Visit 1 on Day 2 for all Schedules (no visit anymore on Day 2 for NC and DLBCL patients in 
Schedule C, starting from protocol version 12.0)

Changes in concomitant therapy

Occurrence of AEs since last visit

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position before the second study drug intake as specified in the flow chart. 
See also Appendix 10.2 for the timing of PK samplings to be performed during PK days 
(see 5.4 and Flow Chart)

Digitalised, if possible triplicate, 12-lead ECGs taken after at least 5 min rest in supine 
position 24h after first dose intake and just before second intake of BI 894999 (see 5.3.4
and Flow Chart)

Safety laboratory parameters, including haematology with differential, biochemistry
including troponin hs and coagulation parameters, and urinalysis by dipstick

Plasma and urine PK samplings just before second intake of BI 894999 (see 5.4, Flow 
Chart and Appendix 10.2). No urine PK samplings from protocol version 12.0 onwards


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
 
 
)

Breakfast a half hour before dosing for the food interaction cohort only, for patients who 
are under fasted conditions on Day 1 of Visit 1 (see Appendix 10.2.2)

Second oral intake of BI 894999 (maintenance dose in Schedule C)

Completion of a diary card indicating the intake of BI 894999 with date and hour

Dispensing of medication bottles for the rest of the cycle if not in the food interaction 
cohort

Snack at least 2h post-dose for the food interaction cohort only, for patients who are under 
fasted conditions on Day 2 of Visit 1 (see Appendix 10.2.2)
Visit 1 on Day 3 for the food interaction cohort only, for both Schedules A and B

Changes in concomitant therapy

Occurrence of AEs since last visit

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position before the second study drug intake as specified in the Flow Chart. 
See also Appendix 10.2.2 for the timing of PK sampling to be performed during PK days 
(see 5.4 and Flow Chart)

Plasma PK sampling just before third intake of BI 894999 (see 5.4, Flow Chart and 
Appendix 10.2)

Third oral intake of BI 894999

Completion of a diary card indicating the intake of BI 894999 with date and hour

Dispensing of medication bottles for the rest of the cycle if in the food interaction cohort
Visit 2 on Day 8 (±1: window only allowed for Schedules A and B) for all Schedules. The tests 
of this visit can be performed locally by the patient with a phone call visit with the Investigator 
but all assessments must be performed, after approval of protocol version 12.0, for NC and 
DLBCL patients in Schedule C.

Changes in concomitant therapy

Occurrence of AEs since last visit 

Compliance check for at home BI 894999 intake via medication bottle(s) and diary card 
completion

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position before the study drug intake

12-lead, if possible digitalized triplicate, ECGs taken after at least 5 min rest in supine 
position. If assessments performed outside the clinical site (after protocol version 12.0 
approval), the original tracing of the ECG must be sent to the Investigator who will provide 
it to the central reading CRO

Safety laboratory parameters including haematology with differential, biochemistry (with 
CK and troponin hs) and coagulation parameters

Plasma PK sample for trough level analysis (before BI 894999 intake for Schedules A and 
B). Not for NC and DLBCL patients in Schedule C after protocol version 12.0

Intake of BI 894999 for Schedules A and B only


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
Completion of a diary card indicating the intake of BI 894999 with date and hour for 
Schedules A and B only

During treatment tumour biopsy for Schedules A and B, between Day 8 and Day 11 (might 
be moved ahead between Day 3 and Day 8 (see 3.1)), between 4 and 8h post-dose intake of 
BI 894999 on the day of the biopsy. This biopsy is optional in the escalation phase a nd in 
extension of MTD cohort for those patients who consented and mandatory in expansion 
Phase Ib (for those patients who had a screening tumour biopsy or archived tumour tissue 
collected) (platelet count and coagulation must be checked prior to each biopsy and must be 
adequate) (see 3.3.2 and 5.5). The on treatment biopsy may remain optional if no easily 
accessible lesions are available
Visit 3 on Day 12 (±1) for both Schedules A and B

Changes in concomitant therapy

Occurrence of AEs since last visit 

Compliance check for at home BI 894999 intake via medication bottle(s) and diary card 
completion

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position before the study drug intake

Plasma PK sample for trough level analysis before BI 894999 intake

Intake of BI 894999

Completion of a diary card indicating the intake of BI 894999 with date and hour
Visit 3 on Day 15 for Schedule C

Changes in concomitant therapy

Occurrence of AEs since last visit 

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position before the study drug intake

Digitalised, if possible triplicate, 12-lead ECGs taken after at least 5 min rest in supine 
position before intake of BI 894999

Intake of BI 894999 loading dose

Completion of a diary card indicating the intake of BI 894999 with date and hour
Visit 4 on Day 14 for both Schedules A and B

Changes in concomitant therapy

Occurrence of AEs since last visit 

Compliance check for at home BI 894999 intake via medication bottle(s) and diary card 
completion

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position before the study drug intake and then according to the Flow Chart

Digitalised triplicate 12-lead ECGs taken after at least 5 min rest in supine position before 
intake of BI 894999 and then at several time points (see 5.3.4 and Flow Chart)

Safety laboratory parameters including haematology with differential, biochemistry (with 
CK and troponin hs), and coagulation parameters (including factors II, V, VII and IX in the 
20 first patients in Phase Ib), and urinalysis via dipstick


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
Whole blood sampling for HEXIM1 (or other genes related to the MOA of BI 894999) 
gene expression before intake of BI 894999 and then at several time points (see 5.5,
Appendix 10.2 and Flow Chart)

Plasma and urine PK samplings (see 5.4, Flow Chart and Appendix 10.2)

Intake of BI 894999

Completion of a diary card indicating the intake of BI 894999 with date and hour.
Visit 4 on Day 15 for Schedule A

Changes in concomitant therapy

Occurrence of AEs since last visit 

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position 24 h after intake of BI 894999 in Cycle 1, Day 14

Digitalised triplicate 12-lead ECGs taken after at least 5 min rest in supine position before 
intake of BI 894999 

Plasma and urine PK samplings (see 5.4, Flow Chart and Appendix 10.2)

Whole blood sampling for HEXIM1 (or other genes related to the MOA of BI 894999) 
gene expression at 24h post-dose, just before intake of BI 894999 for that Day (see 5.5, 
Appendix 10.2 and Flow Chart)

Intake of BI 894999 

Completion of a diary card indicating the intake of BI 894999 with date and hour 
Visit 4 on Day 15 for Schedule B

Changes in concomitant therapy

Occurrence of AEs since last visit 

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position 24 h after last intake of BI 894999 in Cycle 1, on Day 14

Digitalised triplicate 12-lead ECGs taken after at least 5 min rest in supine position 24 
hours after last BI 894999 intake in Cycle 1, on Day 14

Plasma and urine PK samplings (see 5.4, Flow Chart and Appendix 10.2)

Whole blood sampling for HEXIM1 (or other genes related to the MOA of BI 894999) 
gene expression at 24h, 26h, 28h and 32h post-dose after last BI 894999 intake in Cycle 1, 
on Day 14 (see 5.5, Appendix 10.2 and Flow Chart)
Visit 4 on Day 18 (±1) for Schedule B

Changes in concomitant therapy

Occurrence of AEs since last visit 

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position 

Plasma PK sampling for trough level analysis (see 5.4, Flow Chart and Appendix 10.2)

Whole blood sampling for HEXIM1 (or other genes related to the MOA of BI 894999) 
gene expression at the time of the visit (see 5.5, Appendix 10.2 and Flow Chart)
Visit 4 on Day 21 for Schedule C

Changes in concomitant therapy

Occurrence of AEs since last visit 


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
Compliance check for at home BI 894999 intake via medication bottle(s) and diary card 
completion

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position before the study drug intake and then according to the Flow Chart

Digitalised, if possible triplicate, 12-lead ECGs taken after at least 5 min rest in supine 
position before intake of BI 894999 and then at several time points (see 5.3.4 and Flow 
Chart)

Safety laboratory parameters including haematology with differential, biochemistry (with 
CK and troponin hs), coagulation parameters and urinalysis via dipstick

Whole blood sampling for HEXIM1 (or other genes related to the MOA of BI 894999) 
gene expression before intake of BI 894999 and then at several time points (see 5.5, 
Appendix 10.2 and Flow Chart)

Plasma and urine PK samplings (see 5.4, Flow Chart and Appendix 10.2). No urine PK 
samplings from protocol version 12.0 onwards

Intake of BI 894999 maintenance dose

Completion of a diary card indicating the intake of BI 894999 with date and hour.

Optional during treatment tumour biopsy between Day 18 and Day 21 for those patients 
who consented, between 4 and 8h post-dose intake of BI 894999 on the day of tumour 
biopsy (platelet count and coagulation must be checked prior to each biopsy and must be 
adequate) (see 3.3.2 and 5.5)
Visit 4 on Day 22 for Schedule C

Changes in concomitant therapy

Occurrence of AEs since last visit 

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position 24 h after last intake of BI 894999 in Cycle 1, on Day 21

Digitalised, if possible triplicate, 12-lead ECGs taken after at least 5 min rest in supine 
position 24 hours after last BI 894999 intake in Cycle 1, on Day 21

Plasma and urine PK samplings (see 5.4, Flow Chart and Appendix 10.2). No urine PK 
samplings from protocol version 12.0 onwards

Whole blood sampling for HEXIM1 (or other genes related to the MOA of BI 894999) 
gene expression at 24h, 26h, 28h and 32h post-dose after last BI 894999 intake in Cycle 1, 
on Day 21 (see 5.5, Appendix 10.2 and Flow Chart). Only at 24h post-dose for NC and 
DLBCL patients after protocol version 12.0 approval
Visit 5 on Day 22 for both Schedules A and B, on Day 29 for Schedule C

Changes in concomitant therapy

Occurrence of AEs since last visit 

Compliance check for at home BI 894999 intake via medication bottle(s) and diary card 
completion (done on Day 14 for Schedule B and on Day 21 for Schedule C)

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position

Digitalised, if possible triplicate, 12-lead ECGs taken after at least 5 min rest in supine 
position (see 5.3.4 and Flow Chart)

Safety laboratory parameters including haematology with differential, biochemistry (with 
CK and troponin hs), and urinalysis by dipstick.


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
Plasma PK sample for trough level analysis in Schedule C

Intake of BI 894999 only for Schedule A if Day 22 is not corresponding to Day 1 of Cycle 
2

Completion of a diary card indicating the intake of BI 894999 with date and hour only for 
Schedule A if Day 22 is not corresponding to Day 1 of Cycle 2
Further Cycles
10.5.2.2
Visit 1 on Day 1 in all cycles for all Schedules except in Cycle 2 for Schedule B. After 
approval of protocol version 12.0, for NC and DLBCL patients, starting from Cycle 6, if too 
difficult for the patient to travel frequently to the clinical site, this visit may happen via a phone 
call visit between the Investigator and the patient, after all tests are performed locally by the 
patient and this for all even cycles, if allowed by country regulations and if deemed safe by the 
Investigator, after discussion with the Sponsor. In this case, medication dispensation may be 
performed for two cycles at Visit 1 of uneven cycles, starting from Cycle 5 onwards.

Review of patient’s eligibility 

Changes in concomitant therapy

Occurrence of AEs since last visit 

Physical examination including body weight and ECOG performance score

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position 

12-lead digitalized, if possible triplicate, ECGs taken after at least 5 min rest in supine 
position, before intake of BI 894999. If performed locally, the original ECG tracing must 
be sent to the Investigator who will provide it to the central reading CRO

Safety laboratory parameters if previous lab older than 48 hours, including haematology 
with differential, biochemistry (with CK and troponin hs), coagulation parameters, tumour 
markers if applicable (mandatory PSA for mCRPC patients in Phase Ib), and urinalysis via 
dipstick

Pregnancy test for women of childbearing potential

First oral intake of BI 894999 for the cycle (loading dose in Schedule C)

Dispensing of medication bottles for the rest of the cycle (see above)
Visit 1 on Day 1 of Cycle 2 for Schedule B

Review of patient’s eligibility 

Changes in concomitant therapy

Occurrence of AEs since last visit 

Physical examination including body weight and ECOG performance score

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position, before intake of BI 894999

12-lead digitalized triplicate ECGs taken after at least 5 min rest in supine position, before 
intake of BI 894999 

Safety laboratory parameters if previous lab older than 48 hours, including haematology 
with differential, biochemistry (with CK and troponin hs), coagulation parameters
(including factors II, V, VII and IX in the 20 first patients in Phase), tumour markers if 
applicable (PSA mandatory for mCRPC patients in Phase Ib), and urinalysis via dipstick


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
Pregnancy test for women of childbearing potential

PK blood samplings (see Appendix 10.2 and Flow Chart)

Whole blood sampling for HEXIM1 (or other genes related to the MOA of BI 894999) 
gene expression (see Appendix 10.2 and Flow Chart)

First oral intake of BI 894999 for the cycle
Visit 1 on Day 2 of Cycle 2 for Schedule B

Changes in concomitant therapy

Occurrence of AEs since last visit 

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position, before intake of BI 894999

PK blood sampling just before intake of BI 894999 (see Appendix 10.2 and Flow Chart)

Whole blood sampling for HEXIM1 (or other genes related to the MOA of BI 894999) 
gene expression just before intake of BI 894999 (see Appendix 10.2 and Flow Chart)

Second oral intake of BI 894999 for the cycle

Dispensing of medication bottles for the rest of the cycle
Visit 2 on Day 15 (+2/-4: window allowance only for Schedules A and B): only in Cycles 2, 3 
and 4 for both Schedules A and B, for all cycles in Schedule C. All assessments of this visit 
may be performed locally by the patient with a phone call visit with the Investigator if allowed 
by local regulations

Changes in concomitant therapy

Occurrence of AEs since last visit 

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position 

Safety laboratory parameters if previous lab older than 48 hours, including haematology 
with differential, biochemistry (with CK and troponin hs) and coagulation parameters

12-lead, if possible digitalized triplicate, ECGs taken after at least 5 min rest in supine 
position. If done locally, the original ECG tracing must be sent to the Investigator who will 
provide it to the central reading CRO

Intake of BI 894999 second loading dose of the cycle only for Schedule C
Visit 3 on Day 22 in Cycle 2 or Visit 2 on Day 22 in further Cycles for both Schedules A and B, 
Visit 3 on Day 29 for all cycles in Schedule C
The end of cycle evaluation visit will occur just before to start third cycle. In case the patient 
does not continue therapy, the results of imaging have to be recorded and the EOT 
examinations done.

Changes in concomitant therapy

Occurrence of AEs since last visit

Compliance check for at home BI 894999 intake via medication bottle(s)

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min
rest in supine position

12-lead, if possible digitalized triplicate, ECGs taken after at least 5 min rest in supine 
position


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
Safety laboratory parameters if previous lab older than 48 hours, including haematology 
with differential, biochemistry (with CK and troponin hs)

MRI, CT, tumour assessment (by imaging with FDG-PET/CT scan and physical palpation 
in DLBCL patients): to be performed at the end of every even cycle. For DLBCL patients, 
the FDG-PET/CT scan is to be performed at the end of Cycle 2, Cycle 4 and every four 
cycles thereafter. 

