Clinical trial NCT03166631
Conditions: Neoplasms Neoplasm Metastasis Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim
Start date: 2017-09-08; Completion date: 2020-10-28
Enrollment: 62 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The main objective of the dose-escalation parts of the trial is to determine the maximum tolerated dose (MTD), based on the frequency of patients experiencing dose-limiting toxicities (DLTs), and/or the recommended dose for further development of BI 891065 monotherapy as well as of BI 891065 in combination with BI 754091, and to evaluate its safety and tolerability by monitoring the occurrence and severity of adverse events (AEs).

Secondary objectives are the determination of the pharmacokinetic (PK) profile of BI 891065 monotherapy as well as of BI 891065 in combination with BI 754091, and the preliminary assessment of anti-tumour activity.

Detailed description:

Arms: arm 1: BI 891065 alone arm 2: BI 891065 alone arm 3: BI 891065 alone arm 4: BI 891065 alone arm 5: BI 891065 alone arm 6: BI 891065 alone arm 7: BI 891065 alone arm 8: BI 891065 in combination with BI 754091 arm 9: BI 891065 in combination with BI 754091 arm 10: BI 891065 in combination with BI 754091 arm 11: BI 891065 in combination with BI 754091
Interventions: intervention 1: BI 891065 intervention 2: BI 754091
Intervention descriptions: intervention 1: Part A, Part B intervention 2: Part B

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c11957282-07
EudraCT No.:
EU Trial No:
2017-000465-74
BI Trial No.:
1379-0001
BI Investigational 
Product(s):
BI 891065 + BI 754091
Title:
An open-label Phase I dose finding trial with BI 891065 alone 
and in combination with BI 754091 to characterise safety, 
tolerability, pharmacokinetics, pharmacodynamics, and efficacy 
in patients with advanced and/or metastatic malignancies
Lay Title:
A trial to find the safe dose for BI 891065 alone and in 
combination with BI 754091 in patients with incurable tumours 
or tumours that have spread
Clinical Phase:
I
 
Physician 
/ 
Coordinating 
Principal 
Investigator
Trial Clinical 
Monitor:
Phone: 
 Fax: 
Status:
Final protocol (Revised Protocol [based on global amendment 
6])
Version and Date:
Version: 7.0
Date: 12 February 2020
Page 1 of 234
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
Company name
Boehringer Ingelheim
Finished product name
Not applicable
Active ingredient name:
BI 891065 + BI 754091
Protocol date
04 May 2017
Revision date
12 February 2020
Trial number
1379-0001
Title of trial:
An open-label Phase I dose finding trial with BI 891065 alone and in 
combination with BI 754091 to characterise safety, tolerability, 
pharmacokinetics, pharmacodynamics, and efficacy in patients with 
advanced and/or metastatic malignancies
Trial sites:
Multi-centre trial
Clinical phase:
I
Objectives:
To investigate the maximum tolerated dose (MTD)/recommended 
dose for further development based on dose limiting toxicities (DLT), 
safety and tolerability, pharmacokinetics, pharmacodynamics, and 
preliminary efficacy of BI 891065 alone and in combination with 
BI 754091 in patients with advanced and/or metastatic malignancies
Methodology:
Open-label dose escalation followed by expansion cohorts
Number of patients 
entered: 
Approximately 104
Number of patients on 
each treatment:
Part A (dose escalation BI 891065 monotherapy): approximately 
30 patients
Part B (dose escalation BI 891065 in combination with BI 754091): 
approximately 31-37 patients
Part C (expansion cohort with the combination treatment): 
approximately 44 patients in a pre-treated non-small cell lung cancer
(NSCLC) cohort.
Diagnosis:
Parts A: Patients with a confirmed diagnosis of an advanced and/or 
metastatic solid tumour
Part B: Patients with a confirmed diagnosis of advanced, unresectable
and/or metastatic cancers who have failed standard treatment, or for 
whom no therapy of proven efficacy exists, or who are not amenable 


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to standard therapies.  Eligibility is limited to patients with the 
following cancer types: bladder, colon, breast, NSCLC, ovarian, 
pancreatic, renal, esophagogastric, sarcoma, prostate, and melanoma.
Part C: Patients with metastatic NSCLC who developed disease 
progression (per RECIST v1.1) after the first scan (where SD, PR, or 
CR was demonstrated at the first scan), and require new anti-cancer 
therapy after first line treatment with an anti PD-1/anti PD-L1 mAb 
(given either as single agent therapy or in combination with a 
platinum-based chemotherapy regimen).
Main in- and exclusion 
criteria
Main inclusion criteria
- Parts A and B: Adult patients with a diagnosis of advanced, 
unresectable and/or metastatic solid tumours, who have failed 
standard treatment or for whom no therapy of proven efficacy exists 
or who are not amenable to standard therapies. Eligibility is limited to 
the following tumour subtypes in Part B: bladder, colon, breast, 
NSCLC, ovarian, pancreatic, renal, esophagogastric, sarcoma, 
prostate, and melanoma.
- Part C: Adult patients with metastatic NSCLC who developed 
disease progression (per RECIST v1.1) after the first scan (where SD, 
PR, or CR was demonstrated at the first scan), and require new anti-
cancer therapy after first line treatment with an anti PD-1/anti PD-L1 
mAb (given either as single agent therapy or in combination with a 
platinum-based chemotherapy regimen)
- Life expectancy of at least 12 weeks after start of treatment 
according to Investigator’s judgement
- Parts B and C: Patients must have at least one tumour lesion 
amenable to biopsy, and must be willing to undergo biopsy prior to 
first treatment and, unless clinically contraindicated, during therapy.
Main exclusion criteria
- Treatment with another anticancer drug within 4 weeks or within 
5 half-life periods (whichever is earlier) prior to first administration 
of BI 891065
- Known presence of central nervous system (CNS) metastases unless 
asymptomatic and off corticosteroids and/or anti-convulsant therapy 
for at least 2 weeks prior to start of treatment
- Persistent toxicity from previous treatments that has not resolved to 
≤ Grade 1 with the exception of alopecia
- Systemic immunosuppressive medication (steroids of max. 10 mg 
prednisone equivalent per day are allowed, topical [e.g., inhaled]
steroids are not considered as immunosuppressive) within 1 week of 
beginning the study


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- Serious concomitant disease or medical condition affecting 
compliance with trial requirements or which are considered relevant 
for the evaluation of the efficacy or safety of the trial drugs.
Test products:
BI 891065 + BI 754091
dose:
Part A BI 891065 Monotherapy: Dose tiers will start at 5 mg per day 
Dose-escalation steps as determined by the Safety Review Committee 
(SRC)
Part B BI 891065 plus BI 754091: BI 891065 starting dose will be 
determined by the SRC based on data of Part A. Dose-escalation steps 
will be determined by the SRC. BI 754091: a fixed dose once every 
3 weeks; anticipated starting dose of 240 mg (i.e., the dose currently 
selected in the Phase I Trial 1381.1 of BI 754091 monotherapy for 
expansion cohort patients and 1381.2). Based on further data for BI 
754091, the starting dose may be adapted by the SRC.
Part C: Dose of combination BI 754091 (fixed dose as determined in 
Part B) + BI 891065 as determined based on safety and PK data as 
well as target engagement in tumour tissue from Parts A and B.
mode of 
administration:
BI 891065: orally (per os [p.o.])
BI 754091: intravenous (i.v.)
Duration of treatment:
Reiterated treatment cycles of 3 weeks as long as the patient has 
clinical benefit or until undue drug toxicity (both according to the 
Investigator’s judgment) or withdrawal of consent, whichever occurs 
first
Endpoints
Primary Endpoints
Part A: The MTD of BI 891065 monotherapy and the number of 
patients with DLTs during the first treatment cycle.
Part B: The MTD of BI 891065 in combination with BI 754091 and 
the number of patients with DLTs during the first treatment cycle.
Part C: Objective response (OR) by the Investigator’s assessment 
based on RECIST v1.1.
Secondary Endpoints
Part A:
The number of patients with DLTs observed during the entire 
treatment period.
Cmax,ss, AUCτ,ss, and AUC0-tz of BI 891065
OR by Investigator’s assessment based on RECIST v1.1.
Part B:
The number of patients with DLTs observed during the entire 
treatment period.


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Cmax,ss, AUCτ,ss, and AUC0-tz of BI 891065; Cmax and AUC0-tz of 
BI 754091
OR by the Investigator’s assessment based on RECIST v1.1.
Part C:
Duration of OR based on RECIST v1.1.
Safety criteria:
Safety and tolerability of BI891065 as monotherapy and in 
combination with BI 754091 by evaluation of the incidence and 
severity of adverse events according to Common Terminology 
Criteria for Adverse Events (CTCAE) (Version 5.0), QTcF evaluation
Statistical methods:
Descriptive analysis (summary statistics) will be used to describe the 
safety and efficacy endpoints.
In Parts A and B, dose escalation is guided by Bayesian logistic 
regression models (BLRMs) with overdose control that will be fitted 
to binary toxicity outcomes. The estimate of parameters will be 
updated as data are accumulated using the BLRMs. At the end of the 
dose escalation, the toxicity probability at each dose level will be 
calculated to determine an estimate of the MTD.


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FLOW CHART: BI 1379.1 (REFMAL 505) PART A TRIAL ASSESSMENTS
Part A Flow Chart
Trial period
Screening
Part A Dose Escalation
BI 891065 Monotherapy Treatment Period
EOTn
30-Day 
Safety FUo
FU for 
PDp
Cyclea
C1
C2
C3+
Every 6 or 
9 weeks
Visit number
1
2
3
4
5
6
7
8
9
10+
Treatment day
Up to 
28 daysb
1
2
3
8
12
15
16
1 (±2)
1 (±2)
+1 week
±5 days
Informed consent
X
Inclusion / exclusion criteria
X
X
Medical history and demographicsc
X
Report planned hospitalisations
X
Physical examination, height (screening only), 
and weightc,d
X
X
X
X
X
X
X
X
ECOG Performance scorec,d
X
X
X
X
X
X
X
12-Lead Electrocardiograms (single/triplicate)c,e
X
X
X
X
X
X
X
X
Cardiac testing (only if cardiac disease suspected)f
X
Vital signsc
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy testc,g
X
X
X
X
X
X
Safety laboratory (haematology, biochemistry)c
X
X
X
X
X
X
X
X
Safety laboratory (amylase and lipase if 
symptoms of pancreatitis)
X
X
X
X
Safety laboratory (coagulation)c
X
X
X
X
X
Alpha-1 acid glycoprotein (AGP)
X
X
Virology testing (≤28 days of treatment)
X
Safety laboratory (urine)c
X
X
X
X
X
X
X
X
Tumour assessmenth
X
Every 6 weeks (then every 9 weeks after 6 months of treatment)
X
X


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Part A Flow Chart
Trial period
Screening
Part A Dose Escalation
BI 891065 Monotherapy Treatment Period
EOTn
30-Day 
Safety FUo
FU for 
PDp
Cyclea
C1
C2
C3+
Every 6 or 
9 weeks
Visit number
1
2
3
4
5
6
7
8
9
10+
Treatment day
Up to 
28 daysb
1
2
3
8
12
15
16
1 (±2)
1 (±2)
+1 week
±5 days
Blood, urine sampling for pharmacokineticsi,j
X
X
X
X
X
Xj
Xj
X
BI 891065 intake (daily except for C1D2)l
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Dose-limiting toxicity (DLT) assessmentm
X
X
X
X
X
X
X
X
X
X
SAEs/AESIs considered drug-related
X
Patient status
X
X
Review Patient Diary
X
X
X
X
X
X
X
X
X
X
X


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Part A BI 891065 Monotherapy Flow Chart Footnotes
a
Treatment cycles (C) are 21 days (3 weeks). Patients may continue treatment with BI 891065 as long as they are deriving clinical benefit according to the 
Investigator’s judgment.  All circumstances for withdrawal of trial treatment are presented in Section 3.3.4.1.
b
Screening should take place within 28 days of start of study treatment, however, may be extended as outlined in Section 6.2.1.1.
c
Safety laboratory assessments including haematology, serum biochemistry, coagulation, serum pregnancy test, and urinalysis will be performed locally. The 
following screening parameters should be done ≤14 days prior to initiation of treatment: medical history and demographics, physical examination (including height 
and weight), Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, electrocardiogram (ECG), haematology (per Section 5.2.3), clinical 
chemistry (sodium, potassium, phosphate, chloride, creatinine, calcium, venous bicarbonate HCO3, albumin, total protein, aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase, total, direct and indirect bilirubin, lactate dehydrogenase, serum glucose, creatinine kinase [CK: if CK is elevated, 
then CK-MB, Troponin I, and myoglobin should be reactively tested, with further follow-up as clinically warranted], serum urea nitrogen, and serum uric acid), 
urinalysis, and screening pregnancy test. If these assessments are performed within 72 hours of initiation of treatment, they do not need to be repeated on Cycle 1 
Day 1 with the exception of the ECOG performance status, an abbreviated physical examination, vital signs, and single/triplicate ECGs required as outlined in
Section 5.2.4 and Table 10.3: 1. Tumour assessments (scans) should be performed ≤28 days prior to initiation of treatment. Refer to Section 5.2.3 for additional 
details. Vital signs (blood pressure, body temperature, and pulse rate) are checked at every visit prior to blood work and trial treatment and at the discretion of the 
Investigator (see Section 5.2.2).
d
Physical examinations including the measurements of height (screening only) and weight will be done at screening, on Day 1 of each treatment cycle, at the end-of-
treatment (EOT) visit, at the 30-day safety follow-up (FU) visit, and at the FU visits for PD. However, patients will have an additional abbreviated physical 
examination (focused on the specific disease, at the Investigator’s discretion) on Cycle 1 Day 15. ECOG performance status will be done at screening, on Day 1 of 
Cycles 1 and 2, on Day 1 of every other cycle beginning with Cycle 3, at the EOT visit, at the 30-day FU visit, and at FU visits for PD (see Section 5.2.1).
e
Triplicate or single 12-lead electrocardiograms (ECGs) will be done at the time points as outlined in Section 5.2.4 and Table 10.3: 1 and whenever the Investigator 
deems it necessary (see Section 5.2.4 and Appendix 10.3). ECG machines will be provided for Part A to facilitate central readings. While all triplicate ECGs will be 
transmitted to the central vendor, only the baseline, 6-hour, 8-hour, and 24-hour readings will be reviewed directly. The other triplicate ECG readings will be 
analyzed only after the PK analysis points to a tmax.
f
Refer to Section 3.3.3 for details on which patients require cardiac testing (e.g., echocardiogram (ECHO)/multi-gated acquisition (MUGA) scan.
g
Pregnancy tests are mandatory for women with child-bearing potential. A serum beta human chorionic gonadotropin (β-HCG) pregnancy test must be done with
serum at screening. Thereafter, this test can be done in either serum or urine on Day 1 of each cycle, at the EOT visit, and at the 30-day FU visit (see Section 5.2.3).
h
Tumour assessments should be done according to RECIST v1.1 and iRECIST and should include computed tomography (CT) scans of the chest and abdomen and, if 
clinically indicated, imaging of any other known or suspected sites of disease (e.g., pelvis, brain) using an appropriate method (CT scan or magnetic resonance 
imaging [MRI]). The same radiographic procedure must be used throughout the trial. In case of suspected (but not otherwise confirmed) bone metastasis at 
screening, tumour assessment at screening should include a bone scan. If bone lesions are already known or confirmed at screening, correlative imaging (X-ray or 
CT scan) should be performed. Correlative imaging should then be repeated at each tumour assessment (see Section 5.1 for more detail). Assessments will be 
performed by the Investigator at screening and every 2 cycles (6 weeks -5 days) for the first 6 months of treatment, once every 3 cycles (9 weeks ±5 days) thereafter, 