Bone scan every four cycles  only in mCRPC patients and PSA at the same time-points

For patients who show an objective response at the imaging evaluation according to 
RECIST 1.1 for solid tumours (also mCRPC patients with measurable disease according to 
RECIST 1.1) or according to RECIL 2017 for DLBCL patients or are benefiting from the 
treatment and who consented for it, fresh tumour biopsy at any time during response 
(platelet count and coagulation must be checked prior to each biopsy and must be adequate) 
and/or sending of archival tumour tissue or slides (at least 10 slides)

Mandatory 2-3 mL EDTA blood DNA sample on the day of tumour biopsy or at any time 
during response for the patients who undergo a tumour biopsy and/or agree to the sending 
of archival tumour tissue or slides at objective response or benefit from the treatment

MUGA scan or echocardiography for LVEF determination only at the end of Cycle 2, 
always using the same method
End of Treatment (EOT) visit 
10.5.3

Changes in concomitant therapy

Occurrence of AEs since last visit

Compliance check if applicable

Physical examination including body weight and ECOG performance score

Vital signs including blood pressure, pulse and body temperature, taken after at least 2 min 
rest in supine position

12-lead, if possible digitalized triplicate, ECGs taken after at least 5 min rest in supine 
position if previous one older than 48 hours

MUGA scan or echocardiography for LVEF determination (always using the same 
method), if not performed in the last 6 weeks and the patient’s health status allows to do so

Safety laboratory parameters if previous lab older than 48 hours, including haematology 
with differential, biochemistry (with CK and troponin hs), coagulation parameters, and 
urinalysis via dipstick

β-HCG pregnancy test for women of childbearing potential

MRI, CT, tumour assessment (by imaging and physical palpation in DLBCL patients): to 
be performed if not done within the past 6 weeks

Overall clinical benefit assessment by the Investigator for NC patients only

Registration of termination date for study medication
Follow-up (FU) visit 
10.5.4
The first FU visit (EOR) must occur 30 days (+7 days) after the last intake of BI 894999. A 
repeated FU must take place at least every 12 weeks for any necessary follow-up of an AE or 
until disease progression, lost to follow-up, treatment with another anti-cancer therapy or end 


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of the whole trial as specified in Section 8.6. If the patient is unable to attend a site visit, at 
least information on AEs and patient’s status must be obtained by a phone contact.

Changes in concomitant therapy for all changes until 30 days after last BI 894999 intake, 
thereafter, only if taken to treat a study-treatment emergent AE

Occurrence of all AEs since last visit until 30 days after the last BI 894999 intake, 
thereafter, only AEs which are considered study drug related.

Physical examination including ECOG performance score 

12-lead digitalized triplicate ECGs taken after at least 5 min rest in supine position
(optional)

Safety laboratory parameters if previous lab older than 48 hours, including haematology 
with differential, biochemistry (optional) and coagulation parameters (if abnormal at EOT)

MRI, CT, tumour assessment (by imaging and physical palpation in DLBCL patients): to 
be performed if not done within the past 6 weeks

MUGA scan or echocardiography for LVEF determination (optional) (always using the 
same method)

Patient’s status. For NC patients who consented to do so, overall survival status will 
continue to be collected until death, withdrawal of consent to further collect the 
information, lost to follow-up or until 12 months after the end of the trial, whichever comes 
first.


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CLINICALLY RELEVANT CYP1A2, CYP2C8, CYP3A4 SUBSTRATES: 
10.6
Table 10.6: 1: 
list of medications considered clinically relevant substrates of CYP 
1A2, CYP 2C8 and CYP3A4 
CYP1A2 
rosiglitazone
dasatinib
midostaurin
alosetron
torsemide
dexamethasone
naloxegol
amitriptyline 
CYP3A4
diazepam
nateglinide
caffeine
alfentanyl
diltiazem
nelfinavir
clomipramine
alisporivir
docetaxel
neratinib
clozapine
almorexant
domperidone
nifedipine
duloxetine
alpha-dihydroergocryptine
dronaderone
nisoldipine
estradiol
alprazolam
ebastine
ondansetron
fluvoxamine
aplaviroc
eletriptan
paritaprevir
haloperidol
aprepitant
eliglustat
perospirone
imipramine N-DeMe
aripripazole
elvitegravir
pimozide
melatonin
atazanavir
eplerenone
quetiapine
olanzapine
atorvastatin
estradiol
quinidine 3OH
ondansetron
avanafil
everolimus
ridaforolimus
pirfenidone
blonanserin
felodipine
rilpivirine
ramelteon
bosutinub
fentanyl
risperidone
ramosetron
brecanavir
finasteride
ritonavir
riluzole
brotizolam
gleevec
rivaroxaban
selegiline
budesonide
grazoprevir
salmeterol
tacrine
buspirone
haloperidol
saquinavir
tasimelteon
cafergot
ibrutinib
sildenafil
theophylline
caffeine
indinavir
simeprevir
tizanidine
capravirine
irinotecan
simvastatin
verapamil
casopitant
isavuconazole
sirolimus
(R)warfarin
cerivastatin
ivabradine
tacrolimus
zileuton
cilostazol
ivacaftor
tadalafil
zolmitriptan
clarithromycin
levomethadyl
tamoxifen
CYP2C8
cobimetinib
lomitapide
telithromycin
amodiaquine
cocaine
lopinavir
terfenadine
cerivastatin 
codeine-Ndemethylation
lovastatin
ticagrelor
dasabuvir
conivaptan
lumefantrine
tilidine
montelukast
cyclosporine
lurasidone
tipranavir
paclitaxel
danoprevir
maraviroc
tolvaptan
pioglitazone
darifenacin
methadone
trazodone
repaglinide
darunavir
midazolam
triazolam


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Table 10.6: 1: 
list of medications considered clinically relevant substrates of CYP 
1A2, CYP 2C8 and CYP3A4 (continued)
CYP 3C4 (continued)
venetoclax
vincristine
ziprasidone
ulipristal
verapamil
voclosporin
zolpidem
vardenafil
vicriviroc
zaleplon


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RECIL 2017 RESPONSE CRITERIA AND DEAUVILLE SCORE 
10.7
Table 10.7: 1
RECIL 2017: response categories
(R17-3378)
Table 10.7: 2
Deauville scoring system for FDG/PET scan evaluation according to 
RECIL 2017
(R17-3376)


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
GLOBAL AMENDMENT 1
11.1
Number of global amendment
1
Date of CTP revision
02 Sep 2015
EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients with advanced solid tumours, with 
repeated administration in patients with clinical 
benefit
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB 
/ 
IEC 
/ 
Competent 
Authority to be notified of 
change 
with 
request 
for 
approval
X – notification was made on the 27th of Jul 2015 
to 
the 
Competent 
Authorities 
and 
Ethics 
Committees about the precautionary measure taken 
due to potential CYP inducing effect (3A4, 2C8 
and 1A2) of BI 894999 further to a non-clinical 
finding.
Can be implemented without 
IRB 
/ 
IEC 
/ 
Competent 
Authority approval as changes 
involve 
logistical 
or 
administrative aspects only
Section to be changed
1.2.2, 3.3.2 point 6, 4.2.2, addition of Appendix 
10.6
Further to additional pre-clinical results, Flow 
Charts, 3.1.1, 5.5, 7.3.6, 10.2, 10.5  
This protocol revision is also the opportunity to add 
clarification to some other sections:
-
3.1
-
3.1.1
-
4.3
-
5.3.6.1
-
-
5.5
-
6.2.1
-
8.4.1


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Description of change
-1.2.2: Addition of the pre-clinical findings of 
potential drug inducing effect of BI 894999 on 
CYP3A4, 1A2 and 2C8 
- 3.3.2: precision in inclusion criterion 6 that 
women 
of 
childbearing 
potential 
using 
a 
contraceptive pill as a method of birth control 
need to add a barrier method 
- 4.2.2: potential drug inducing effect of BI 894999 
on CYP3A4, 1A2 and 2C8 with possible result of 
reduction of plasma concentrations of concurrent 
medications which are substrates of these CYP 
enzymes, including contraceptive pills and the 
potential resulting decrease of their effectiveness: 
caution added in 4.2.2.1 about the use of 
concomitant medication which are substrates, 
request for women of childbearing potential using 
a contraceptive pill to add a barrier method in 
section 4.2.2.3
- Appendix 10.6: Addition of non-exhaustive list of 
CYP 3A4,  2C8 and 1A2 substrates
Further to additional pre-clinical findings:
Addition of whole blood samples for HEXIM1 
gene expression analyses at 24h post-dose of BI 
894999 intake on Days 1 and 14 of Cycle 1 and 
deletion of all peripheral blood mononuclear cells 
(PBMC) samples for HEXIM1 protein expression 
in Flow Charts, Sections 3.1.1, 4.1.4.1, 5.5, 6.2, 
7.3.6, 10.2, 10.5  
Additional changes:
- Section 3.1: 
- If no patient from first cohort experiences a 
drug-related CTCAE grade ≥2, the dose may be 
increased from 0.2 mg to 1 mg in second cohort 
and if no patient from second cohort experiences 
a drug-related CTCAE grade ≥2, the dose may 
be increased from 1 mg to 5 mg in third cohort
- Extension to more patients in a cohort due to a 
drug-related CTCAE grade ≥2 will only apply if 
the AE happens in a single patient cohort
- Section 3.1.1
DMC membership is given in extenso in the DMC 
charter, apart from the protocol
- Section 4.3:


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The compliance calculation will be done by 
counting the number of tablets from each strength 
actually taken x100 divided by the number of 
tablets from each strength which should have 
been taken
- Section 5.3.6.1:
DLT definitions: last bullet: any drug-related 
adverse event preventing from taking his 
treatment according to the given schedule (more 
than 2 consecutive doses missed): this concerns 
the AEs except those described in the 4 previous 
bullets of DLTs definitions.
“Protocol-specified significant events”: this term 
is replaced by “AESIs”
Intensity of Adverse Events: “intensity” is 
replaced by “severity”
-
- Section 6.2.1:
For the medical history, the number of metastatic 
sites will not be requested anymore
- Section 8.4.1: the term “side effect” is replaced by 
“adverse reaction”
Rationale for change
New pre-clinical findings need to be provided to 
the investigators and patients to make them aware 
of potential drug-drug interactions, specifically in 
relation to the contraceptive pill if this is being 
taken by women of child-bearing potential. This 
amendment includes additional safety measures in 
women of childbearing potential to not only rely on 
contraceptive pills for contraception, but they have 
to also use a barrier method of contraception as 
well.
Further additional preclinical 
PK/Pharmacodynamics modelling work showed 
the dynamics of HEXIM 1 (as a 
pharmacodynamics marker) over a 24 hour period 
post-dosing.  Given this new data, adding an extra 
sampling time point at 24h post-dose (on Day 1 and 
Day 14) would help understand the dynamics of 
HEXIM 1 in patients. Since the PBMC sampling 
(for analysis of HEXIM 1 protein) is only 
performed at 24h post-dose, this does not provide 


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information about the dynamics of HEXIM 1 
induction over the 24h period post-dose,  the 
PBMC collection is therefore not considered to be  
of additional  value to the biomarkers analysis and 
is removed from the protocol.
Additional changes:
- Section 3.1: 
- Clarification for the escalation rules used from 
first to second cohort and from second to third 
cohort
- Clarification on which cohorts are concerned by 
addition of patients in case of drug-related 
CTCAE grade ≥ 2 and how many patients 
needed under BLRM, once a drug-related 
CTCAE grade ≥ 2 occurred in Cycle 1 
- Section 3.1.1:clarification where to find in-
extenso DMC membership 
- Section 4.3: clarification on the way to calculate 
the compliance due to the different possible tablet 
strengths 
- Section 5.3.6.1:
Clarification on DLT definitions to make sure 
there is common and same understanding for 
everyone
“Protocol-specified significant events” is a term 
that is not used anymore in the protocol and 
corresponds to the term “AESIs” used for this 
protocol.
Intensity of AE: as the CTCAE grading is a 
severity scale, the term “severity” is more 
appropriate.
-
- Section 6.2.1: as the metastatic sites are described, 
there is no need to have the number in addition for 
the study interpretation of results
- Section 8.4.1: as the drug is not yet marketed, 
there are not yet known side effects and the term 
“adverse reaction” is the appropriate term 
GLOBAL AMENDMENT 2
11.2
Number of global amendment
2
Date of CTP revision
08 Apr 2016


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EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients with advanced malignancies, with repeated 
administration in patients with clinical benefit
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB 
/ 
IEC 
/ 
Competent 
Authority to be notified of 
change 
with 
request 
for 
approval
Can be implemented without 
IRB 
/ 
IEC 
/ 
Competent 
Authority approval as changes 
involve 
logistical 
or 
administrative aspects only
Section to be changed
Title, synopsis, Flow Charts, 1.2.1, 2.1, 2.2, 2.3, 
3.1, 3.1.1, 3.2, 3.3.1, 3.3.2, 3.3.3, 3.3.4, 4.1.1, 4.1.2, 
4.1.3, 4.1.4, 4.2.1, 4.2.2, 5.1.1, 5.1.2, 5.3.6, 5.4.5, 
5.5.1, 6.1, 6.2, 7.1, .1, 7.3.27.3.6, 7.4, 7.7, 9, 10.2, 
10.3, 10.4, 10.5
Description of change
Changes across all these sections concern:
-
The addition of a second Schedule, 
Schedule B, of intermittent administration 
of trial medication (two weeks on, one 
week off in 3-week cycles) in solid tumours 
in order to also determine the MTD with 
this Schedule. The Schedule B dose finding 
will run in parallel to Schedule A in patients 
with solid tumours, starting from the 
highest dose tested in Schedule A in 
patients with solid tumours and considered 
safe to start with by the DMC
-
The Schedule A of continuous dosing of 
trial medication (in 3-week cycles) will be 
administered in patients with solid tumours 
in order to determine the MTD with this 
Schedule and, starting from this MTD 
minus one dose level, an additional cohort 
of NHL patients will be included with 


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Schedule A in order to determine the MTD 
in patients with NHL. Once the MTD is 
determined in this NHL cohort, the cohort 
will be further extended at MTD until a 
total of 15 up to 27 patients are included in 
the NHL cohort.
The addition of the NHL cohort also leads 
to the change from “advanced solid 
tumours” to a more global designation of 
“advanced malignancies” in the title of the 
study to include both solid tumours and 
hematologic malignancies of the NHL type.
-
Once the MTD is determined for both 
Schedules A and B in patients with solid 
tumours, the DMC will determine the best 
Schedule and the MTD cohort of the chosen 
Schedule will be further extended up to 12 
patients
These changes imply 
-
the introduction of specific Flow Charts for 
Schedule B with additional days of visits 
and additional PK and pharmacodynamics 
tests to be performed in Cycles 1 and 2
-
the addition of pre-clinical information on 
tests performed in lymphoma and the 
rationale to test this BET inhibitor in 
patients with Non-Hodgkin lymphoma as 
well
-
the addition of MTD determination for 
Schedule B and for the NHL cohort in the 
objectives and in the endpoints
-
the addition of
specific inclusion and 
exclusion criteria for the NHL cohort
-
the specification on how to capture 
oncological history for NHL patients
-
the addition of physical tumour evaluation 
of NHL patients
-
the introduction of the notion of Tumour 
Lysis Syndrome (TLS) prevention left to 
investigator’s judgement, in NHL patients
-
the addition of specific DLT definitions for 
NHL patients
-
the change in sample size
Additional changes:
- Synopsis, Section 5.12, Section 5.1.3: to decrease 