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at the EOT visit (if not performed within the previous 4 weeks), and at the discretion of the Investigator. Baseline tumour assessments must be performed within 
28 days before first drug intake.
i
Pharmacokinetic (PK) sampling (blood and urine) will be done during Cycles 1 and 2. The visit days and sampling time points as outlined in the Appendix 10.3
tables are to be followed. The permitted visit windows noted in the table footnotes should only be used if medically indicated.
j
Serum aliquot B samples for PK might be used for identification of metabolites at Days 1 (prior to treatment), 15, and 16 at the same time points as the PK samples. 
Details can be found in Section 5.3.2.3.
l
Dosing of BI 891065 will be determined by the Safety Review Committee and communicated separately as each new cohort opens for recruitment. Patients will be 
observed after their first 3 doses of BI 891065 as outlined in Section 5.2.6.4.3. Patients will fast a minimum of 10 hours prior to select visits as outlined in 
Section 4.1.5.1. Patients should not take BI 891065 prior to certain visits that require pre-dose blood sampling as detailed in Table 10.3: 1.
m
Dose-limiting toxicities (DLTs) will be collected throughout the trial and will be assessed for dose-escalation decisions following the first cycle of BI 891065 
monotherapy (see Section 0).
n
An EOT visit should be performed for all patients who permanently discontinue trial medication. If the decision to permanently discontinue treatment is taken at a 
scheduled visit, the EOT visit should be performed instead of the scheduled visit (preferably within 7 days and no later than 14 days after the last treatment). Please 
note that a patient with an initial radiologic PD does not have to be automatically withdrawn from treatment (see Section 3.3.4.1).
o
The residual effect period (REP) starts after last dose of trial medication and ends 30 days later. A 30-day safety FU visit should take place before any other anti-
cancer treatment starts.
p
Follow-up for PD visits for tumour assessment by imaging (CT scan or MRI) for patients who discontinue trial treatment without having PD based on RECIST v1.1
and/or iRECIST should be performed every 6 weeks (±5 days) for the first 6 months of treatment and then every 9 weeks (±5 days) thereafter until PD or another 
withdrawal criterion is met (see Section 6.2.3.3). At these visits, serious adverse events (SAEs) and adverse events of special interest (AESIs) occurring during the 
trial that are considered to be related to trial treatment or procedures will be followed until resolution.


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FLOW CHART: BI 1379.1 (REFMAL 505) PART B TRIAL ASSESSMENTS
Part B Flow Chart
Trial period
Screening
Part B Dose Escalation
BI 891065 + BI 754091 Combination Treatment Period
EOTp
30-day 
Safety 
FUq
FU for 
PDr
Cyclea
C1
C2
C3+
Every 6 
or 9 
weeks
Visit number
1
2
3
4
5
6
7
8
9
10+
Treatment day
Up to 28 daysb
1
2
8
12
15
16
17
1 (±2)
1 (±2)
+1 week
±5 days
Informed consent
X
Inclusion / exclusion criteria
X
X
Medical history and demographicsc
X
Report planned hospitalisations
X
Physical examination, height (screening only), and 
weightc,d
X
X
X
X
X
X
X
X
Vital signsc,e
X
X
X
X
X
X
X
X
X 
X
X
X
ECOG Performance scorec,d
X
X
X
X
X
X
X
Electrocardiograms (single/triplicate)c,e
X
X
X
X
X
X
X
X
Cardiac testing (only if cardiac disease suspected)f 
X
Serum pregnancy testc,g
X
X
X
X
X
X
Safety laboratory (haematology, biochemistry)c
X
X
X
X
X
X
X
Safety laboratory (amylase and lipase if symptoms 
of pancreatitis)
X
X
X
X
Safety laboratory (coagulation)c
X
X
X
X
X
Alpha-1 acid glycoprotein (AGP)
X
X
Virology testing (≤28 days of treatment)
X
Safety laboratory (urine)c
X
X
X
X
X
X
X
Tumour assessmentc,h
X
Every 6 weeks (then every 9 weeks after 6 months of treatment)
X
X
Blood sampling for BI 891065 pharmacokineticsi
X
X
X
X
Xj
Xj
Xj
X
Blood sampling for BI 754091 pharmacokineticsi
X
X
X
X
X
X
X
X
X
X
X
Food administration for Food Interaction Assessmentj
X


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Part B Flow Chart
Trial period
Screening
Part B Dose Escalation
BI 891065 + BI 754091 Combination Treatment Period
EOTp
30-day 
Safety 
FUq
FU for 
PDr
Cyclea
C1
C2
C3+
Every 6 
or 9 
weeks
Visit number
1
2
3
4
5
6
7
8
9
10+
Treatment day
Up to 28 daysb
1
2
8
12
15
16
17
1 (±2)
1 (±2)
+1 week
±5 days
Tumour biopsy (cIAP degradation)m
X
X
BI 891065 intaken
X
X
X
X
X
X
X
X
X
BI 754091 administrationn
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
Dose-limiting toxicity (DLT) assessmento
X
X
X
X
X
X
X
X
X
X
SAEs/AESIs considered drug-related
X
Patient status
X
X
Review Patient Diary
X
X
X
X
X
X
X
X
X
X
X


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Part B Dose Escalation BI 891065 + BI 754091 Flow Chart Footnotes
a
Treatment cycles (C) are 21 days (3 weeks). Patients may continue treatment with BI 891065 and BI 754091 as long as they are deriving benefit according to the 
Investigator’s judgment. All circumstances for withdrawal of trial treatment are presented in Section 3.3.4.1.
b
Screening should take place within 28 days of start of study treatment, however, may be extended as outlined in Section 6.2.1.1.
c
Safety laboratory assessments including haematology, serum biochemistry, coagulation, serum pregnancy test, and urinalysis will be performed locally. The 
following screening parameters should be done ≤14 days prior to initiation of treatment: medical history and demographics, physical examination (including height 
and weight), Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, electrocardiogram (ECG), haematology (per Section 5.2.3), clinical 
chemistry (sodium, potassium, phosphate, chloride, creatinine, calcium, venous bicarbonate HCO3, albumin, total protein, aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase, total, direct and indirect bilirubin, lactate dehydrogenase, serum glucose, creatinine kinase [CK: if CK is elevated, 
then CK-MB, Troponin I/Troponin T, and myoglobin should be reactively tested, with further follow-up as clinically warranted], serum urea nitrogen, serum uric 
acid, and thyroid panel [TSH, free T4, and free T3]), urinalysis, and screening pregnancy test. If these assessments are performed within 72 hours of initiation of 
treatment, they do not need to be repeated on Cycle 1 Day 1 with the exception of the ECOG performance status, an abbreviated physical examination, vital signs, 
and single/triplicate ECGs as outlined in Section 5.2.4 and Table 10.3: 2 required prior to first administrations of trial treatments. Tumour assessments (scans) should 
be performed ≤28 days prior to initiation of treatment. Refer to Section 5.2.3 for additional details. Vital signs (blood pressure, body temperature, and pulse rate) are 
checked at every visit prior to blood work and trial treatment and at the discretion of the Investigator (see Section 5.2.2).
d
Physical examinations including the measurements of height (screening only) and weight will be done at screening, on Day 1 of each treatment cycle, at the end-of-
treatment (EOT) visit, at the 30-day safety follow-up (FU) visit, and at the FU visits for PD. However, patients will have an additional abbreviated physical 
examination (focused on the specific disease, at the Investigator’s discretion) on Cycle 1 Day 15. ECOG performance status will be done at screening, on Day 1 of 
Cycles 1 and 2, on Day 1 of every other cycle beginning with Cycle 3, at the EOT visit, at the 30-day FU visit, and at FU visits for PD (see Section 5.2.1).
e
Triplicate or single 12-lead electrocardiograms (ECGs) will be done at time points as outlined in Section 5.2.4 and Table 10.3: 2 and whenever the Investigator 
deems it necessary (see Section 5.2.4 and Table 10.3: 2). ECG machines will be provided for Part B to facilitate central readings. While all ECGs will be transmitted 
to the central vendor, only the baseline, 6-hour, 8-hour, and 24-hour (post BI 891065 dose) readings will be reviewed directly. The other readings will be analysed 
only after the PK analysis points to a tmax.
f
Refer to Section 3.3.3 for details on which patients require cardiac testing (e.g., echocardiogram (ECHO)/multi-gated acquisition (MUGA) scan.
g
Pregnancy tests are mandatory for women with child-bearing potential. A serum beta human chorionic gonadotropin (β-HCG) pregnancy test must be done with
serum screening. Thereafter, this test can be done in either serum or urine on Day 1 of each cycle, at the EOT visit, and at the 30-day FU visit (see Section 5.2.3).
h
Tumour assessments should be done according to RECIST v1.1 and iRECIST and should include computed tomography (CT) scans of the chest and abdomen and, if 
clinically indicated, imaging of any other known or suspected sites of disease (e.g., pelvis, brain) using an appropriate method (CT scan or magnetic resonance 
imaging [MRI]). The same radiographic procedure must be used throughout the trial. In case of suspected (but not otherwise confirmed) bone metastasis at 
screening, tumour assessment at screening should include a bone scan. If bone lesions are already known or confirmed at screening, correlative imaging (X-ray or 
CT scan) should be performed. Correlative imaging should then be repeated at each tumour assessment (see Section 5.1 for more detail). Assessments will be 
performed by the Investigator at screening and every 2 cycles (6 weeks ±5 days) for the first 6 months of treatment, once every 3 cycles (9 weeks ±5 days) thereafter, 


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at the EOT visit (if not performed within the previous 4 weeks), and at the discretion of the Investigator. Baseline tumour assessments must be performed within 
28 days before first drug intake.
i
Pharmacokinetic (PK) blood sampling will be done during select treatment cycles. Please follow the visit days and sampling time points as outlined in the tables in 
Appendix 10.3. The permitted visit windows noted in the table footnotes should only be used if medically indicated. Please note that there are separate assays for 
determination of BI 891065 and BI 754091. Therefore, 2 tubes must be drawn at each time point, when appropriate.  
j
The effect of food will be tested in this part of the study until sufficient data is obtained. Only q.d. patients enrolled in Part B will participate in the food effect study.
Please see Section 6.2.2.1 for details.
m
The following tumour biopsies will be mandatory for all patients in the Part B dose-escalation portion of the trial:
-
One fine needle biopsy must be freshly taken between screening and first trial drug treatment.
-
One fine needle biopsy from the same lesion on treatment as soon as possible after the 21-day observation period is completed and the patient has been on the 
uninterrupted and unchanged dose of BI 891065 for at least two continuous weeks. Biopsy collection should be delayed until these conditions are met. If it is 
absolutely impossible to obtain a biopsy from the same lesion, another lesion may be chosen.
n
Dosing amounts, dosing frequency (e.g. b.i.d or q.d.) and escalations of the combination of BI 891065 + BI 754091 will be determined by the Safety Review 
Committee and communicated separately as each new cohort opens for recruitment. On BI 754091 infusion days, BI 891065 will be administered approximately 30 
minutes after the end of the BI 754091 infusion. Patients will be observed after their dose of BI 891065 and BI 754091 given at Cycle 1 Day 1 (for 8 hours) and 
Cycle 2 Day 1 (for 6 hours) as outlined in Section 5.2.6.4.3. Patients will fast a minimum of 10 hours prior to select visits as outlined in Section 4.1.5.1. Patients 
should not take BI 891065 prior to certain visits that require pre-dose blood sampling as detailed in Table 10.3: 2 and Table 10.3: 3. For patients taking b.i.d. dosing, 
the evening dose should be skipped (Day 1 and Day 15 of Cycle 1).  For all patients, the morning dose on Day 2 and Day 16 should be taken in the clinic (after pre-
dose blood sampling is taken).   
o
Dose-limiting toxicities (DLTs) will be collected throughout the trial and will be assessed for dose-escalation decisions following the first cycle of BI 891065 plus 
BI 754091 combination therapy (see Section 0).
p
An EOT visit should be performed for all patients who permanently discontinue trial medication. If the decision to permanently discontinue treatment is taken at a 
scheduled visit, the EOT visit should be performed instead of the scheduled visit (preferably within 7 days and no later than 14 days after the last treatment). Please 
note that a patient with an initial radiologic PD does not have to be automatically withdrawn from treatment (see Section 3.3.4.1).
q
The residual effect period (REP) starts after last dose of trial medication and ends 30 days later. A 30-day safety FU visit should take place before any other anti-
cancer treatment starts.


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r
Follow-up for PD visits for tumour assessment by imaging (CT or MRI) for patients who discontinue trial treatment without having PD based on RECIST v1.1 
and/or iRECIST should be performed every 6 weeks (±5 days) for the first 6 months of treatment and then every 9 weeks (±5 days) thereafter until PD or another 
withdrawal criterion is met. At these visits, serious adverse events (SAEs) and adverse events of special interest (AESIs) occurring during the trial that are considered 
to be related to trial treatment or procedures will be followed until resolution.


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FLOW CHART: BI 1379.1 (REFMAL 505) PART C (NSCLC) TRIAL ASSESSMENTS
Part C Lung Flow Chart
Trial period
Screening
Part C Dose Expansion in Patients with NSCLC
BI 891065 + BI 754091 Combination Treatment
EOTn
30-day 
Safety 
FUo
FU for 
PDp
Cyclea
C1
C2+
Every 6
or 
9 weeks
Visit number
1
2
3
4
5
6
7+
Treatment day
Up to 
28 daysb
1
2
8
15
16
1 (±2)
+1 week
±5 days
Informed consent
X
Inclusion / exclusion criteria
X
X
Medical history and demographics
X
Report planned hospitalisations
X
Physical examination, height (screening only) 
and weightc,d
X
X
X
X
X
X
X
ECOG Performance scorec,d
X
X
X
X
X
X
Vital signsc
X
X
X
X
X
X
X
X
X
Electrocardiograms (single/triplicate)c,e
X (single)
X
X
X (single)
X
X
X (single)
X
(single)
Cardiac testing (only if cardiac disease 
suspected)f
X
Serum pregnancy testg
X
X
X
X
X
Safety laboratory (haematology, biochemistry)c
X
X
X
X
Safety laboratory (amylase and lipase if 
symptoms of pancreatitis)
X
X
X
X
Safety laboratory (coagulation)c
X
X
X
X
Alpha-1 acid glycoprotein (AGP)
X
X (C2)
Virology testing (≤28 days of treatment)
X


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Part C Lung Flow Chart
Trial period
Screening
Part C Dose Expansion in Patients with NSCLC
BI 891065 + BI 754091 Combination Treatment
EOTn
30-day 
Safety 
FUo
FU for 
PDp
Cyclea
C1
C2+
Every 6
or 
9 weeks
Visit number
1
2
3
4
5
6
7+
Treatment day
Up to 
28 daysb
1
2
8
15
16
1 (±2)
+1 week
±5 days
Safety laboratory (urine)c
X
X
X
X
Tumour assessmentc,h
X
Every 6 weeks (then every 9 weeks after 6 months of treatment)
X
X
Blood sampling for BI 891065 pharmacokineticsi
X
X
X
X
X
X (C2 only)
Blood sampling for BI 754091 pharmacokineticsi
X
X
X
X
X
Xi
X
X
Tumour biopsyl
X
X (C3)
(X)
BI 891065 intake m
X
X
X
X
X
X
BI 754091 administration
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
Dose-limiting toxicity (DLT) assessment
X
X
X
X
X
SAEs/AESIs considered drug-related
X
Patient status
X
X
Review Patient Diary
X
X
X
X
X
X
X
X
X
X
Optional assessments are noted in parentheses. Please refer to the specific footnotes.