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the number of secondary PK endpoints, some of 
the PK endpoints are now considered as further 
endpoints
- Section 3.3.3.1, point 13: the steroids are allowed 
for palliative intent at study entry provided they 
are given at a stable dose for the four weeks 
before study screening
- Section 4.1.4.1: 
- During the first cycle, a drug-free interval (not 
including the one week schedule treatment break 
in Schedule B) may only occur in case of a DLT
or at the end of the evaluation period of 21 days, 
for recovery of another drug-related AE of 
CTCAE grade 3 or 4
- Section 4.1.4.2: Treatment with the trial drug has 
also to be discontinued temporarily in case of 
another drug-related AE of CTCAE grade 3 or 4 
than a DLT to allow recovery to at least CTCAE 
grade 1 or baseline level (except CTCAE grade 2 
peripheral sensory neuropathy as well as CTCAE 
grade 2 anaemia or lymphopenia) They may then 
re-start at the same dose.
- Section 4.2.1: steroids are allowed for treatment 
of 
adverse 
reactions 
or 
tumour-associated 
symptoms but should be kept at the lowest 
possible dose for the shortest possible duration if 
introduced during study treatment period
- Section 5.3.4
- correction of Bazett’s and Fridericia’s formulas
- Section 5.3.6.1:
- DLT definitions: last bullet for solid tumours: a 
drug-related grade 2 oral mucositis/stomatitis 
preventing from taking his treatment according 
to the given schedule (more than 2 consecutive 
doses missed)
- Instructions for reporting of new cancers of new 
histology
- Sections 5.3.7 and 8.4.2:
Additional information on Investigator’s and BI 
obligations for SAE and/or AESI reporting
- Sections 5.4.5, 5.5.1.2, 5.5.1.2.2, 7.3.6, 7.4, 10.5: 
when the pharmacodynamics exploration speaks 
about modulation of HEXIM1 gene expression, it 
will also include additional other genes related to 
the MOA of BI 894999
- Flow Charts for both Schedules and Sections 3.1, 


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3.3.1, 5.5.1.1.1, 5.5.1.2: for patients who are 
responding to the treatment (objective response 
according to RECIST 1.1) or have a clinical 
benefit and if they have given consent for it, 
optional collection of archival tumour tissue 
and/or fresh tumour biopsy at the time of response 
or benefit for additional analyses centred around 
but not limited to the MOA of BI 894999 and the 
molecular nature of the disease. Analyses will 
include both RNA and DNA analysis in an 
attempt to identify biomarkers of efficacy. In case 
tumour tissue is given, a mandatory 2-3 mL 
EDTA blood DNA sample will be obtained from 
those patients
- Flow Charts for both Schedules and Sections 3.1, 
3.3.1, 5.5.1.1.1, 5.5.1.2: fresh tumour biopsies at 
screening and at steady state in Cycle 1 are now 
optional for the whole Phase Ia, including the 
extension cohort at MTD and remain mandatory 
for the phase Ib patients
Rationale for change
- Addition of a second Schedule with intermittent 
dosing: this was already foreseen as a possibility 
in the first version of the protocol in case of 
intolerability of the continuous dosing schedule. 
As 2 DLTs occurred in 2 patients treated at a dose 
of 5 mg which is lower than expected from pre-
clinical models, the DMC decided to also test in 
parallel an intermittent dosing schedule in an 
attempt to improve tolerability of BI 894999.
- Addition of a NHL cohort: additional pre-clinical 
investigations both in vitro and in vivo have 
shown activity in lymphoma, particularly NHL. 
Recent preliminary data of Phase I trials with 
other BET inhibitors have also reported promising 
results in patients with NHL. Both pre-clinical 
data with BI 894999 and clinical results from 
other BET inhibitors warrant further investigation 
with BI 894999 in patients with NHL.
Additional changes
- Synopsis and sections 5.1.2 and 5.1.3: according 
to BI standards, there should not be more than 10 
secondary endpoints and each PK endpoint is 
considered separately. For this reason, the 
secondary PK endpoints were limited with some 
PK parameters becoming further endpoints.


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- Sections 3.3.3.1, point 13 and 4.2.1: the steroids 
must be given at a stable dose for the four weeks 
before study screening and kept at the minimum if 
introduced during study treatment period to avoid 
as much as possible interference with the RECIST 
evaluation
- Section 4.1.4.1: 
- During the first cycle, a drug-free interval (not 
including the one week schedule treatment break 
in Schedule B) may only occur in case of a DLT 
or drug-related CTCAE grade 3 or 4 at the end 
of the evaluation period of 21 days: clarification 
that a drug free interval in the first cycle (other 
than the normal scheduled one in Schedule B) is 
not allowed except when the patient experiences 
a DLT or a drug-related CTCAE grade 3 or 4 at 
the end of the 21 days period of the first cycle
- Section 4.1.4.2: clarification of treatment break at 
the end of a cycle for drug-related AE of CTCAE 
grade 3 or 4 to be consistent with instructions 
given in Section 3.1.
- Section 5.3.4
- correction of an error in Bazett’s and Fridericia’s 
formulas
- Section 5.3.6.1:
- DLT definitions: last bullet for solid tumours: a 
drug-related grade 2 oral mucositis/stomatitis 
preventing the patient from taking his treatment 
according to the given schedule (more than 2 
consecutive doses missed): clarification of this 
DLT definition to avoid misinterpretation with a 
too broad definition which would make any 
drug-related AE a possible DLT
- Instructions for reporting of new cancers of new 
histology: according to BI new
protocol 
template
- Sections 5.3.7 and 8.4.2: changes to conform with 
new BI protocol template regarding SAEs/AESI 
reporting obligations
- Sections 5.4.5, 5.5.1.2, 5.5.1.2.2, 7.3.6, 7.4, 10.5: 
when the pharmacodynamics exploration speaks 
about modulation of HEXIM1 gene expression, it 
will also include additional other genes related to 
the MOA of BI 894999: clarification that the gene 
expression analysis will not be limited to only 
HEXIM1 gene expression but also to other genes 


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related to the MOA of BI 894999, according to 
actual scientific knowledge
- Flow Charts for both Schedules and Sections 3.1, 
3.3.1, 5.5.1.1.1, 5.5.1.2: for patients who are 
responding to the treatment (objective response 
according to RECIST 1.1) or have a clinical 
benefit and if they have given consent for it, 
optional collection of archival tumour tissue 
and/or fresh tumour biopsy at the time of response 
or benefit: this will allow further understanding of 
the mechanism of action of the BET inhibitor and 
its interaction with certain tumour types
- Flow Charts for both Schedules and Sections 3.1, 
3.3.1, 5.5.1.1.1, 5.5.1.2: fresh tumour biopsies at 
screening and at steady state in Cycle 1 are now 
optional for the whole Phase Ia, including the 
extension cohort at MTD and remain mandatory 
for the phase Ib patients: the pharmacodynamics 
information that would be gained from all comers 
tumours in the phase Ia part would be limited and 
would not compensate for the burden to the 
patients
GLOBAL AMENDMENT 3
11.3
Number of global amendment
3
Date of CTP revision
23 Nov 2016
EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients 
with 
advanced 
malignancies, 
with 
repeated administration in patients with clinical 
benefit
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB 
/ 
IEC 
/ 
Competent 
Authority to be notified of 
change 
with 
request 
for 
approval
– Notification was made on the 7th of Oct 2016 to 
the Competent Authorities and Ethics Committees 
about the precautionary measures taken due to 
cardiac findings in patients already participating in 
the trial.
Can be implemented without 
IRB 
/ 
IEC 
/ 
Competent 


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Authority approval as changes 
involve 
logistical 
or 
administrative aspects only
Section to be changed
Flow Charts, 1.2.3, 2.3, 5.3.3, 5.3.4, 5.3.5, 6.2, 6.1, 
10.4, 10.5
Description of change
In sections: Flow Charts, 1.2.3, 2.3, 5.3.3, 5.3.4, 
5.3.5, 6.2, 6.1, 10.4, 10.5
-
Each time a safety laboratory sampling is 
performed, 
addition 
of 
CK-MB 
and 
mandatory 
troponin 
T 
hs 
level 
determination even if normal CK results
-
Each time an ECG is performed, it has to be 
acquired as triplicate digitalized 12-lead 
ECG with the CRO device and sent to CRO 
for central reading
-
Addition of a visit every week, starting 
from Cycle 2 onwards with the following 
examinations to be performed at these 
visits:
-
Occurrence of AEs since last visit
-
Changes in concomitant medications 
since last visit
-
Digitalized triplicate ECGs to be sent to 
central reading CRO for review by 
cardiologist and interval measurements
-
Safety laboratory blood sampling for 
determination of at least CK, CK-MB 
and troponin T hs levels and any other 
additional 
parameter 
judged 
to
be 
controlled by the investigator 
Rationale for change
These measures were taken as urgent safety 
measures at the time when some cardiac findings 
were observed in some patients included in the trial 
and before the cardiologic findings were evaluated 
by an external expert cardiologist to try to
understand their clinical significance. This is 
applicable to the ongoing patients who are shown 
to benefit from the treatment in order to allow them 
to continue the treatment under close cardiac safety 
monitoring. 
Any further recruitment is stopped in the trial.


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GLOBAL AMENDMENT 4
11.4
Number of global amendment
4
Date of CTP revision
12 May 2017
EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients with advanced malignancies, with repeated 
administration in patients with clinical benefit
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB 
/ 
IEC 
/ 
Competent 
Authority to be notified of 
change 
with 
request 
for 
approval
Can be implemented without 
IRB 
/ 
IEC 
/ 
Competent 
Authority approval as changes 
involve 
logistical 
or 
administrative aspects only
Section to be changed
Synopsis, Flow Charts, 2.2, 2.3, 3.1, 3.2, 3.3.3.2, 
4.1.1, 4.1.2, 4.1.4, 4.1.6, 5.1.1.1, 5.1.2, 5.3.3, 
5.3.5.1, 5.3.6.1, 6.1, 7.1, 7.3.1, 7.3.2, 8.6, 10.5
Description of change
Section 2.3:
-
Results of the external cardiology review 
showed that a small increase in serum 
troponin, 
temporally 
related 
to 
drug 
administration was
observed in some 
patients. There was no observed clinically 
relevant QT prolongation, no suggestion of 
any rate change, conduction abnormality or 
evidence of drug-induced ischaemia.
-
Thrombocytopenia 
is 
considered 
an 
expected AE associated with BI 894999.
Synopsis, Flow Charts for both Schedules, Sections
2.3, 5.3.3, 5.3.5, 6.2, 10.4, 10.5: 
-
-
Triplicate digitalized ECGs will happen 
once a week during Cycle 1 (addition of 


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this examination at Day 8 visit)
-
In Cycle 2, as well as in Cycles 3 and 4, in 
addition to the first visit of the Cycle, one 
intermediate visit is foreseen at Day 15 
(window of -4 or +2 days) where collection 
of digitalized triplicate ECGs and measures 
of CK and troponin T hs will happen. CK-
MB is no more systematically requested 
together with CK measures. From Cycle 5 
onwards, the intermediate visit of Day 5 
becomes optional
-
The LVEF evaluation will be performed at 
screening for all new patients in the trial 
and will serve as baseline. An evaluation 
during treatment will then be performed at
the end of Cycle 2 and if compatible with 
the patient’s health status, also at the EOT.
Synopsis, Sections 2.2, 3.1, 3.2, 4.1.2, 4.1.4, 5.1.1, 
5.1.2, 6.1, 7.1, 7.3.1, 7.3.2, 10.3: 
-
Patients in the NHL cohort will be treated 
with the Schedule selected by the DMC 
once MTD has been determined for both 
Schedules A and B in patients with solid 
tumours.
Additional changes in this revised version of the 
protocol:
-
Section 3.3.3.2: exclusion criterion 12 in 
NHL patients
includes no myocardial 
infarction within 6 months prior to study 
entry
-
Sections 4.1.1and 4.1.6: availability of 2 mg 
tablets
-
Section 
5.3.6.1, 
definition 
of 
DLTs: 
precision that the possible treatment break 
of 14 days in Schedule A or 21 days in 
Schedule B at the end of a Cycle does not 
count in the
period of more than 2 
consecutive 
doses 
missed 
for 
DLT 
definition
Rationale for change
Section 2.3: 
Assessment by external cardiologists concluded 
that the cause of this troponin elevation is unclear.  
Due to the low magnitude of elevations and the 


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lack of associated cardiac findings in these patients, 
the cardiac findings do not preclude further clinical 
development. Patients may continue on treatment 
with appropriate monitoring
Synopsis, Flow Charts for both Schedules, Sections 
2.3, 5.3.3, 5.3.5, 6.2, 10.4, 10.5: 
Cardiac monitoring was adapted to balance the 
need to continue close cardiac monitoring and the 
burden for the patients benefiting from prolonged 
treatment to have to come too frequently to the 
clinic.
Synopsis, Sections 2.2, 3.1, 3.2, 4.1.2, 4.1.4, 5.1.1, 
5.1.2, 6.1, 7.1, 7.3.1, 7.3.2, 10.3: 
Since this study will serve for a go/no go decision 
in further development of BI 894999 in NHL 
patients, it is important that the patients in the NHL 
cohort in this study are treated with the Schedule 
selected by the DMC in order to determine the 
recommended phase II dose in this patient 
population in case of further development in this 
indication.
Other changes were incorporated to clarify or adapt 
the protocol, 
-
such as the exclusion criterion of recent 
myocardial infarction in NHL patients to 
reflect the same exclusion criterion than for 
patients with solid tumours
-
the availability of 2 mg tablets as confirmed 
with an amendment to the IMPD, already 
submitted
-
or the clarification of which period is 
considered for DLT in case more than two 
doses are missed.
GLOBAL AMENDMENT 5
11.5
Number of global amendment
5
Date of CTP revision
18 Oct 2017
EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients with advanced malignancies, with repeated 


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administration in patients with clinical benefit
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB 
/ 
IEC 
/ 
Competent 
Authority to be notified of 
change 
with 
request 
for 
approval
Can be implemented without 
IRB 
/ 
IEC 
/ 
Competent 
Authority approval as changes 
involve 
logistical 
or 
administrative aspects only
Section to be changed
Synopsis, Flow Charts, 1.1, 1.2.1, 2.1, 2.2, 2.3, 3.1,
3.1.1, 3.2, 3.3.1, 3.3.2.1, 3.3.2.2, 3.3.3.1, 3.3.1.2, 
4.1.2, 4.2.1, 4.2.2.1, 4.3, 5.1, 5.2.1, 5.3.1.1, 5.3.3, 
5.3.6.1, 5.5, 5.7, 6.1, 6.2, 7.1, 7.3.1, 7.3.2, 7.3.3.2, 
7.3.6, 7.4, 7.7, 8.6, 9., 10.3, 10.5, 10.7
Description of change
-
In Synopsis, Flow Charts, 2.2, 2.3, 3.1, 3.1.1, 
3.2, 3.3.1, 3.3.2.2, 3.3.3.2, 4.1.2, 4.2.1, 4.2.2.1, 
5.1, 5.2.1, 5.3.1.1, 5.3.6.1, 5.7, 6.1, 6.2, 6.2.1, 
7.1, 7.3.1, 7.3.2, 7.7, 9., 10.3, 10.5, 10.7: 
-
The NHL cohort will be restricted to 
DLBCL patients. The tumour assessment in 
this patient population will be based on 
RECIL 2017 criteria with FDG-PET/CT 
scans 
-
Previous treatment with a BET inhibitor is 
added as an exclusion criterion
-
The 
medical 
history 
will 
include 
specificities for DLBCL
-
Statistical analysis gives precisions when 
MTD is considered reached in the DLBCL 
indication 
-
The interim analysis for LSLV primary 
endpoint will be based only on patients with 
solid tumours in Phase Ia and not including 
the DLBCL cohort
-
Appendix 10.7 describes the response 
criteria according to RECIL 2017  in 
DLBCL patients
-
In Synopsis, Flow Charts, 1.1, 1.2.1, 3.1, 3.1.1, 
3.2, 3.3.1, 3.3.2.1, 3.3.3.1, 4.1.2, 4.2.1, 5.1.2, 