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Part C Dose Expansion in Patients with NSCLC Flow Chart Footnotes
a
Treatment cycles (C) are 21 days (3 weeks). Patients may continue treatment with BI 891065 and BI 754091 as long as they are deriving benefit according to the 
Investigator’s judgment. All circumstances for withdrawal of trial treatment are presented in Section 3.3.4.1
b
Screening should take place within 28 days of start of study treatment, however, may be extended as outlined in Section 6.2.1.1.
c
Safety laboratory assessments including haematology, serum biochemistry, coagulation, serum pregnancy test, and urinalysis will be performed locally. The 
following screening parameters should be done ≤14 days prior to initiation of treatment: medical history and demographics, physical examination (including height 
and weight), Eastern Cooperative Oncology Group (ECOG) performance status, vital signs, electrocardiogram (ECG), haematology (per Section 5.2.3), clinical 
chemistry (sodium, potassium, phosphate, chloride, creatinine, calcium, venous bicarbonate HCO3, albumin, total protein, aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase, total, direct and indirect bilirubin, lactate dehydrogenase, serum glucose, creatinine kinase [CK: if CK is elevated, 
then CK-MB, Troponin I/Troponin T, and myoglobin should be reactively tested, with further follow-up as clinically warranted], serum urea nitrogen, serum uric 
acid, and thyroid panel [TSH, free T4, and free T3]), urinalysis, and screening pregnancy test. If these assessments are performed within 72 hours of initiation of 
treatment, they do not need to be repeated on Cycle 1 Day 1 with the exception of the ECOG performance status, an abbreviated physical examination, vital signs, 
and single ECGs required prior to first administrations of trial treatments. Tumour assessments (scans) should be performed ≤28 days prior to initiation of treatment. 
Refer to Section 5.2.3 for additional details. Vital signs (blood pressure, body temperature, and pulse rate) are checked at every visit prior to blood work and trial
treatment and at the discretion of the Investigator (see Section 5.2.2).
d
Physical examinations including the measurements of height (screening only) and weight will be done at screening, on Day 1 of each treatment cycle, at the end-of-
treatment (EOT) visit, at the 30-day safety follow-up (FU) visit, and at the FU visits for PD. However, patients will have an additional abbreviated physical 
examination (focused on the specific disease, at the Investigator’s discretion) on Cycle 1 Day 15. ECOG performance status will be done at screening, on Day 1 of 
Cycles 1 and 2, on Day 1 of every other cycle beginning with Cycle 3, at the EOT visit, at the 30-day FU visit, and at FU visits for PD (see Section 5.2.1).
e
Triplicate electrocardiograms (ECGs) are required in connection with pharmacokinetic sample collection as outlined in Table 10.3: 3. When triplicate ECGs are not 
done, single 12-lead ECGs will be done per the flow chart above for safety purposes at screening, on Cycle 1 Day 8, on Day 1 of each additional cycle, at the EOT 
visit, and whenever the Investigator deems it necessary (see Section 5.2.4).
f
Refer to Section 3.3.3 for details on which patients require cardiac testing (e.g., echocardiogram (ECHO)/multi-gated acquisition (MUGA) scan.
g
Pregnancy tests are mandatory for women with child-bearing potential. A serum beta human chorionic gonadotropin (β-HCG) pregnancy test must be done with
serum at screening. Thereafter, this test can be done in either serum or urine on Day 1 of each cycle, at the EOT visit, and at the 30-day FU visit (see Section 5.2.3).
h
Tumour assessments should be done according to RECIST v1.1 and iRECIST and should include computed tomography (CT) scans of the chest and abdomen and, if 
clinically indicated, imaging of any other known or suspected sites of disease (e.g., pelvis, brain) using an appropriate method (CT scan or magnetic resonance 
imaging [MRI]). The same radiographic procedure must be used throughout the trial. In case of suspected (but not otherwise confirmed) bone metastasis at 
screening, tumour assessment at screening should include a bone scan. If bone lesions are already known or confirmed at screening, correlative imaging (X-ray or 
CT scan) should be performed. Correlative imaging should then be repeated at each tumour assessment (see Section 5.1 for more detail). Assessments will be 
performed by the Investigator at screening and every 2 cycles (6 weeks ±5 days) for the first 6 months of treatment, once every 3 cycles (9 weeks ±5 days) thereafter, 
at the EOT visit (if not performed within the previous 4 weeks), and at the discretion of the Investigator. Baseline tumour assessments must be performed within 
28 days before first drug intake.


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i
Pharmacokinetic (PK) blood sampling will be done during select treatment cycles. Please follow the visit days and sampling time points as outlined in Table 10.3: 3. 
The permitted visit windows noted in the table footnotes should only be used if medically indicated. Please note that there are separate assays for determination of BI 
891065 and BI 754091. Therefore, 2 tubes must be drawn at each time point.
l
The following tumour biopsies will be mandatory for all patients in Part C of the trial:
-
The equivalent of two 14-16G needle biopsies must be freshly taken between screening and the day before the first trial drug treatment. If archival formalin-
fixed paraffin-embedded (FFPE) tumour material is available that is not older than 6 months, 26 4-5µm sections would be acceptable as well.
-
The equivalent of two 14-16G needle biopsies on treatment at the beginning of Cycle 3 (i.e., after 6 weeks of treatment). If possible the biopsy should be 
collected from the same lesion as the pre-treatment biopsies.  In case study drug was interrupted for 3 weeks or longer, consult with the Sponsor regarding 
whether or not to delay the biopsy.  
-
Another biopsy (optional) should be taken upon PD (according to RECIST v1.1 and iRECIST), if possible (see Section 5.4.2.3).
m
Patients should not take BI 891065 prior to certain visits that require pre-dose blood sampling as detailed in Table 10.3: 4.  Patients could be assigned q.d. or b.i.d. 
dosing. For patients taking b.i.d. dosing, the evening dose on infusion days should be skipped (Day 1 and Day 15 of Cycle 1). For all patients, the morning dose on 
Day 2 and Day 16 should be taken in the clinic (after pre-dose blood sampling is taken). On BI 754091 infusion days, BI 891065 will be administered approximately 
30 minutes after the end of the BI 754091 infusion.. Patients will be observed after their first dose of BI 891065 on Cycle 1 Day 1 and Cycle 2 Day 2 for 4 hours as 
outlined in Section 5.2.6.4.3. 
n
An EOT visit should be performed for all patients who permanently discontinue trial medication. If the decision to permanently discontinue treatment is taken at a 
scheduled visit, the EOT visit should be performed instead of the scheduled visit (preferably within 7 days and no later than 14 days after the last treatment). Please
note that a patient with an initial radiologic PD does not have to be automatically withdrawn from treatment (see Section 3.3.4.1).
o
The residual effect period starts after last dose of trial medication and ends 30 days later. A 30-day safety FU visit should take place before any other anti-cancer 
treatment starts.
p
Follow-up for PD visits for tumour assessment by imaging (CT or MRI) for patients who discontinue trial treatment without having PD based on RECIST v1.1 
and/or iRECIST should be performed every 6 weeks (±5 days) for the first 6 months of treatment and then every 9 weeks (±5 days) thereafter until PD or another 
withdrawal criterion is met At these visits, serious adverse events (SAEs) and adverse events of special interest (AESIs) occurring during the trial that are considered 
to be related to trial treatment or procedures will be followed until resolution.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART: BI 1379.1 (REFMAL 505) PART A TRIAL ASSESSMENTS ..............6
FLOW CHART: BI 1379.1 (REFMAL 505) PART B TRIAL ASSESSMENTS ............10
FLOW CHART: BI 1379.1 (REFMAL 505) PART C (NSCLC) TRIAL 
ASSESSMENTS..................................................................................................15
TABLE OF CONTENTS ......................................................................................................19
ABBREVIATIONS................................................................................................................24
1.
INTRODUCTION...............................................................................................26
1.1
MEDICAL BACKGROUND.............................................................................26
1.2
DRUG PROFILES..............................................................................................27
1.2.1
BI 891065 
...............................................................................27
1.2.2
BI 754091 
................................................................................28
1.2.3
Combination of BI 891065 and BI 754091........................................................28
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................29
1.4
BENEFIT - RISK ASSESSMENT.....................................................................30
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................31
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........31
2.1.1
Main objectives....................................................................................................31
2.1.2
Primary endpoints...............................................................................................32
2.1.2.1
Part A ....................................................................................................................32
2.1.2.2
Part B.....................................................................................................................32
2.1.2.3
Part C (NSCLC)....................................................................................................33
2.1.3
Secondary endpoints...........................................................................................33
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................34
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................34
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................37
3.3
SELECTION OF TRIAL POPULATION .......................................................38
3.3.1
Main diagnosis for trial entry ............................................................................38
3.3.2
Inclusion criteria .................................................................................................38
3.3.3
Exclusion criteria ................................................................................................39
3.3.4
Withdrawal of patients from therapy or assessments .....................................41
3.3.4.1
Withdrawal from trial treatment ...........................................................................41
3.3.4.2
Withdrawal of consent for trial participation........................................................43


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3.3.4.3
Discontinuation of the trial by the Sponsor ..........................................................43
3.3.4.4
Replacement of patients who have received at least one dose of BI 891065 or BI 
754091...................................................................................................................43
3.3.4.5
Trial enrolment stopping rules in case of unacceptable toxicities ........................44
4.
TREATMENTS...................................................................................................44
4.1
INVESTIGATIONAL TREATMENTS ...........................................................44
4.1.1
Identity of the Investigational Medicinal Products..........................................44
4.1.2
Selection of doses in the trial..............................................................................45
4.1.2.1
Starting dose of BI 891065 ...................................................................................45
4.1.2.2
Starting dose of BI 754091 ...................................................................................45
4.1.3
Dose-escalation scheme.......................................................................................46
4.1.3.1
Cohorts at dose levels <25 mg BI 891065 daily...................................................46
4.1.3.2
Cohorts at dose levels ≥25 mg BI 891065 daily...................................................46
4.1.4
Method of assigning patients to treatment groups...........................................47
4.1.5
Administration of doses for each patient..........................................................48
4.1.5.1
Administration of BI 891065................................................................................48
4.1.5.2
Administration of BI 754091................................................................................49
4.1.6
Continuation of treatment..................................................................................49
4.1.7
Dose reductions and dose delays........................................................................49
4.1.8
Definition of dose-limiting toxicity ....................................................................51
4.1.9
Definition of maximum-tolerated dose..............................................................53
4.1.10
Definition of evaluable patient...........................................................................53
4.1.11
Blinding and procedures for unblinding...........................................................53
4.1.12
Packaging, labelling, and re-supply...................................................................53
4.1.13
Storage conditions...............................................................................................53
4.1.14
Drug accountability.............................................................................................53
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................54
4.2.1
Other treatments and emergency procedures..................................................54
4.2.2
Restrictions ..........................................................................................................55
4.2.2.1
Restrictions regarding concomitant treatment ......................................................55
4.2.2.2
Restrictions on diet and life style..........................................................................57
4.2.2.3
Contraception requirements..................................................................................57
4.3
TREATMENT COMPLIANCE........................................................................57
4.3.1
BI 891065 .............................................................................................................57
4.3.2
BI 754091 .............................................................................................................58
5.
ASSESSMENTS..................................................................................................58
5.1
ASSESSMENT OF EFFICACY........................................................................58
5.1.1
NSCLC tumour assessment and solid tumour assessment..............................58
5.2
ASSESSMENT OF SAFETY.............................................................................59
5.2.1
Physical examination ..........................................................................................59
5.2.2
Vital signs.............................................................................................................59
5.2.3
Safety laboratory parameters ............................................................................59
5.2.4
Electrocardiogram ..............................................................................................61


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5.2.5
Other safety parameters.....................................................................................63
5.2.6
Assessment of adverse events.............................................................................63
5.2.6.1
Definition of adverse event...................................................................................63
5.2.6.2
Definition of serious adverse event.......................................................................63
5.2.6.3
Adverse events considered “Always Serious”......................................................64
5.2.6.4
Adverse events of special interest (AESIs)...........................................................64
5.2.6.5
Severity of adverse events.....................................................................................68
5.2.6.6
Causal relationship of adverse events...................................................................68
5.2.6.7
Adverse event collection and reporting ................................................................69
5.2.6.8
Pregnancy..............................................................................................................70
5.2.6.9
Exemptions to AE/SAE reporting.........................................................................71
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................71
5.3.1
Assessment of pharmacokinetics .......................................................................71
5.3.2
Methods of sample collection .............................................................................72
5.3.2.1
Plasma sampling for BI 891065 pharmacokinetics...............................................72
5.3.2.2
Plasma sampling for BI 754091 pharmacokinetics...............................................72
5.3.2.3
Plasma sampling for metabolism analysis of BI 891065......................................73
5.3.2.5
Urine sampling and analysis for pharmacokinetics of BI 891065 (Part A only)..73
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................74
5.4.1
Methods of sample collection .............................................................................75
5.4.3
Biobanking (solid tumours)................................................................................76
5.5
OTHER ASSESSMENTS...................................................................................77
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................77
6.
INVESTIGATIONAL PLAN.............................................................................77
6.1
VISIT SCHEDULE.............................................................................................77
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................78
6.2.1
Screening..............................................................................................................78
6.2.1.1
Screening period ...................................................................................................78
6.2.1.2
Baseline conditions ...............................................................................................79
6.2.1.3
Medical history .....................................................................................................79
6.2.1.4
Concomitant therapies...........................................................................................79
6.2.2
Treatment period ................................................................................................79


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6.2.2.1
Food-interaction assessment .................................................................................79
6.2.3
Follow up periods and trial completion ............................................................80
6.2.3.1
End-of-treatment (EOT) visit................................................................................80
6.2.3.2
30-day safety follow-up visit (end of residual-effect period) ...............................80
6.2.3.3
Extended follow-up period....................................................................................80
6.2.3.4
Trial completion for an individual patient ............................................................81
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................81
7.1
STATISTICAL DESIGN - MODEL.................................................................81
7.1.1
Part A ...................................................................................................................81
7.1.2
Part B ...................................................................................................................85
7.1.3
Part C ...................................................................................................................89
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................89
7.3
PLANNED ANALYSES.....................................................................................89
7.3.1
Primary endpoint analyses.................................................................................89
7.3.2
Secondary endpoint analyses .............................................................................90
7.3.4
Safety analyses.....................................................................................................90
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................91
7.4
INTERIM ANALYSES ......................................................................................92
7.5
HANDLING OF MISSING DATA ...................................................................92
7.6
RANDOMISATION ...........................................................................................93
7.7
DETERMINATION OF SAMPLE SIZE .........................................................93
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........95
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................96
8.2
DATA QUALITY ASSURANCE ......................................................................96
8.3
RECORDS...........................................................................................................96
8.3.1
Source documents ...............................................................................................97
8.3.2
Direct access to source data and documents.....................................................98
8.3.3
Storage period of records ...................................................................................98
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................98
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........99
8.6
TRIAL MILESTONES.......................................................................................99
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................100
9.
REFERENCES..................................................................................................102
9.1
PUBLISHED REFERENCES..........................................................................102
9.2
UNPUBLISHED REFERENCES....................................................................106
10.
APPENDICES...................................................................................................107
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST ...107
10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS............110


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10.3
TIME SCHEDULES FOR PHARMACOKINETIC (PK) 
 SAMPLING.............................................................................117
10.4
PHARMACOKINETIC ANALYSES.............................................................127
10.5
STATISTICAL APPENDIX............................................................................129
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................146


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ABBREVIATIONS
ADA
Anti-drug antibodies
AE
Adverse event
AESI
Adverse event of special interest
AGP
Alpha-1 acid glycoprotein
ALT
Alanine transaminase
AST
Aspartate aminotransferase
AUC
Area under the curve
β-HCG
Beta human chorionic gonadotropin
BI
Boehringer Ingelheim
b.i.d.
Twice a day
BLRM
Bayesian Logistic Regression Model
cIAP
Cellular inhibitor of apoptosis
CK
Creatinine kinase
CK-MB
Creatinine kinase - cardiac muscle subunit
Cmax
Maximum measured plasma concentration
CNS
Central nervous system
Cpre
Pre-dose plasma concentration
CR
Complete response
CRF
Case report form
CRS
Cytokine release syndrome
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical trial protocol
CYP
Cytochrome P450
DILI
Drug-induced-liver-injury
DLT
Dose-limiting toxicities
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EOT
End of treatment
EudraCT
European Clinical Trials Database
EWOC
Escalation with overdose control
FACS
Fluorescence activated cell sorting
FDA
Food and Drug Administration
FLC
Serum free light chain
FU
Follow up
G
Gauge
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HIV
Human immunodeficiency virus
IAP
Inhibitor of apoptosis
ICH
International Conference of Harmonization
i.e.
Id est


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IMiD
Immunomodulator
iRECIST
Immune Response Evaluation Criteria in Solid Tumors
ISF
Investigator site file
i.v.
Intravenous
mAb
Monoclonal antibody
MDSC
Myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRD
Minimal residual disease
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
MUGA
Multi-gated acquisition scan
NIH
National Cancer Institute
NSCLC
Non-small cell lung cancer
OR
Objective response
OS
Overall survival
PBMC
Peripheral blood mononuclear cells
PD
Progressive disease
PDc
Pharmacodynamics
PD-1
Programmed cell death protein 1
PD-L1
Programmed cell death ligand 1
PFS
Progression-free survival
PK
Pharmacokinetics
p.o.
Per os (oral)
PR
Partial response
q.d.
Once a day
RECIST
Response Evaluation Criteria in Solid Tumors
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
ROS1
ROS Proto-Oncogene 1
SAE
Serious adverse event
sCR
Stringent complete response
SRC
Safety Review Committee
TLS
Tumour lysis syndrome
TNFα
Tumour necrosis factor alpha
t1/2
Terminal half-life
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of normal
US
United States
VGPR
Very good partial response
XIAP
X-linked inhibitor of apoptosis protein