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5.1.3, 5.2.1, 5.5.1, 5.7, 6.1, 6.2, 7.1, 7.3.2, 
7.3.3.2, 7.4, 7.7, 9, 10.5: 
-
Specification of the four tumour types 
selected for the Phase Ib: SCLC, mCRPC, 
CRC and NC
-
Explanation on the way to perform tumour 
assessments in mCRPC patients when 
patients 
have 
non-evaluable 
disease 
according to RECIST 1.1, with the addition 
of bone scans and PSA measures for tumour 
assessment according to PCWG3
-
Description of additional pre-clinical work
performed on these indications
-
Sample size description for each of the four 
cohorts in Phase Ib
-
Addition of specific selection criteria: 
biopsies not mandatory for mCRPC patients 
who only have bone metastases and for NC
patients, specific inclusion criteria for 
mCRPC patients, extension of exclusion 
criteria to patients with previous BET 
inhibitor 
treatment, 
allowance 
of 
concomitant LHRH antagonists
-
Addition of specific endpoints for mCRPC 
patients, based on PSA and radiological 
PFS and explanation on tumour assessment 
for this patient population
-
Description 
of 
the 
2-stage 
Bayesian 
Hierarchical Model (BHM) approach that 
will be used for the Phase Ib with a futility 
analysis after 9 patients in each cohort.
-
Addition of further efficacy analyses in the 
mCRPC patients cohort based on PSA 
values
-
Added reference on PCWG3
-
In Flow Charts, 2.3, 5.3.3, 10.5:
-
Coagulation parameters measured more 
frequently with addition of measures on first 
visit of each new cycle and at EOT
-
Synopsis: the analysis of the primary endpoint 
of Phase Ib will happen when the last ongoing 
patient will have reached the 4 cycles of 
treatment or stopped trial treatment and 
underwent EOR visit. The report will then be 
updated when the end of trial is reached.
-
In 4.3: the compliance limits are now set 


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between 80 and 100%
-
In 5.3.6.1, DLT definition both for solid 
tumours and DLBCL patients was clarified for 
electrolytes abnormalities to specify that a 
control must be performed at 72h for precision 
of duration of the grade 3.
-
In 5.5.1.2: specification of the type of tumour 
biopsies requested (fresh or from archival tissue) 
and for which patients as well as the method of 
preparation (FFPE instead of fresh frozen) and 
the type of analytical determinations on the 
tumour samples
Rationale for change
Restriction of the NHL to a DLBCL cohort will 
allow analyses of results in a more homogeneous 
patient population. RECIL 2017 was set up for 
lymphoma evaluation. It will be more specific than 
RECIST 1.1 for evaluation in DLBCL although 
easier to use than Cheson criteria.
The choice of the four types of solid tumours to test 
in Phase Ib is based on additional pre-clinical work.
Almost half of the mCRPC patients will only 
present with bone metastases, hence necessitating 
specific tumour assessments based on bone scans 
and PSA evaluation when RECIST 1.1 would not 
be useable because of absence of target lesions to 
follow-up.
The 
increase 
frequency 
of 
monitoring 
for 
coagulation parameters is based on observation of 
factor VII decrease with another BET inhibitor as 
this might be a class effect.
The analysis of the primary endpoint in Phase Ib 
will happen without waiting for last patient last 
visit to allow earlier decisions on further 
development based on these results.
The use of 2-stage BHM approach with futility 
analysis after 9 patients in each patient cohort of 
Phase Ib will allow closing a cohort earlier if no 
efficacy signals are seen and avoid unnecessary 
exposure of additional patients of the same patient 
population.


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The upper compliance limit is now set at 100% 
because the patient must be reminded as soon as 
he/she would take more than requested per 
protocol.
The delay for controlling electrolytes abnormalities 
will avoid having to consider grade 3 drug related 
abnormalities as DLTs because no control was 
performed at 72 h to determine the duration of the 
grade 3.
Additional biomarkers’ testing has shown that 
FFPE biopsies are suitable for analyses, which is an 
easier 
handling 
of 
samples 
for 
shipments. 
Biomarkers analyses will follow the evolution of 
knowledge on BET inhibition mechanism of action.
GLOBAL AMENDMENT 6
11.6
Number of global amendment
6
Date of CTP revision
25 Jun 2018
EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients with advanced malignancies, with repeated 
administration in patients with clinical benefit
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB 
/ 
IEC 
/ 
Competent 
Authority to be notified of 
change 
with 
request 
for 
approval
Can be implemented without 
IRB 
/ 
IEC 
/ 
Competent 
Authority approval as changes 
involve 
logistical 
or 
administrative aspects only
Section to be changed
Flow Charts Schedule B, 2.3, 3.1, 3.3.1, 3.3.2.1, 
3.3.3.1, 4.1.4.1, 4.1.4.3, 4.2.1, 5.3.3, 5.3.6.1, 
5.5.1.2, 7.3.6, 9, 10.5.1, 10.5.2


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Description of change
Safety lab parameters in Flow Charts Schedule B 
and Sections 2.3, 3.1, 4.2.1, 5.3.3, 10.5.2.1, 
10.5.2.2:
-
Addition of measurement of coagulation 
parameters: aPTT, PT in seconds and INR 
on C1D8, day of tumour biopsy in C1 if 
different day than C1D8, on C1D14 and on 
Day 15 in C2, C3 and C4
-
glucose measurements must happen in 
fasting condition after an overnight fast
-
Addition of evaluation of coagulation 
factors II, V, VII and IX on C1D1 pre-dose, 
on C1D14 and on C2V1D1 in 20 patients. 
-
In case of thrombocytopenia of CTCAE 
grade 4, mandatory prophylactic platelet 
transfusion when platelet count below 
      20 000/mm3
Tumour biopsy: Flow Charts in Schedule B, 2.3, 
3.1, 3.3.1, 4.1.4.1, 5.5.1.2, 7.3.6
-
Change of tumour biopsy in C1 under 
treatment with BI 894999 from between 
Day 11 and Day 14 to between Day 8 and 
Day 11. Further change to between Day 3 
and Day 8 of C1 in case the tumour biopsy 
cannot happen in 5 of the 20 first patients 
because of abnormal coagulation and/or a 
platelet count below 50 000/mm3 on the day 
of tumour biopsy when performed between 
D8 and D11.
-
Need for coagulation parameters (aPTT, PT 
in sec and INR) to be within normal ranges 
on the day of biopsy for biopsy to be 
performed and no request for biopsies in 
patients with therapeutic level of INR due 
to treatment with vitamin K antagonist or a 
novel oral anticoagulant 
-
Clarification that tumour biopsy must 
happen between 4h and 8h after drug intake
-
Clarification that tumour biopsy should be 
taken from same lesion at baseline and 
under treatment in C1 whenever possible 
and when applicable
Sections 4.1.4.3 and 3.3.3
-
Clarification on when to interrupt BI 
894999 and when to reduce the dose


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Clarification in handling of a drug-related CTCAE 
grade 3 troponin increase is seen: interruption of 
study medication and additional cardiac testing to 
rule out a new emerging cardiotoxicity. If ruled 
out, the treatment may be resumed at a reduced 
dose (DLT rule). Intensified cardiac monitoring 
will be performed in these cases by evaluation of 
LVEF before the re-start of treatment and every 2 
cycles thereafter to detect any new impaired wall 
motility or an indisputable drop of LVEF 
(percentage points reduction of ≥10 from baseline 
value or drop of LVEF below 50%, corresponding 
to a CTCAE grade 2) which would lead to drug 
discontinuation. 
-
Addition of exclusion criterion of LVEF 
lower than 50%
Other changes:
-
Section 3.3.3.1: NC patients may have a 
performance status of 2 for inclusion and 
may have already been treated with another 
BET inhibitor prior to study entry.
-
Flow Charts in Schedule B, 10.5.1, 
10.5.2.2: suppression of mandatory bone 
aspirate and biopsy in DLBCL patients in 
screening in case of negative FDG-PET 
uptake in bone marrow and
during 
treatment, if a CR is seen.
Rationale for change
Safety lab parameters:
-
Additional 
coagulation 
measures 
and 
evaluation of coagulation factors II, V, VII 
and IX: decrease of coagulation factor VII 
has been described with other BET 
inhibitors. 
Monitoring 
of 
coagulation 
parameters in the 1367.1 study revealed that 
some 
patients 
present 
with 
mild 
prolongation of prothrombin time (PT) and 
increase in international normalized ratio 
(INR) on Day 14 of Cycle 1. The additional 
measures are taken to better characterize the 
possible influence of BI 894999 on 
coagulation
-
Hyperglycaemia has been described with 
other BET inhibitors. The fact to mandate 
fasting glucose measures after an overnight 
fast will allow to characterize a possible 


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influence of BI 894999 on the glycaemia
-
To prevent the risk of bleeding related to BI 
894999 induced thrombocytopenia, the 
protocol recommends a platelet transfusion 
for any platelet count below 20 000/mm3
Tumour biopsy:
Since the monitoring of coagulation parameters in 
the 1367.1 study revealed that some patients 
present with mild prolongation of prothrombin time 
(PT) and increase in international normalized ratio 
(INR) on Day 14 of Cycle 1 which is the time at 
which biopsy under treatment was foreseen, tumour 
biopsies will only be performed if the platelet count 
is above 50 000/mm3 without the support of a 
transfusion and coagulation parameters (aPTT, PT 
in sec and INR) are within normal limits on the day 
of the biopsy. The day of biopsy will be moved 
ahead between Day 8 and Day 11 at a time of 
Cycle 1 when platelet count has not reach yet the 
nadir under BI 894999 treatment 
To avoid the need for switching patients from a 
vitamin K antagonist treatment or novel oral 
anticoagulant to low molecular weight heparin for 
the performance of biopsies, patients under these 
oral anticoagulation therapies are not requested 
anymore to undergo tumour biopsies.
Clarification of significance of troponin CTCAE 
grade 3 considered as drug-related: CTCAE grade 
3 troponin increases were seen in several patients 
under 
BI 
894999 
without 
evidence 
of 
cardiotoxicity shown from additional cardiac 
evaluation performed in these patients and without 
any concomitant signs of myocardial infarction. 
The real significance of increased troponin in this 
patient population is not totally understood. For 
this reason, in patients showing a CTCAE grade 3 
troponin increase considered drug-related by the 
investigator, the drug intake will be interrupted as 
for any DLT until additional cardiac work-up can 
rule out emerging cardiotoxicity. In this case, the 
patient will be allowed to resume the treatment at a 
reduced dose after a new LVEF evaluation, to be 
repeated 
every 
two 
cycles 
thereafter, 
with 
instructions in case of significant drop of LVEF. 


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For this reason LVEF lower than 50% has been 
added as an exclusion criterion.
Suppression of mandatory bone aspirate and biopsy 
in DLBCL patients in screening and in case of CR 
was decided because the main objective of this 
phase I study is the characterization of the safety 
and not the efficacy. This will decrease the burden 
of examinations in DLBCL patients.
GLOBAL AMENDMENT 7
11.7
Number of global amendment
7
Date of CTP revision
05 Sep 2018
EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients with advanced malignancies, with repeated
administration in patients with clinical benefit
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB 
/ 
IEC 
/ 
Competent 
Authority to be notified of 
change 
with 
request 
for 
approval
Can be implemented without 
IRB 
/ 
IEC 
/ 
Competent 
Authority approval as changes 
involve 
logistical 
or 
administrative aspects only
Section to be changed
Clinical Trial Protocol Synopsis, footnote 5 of 
Flow Chart Schedule B first cycle, Abbreviations, 
2.1, 2.3, 3.1, 3.3.1, 3.3.2.1, 3.3.3, 3.3.4.1, 4.1.1, 
4.1.3.1, 4.1.4.2, 4.1.4.3.1, 4.1.8, 5.3.5.1, 5.3.6.1, 
5.5.1.2.2, 7.7, 8, 8.1, 8.2, 8.3.2, 8.4.2, 8.6, 9, 10.6
Description of change
Clinical Trial Protocol Synopsis, footnote 5 of 
Flow Chart Schedule B first cycle, 2.1, 2.3, 3.1, 
3.1.1, 3.3.2.1, 3.3.4.1, 4.1.3, 4.1.4.2, 8.1
-
NC cohort will recruit up to 20 patients 
instead of an estimated number of 5 


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patients, increasing the sample size by 15 
patients, up to 158 patients in total for the 
study
-
NC
cohort will allow recruitment of 
patients ≥15 years of age at the time of 
consent. When patients are aged between 15 
and <18 years, they will have to sign an 
assent form while parents (both or one 
according to national regulation) or the 
legal guardian must sign informed consent 
forms
-
NC patients may be included even with 
non-measurable disease
-
for NC patients, washout for monoclonal 
antibodies must be discussed with the 
sponsor
-
Addition of a DMC meeting once the first 
and once the second adolescent patient 
completes Cycle 1 to assess whether the 
adult dose is tolerable in adolescents
-
NC patients who are progressing at the end 
of a cycle but who still have a clinical 
benefit and no other treatment option 
available may continue receiving the study 
treatment as long as they derive benefit.
-
Addition of reference R18-2451
Sections 3.1, 3.3.4.1, 4.1.4.2, 4.1.4.3.1, 5.3.6.1
-
Removal of the maximum treatment break 
period between two cycles: if a patient 
requires more than an additional break of 14 
days in Schedule B, in addition to the one 
week off of the schedule, the patient is 
allowed to start a next cycle. If it is due to a 
drug related AE, the treatment should be 
continued at a reduced dose. This is also 
updated in the DLT definitions for solid 
tumours and for DLBCL
-
Removal of the limitation of dose reduction 
to twice for a single patient
Section 2.3
-
Explanation on increased troponin levels 
handling 
is 
updated 
to 
match 
the 
information in the IB
-
Addition of reference R18-2390 on the 


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BET-inhibitor GSK 525762 publication 
reporting prolonged coagulation times
Sections 3.1, 3.1.1
-
DMC meetings will happen on regular basis 
as well during phase Ib (at least once every 
3 months)
Section 3.3.3
-
Radiotherapy given with curative intent is 
not allowed in the four weeks before the
start of trial treatment or during the trial 
while palliative radiotherapy is allowed 
without wash out
Sections 4.1.8, 8, 8.1, 8.2, 8.3.2, 8.4.2, 8.6
-
As the trial will be extended also to the 
USA to help with the recruitment of NC
patients, the specific requirements for USA 
were added and each time speaking about 
IEC, it is now referring to IRB / IEC
Section 4.2.2.1 and Appendix 10.6
-
The list of CYP1A2, CYP 2C8 and CYP 
3A4 was updated to clinically relevant 
substrates.
Section5.5.1.2.2: 
-
analyses of the tumour biopsies will include 
pharmacodynamics changes such as the 
HEXIM1 modulation and for efficacy will 
include the analysis of modulation of target 
genes such as Myc and genes associated 
with apoptosis
Rationale for change
Extension of NC cohort up to 20 patients and 
allowance of NC patients ≥ 15 years of age at the 
time of consent, allowance of NC patients who are 
progressing under trial treatment to continue with 
the treatment if they derive clinical benefit and no 
other treatment option is available: NC is a very 
aggressive malignancy for which no standard of 
care has been established. As this rare disease is 
observed in adolescents and young adults, for this 
indication, the trial will allow inclusion of minor 
patients aged 15 years or more. Indeed, the dose, 
safety and metabolism in adolescents of ≥15 years 


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are expected to be similar to adults because body 
size is expected to be close to adults and organ 
maturation is expected to be completed. However, 
to confirm the hypothesis that safety is similar in 
adolescents and adults, a mandatory DMC meeting 
will take place after the first and second adolescent 
patient complete Cycle 1 to assess whether the 
adult dose is tolerable in adolescents. In this 
population the benefit is expected to outweigh the 
risks because there is no standard treatment 
available and BI 894999 is specifically targeting 
the NUT-BRD fusion that is characteristic for the 
disease. The trial will also be extended to the USA 
to help with the recruitment of NC patients.
NC patients will be allowed in the trial even if they 
have no measurable disease because PFS will also 
be an important point of efficacy evaluation in 
addition to RECIST evaluation in this rare and 
aggressive disease and to give a maximum of NC
patients the possibility to participate to the trial 
when no other treatment option is available.
Removal of the maximum treatment break period 
between two cycles and removal of the limitation 
of dose reduction to twice for a single patient: this 
is to avoid that a patient deriving clinical benefit 
from the drug would have to stop if an AE does not 
recover within 14 days or that a patient who still 
has drug related AEs necessitating a further dose 
reduction after having already had two would need 
to stop the trial drug while deriving benefit from it.
DMC meetings will also be held in an official way 
in the phase Ib to make sure there is close follow-
up on the global safety profile of the drug and 
decisions on further treatment of the patients in the 
trial are made by all principal investigators together 
with the BI trial staff.
Clarification of the differentiation between curative 
and palliative radiotherapy in the exclusion criteria
Some additional precision on the intended analyses 
on tumour tissue from biopsies