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Despite the recent advancements in cancer treatment, cancer remains a leading cause of death 
globally. In the United States (US), approximately 1,685,210 new cancer cases were expected 
to be diagnosed in 2016. The American Cancer Society estimated that there would be 
approximately 595,000 deaths due to cancer in the US during 2016 (R16-4925). The type of 
cancer chosen for the expansion cohort in this trial is non-small-cell lung cancer (NSCLC).
Non small-cell lung cancer
Lung cancer remains the most common cancer in the world. In the US, the American Cancer 
Society estimated that approximately 224,390 new cases of lung cancer and 158,080 deaths 
from lung cancer were expected in 2016 (P16-11525). The most prevalent (80% to 85%) of 
all lung cancers is NSCLC. At initial diagnosis, 55% of patients have distant spread of 
disease (R16-4724). According to the US National Cancer Institute (NIH), the 5-year relative 
survival of distant stage disease is 4.9% (R16-4740). Real-world data (FRAME study [R16-
3671]), has shown median overall survival (OS) in patients with advanced or metastatic 
NSCLC of 10.3 months. This is in the range (7.4 to 11.8 months) obtained from Phase III 
studies (R04-1314; R08-4164; R12-3987; R07-4508).
Treatment of advanced stage NSCLC is changing at the moment. Pembrolizumab was 
approved that year by the Food and Drug Administration (FDA) for 1st-line treatment of 
patients with metastatic NSCLC with high levels of programmed cell death protein ligand 1
(PD-L1) (tumour proportion score ≥50%) (R16-5013). First-line treatment of patients with 
advanced NSCLC who are not pembrolizumab candidates consists of 4 to 6 cycles of 
platinum-based chemotherapy. The 2nd line treatment of NSCLC has also been markedly 
transformed by the introduction of PD-1/PD-L1 immune checkpoint inhibitor monoclonal 
antibodies (mAbs) (nivolumab, durvalumab and atezolizumab in addition to pembrolizumab). 
Treatment of patients with advanced NSCLC with nivolumab, pembrolizumab, or 
atezolizumab monotherapy results in very durable responses in approximately 15% to 20% of 
patients (R15-3715; R15-6023; R16-0876).


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1.2
DRUG PROFILES
1.2.1
BI 891065


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1.2.2
BI 754091
1.2.3
Combination of BI 891065 and BI 754091
The rationale for combining BI 891065 and anti-PD-1 is the “one two punch” combination 


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For a more detailed description of BI 891065 and BI 754091, profiles please refer to the
current Investigator’s Brochures.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Most patients with locally advanced or metastatic tumours will succumb to their disease, 
justifying the substantial need for novel therapeutic strategies to improve the outcome for 
patients with advanced or metastatic malignancies. Immune checkpoint inhibition has been 
shown to be a promising therapeutic strategy. Despite encouraging clinical results with 
immune checkpoint inhibitors, up to 80% of treated patients do not respond to current 
checkpoint inhibitor monotherapy (R15-3588; R15-3778).
Preclinical studies of BI generated evidence of a tumour regression effect of the combination 
of 
 BI 891065 and 
 
This trial is the first study with BI 891065 monotherapy as well as BI 891065 in combination 
with BI 754091 in humans and will consist of 3 parts:

Part A: Dose escalation of BI 891065 as monotherapy, followed by

Part B: Dose escalation of BI 891065 in combination with BI 754091, followed by

Part C: An expansion phase of BI 891065 in combination with BI 754091 in the selected 
indication.
Parts A and B of the trial will be undertaken in patients with advanced/refractory solid 
tumours. Part A will determine the MTD and/or the recommended dose for Part B as well as
investigate the safety, PK, and pharmacodynamics (PDc) of BI 891065 monotherapy. Target 
engagement will be determined in peripheral blood 
 
 Dose escalation in Part A will be guided by a BLRM with 
overdose control. The data obtained from the trial will determine the MTD estimate based on 
a BLRM employing an escalation with overdose control (EWOC) principle (R13-4803). The 
BLRM estimates the MTD by updating estimates of the probability of observing a DLT in the 
MTD evaluation period (first treatment cycle) for each dose level in the trial as patient 
information becomes available. At any time in the trial, it will not be permitted to escalate to 
a dose which does not fulfil the EWOC criterion (refer to Section 7).
In both Parts A and B, the Safety Review Committee (SRC) will recommend and decide on 
the size for the next dose escalation cohort. After all patients in a cohort in Part A and Part B 


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have either experienced a DLT or have been observed for at least the MTD evaluation period 
without experiencing a DLT, the BLRM will be updated with the newly accumulated data.
Part C will be in the selected indication (NSCLC) in order to assess efficacy (objective 
response [OR]) and reconfirm safety and tolerability at the combination doses determined in 
Part B.
The therapeutic benefit or specific adverse events in patients cannot always be anticipated 
during the trial setup. Later on, there may be new scientific knowledge about biomarkers and 
other factors contributing to diseases or the action of a drug. In order to be able to address 
future scientific questions, patients will be asked to voluntarily donate biospecimens for 
banking.
1.4
BENEFIT - RISK ASSESSMENT
BI 891065 and BI 754091 inhibit tumour growth and induce tumour regression in pre-clinical 
models. BI 891065 has not yet been studied in humans, and BI 754091 is currently being 
assessed in a first-in-human trial. Based on pre-clinical results, BI 891065 showed single 
agent anti-tumour activity in several tumour models. Furthermore, the inhibitory effects of 
the combination of both compounds have been demonstrated in tumour models and may 
translate into a clinical benefit in cancer patients.
Only a minimum number of patients should be exposed to doses of BI 891065 that are 
presumed to be below the threshold of activity. Therefore, a Bayesian Logistic Regression 
Model (BLRM) design will be used in order to escalate the dose into a dose range where
efficacy or target engagement may be seen while still minimizing the risk of undue toxicity.
For Part B, to ensure patient safety, the starting dose of BI 891065 when combined with 
BI 754091 will not be higher than 75% of the BI 891065 MTD/ recommended dose for 
further development defined in Part A. For more details of the selection of doses, please refer 
to Section 4.1.2.
Since this is the first-in-human trial for BI 891065, patients in Part A will remain under 
surveillance for 10 hours after first administrations of BI 891065 and for at least 8 hours after 
administration of the second and third administrations of BI 891065. For Part B, patients will 
remain under surveillance after the administration of BI 891065 in combination with BI 
754091 for 8 hours after the first dose of BI 891065 in Cycle 1, and then for 6 hours after the 
first dose of BI 891065 in Cycle 2. For Part C, patients will remain under surveillance for 4 
hours after the first dose of BI 891065 in both Cycle 1 and Cycle 2 (see Section 5.2.6.4.3).
All trial sites will have emergency resuscitation services and access to intensive care 
available.
Specific attention will be given to symptoms of immune-mediated events (see 
Appendix 10.1), infusion-related reactions (see Section 5.2.6.4.2), and cytokine release 
syndrome (CRS; see Section 5.2.6.4.3). Infusion-related reactions or CRS, amongst others,
are defined as adverse events of special interest (AESI) and have to be reported according to 
the rules defined for serious AE (SAE)-reporting (see Section 5.2.6.7). Safety data from trials


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1381.1 and 1381.2 will also be integrated in the safety assessments for the combination of the 
compounds.
Previous anti-PD-l mAbs have been associated in the clinical setting with inflammatory 
adverse reactions resulting from increased or excessive immune activity (irAEs), likely to be 
related to the mechanism of action. These adverse reactions, which can be severe, may 
involve the gastrointestinal, skin, liver, endocrine, respiratory, renal, or other organ systems.
The assessment of biomarkers in tumour tissue in Part B and Part C is important for clinical 
development (see Section 5.4). Only patients with at least 1 tumour lesion amenable to biopsy
will be enrolled in Part B and Part C (see Section 3.3.2).
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety (see Section 5.2.6).
A Safety Review Committee (SRC) will be responsible for the continuous assessment of the 
trial data to ensure overall safety of the patients treated. Based on the models and on 
additional information (patient profiles), the members of the SRC will reach a joint 
recommendation on the next dose level of BI 891065 and/or of the dose combination to be 
investigated and the size for the next dose-escalation cohort. They will also provide the 
Investigators and the Sponsor with advice about the conduct of the trial and the integrity of 
the data (see Section 8.7).
In summary, the present trial will implement a number of safety measures to mitigate 
possible risks. Therefore, a potential benefit is offered to patients with advanced and/or 
metastatic malignancies
 
Treatment with both compounds is expected to 
provide patients with clinical benefit at an acceptable risk.
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of the dose-escalation parts of the trial is to determine the maximum 
tolerated dose (MTD), based on the frequency of patients experiencing dose-limiting 
toxicities (DLTs), and/or the recommended dose for further development of BI 891065 
monotherapy as well as of BI 891065 in combination with BI 754091, and to evaluate its
safety and tolerability by monitoring the occurrence and severity of adverse events (AEs).
Secondary objectives are the determination of the pharmacokinetic (PK) profile of BI 891065 
monotherapy as well as of BI 891065 in combination with BI 754091, and the preliminary 
assessment of anti-tumour activity.