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GLOBAL AMENDMENT 8
11.8
Date of Amendment
05 Nov 2018
EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients with advanced malignancies, with repeated 
administration in patients with clinical benefit
Global 
Amendment 
due 
to 
urgent safety reasons
Global Amendment 
Section to be changed
Clinical Trial Protocol Synopsis, Flow Charts 
Schedule B first cycle and second and further 
treatment cycles, 2.3, 3.3.1, 3.3.2, 3.3.3, 4.1.1, 
4.1.4.1, 5.1.2, 5.1.3, 5.2.1, 5.3.3, 5.3.6.1, 5.5.1, 
5.5.1.2, 7.3.2, 7.3.3.2, 10.5.1, 10.5.2, 10.5.3, 10.5.4
Description of change
Trial synopsis, Sections 5.1.2, 5.1.3, 7.3.2 and 
7.3.3.2:
-
disease control rate is put as a further 
endpoint and not a secondary endpoint 
anymore
-
precision that a minor response according to 
RECIL 2017 is not included in the 
evaluation of objective responses
Flow Charts for Schedule B, Sections 2.3, 5.3.3, 
10.5.1, 10.5.2 and 10.5.3
-
Clarification that troponin hs is required 
each time a safety lab is requested per 
protocol and that the highly sensitive 
troponin assay may be a T hs or a I hs assay
Section 5.3.3: coagulation parameters
-
Addition that additional coagulation 
investigations are to be performed as 
appropriate when abnormal coagulation 
parameters are detected in the routine safety 
laboratory assessments
Flow Chart for Schedule B Cycle 1 and Sections 
3.3.3.1, 3.3.3.2, 5.3.3 and 10.5.1:
-
Addition of Hep B, Hep C and HIV testing 
at screening to exclude active infection


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Flow Charts for Schedule B, Sections 5.2.1, 10.5.1, 
10.5.3 and 10.5.4
-
Imaging evaluation for tumour assessment 
at screening and for EOT and FU do not 
need to be repeated if performed in the last 
6 weeks (prior to start of trial treatment at 
screening) instead of 4 weeks.
Section 5.3.6.1
-
Addition in the DLT definitions of CTCAE 
grade≥ 3 thrombocytopenia coupled with 
grade ≥ 2 of bleeding
Section 3.3.2:
-
Minimal previous standard treatments are 
added for CRC, SCLC, mCRPC and 
DLBCL patients
Sections 3.3.1, 3.3.2 inclusion criterion 12, 5.5.1, 
5.5.1.2 and 10.5.1: 
-
clarification that tumour biopsies are 
optional for NC patients and not required 
for patients with therapeutic INR because of 
treatment with a vitamin K antagonist or a 
novel oral anticoagulant 
4.1.1 and 4.1.4.1: the drug intake is as follows:
Once daily intake, in the morning, after an 
overnight fast, 1 hour before breakfast, to swallow 
without crushing, with at least 250 mL of water 
(except for the food interaction cohort.
Rationale for change 
These changes are performed further to the review 
of protocol version 7.0 by the BfArM authorities of 
Germany and of protocol version 8.0 by the US 
FDA.
The change of request of an overnight fast before 
drug intake is adapted further to the results from 
the 
 sub-study in phase Ia solid tumours 
which showed that food intake before drug intake 
caused approximately 30% decrease in the extent 
of absorption. There was no or only very limited 
effect of food on the rate of absorption.


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GLOBAL AMENDMENT 9
11.9
Date of Amendment
05 Feb 2019
EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients with advanced malignancies, with repeated 
administration in patients with clinical benefit
Global 
Amendment 
due 
to 
urgent safety reasons
Global Amendment 
Section to be changed
Clinical Trial Protocol Synopsis, Flow Charts for 
Schedules A and B and addition for Schedule C 
first cycle and second and further treatment cycles, 
1.2.1, 1.2.3,1.3, 2.2, 3.1, 3.1.1, 3.2, 3.3.1, 3.3.2.1, 
3.3.3.2, 4.1.1, 4.1.2, 4.1.3, 4.1.4, 4.1.6, 4.2.1, 5.1.1, 
5.1.2, 5.1.3, 5.2.1, 5.3.6.1, 5.5, 6.1, 6.2, 6.2.1, 7.1, 
7.3.1, 7.3.2, 7.3.3.1, 7.3.6, 7.4, 7.7, 8, 8.6, 9.1, 
10.2.1, 10.3, 10.4, 10.5
Description of change
Synopsis,  Flow Charts for Schedule C first cycle 
and for second and further cycles, 2.2, 3.1, 3.1.1, 
4.1.1, 4.1.2, 4.1.3.1, 4.1.3, 4.1.4, 5.1.1.1, 5.1.2, 
5.2.1, 5.3.6.1, 6.1, 6.2, 7.1, 7.3.1, 7.3.2, 7.3.6, 7.4, 
7.7, 8, 10.2.1, 10.3.2, 10.4, 10.5:
-
Addition of a third intermittent schedule, 
Schedule C, to be tested in Phase Ia, with a 
loading dose on Day 1 followed by a 
maintenance dose on the six next days and a 
week off, repeated every two weeks in 4-
week cycles
This implies a change in the total number of 
patients with 18 additional patients foreseen to 
reach and confirm MTD in Schedule C.
Schedule C recruitment will start in Belgium in 
the two sites participating since the beginning 
of the study in July 2015 and with priority in 
these sites to recruitment for Schedule C (with 
the possibility later on to extend to further 
Belgian sites if needed) and with priority in 
these sites to recruitment for Schedule C.
When a dose reduction is needed in Schedule C 
for a single patient, it will happen with a 
decrease by steps of 1 mg for the loading dose 
and 0.5 mg for the maintenance dose, each time 


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a reduction is necessary, not going lower than 1 
mg for the maintenance dose.
Synopsis, 1.2.1, 1.3, 2.2, 3.1, 4.1.1, 4.1.2, 4.1.3, 
4.1.6, 5.1.3, 6.1, 7.1, 7.4, 10.3.1
-
Clarification on what already happened in 
the trial until this version of the protocol 
and what still needs to be done for Phase Ia 
and Phase Ib. What already happened is 
now put in past tense, what is ongoing is in 
the present tense and what will happen in 
the future is in the future tense
-
Clarification that 0.2 mg, 5 mg and 20 mg 
tablets strengths are no longer available for 
the trial
3.3.3.2
-  Deletion of request for a stable dose of 
steroids in the last four weeks prior to study 
treatment of a DLBCL patient 
Both Flow Charts for Schedule B, 3.3.1, 5.5.1,
10.5.1, 10.5.2 :
-
Clarification that the EDTA DNA sample is 
mandatory when there is tumour tissue 
obtained from the patient, being it archival 
tumour tissue or tissue from a fresh tumour 
biopsy, but only to be taken once in the 
course of the trial for patients having 
consented to a fresh tumour biopsy or 
sending of archival tumour tissue
-
Clarification that the on treatment biopsy in 
Phase Ib may remain optional if no easily 
accessible lesions are available
3.1 
- clarification that the patient’s overnight 
hospitalization in Cycle 1 for the periods of 
intensive PK is left to the discretion of the 
investigator 
and 
based 
on 
patient’s 
convenience but is not mandatory
3.3.2.1, criterion 10 c.:
-
Addition of bevacizumab for patients 
eligible to this treatment and of an anti-
EGFR in RAS wild type metastatic CRC


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3.3.2.2, criterion 1:
-
Specification of CAR-T cells and other 
non-listed therapies as part of standard 
possible treatment, depending on the 
country where the patient is treated
4.2.1: deletion of the request to register a new anti-
cancer treatment after the REP on a separate page 
of follow-up therapy.
6.2.1: deletion of the request to record the date of 
progression after previous line(s) of therapy for 
advanced or metastatic disease.
Rationale for change 
-
Further to the results from modelling of 
toxicity observed on thrombocytes and 
results of PK and pharmacodynamics, an 
additional dose escalation will be performed 
with a Schedule C
-
As the protocol is now ongoing since July 
2015 and several changes were brought to 
the design, it will make the understanding 
easier for new readers on what was done 
and what is still ongoing, explaining the 
DMC decisions until now.
-
In DLBCL patients in need of a treatment, it 
is not always possible to wait until they 
reach a stable dose of corticosteroids for 
four weeks before treatment as the steroids 
are used to allow the transition between 
previous treatment and the trial treatment.
-
It was unclear in the previous versions of 
the protocol how many EDTA DNA 
samples had to be performed for a single 
patient and when.
-
For some patients, it may be difficult to 
obtain a second tumour biopsy a few weeks 
after the first one if there is no easily 
accessible lesion and the difficulty to obtain 
a second biopsy should not prevent patients 
in need for an experimental treatment from 
entering the trial
-
Overnight hospitalization on the intensive 
PK periods is not mandatory if not deemed 
necessary by the investigator and/or not 
deemed more convenient for the patient


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-
In sections 3.3.2.1,Criterion 10.c. and 
section 3.3.2.2, Criterion 1, the clarification 
on specification of previous treatment is 
performed further to a request from the 
French Agency “ANSM”
-
No record on a specific page of which next 
line of anti-cancer treatment is given and no 
record of dates of previous cancer 
progressions were performed until now and 
are not necessary in this early stage trial
GLOBAL AMENDMENT 10
11.10
Date of Amendment
24 Sep 2019
EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients with advanced malignancies, with repeated 
administration in patients with clinical benefit
Global 
Amendment 
due 
to 
urgent safety reasons
Global Amendment 
Section to be changed
Synopsis, Flow Charts, Abbreviations, 1.3, 2.2, 3.1, 
3.1.1, 3.2, 3.3.2 (inclusion criterion 12), 3.3.3.1 
(exclusion criteria 13 and 14), 4.1.2, 4.1.4, 4.1.4.2, 
4.2.2.1, 5.1.1.1, 5.1.1.2, 5.1.2, 5.1.3, 5.2.1, 5.3.1.1, 
6.1, 6.2, 6.2.3.1, 6.2.3.2, 7.1, 7.3, 7.3.1, 7.3.2, 
7.3.3.2, 7.7, 8, 8.6, 10.3.2, 10.5
Description of change
Overall change in the whole document: the naming 
for NUT midline carcinoma is adapted to NUT
carcinoma with abbreviation of NC instead of 
NMC
Changes for the NC patients: Synopsis,  Flow 
Charts for Schedules B and C, 1.3, 2.2, 3.1 (design 
for Phase Ib), 3.1.1, 3.3.2.1, 3.3.3.1, 4.1.2, 4.2.2, 
5.1.1.2, 5.2.1, 6.1, 6.2.1, 6.2.3.1, 7.1, 7.3.2, 7.3.3.2,  
7.7
-
Possibility for DMC to recommend adding 
a NC cohort treated with Schedule C in 
Phase Ib once MTD is known in Phase Ia in 
patients with solid tumours, in order to 
recommend the schedule and dose for 
further development in NC patients. If the 


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DMC recommends the start of NC cohort 
with Schedule C, the Schedule B NC cohort 
will then be closed to recruitment. If the 
DMC recommends Schedule B, recruitment 
of NC patients will continue with Schedule 
B and Schedule C NC cohort will not open
-
Total number of patients is estimated to up 
to 196 with an addition of up to 40 patients 
in Schedule C NC cohort and up to 40 
patients in Schedule B NC cohort if 
Schedule C NC cohort is not opened to 
recruitment
-
Addition of overall survival (OS) as 
secondary endpoint for the NC patients who 
consented to collect this information
-
Addition of overall clinical benefit as 
judged by investigator and of time to 
treatment failure for the NC patients in the 
further endpoints
-
Germany will now also participate to the 
recruitment of patients aged between 15 and 
<18 years with MRI used for the imaging 
assessments (no CT scans for the trial 
imaging assessments
in this adolescent 
population)
-
NC patients do not need to have a 
progressive disease shown by RECIST 1.1 
in the past 6 months (inclusion criterion 12)
-
Other investigational or marketed anti-
cancer treatments are not allowed in the 
previous two weeks or five times the half-
life of the drug for NC patients (exclusion 
criteria 13 and 14)
-
For NC patients, allowance to perform 
palliative radiotherapy on target lesions as 
well as on non-target and to lesions 
indicating progressive disease for patients 
who are deriving clinical benefit from the 
study treatment
-
Addition to the data of the collection of the 
methodology used to diagnose NC, of the 
NUT fusion partner and of the threshold for 
a positive NC
-
Possibility of addition of a fifth cohort in 
Phase Ib in the statistical model: NC cohort 
treated with Schedule C


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Synopsis, Flow Charts for Schedule C, 1.3, 2.2, 
3.1, 3.1.1, 3.2, 4.1.2, 4.1.4, 4.1.4.2, 5.1.1.1, 5.1.2, 
6.1, 7.1, 7.3.1, 7.3.2, 7.7, 10.5
-
The MTD will also be determined for 
Schedule C in patients with DLBCL and 
once both MTD in Schedules B and C are 
known for this patient population, the DMC 
will recommend the best Schedule to select 
between B and C to further extend the MTD 
cohort
-
In the first cohort of DLBCL patients 
treated with Schedule C, the loading dose 
will be 4 mg and the maintenance dose 2 
mg
-
For the determination of the MTD in 
Schedule B in DLBCL, a total of 12 
DLBCL patients treated with Schedule B 
will be sufficient
mCRPC and CRC cohorts of expansion Phase Ib 
with Schedule B were closed for futility.
Flow Charts Schedule A: the missing cross for the 
collection of body weight at the FU visit was 
added.
RDC 
and
Electronic 
Data 
Capture
(EDC)
mentioned as data capture systems
Rationale for change 
Changes for the NC patients: Synopsis,  Flow 
Charts for Schedules B and C, 1.3, 2.2, 3.1 (design 
for Phase Ib), 3.1.1, 3.3.2.1, 3.3.3.1, 4.1.2, 4.2.2, 
5.1.1.2, 6.1, 6.2.1, 6.2.3.1, 7.1, 7.3.2, 7.3.3.2,  7.7
-
If Schedule C appears to have a better 
tolerability profile than Schedule B in 
patients with solid tumours, NC patients 
may also better benefit from Schedule C 
and have a better treatment coverage 
without interruptions due to toxicity such as 
thrombocytopenia.
-
At the present time there is no recognized 
standard treatment for NC patients. The 
number of patients in this trial is extended 
for NC patients, being it in cohort of 
Schedule B or in cohort with Schedule C if 
Schedule C appears better, to make it 


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possible for patients to have the possibility 
to join a trial until opening of other trials in 
this indication.
-
Because NC patients may be entered in the 
trial without target lesions, there is a need to 
be able to evaluate the efficacy with other 
criteria than the RECIST 1.1 imaging. This 
is the reason for adding overall survival for 
NC patients. Also because patients may 
continue beyond progression if they derive 
clinical benefit, time to treatment failure 
was added to the PFS. Overall clinical 
benefit judged by the investigator is an 
indirect way of adding the quality of life 
dimension in this very ill patient population
-
Germany further evaluated the possibility of 
including adolescent patients without the 
radiation burden of imaging by CT scan. 
They agreed to include adolescent patients 
aged between 15 and < 18 at the condition 
that these patients would not undergo CT 
scans but only MRI imaging evaluations. In 
other countries, the choice of CT or MRI is 
left to the investigator for all patients but 
the same method is to be used along the 
study for a single patient
-
Inclusion criterion 12 of section 3.3.2: As 
there is no established effective treatment 
for NC patients, a newly diagnosed NC
patient can be included in the study if the 
investigator considers that the patient has 
no other treatment options.
-
Exclusion criteria 13 and 14: because NC 
patients are usually progressing fast and 
cannot afford long wash-out periods 
without treatment, the maximum wash-out 
duration for drug with longer half-lifes was 
reduced to 2 weeks instead of 4.
-
Section 4.2.2.1: amendment introduced in 
order to allow NC patients who have a 
mixed radiological response to the study 
treatment to remain on treatment if the 
investigator considers that the patient is 
deriving clinical benefit. Lesions that are 
irradiated will not be considered evaluable 
as per RECIST 1.1


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-
Recording of additional characteristics of 
the NC diagnosis should help better 
defining the patient population deriving the 
most benefit from the BI 894999 treatment
The addition of MTD determination of Schedule C 
in a DLBCL patient population is aimed to try and 
overcome the toxicity mainly thrombocytopenia 
grade 4 seen with Schedule B higher doses and to
be able to increase the total dose given to these 
patients with less interruptions due to toxicity.
Flow Charts of Schedule A: addition of missing 
crosses for body weight at FU to correct an 
omission in previous versions of the protocol
Electronic Data Capture (EDC) mentioned as data 
capture system in addition to RDC because BI will 
transition the trial from an actual RDC system to an 
EDC system during the month of September 2019.
GLOBAL AMENDMENT 11
11.11
Date of Amendment
24 Jun 2020
EudraCT number
2015-001111-12
BI Trial number
1367.1
BI Investigational Product(s)
BI 894999
Title of protocol
An open label, Phase Ia/Ib dose finding study with 
BI 894999 orally administered once a day in 
patients with advanced malignancies, with repeated 
administration in patients with clinical benefit
Global 
Amendment 
due 
to 
urgent safety reasons
Global Amendment 
Section to be changed
Synopsis, Flow Charts, 1.3, 2.2, 2.3, 3.1, 3.3.2.1, 
3.3.3, 4.1.2, 4.1.4, 4.1.4.1, 4.1.4.2, 4.1.4.3.1, 5.3.4, 
5.4.2.2, 5.5.1.1, 6.1, 6.2, 7.7, 10.2.1: 3, 10.2.1: 4, 
10.5.2, 10.5.3
Description of change
Synopsis: 
-
increase of the number of participating 
countries up to 10
Synopsis and Section 7.7: 
-
adaptation of the sample size to reflect 
actual number of patients already treated 


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and planned ones still to be recruited
Sections 2.3, 3.3.3, 3.3.4.1, 4.1.4, 4.1.4.3.1: 
-
Section 2.3: statement of evaluation of the 
benefit-risk in relation to the COVID-19 
pandemic
-
Section 3.3: exclusion of active or recent 
infection within previous 6 weeks with 
SARS-CoV-2
-
Section 3.3.4.1: withdrawal of a patient who 
would 
have 
a 
COVID-19 
infection 
confirmed
a 
PCR 
test 
during 
his 
participation to the trial and for whom the 
benefit-risk balance would not be in favour 
of resuming treatment after recovery
-
Section 
4.1.4: 
possibility 
for 
the 
investigator to judge the benefit-risk 
balance for a patient’s safety to continue 
trial treatment but to restrict site visits and 
perform safety assessments via local tests 
and phone visits with the patients during 
COVID-19 pandemic
-
Section 4.1.4.3.1: interruption of BI 894999 
treatment in case of COVID-19 infection 
until recovery and then decision by 
Investigator and Sponsor if treatment may 
be resumed or not according to benefit-risk 
balance
Changes for the NC and DLBCL patients from 
Schedule C starting from protocol version 12.0 
onwards: 
-
addition of specific Flow Charts for Cycle 1 
and further Cycles
-
Sections 4.1.4.1 and 10.5.2: suppression of 
Day 2 part of the visit 1 and for the need to 
keep patients after 4h post-dose on Day 1 in 
Cycle 1
-
Flow Chart for Schedule C DLBCL and NC 
patients and Section 10.5.2; possibility to 
perform Cycle 1 Visit 2 of Day 8 locally 
with a remote phone call visit by the 
Investigator, if allowed by local regulations
-
Sections 6.2 and addition of 10.2.1: 4: 
decrease in the number of PK blood 
samples with suppression of PK on Day 15 


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of Cycle 1
-
Sections 5.5.1.1 and 10.2.1: 4: decrease in 
the number of pre-specified PGx blood 
samples 
for 
patients 
recruited 
under 
protocol version 12.0 
-
Section 6.1: possibility for a patient unable 
or unwilling to attend a clinic visit to have 
the evaluation performed by a remote visit 
if deemed safe by the Investigator, after 
agreement with the Sponsor, if allowed by 
local regulations
-
Section 4.1.4.2: after Cycle 1, the tests of 
Day 15 visit may be performed locally with 
a phone call visit with the investigator to 
discuss results and safety with the patient, if 
allowed by local regulations
-
Section 4.1.4.2: starting from Cycle 6 
onwards, tests of Visit 1 of even Cycles 
may be performed locally followed by a 
phone call visit with the Investigator, if 
allowed by local regulations
-
Section 4.1.4.2: if deemed safe by the 
Investigator to have Visit 1 of even cycles 
performed locally with a phone call visit, 
medication dispensation may happen for 
two cycles at uneven cycles, starting from 
Cycle 5 or a direct shipment from site to 
patient may happen provided that the 
shipment occurs with a courier approved by 
the Sponsor in order to ensure correct 
conditions of shipments, if allowed by 
country regulations. 
-
Flow Charts for Schedule C NC and 
DLBCL patients, Sections 5.3.4, 10.5.2: 
ECGs should be performed in triplicate for 
central reading by CRO but this is not 
always possible for the sites. So, the 
recommendation is to perform it in 
digitalized way and in triplicate whenever 
possible but if not, when patient is on site, it 
should be digitalized with ECG device 
provided by the central reading CRO and if 
not done on site, the original tracing must 
be provided to the central reading CRO for 
assessment.


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Flow Chart for Schedule C: specification of the 
Flow Charts for Solid Tumour Patients from Phase 
Ia for whom no changes except the suppression of 
the urine collection for PK.
Sections 5.4.2.2 and 10.2.1: 3: suppression of urine 
collection for PK fo all patients starting with 
protocol version 12.0
Sections 1.3, 2.2, 3.1, 3.1.1, 4.1.2, 6.1: update of 
the actual situation of the trial at the time of the 
protocol version 12.0 with MTD determined for 
Schedule C in DLBCL patients, the opening of 
Schedule C in DLBCL patients, the MTD 
determination of Schedule C in patients with solid 
tumours and the decision of DMC to open the NC 
cohort to Schedule C while closing the Schedule B 
cohort. These updates are also reflected in the use 
of past tense for parts of the study already finished 
at this stage of protocol revision.
Section 3.3.2.1: inclusion criterion 2: in Germany
and in South Korea, only legally adult patients may 
be included in the trial.
Rationale for change 
The COVID-19 pandemic requires adaptations to 
the benefit-risk evaluation for ongoing and new 
patients in the trial with additional guidance to 
ensure patient’s safety by decreasing in-patients 
visits to the sites if needed and by giving 
instructions in case a patient is tested positive to 
SARS-CoV-2.
Changes for the DLBCL and NC patients of 
Schedule C: decrease in the number of visits and in 
the number of PK and biomarkers samples is done 
to lighten the burden of the trial for these heavily ill 
patients. The allowance for some visits to be 
performed remotely by the investigator for these 
patients after all tests having been done locally is 
also to decrease the number of travels to the 
minimum acceptable according to the individual
benefit-risk
evaluation 
as 
judged 
by 
the 
Investigator in the post-COVID-19 situation with 
possible travel restrictions. For the same reason, the 
protocol version 12.0 allows the possibility to 
dispense the drug for two consecutive cycles 
starting from Cycle 5 onwards if the patient is 
tolerating the drug well or to have a direct shipment 


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from site to patient in secured acceptable shipment 
conditions, if allowed by the country regulations.
Stop of urine collection for PK because the urine 
PK profile of the drug is enough characterized with 
the already collected samples.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03063854
14.0
clinical-trial-protocol-version-12
An open label, Phase Ia/Ib dose finding study with BI 894999 orally administered
once a day in patients with advanced malignancies with repeated administration in
patients with clinical benefit
Author-Clinical Trial Leader
25 Jun 2020 09:54 CEST
Author-Trial Clinical
Pharmacokineticist
25 Jun 2020 10:06 CEST
Author-Trial Statistician
25 Jun 2020 14:16 CEST
Approval-Therapeutic Area 
25 Jun 2020 14:26 CEST
Approval-Team Member Medicine
29 Jun 2020 07:35 CEST
Verification-Paper Signature
Completion
29 Jun 2020 08:53 CEST


Boehringer Ingelheim 
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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03063854
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SAP_001.pdf: 
001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c38064615-01
BI Trial No.:
1367.1
Title:
An open label, Phase Ia/Ib dose finding study with BI 894999 
orally administered once a day in patients with advanced 
malignancies with repeated administration in patients with clinical 
benefit
Revised protocol version 12.0 [c03063854-14]
Investigational
Product(s):
BI 894999
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
19 JAN 2022 SIGNED
Version:
Revised
Page 1 of 41
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2022 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights 
reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim                                                                                   
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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...............................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ...9
5.
ENDPOINTS(S) ................................................................................10
5.1
PRIMARY ENDPOINT(S) ..............................................................10
5.1.1
Phase Ia ..............................................................................................10
5.1.2
Phase Ib..............................................................................................10
5.2
SECONDARY ENDPOINT(S) ........................................................10
5.2.1
Key secondary endpoint(s)...............................................................10
5.2.2
Secondary endpoint(s) ......................................................................11
6.
GENERAL ANALYSIS DEFINITIONS........................................20
6.1
TREATMENT(S)..............................................................................20
6.2
IMPORTANT PROTOCOL DEVIATIONS .................................21
6.3
SUBJECT SETS ANALYSED.........................................................23
6.5
POOLING OF CENTRES ...............................................................24
6.6
HANDLING OF MISSING DATA AND OUTLIERS..................24
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS.25
7.
PLANNED ANALYSIS....................................................................26
7.1
DEMOGRAPHIC AND OTHER BASELINE 
CHARACTERISTICS......................................................................27
7.2
CONCOMITANT DISEASES AND MEDICATION...................27
7.3
TREATMENT COMPLIANCE......................................................27
7.4
PRIMARY ENDPOINT(S) ..............................................................27
7.5
SECONDARY ENDPOINT(S) ........................................................28
7.5.1
Key secondary endpoint(s)...............................................................28
7.5.2
(Other) Secondary endpoint(s) ........................................................28


Boehringer Ingelheim                                                                                   
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7.7
EXTENT OF EXPOSURE...............................................................31
7.8
SAFETY ANALYSIS........................................................................31
7.8.1
Adverse Events..................................................................................31
7.8.2
Laboratory data ................................................................................34
7.8.3
Vital signs...........................................................................................35
8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION...............................................................................38
9. 
REFERENCES..................................................................................39
11.
HISTORY TABLE............................................................................41


Boehringer Ingelheim                                                                                   
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LIST OF TABLES
Table 5.2.2: 1 Censoring rules for PFS ....................................................................................12
Table 5.2.2: 2 Censoring rules for OS......................................................................................13
Table 6.1: 1
Definition of analysing treatment periods for safety analysis ..........................20
Table 6.2: 1
Important protocol deviations...........................................................................21
Table 7.8.1: 1 Definitions of Special Search Categories .........................................................33
Table 11: 1
History table .....................................................................................................41


Boehringer Ingelheim                                                                                   
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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis Dataset
AE
Adverse Event
AESI
Adverse Event of Special Interest
ATC
Anatomical, Therapeutic, Chemical
AUC
Area Under the Curve
BI
Boehringer Ingelheim
BIcMQ
Boehringer Ingelheim customised MedDRA Query
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
BLRM
Bayesian logistic regression model
BOR
Best Overall Response
BRPM
Blinded report planning meeting
C
Concentration
CR
Complete Response
CRF
Case Report Form
CT
Concomitant Therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DC
Disease Control
DLT
Dose Limiting Toxicity
ECG
Electrocardiogram
ECGS
ECG Set
EoT
End of Text
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
ICH
International Conference on Harmonisation
IPV
Important Protocol Violation
LVEF
Left Ventricular Ejection Fraction
MedDRA®
Medical Dictionary for Regulatory Activities


Boehringer Ingelheim                                                                                   
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Term
Definition / description
MQRM
Medical Quality Review Meeting
MTD
Maximum Tolerated Dose
MTDS
MTD Set
NHL
Non-Hodgkin Lymphoma
OR
Objective Response
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-Free Survival
PGS
Pharmacogenomics Set
PK
Pharmacokinetics
PKS
Pharmacokinetics analysis Set
PR
Partial Response
PSA
Prostate-Specific Antigen
PT
Preferred Term
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
RPM
Report Planning Meeting
SAE
Serious Adverse Event
ScS
Screened Set
SD
Stable Disease
SDL
Subject Data Listing
SS
Steady State
SSC
Special Search Category
StD
Standard deviation
SMQ
Standardised MedDRA query
SOC
System Organ Class
TBD
To Be Determined
ToC
Table of contents
TS
Treated Set


Boehringer Ingelheim                                                                                   
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Term
Definition / description
TSAP
Trial statistical analysis plan
ULN
Upper Limit of Normal
UPROZ
Urine Protein
WHO DD
World Health Organization Drug Dictionary


Boehringer Ingelheim                                                                                   
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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 Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomization.
SAS® Version 9.4 will be used for all analyses.
R Version 4.0.2 and JAGS Version 4.3.0 or the latest versions will be used for the BLRM 
analyses.


Boehringer Ingelheim                                                                                   
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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Due to the decision to discontinue the development of BI 894999 without expected out-
licensing activities, an Abbreviated Report will be written. The analyses on safety will be 
conducted as stated in CTP, and an abbreviated set of tables and listings will be provided for 
other parts. Below are the main changes to the statistical methods described in the CTP and 
subsequent amendments are detailed in this TSAP:

For the analysis of secondary efficacy endpoint objective response, only frequency tables 
including the corresponding percentages will be calculate for each cohort. The Bayesian 
hierarchical modelling analysis for Phase Ib part for the shrinkage estimators of response 
rate endpoints will not be carried out. 

 
 

Further efficacy analyses will not be conducted.

Where considered appropriate, the potential impact of Coronavirus Disease 2019 
(COVID-19) on the study will be assessed by producing additional subject data listing of 
protocol deviations.

The collected urine samples for the pharmacokinetic analysis will not be further analysed. 
Only information on urine intervals sampling times, urine volumes and urine 
concentrations of BI 894999 (if within their stability period) will be presented in subject 
data listing format.
The detailed changes to the pre-planned analyses are provided in Sections 5 and 7 below.


Boehringer Ingelheim                                                                                   
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5.
ENDPOINTS(S)
The Phase Ia/Ib trial consists of dose escalation part (Phase Ia) and expansion part (Phase Ib). 
The main objective of the dose escalation part of the trial is to determine the maximum 
tolerated dose (MTD) of BI 894999 using three different schedules (Schedule A with 
continuous dosing, Schedule B with two weeks on treatment and one week off in 3-week 
cycles, Schedule C with a loading dose on Day 1 followed by a maintenance dose on the six 
next days and a week off, repeated every two weeks in 4-week cycles) in patients with solid
tumours and to determine the MTDs using Schedules B and C in patients with diffuse large B-
cell lymphoma (DLBCL) and provide safety data in terms of drug-related adverse events 
(AEs) for the recommendation of the dose and schedule of treatment for the expansion Phase 
Ib of this trial.
The main objective of the expansion part is to further collect safety information at the dose 
recommended by the data monitoring committee (DMC) for Phase Ib in patients with 
colorectal cancer (CRC), metastatic castrate resistant prostate cancer (mCRPC), small cell 
lung cancer (SCLC) and NUT carcinoma (NC) in Schedule B; and in patients with NC in 
Schedule C.
Please refer to Section 5.1 and 7.3 in the CTP for more details on the endpoints for this study.
5.1
PRIMARY ENDPOINT(S)
5.1.1
Phase Ia

Number of patients with DLT (defined in Section 5.3.6.1 of the CTP) observed during the 
first treatment cycle (the first 21 days for Schedules A and B, the first 28 days for 
Schedule C) for each schedule in patients with solid tumours and for the Schedules B and 
C in the DLBCL cohort.
The MTD is defined as the highest dose of BI 894999 with less than 25% risk of the true DLT 
rate being above 33% during the MTD evaluation period (i.e., the first treatment cycle). The 
MTD determination will be based on the treated set population in Phase Ia excluding patients 
that have to be replaced for analysis of the MTD.
5.1.2
Phase Ib

Number of patients with DLTs observed during the entire treatment period (as assessed 
approximately every 3 weeks, at the end of each new cycle after Cycle 2 for Schedule B, 
every 4 weeks for Schedule C in the NC cohort) for patients enrolled and treated in the 
Phase Ib part, i.e., SCLC patients, mCPRC patients, CRC patients, Schedule B in NC 
patients and Schedule C in NC patients.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
No key secondary endpoint is defined for this study.


Boehringer Ingelheim                                                                                   
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5.2.2
Secondary endpoint(s)
For Phase Ia only

Number of patients with DLTs observed during all treatment cycles for each of the 
schedules (A, B and C) in patients with solid tumours and for the Schedules B and C in 
the DLBCL cohort
For Phases Ia and Ib

Pharmacokinetic (PK) parameters after single dose and at steady state (Cmax, AUC0-24, 
Cmax,ss and AUCτ,ss) measured during the first cycle

Objective response (OR)
OR is defined as best overall response (BOR) of complete response (CR) or partial 
response (PR) with tumour assessment during treatment period for each schedule. For 
DLBCL patients, a minor response according to RECIL 2017 is not part of an objective 
response.
BOR is determined from first treatment administration until the earliest of disease 
progression, death or last evaluable tumour assessment before start of subsequent anti-
cancer therapy, loss to follow-up or withdrawal of consent, according to the following 
criteria depending on the type of cancer:
o
Based on tumour assessment of CT and/or MRI according to Response Evaluation 
Criteria In Solid Tumours (RECIST) version 1.1 (2) in patients with solid tumours 
including mCRPC patients with measurable disease, every 2 cycles
o
Based on bone scan and PSA level according to Prostate Cancer Clinical Trials 
Working Group 3 (PCWG3) in mCRPC patients of Phase Ib without measurable 
disease according to RECIST 1.1, every 4 cycles
o
Based on FDG-PET/CT scans according to Response Evaluation Criteria In 
Lymphoma 2017 (RECIL 2017) in DLBCL patients, every 2 cycles
For Phase Ib only

Progression-free survival (PFS) defined as the time from date of start of BI 894999 to the 
date of objective disease progression (PD) or death, whichever is earlier for SCLC 
patients, CRC patients, mCRPC patients with measurable disease by RECIST 1.1 and NC 
patients, with tumour assessment every 2 cycles according to RECIST 1.1 during 
treatment period
Or
Radiological PFS with tumour assessment by bone scan every 4 cycles for mCRPC 
patients with non-measurable disease by RECIST 1.1
For patients with ‘event’ as an outcome for PFS:


Boehringer Ingelheim                                                                                   
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o
PFS [days] = date of outcome – date of first treatment administration + 1.
For patients with ‘censored’ as an outcome for PFS:
o
PFS (censored) [days] = date of outcome – date of first treatment administration + 1.
The censoring rules for PFS outcome (event or censored) along with the date of outcome 
are given in Table 5.2.2: 1. Clinical disease progression will not be considered for 
determination of a PFS event, unless the outcome of the progression is death.
If patients would have their radiological examinations over a number of days, i.e. target 
lesions assessed on day x, non-target lesions assessed on day y and new lesion (if 
applicable) on day z, the earliest date of the multiple assessments should be considered.
Table 5.2.2: 1 Censoring rules for PFS
Situation
Outcome 
(event or 
censored)
Date of outcome
No baseline radiological assessment 
(no death before second scheduled 
radiological assessment)
censored
Date of first treatment 
administration
Death with no radiological 
assessment performed post-baseline 
(1st scenario takes precedence)
event
Date of death
No radiological assessment 
performed post-baseline, vital status 
is unknown or patient is known to be 
alive
censored
Date of first treatment 
administration
Progressed according to radiological 
assessment (irrespective of missed 
radiological assessments)
event
Date of radiological assessment 
of progression
Death without progression
event
Date of death 
Alive and not progressed 
(irrespective of missed radiological 
assessments)
censored
Date of last radiological 
assessment
Subsequent anti-cancer therapy before progression or death (check interval 
between start of new medication and earliest of subsequent PD or death )
Interval <= 7 days
event
Earliest date of radiological 
assessment of progression or 
death
Interval > 7 days
censored
Date of last radiological 
assessment before initiation of 
subsequent anti-cancer therapy


Boehringer Ingelheim                                                                                   
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
Best overall response (BOR)

Prostate-specific antigen (PSA) response in patients with mCRPC
PSA response is defined as a decline in PSA value ≥50% from baseline (which is 
confirmed by a second value 3 to 4 weeks apart).

Overall survival (OS) in patients with NC.
OS is defined as the time from first administration of BI 894999 until death from any 
cause in patients with NC. The analysis of OS is limited for NC patients after approval of 
protocol version 11.0 and who gave consent to the collection of OS.
For patients with ‘event’ as an outcome for OS:
o
OS [days] = date of outcome – date of first treatment administration + 1.
For patients with ‘censored’ as an outcome for OS:
o
OS (censored) [days] = date of outcome – date of first treatment administration + 1.
The censoring rules for OS (i.e. outcome and date of outcome) are given in Table 5.2.2: 
2.
Table 5.2.2: 2 Censoring rules for OS
Status at time of analysis
Outcome (event or 
censored)
Date of outcome
Patient died and the date of 
death is known 
event
Date of death
Patient died and date of 
death is unknown
event
Date of last contact when the patient 
is known to be alive + 1 day
Patient alive
censored
Date of last contact when the patient 
is known to be alive
Unknown
censored
Date of last contact when the patient 
is known to be alive


Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
This is an open label, non-randomised study with a dose escalation Phase Ia and an expansion 
Phase Ib. For basic study information on treatments to be administered, assignment of 
treatment groups, selection of doses, refer to CTP Section 4.
Patients will be analysed by the initial study treatment administered on the first day of the first 
treatment cycle. The following “analysing treatment” (see Table 6.1: 1) will be used for 
reporting treatment emergent adverse events (AEs) and safety laboratory variables and the 
inequalities start date ≤ onset date of AE≤stop date will determine if an AE will be assigned 
to the “analysing treatment” or not.
For the on-treatment and follow-up periods, AE frequency tabulations will contain a “total” 
column, representing all doses of BI 894999 combined. Subject data listings of AEs will not 
have a “total” column. The data will be presented for each dose cohort separately. To justify 
the MTD determination, DLTs occurring during the MTD evaluation period will be presented 
separately from those occurring during the entire on-treatment period.
Table 6.1: 1
Definition of analysing treatment periods for safety analysis
Analysing 
Treatment Period
Start Date
Stop Date
Screening
Date of informed consent
Date of the first administration 
of study treatment – 1 day
On-treatment
Date of the first 
administration of study 
treatment
For discontinued patients: date 
of the last administration of 
study treatment + 30 days, or 
death, whichever comes first.
For on-going patients: DBL date
Follow-up (Post-
treatment)
Last day of on-treatment 
period + 1 day
Note: on-going patient have 
no follow-up period
Date of the last contact, or 
death, or DBL date, whichever 
comes first
MTD evaluation 
period*
Date of the first 
administration of study 
treatment
Date of the first administration 
of study treatment + 21 days
(Schedule A and B) / + 28 days 
(Schedule C), or DBL date, or 
the start date of the second 


Boehringer Ingelheim                                                                                   
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treatment cycle – 1 day, 
whichever is earlier
   Note: a 30-day residual effect period (REP) is defined for this study. DBL = database lock. *The MTD evaluation period is
only applied to patients in the dose escalation Phase Ia of the trial.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the 
database (i.e., enrolled patients). Consistency check listings (for identification of violations of 
time windows) and a list of protocol deviations will be provided to be discussed at the 
Medical Quality Review Meetings (MQRMs) and report planning meetings (RPMs). At this 
meeting, it will be decided whether a discrepant data value can be used in analyses or whether 
it must be queried in the clinical database. Each protocol deviation must be assessed to 
determine whether it is an important Protocol Deviation (iPD). For definition of iPDs, and for 
the process of identification of these, refer to the BI reference document "Identify and 
Manage Important Protocol Deviations (iPD)" (3). Table 6.2: 1 contains the categories which 
are considered to be iPDs in this trial.
If any iPDs are identified, handling of iPDs in analysis will be documented in the meeting 
minutes of MQRMs and RPMs. The final list of iPDs and the decision whether a patient will 
be excluded from the analysis will be confirmed at the final RPM before DBL. No per 
protocol set is defined for this phase I study, but patients with an iPD will be identified and 
reported in the CTR.
Table 6.2: 1
Important protocol deviations
Category/
Code
Description
Comments
Excluded 
from
A
Entrance criteria violated #
A1
Inclusion criteria not met
None
A2
Exclusion criteria met
None
B
Informed consent #
B1
Informed consent not available/not 
done
B1.1
Informed consent not available/not 
done
Informed consent date missing
All
B1.2
Pharmacogenomics informed 
consent not available/not done
Patient consented to the main study but 
not consented to the pharmacogenomic
part
PGS
B2
Informed consent too late
Informed consent (main consent and/or 
pharmacogenomics consent) date was 
after screening visit date
None
C
Trial medication


Boehringer Ingelheim                                                                                   
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C1
Incorrect trial medication taken
Medication kit assigned not matching 
IRT assignment
None
C2
Dose adjustment
C2.1
Dose reduction not following the 
protocol
Refer to Section 4.1.4 of the CTP
None
C2.2
Intra-patient dose escalation
None
C3
Treatment discontinuation
C3.1
Continuation of treatment although 
criteria for re-treatment not met
Refer to Section 4.1.4 of the CTP
None
C3.2
Discontinuation of trial medication 
not following the protocol
Refer to Section 3.3.4 of the CTP
None
C3.3
Withdrawal of patient not 
according to the protocol
Refer to Section 3.3.4 of the CTP
None
C4
Non-compliance with study 
medication
C4.1
Wrong dosage/dosing schedule
Incorrect daily dose taken leading to 
overdose (not intra-patient dose 
escalation) or under dose (>2 tablets 
away from planned daily dose)
None
C4.2
Non-compliance
Number of tablets taken out of 80-
120% medication compliance range 
not due to AE
None
D
Concomitant medication
D1.1
Prohibited medication use
Refer to Section 4.2.2.1 of the CTP
None
D1.2
Administration of non-protocol 
investigational anti-cancer 
treatment during treatment period
Refer to Section 4.2.2.1 of the CTP
None
E
Missing data
E1
Critical safety procedures not done
None
G
Other protocol deviations #
G1
Negative pregnancy test result not 
obtained for women of child 
bearing potential
Negative pregnancy test result not 
obtained at screening or EOT
None
# PD will be detected by automatic programming.
To assess the the potential impact of Coronavirus Disease 2019 (COVID-19) on the study, 
additional subject data listing of protocol deviations related to COVID-19 will be produced. 
The start date for COVID-19 having an impact on the trial will be taken as the earliest date of 
a COVID-19 related protocol deviation, discontinuation due to COVID-19, onset of a severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) related AE or COVID-19 related 
global BI recruitment hold (17 MAR 20).


Boehringer Ingelheim                                                                                   
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6.3
SUBJECT SETS ANALYSED

Screened Set (ScS): includes all patients who have signed the informed consent form 
and will be used for patient disposition.

Treated Set (TS): includes all patients who were dispensed study treatment and were 
documented to have taken at least one dose of the study treatment. The TS is used for 
both efficacy and safety analyses, and for summary of demographics, baseline 
characteristics, disease history, and concomitant therapies.
The following subsets within TS are defined for specific analyses:
o
MTD Evaluation Set (MTDS): includes all patients in the TS who were not 
replaced for the MTD determination. The MTD Evaluation Set is used for the 
primary analyses of DLTs and MTD determination. Rules for replacement of 
patients are defined in the CTP Section 3.3.4. The list of replaced patients will 
be provided by the Clinical Trial Leader (CTL) no later than the last RPM and 
should be documented in the RPM minutes.
o
Solid Tumour Schedule A in Phase Ia dose escalation (Solid A): includes all 
solid tumour patients in the TS who were treated in Phase Ia with Schedule A 
and are evaluable for MTD.
o
Solid Tumour Schedule B in Phase Ia dose escalation (Solid B): includes all 
solid tumour patients in the TS who were treated in Phase Ia with Schedule B 
and are evaluable for MTD.
o
Solid Tumour Schedule C in Phase Ia dose escalation (Solid C): includes all 
solid tumour patients in the TS who were treated in Phase Ia with Schedule A 
and are evaluable for MTD.
o
DLBCL Schedule B in Phase Ia dose escalation (DLBCL B): includes all 
DLBCL patients in the TS who were treated in Phase Ia with Schedule B and 
are evaluable for MTD.
o
DLBCL Schedule C in Phase Ia dose escalation (DLBCL C): includes all 
DLBCL patients in the TS who were treated in Phase Ia with Schedule C and 
are evaluable for MTD.
o
Treated Set in Phase Ib dose expansion (TS PhIb): includes all patients in the 
TS who were treated in Phase Ib. TS PhIb is used for analyses of progression-
free survival (PFS), best overall response (BOR).
o
SCLC Schedule B in Phase Ib dose expansion (SCLC): includes all SCLC 
patients in the TS who were treated in Phase Ib with Schedule B
o
СRС Schedule B in Phase Ib dose expansion (CRC): includes all CRC patients 
in the TS who were treated in Phase Ib with Schedule B


Boehringer Ingelheim                                                                                   
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o
mCRPC Schedule B in Phase Ib dose expansion (mCRPC): includes all 
mCRPC patients in the TS who were treated in Phase Ib with Schedule B. 
mCRPC B is used for PSA analyses.
o
NC Schedule B in Phase Ib dose expansion (NC B): includes all NC patients in 
the TS who were treated in Phase Ib with Schedule B.
o
NC Schedule C in Phase Ib dose expansion (NC C): includes all NC patients in 
the TS who were treated in Phase Ib with Schedule C.
o
NC Schedules B and C in Phase Ib dose expansion (NC PhIb): includes all NC 
patients in the TS who were treated in Phase Ib with Schedules B and C. 
Patients in NC PhIb and after approval of protocol version 11.0 and gave 
consent to the collection of overall survival status will be used for the analysis 
of overall survival (OS).

PK analysis Set (PKS): includes all patients in the TS who have at least one evaluable 
PK parameters and PKS is used for pharmacokinetic analyses.
 
 
 
 
6.5
POOLING OF CENTRES
This section is not applicable because centre / country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Every effort should be made to collect complete data at each visit for each patient. If not 
specified otherwise, missing data will not be imputed and remain missing. Potential outliers 
will be reported and analysed as observed.
Missing or incomplete AE dates will be handled according to the Boehringer Ingelheim (BI) 
guideline (4).
Missing data and outliers of PK data will be handled according to the BI standards (5).


Boehringer Ingelheim                                                                                   
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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study days and visits will be labelled according to the CTP’s flow chart.
Unless otherwise specified, baseline is defined as the time point closest to and prior to the 
first administration of study treatment. Note that for some study procedures (e.g. body weight, 
vital signs, laboratory tests) baseline may be the measurement made on the same day the 
study treatment was started. In such cases these measurements will be assumed to have been 
taken according to the protocol, i.e. prior to the first administration of study treatment.
For laboratory parameters for which not only the examination date but also the sampling time 
was recorded, examination time should be taken into consideration when defining baseline. 
That is a laboratory measurement on the same date as the first administration of study 
treatment is considered as baseline if and only if the examination time of this laboratory 
measurement is before the first administration of study treatment.


Boehringer Ingelheim                                                                                   
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7.
PLANNED ANALYSIS
In general the display format of the analysis results will follow BI guideline (6) as much as 
possible.
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / Standard Deviation 
(StD) / Min / Median / Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles will be preferred to mean, standard deviation, minimum and maximum.
In general, means, medians, and percentiles will be presented to one more decimal place than 
the raw data and StDs will be presented to two more decimal places than the raw data. 
Minima and maxima will be presented to the same number of decimal places as the raw data.
For time-to-event analysis tables, the set of statistics is: number of patients [N (%)], number 
of patients with event [N (%)], <Time to event> [<unit>] followed by P25 (25th percentile), 
median + 95% confidence interval, P75 (75th percentile). If not specified otherwise, the 
duration as well as the time to event will be displayed in weeks and a final decision will be 
made at the last RPM.
Tabulations of frequencies for categorical data will include all possible categories (even if 
there is no count in a category) and will display the number of observations in a category as 
well as the percentage (%) relative to the number of patients in the respective treatment group 
(unless otherwise specified, all patients in the respective patient set whether they have non-
missing values or not). Percentages will be rounded to one decimal place. The category 
missing will be displayed only if there are actually missing values.
If a table presents only categorical data, “[N (%)]” will be displayed in the column headers 
only.
Abbreviations (e.g. Wors.) or acronyms (e.g. PD) will not be displayed in tables and Subject 
Data Listings (SDLs) without any explanation. They will be either spelled out or explained in 
footnotes.
If applicable, conversion from days to weeks, months and years will be as follows:

Weeks = days ÷ 7

Months = 12 × days ÷ 365.25

Years = days ÷ 365.25.
Descriptive statistics for PK variables include: N / geometric mean / geometric coefficient of 
variation / arithmetic mean / arithmetic coefficient of variation / StD / Min / P10 (10th 
percentile) / Q1 (25th percentile) / median / Q3 (75th percentile) / P90 (90th percentile) / 
Max.


Boehringer Ingelheim                                                                                   
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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only standard descriptive statistics and summary tables are planned for this section of the 
report. Data will be summarised by treatment group (i.e. dose cohort and dosing schedule in 
Phase Ia; expansion cohort in Phase Ib) and a “total” column will be included in the summary 
table.
The following age categories will be used:

≤ 65 years

> 65 to ≤ 75 years

> 75 years.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant diseases will be coded similarly as AEs based on the most current Medical 
Dictionary for Regulatory Activities (MedDRA®) version. Concomitant therapies (CTs) will 
be coded according to the World Health Organization Drug Dictionary (WHO DD). CTs will 
be classified according to the Anatomical, Therapeutic, Chemical (ATC) classification 
system. The third ATC level will be used to categorise CTs by therapy type. In situations 
where a medical product may be used for more than one equally important indication, there 
are often several classification alternatives. As appropriate, patients receiving CTs with more 
than one possible ATC level-three category will be counted more than once; footnotes will 
clarify this possible double counting in tables.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINT(S)
Phase Ia
The primary objective of Phase Ia is to determine the MTD. The purpose of the primary 
analysis is to summarise and document the data that led to the selection of the MTD.  
Therefore an overall summary of the number of patients with DLT(s) which occurred during 
the MTD evaluation period (see definition in Table 6.1: 1) will be provided for each dose 
cohort and for each patient set Solid A, Solid B, Solid C, DLBCL B, DLBCL C and MTDS
(see definitions in Section 6.3). Patients who were treated but replaced for the assessment of 
DLT and dose escalation will be excluded from the summary table. A summary of the number 
of patients with DLTs occurring during the entire on-treatment period will also be given by 
initial treatment and displayed in a similar format to the summary of DLTs occurring in the 
MTD evaluation period.
The dose escalation and determination of MTD is guided by a Bayesian logistic regression 
model (BLRM) with overdose control. The MTD is defined as the highest dose for a given 
dosing schedule that is expected to cause less than 25% risk of the true DLT rate being above 


Boehringer Ingelheim                                                                                   
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33% during the MDT evaluation period. Estimation of the MTD during the dose escalation 
phase of this study is based on the estimation of the posterior probability of the incidence of 
DLT in the toxicity categories during the MTD evaluation period for all evaluable patients. 
The BLRM used is specified in CTP Section 7.1. Results from the BLRM will be presented 
using the actual dose escalation information.
Phase Ib 
The number of patients with DLTs observed during the entire treatment period for each cohort 
will be analysed descriptively. BLRM will be re-run using the number of patients with DLTs 
observed during the entire treatment period for Schedule B and Schedule C.
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
The number of patients with DLT(s) which occurred during the entire treatment period for the 
patient sets will be summarised for each dose cohort.
Best overall response, objective response will be summarised descriptively. The number of 
treated patients and the frequency of patients by best overall response category and objective 
response (yes / no) including the corresponding percentages will be calculated for each patient 
set. Percent change in PSA from baseline and PSA response for mCRPC patients will be 
presented in listings.
PFS based on investigator's assessment and OS will be assessed based on the Kaplan-Meier 
method. Point estimates together with confidence intervals (based on Greenwood's method) 
will be provided for median time to event and quartiles.
The analysis of standard PK parameters is performed according to (5). Descriptive statistics 
for PK will be given as: N, geometric mean, geometric coefficient of variation, arithmetic 
mean, arithmetic coefficient of variation, standard deviation, minimum, 10th percentile (P10), 
25th percentile (Q1), median, 75th percentile (Q3), 90th percentile (P90) and maximum.


Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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7.7
EXTENT OF EXPOSURE
Standard descriptive statistics over all treatment cycles will be calculated. This will include a 
summary of the variables defined in Section 5.4.1 and will comprise a mixture of frequency 
and percentages, as well as summary statistics.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. Patients who were replaced within the 
MTD evaluation period will be excluded from the determination of MTD but will be included 
in all other safety assessments.
7.8.1
Adverse Events
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and NOT on the number of AEs. The 
reporting and analyses of AEs will follow the BI guideline (7). AEs will be coded with the 
most recent version of MedDRA®. The severity of AEs will be scaled according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
For analysis of AE attributes such as duration, severity, etc., multiple AE occurrence data on 
the Case Report Form (CRF), will be collapsed into AE episodes provided that all of the 
following applies:

The same MedDRA lowest level term was reported for the occurrences


Boehringer Ingelheim                                                                                   
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
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence.
For further details on summarization of AE data, please refer to (4, 7).
The analysis of AEs will be based on the concept of treatment emergent adverse events. That 
means that all adverse events occurring between the date of the first administration of study 
treatment till the date of the last administration of study treatment + residual effect period will 
be assigned to the on-treatment period labelled with the study treatment assigned on Day 1 of 
the first treatment cycle. All AEs occurred before the first administration of study treatment
will be assigned to ‘screening’ and all AEs occurred after the residual effect period will be 
assigned to ‘follow-up’ (for listings only). For details on the treatment definition, see Section 
6.1.
An overall summary of AEs will be presented with an additional entry for patients with 
DLT(s) and will also include the number of patients with AEs by the worst CTCAE grade.
Adverse events of special interest (AESIs): see Section 5.3.6.1 of the CTP for details.
Other significant AEs according to ICH E3:
According to ICH E3 (8), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a MQRM.
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT), and will be sorted by the highest CTCAE grade. 
Separate tables will be provided for patients with

DLTs during the MTD evaluation period

DLTs during the entire treatment period

AESIs

serious adverse events (SAEs)

related AEs

serious related AEs

other significant AEs according to ICH E3

AEs leading to death

AEs leading to dose reduction

AEs leading to permanent discontinuation of study treatment.


Boehringer Ingelheim                                                                                   
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The system organ classes will be sorted alphabetically, and preferred terms will be sorted by 
frequency (within system organ class).
Special Search Categories:
Special search categories (SSC) for AEs are defined in Table 7.8.1: 1. For SSC which 
contains sub-searches and / or two sensitivity levels (broad and narrow) all possibilities will 
be displayed on the SSC level in tables. The frequency of patients with AEs will also be 
summarised by treatment, SSC and preferred term and will be sorted by the highest CTCAE 
grade.
Table 7.8.1: 1 Definitions of Special Search Categories
Nr
Subject
Definition (for programmers)
Other monitoring options
1
Bone marrow suppression (all cell 
lines)
20000027
20000029
20000030
2
Neutropenia
BicMQ Neutropenia
BicMQ Leukopenia
3
Thrombocytopenia
20000081
4
Bleeding
20000040
20000039
5
Infections, pneumonia, sepsis, febrile 
neutropenia
10021881
10024970
10040054
6
Mucositis
BicMQ Mucositis
7
Diarrhea
BicMQ Diarrhea
8
Abdominal pain
10017926 
9
Anorexia, nausea
BicMQ Nausea
10
Hyponatriemia
NA
Ref lab data, Review individual 
PTs manually
11
Hepatic enzyme elevation
20000006
BicMQ ALT 
BicMQ AST
BicMQ ALKP
BicMQ Bilirubin
12
Hyperglycemia
Hyperglycaemia/new onset diabetes 
mellitus (SMQ)
SMQ code: 20000041
Only the narrow search is needed
13
Dysgeusia
NA
Review individual PTs manually
14
Skin rash
BicMQ Skin eruptions
15
Fatigue
BicMQ Asthenic conditions
16
Overdose: dehydration, oral 
ulceration, liquid stool, (ruffled fur)
NA
Review individual PTs manually
17
Decrease in urine volume and 
electrolyte excretion, dehydration
BicMQ Volume Depletion (Dehydration)
18
Increased heart rate
NA
Ref vital signs, Review individual 
PTs manually


Boehringer Ingelheim                                                                                   
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Nr
Subject
Definition (for programmers)
Other monitoring options
19
BW loss
BicMQ Weight loss
20
Hypertriglyceridemia
BicMQ Triglycerides
21
Decreases of cholesterol
NA
Ref lab data
22
Decreases of total protein (albumin 
& globulin)
NA
Ref lab data
23
Phototoxicity
10072982
   BicMQ – Boehringer Ingelheim customised MedDRA Query
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will follow the BI guideline 
(9). The same on-treatment period as defined for the analysis of AEs will be applied for the 
laboratory parameters. Patients having at least one post-baseline laboratory value will be 
displayed in the descriptive analyses.
Descriptive statistics, including change from baseline and frequency of patients with 
transitions relative to the reference range, will be provided. CTCAE grades for applicable 
laboratory parameters will be calculated according to CTCAE version 4.03. The following 
outputs will be presented:

worst CTCAE grade experienced during the on-treatment period

transitions of CTCAE grade from baseline to worst laboratory value, from worst to last 
laboratory value during the on-treatment period, and from baseline to last laboratory 
value.
Patients with missing CTCAE grade at baseline or no baseline value but with post-baseline 
values will be displayed in the category “Missing CTCAE grade at baseline”.
Possible clinically significant abnormal laboratory values:
Possible clinically significant abnormal laboratory values are defined as those laboratory 
values that are of CTCAE Grade ≥ 2 and show an increase from baseline value by at least one 
CTCAE grade. For those parameters for which no CTCAE has been defined, BI standard 
definition will be used to determine possible clinical significance. Frequency of patients with 
possible clinically significant abnormal laboratory values will be provided whenever 
applicable. If no baseline value is available but the patient had a post-baseline laboratory 
value of CTCAE Grade ≥ 2 an increase from baseline will be assumed, i.e. the laboratory 
value considered as possible clinically significant.
Laboratory values of special interest:
Laboratory parameters of special interest are white blood cells, neutrophils, lymphocytes, 
platelets, CK, CK-MB, troponin T, hemoglobin, AST, ALT, ALKP, and bilirubin. However, 
all laboratory parameters will be displayed in the same laboratory tables.
Potential Hy’s law cases:


Boehringer Ingelheim                                                                                   
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Special attention will be paid to patients fulfilling the criteria for potential Hy’s law cases.
For patients with normal hepatic function at baseline:

an elevation of AST and / or ALT ≥ 3 fold the Upper Limit of Normal (ULN) combined 
with an elevation of total bilirubin ≥ 2 fold ULN measured in the same blood draw 
sample,
and / or
marked peak aminotransferase (ALT and / or AST) elevation ≥ 10 fold ULN.
For patients with abnormal hepatic function at baseline (e.g. due to primary liver cancer or 
hepatic metastases)

an elevation of AST and / or ALT > 5 fold ULN combined with an elevation of bilirubin 
> 2 fold ULN measured in the same blood draw sample.
The events can occur in any order, but must occur within 14 days of the previous event, i.e. 
the second event must occur within 14 days of the first event, and the third event must occur 
within 14 days of the second event, etc.
Handling of laboratory parameters with CTCAE grade -1:
For uric acid, glomerular filtration rate (GFR) and hypokalemia, the CTCAE grade cannot 
always be assigned by the laboratory parameter itself as two different CTCAE grades have the 
same laboratory constellation, but are distinguished by additional clinical parameter. In this 
case a CTCAE grade of “-1” will be assigned initially. For all analyses patients with a 
CTCAE grade of “-1” will be treated as
Grade 1 for uric acid
Grade 3 for GFR
Grade 1 for hypokalemia (Only when CTCAE version 4.03 is used).
Handling of urine protein (UPROZ):
With CTCAE version 4, the CTCAE grade 3 for proteinuria is defined based on 24 hrs values 
[g/24 hrs] only; no dipstick definition is available based on quantitative results. 
High values of UPROZ (+++, ++++; labstd = 3, 4) would therefore be assigned to CTCAE 
grade -9, which by default is equivalent to CTCAE grade 0. To circumvent this, high values 
of UPROZ (+++, ++++; labstd = 3, 4) will be assigned to CTCAE grade 2.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.


Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database after completion of enrolment.


Boehringer Ingelheim                                                                                   
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9.
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
R09-0262: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et 
al. New response evaluation criteria in solid tumours: Revised RECIST guideline 
(version 1.1). Eur J Cancer 2009; 45: 228-247.
3
BI-KMED-COPS-HTG-0135: “Identify and Manage Important Protocol Deviations 
(iPD)”, current version; IDEA for CON.
4
BI-KMED-BDS-HTG-0035: “Handling of missing and incomplete AE dates”, current 
version; IDEA for CON.
5
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; IDEA for CON.
6
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project 
Summaries”, current version; IDEA for CON.
7
BI-KMED-BDS-HTG-0066: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials”, current version; IDEA for CON.
8
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.
9
BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; IDEA for CON.


Boehringer Ingelheim                                                                                   
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Boehringer Ingelheim                                                                                   
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11.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
08-FEB-2017
None
This is the final TSAP without any 
modification.
Revised
19-JAN-2022
All 
Sections
This is a revised TSAP with the 
following revisions:

Reflect changes in CTP version 
12.0, i.e., treatment groups, 
endpoints and analyses of solid 
tumours in Schedule C, DLBCL 
in Schedules B and C, cohorts in 
Phase Ib expansion part.

Reflect decision of abbreviated 
report (details see Section 4).