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In the expansion cohort of the trial, the main objectives are to assess efficacy and to further 
assess the safety, PK, and PDc profiles at the investigated dose level.
2.1.2
Primary endpoints
2.1.2.1
Part A
The primary endpoints for Part A of the trial are the MTD of BI 891065 and the number of 
patients with DLTs during the first treatment cycle. The MTD is defined as the highest dose 
with less than 25% risk of the true DLT rate being equal to or above 33%.
The primary endpoints of this part will be evaluated based on a timeframe from first 
treatment administration until the end of the MTD evaluation period (the end of the first 
cycle).
For doses below 25 mg, single patient cohorts will be treated at 5 mg and 15 mg if not 
specified otherwise by the SRC. A BLRM employing the EWOC principle will be used 
during the escalation phase for selection of doses to investigate and for estimation of the 
MTD. Cohorts of patients will receive escalating doses of BI 891065 until the MTD is 
reached or the highest possible dose has been tested. Each cohort will consist of newly 
enrolled patients. Estimation of the MTD during the escalation phase of the trial will be based 
upon the estimation of the probability of a DLT in Cycle 1 in the set of evaluable patients 
(where evaluable patients refer to patients not fulfilling the criteria for replacement 
[Section 3.3.4.4]) for the MTD. The corresponding methodology is described in Section 7
and in the statistical appendix (see Appendix 10.5). The MTD estimate established during the 
dose escalation of Part A will be re-investigated at the end of Part A by re-running the BLRM
using the DLT information from all treatment cycles to determine the recommended dose 
range for Part B.
2.1.2.2
Part B
The primary endpoints for Part B of the trial are the MTD of BI 891065 in combination with 
BI 754091 and the number of patients with DLTs during the first treatment cycle. Q.D. and 
b.i.d. dosing schedules may be explored in Part B. The MTD is defined as the highest dose 
combination with less than 25% risk of the true DLT rate being equal to or above 33%.
The primary endpoints of this part will be evaluated based on a timeframe from first 
treatment administration until the end of the MTD evaluation period (the end of the first 
cycle).
Another BLRM employing the EWOC principle will be used during the escalation phase for 
selection of dose combinations and for estimation of the MTD. It is planned that cohorts of 
patients will receive escalating doses of BI 891065 in combination with BI 754091 (at the 
dose pre-specified by the SRC) until the MTD is reached or the highest tolerated dose of BI 
891065 determined in Part A has been tested. Each cohort will consist of newly enrolled 
patients. Estimation of the MTD during the combination escalation phase of the trial will be 
based upon the estimation of the probability of a DLT in Cycle 1 in the set of evaluable 


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patients for MTD. The corresponding methodology is described in Section 7 and in the 
statistical appendix (see Appendix 10.5). The MTD estimate established during the dose 
escalation of Part B will be re-investigated at the end of Part B by re-running the BLRM
using the DLT information from all treatment cycles to determine the recommended dose 
combination for further development.
2.1.2.3
Part C (NSCLC)
The dose of each of the study drugs used for Part C will be determined from the data of
Parts A and B.
The primary endpoint is OR by Investigator’s assessments.
For patients with NSCLC, OR is defined as best overall response of CR or partial response
(PR), where best overall response is determined according to Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 from the start of treatment until the earliest of PD, death 
or last evaluable tumour assessment before start of subsequent anti-cancer therapy.
Tumour imaging will be performed at baseline and then every 6 weeks for the first 6 months 
and then every 9 weeks thereafter as required by RECIST / iRECIST (R17-0923) until the 
earliest of PD, death or the last evaluable tumour assessment before start of subsequent anti-
cancer therapy or until the end of the trial as defined in Section 8.6.
2.1.3
Secondary endpoints
The secondary endpoints in this trial are:
For Part A

The number of patients with DLTs observed during the entire treatment period.

Cmax,ss, AUC0-tz and AUCτ,ss of BI 891065 in the first treatment cycle.

OR based on RECIST v1.1.
For Part B

The number of patients with DLTs observed during the entire treatment period.

Cmax,ss, AUC0-tz and AUCτ,ss of BI 891065; Cmax and AUC0-tz of BI 754091 in the first 
treatment cycle.

OR based on RECIST v1.1.
For Part C

Duration of OR based on RECIST 1.1 defined as the time from first documented CR or 
PR until the earliest of PD or death among patients with OR.
For all three parts, the first treatment cycle, used as the analysis period for the PK endpoints, 
relates to the time frame from start of treatment until 3 weeks after start of treatment. All 
other secondary endpoints will be analysed based on the entire treatment period. This relates 
to the timeframe from start of treatment until 30 days after last trial medication.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is an open-label, first-in-human, Phase I dose-finding trial with BI 891065 as 
monotherapy and in combination with BI 754091 to characterise safety, tolerability, PK/PDc, 
and preliminary efficacy in patients with advanced and/or metastatic malignancies.
Part A of the trial will include patients with advanced/refractory solid tumours to determine 
the MTD and/or the recommended dose for Part B as well as to investigate the safety, PK, 
and PDc of BI 891065 monotherapy. Target engagement will be determined in peripheral 
blood (cIAP degradation in PBMCs). The data obtained from the trial will determine the 


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MTD estimate based on a BLRM employing the EWOC principle (R13-4803). The BLRM 
estimates the MTD by updating estimates of the probability of observing a DLT in the MTD 
evaluation period (first treatment cycle) for each dose level in the trial as patient information 
becomes available. At any time in the trial, it will not be permitted to escalate to a dose which 
does not fulfil the EWOC criterion (refer to Section 7). Dose-escalation will in addition be 
restricted to a maximum of 100% from the previous dose for any dose ≥15 mg BI 891065
(see Section 4.1.3). Successive cohorts of patients will receive increasing or decreasing doses 
of BI 891065 until the MTD is reached; the maximum dose level planned is 400 mg. For any 
dose-escalation cohort >15 mg BI 891065, at least 3 patients will be required (refer to 
Section 7). However, in the case that only 2 patients are evaluable for the MTD and neither 
has experienced a DLT within the MTD evaluation period, then dose-escalation can occur 
based on these 2 patients. Additional patients on the same dose level will not start treatment 
before the previous patient has received the first dose for 2 days.
Part B will be a dose escalation of BI 891065 in combination with a dose of 240 mg 
BI 754091 once every 3 weeks (the dose used for the expansion portion of Trial 1381.1). 
While it is planned that this dose will be stable, under exceptional circumstances changes 
may be made by the SRC. Should it be decided that a different starting dose of BI 754091 is 
warranted in the combination with BI 891065, this BI 754091 dose is not to exceed the 
highest dose assessed as safe for BI 754091 monotherapy, and in any case must not exceed
2000 mg for the single dose (technical limit). Patients with select advanced/refractory solid 
tumours without established treatment options will be entered in order to determine the MTD 
and/or recommended dose for the expansion cohort in Part C of BI 891065 in combination 
with BI 754091, to assess safety and tolerability, and to explore PK/PDc. Target engagement 
of BI 891065 in combination with BI 754091 will be investigated in tumours (cIAP 
degradation in tumour tissue).
The starting dose of BI 891065 for Part B will be defined based on the safety and PK/PDc
observations in Part A. If an MTD is identified in Part A, the starting dose of BI 891065 for 
Part B will be ≤75% of the MTD. If no MTD is identified, but target engagement is 
confirmed by cIAP degradation in PBMCs, the starting dose of BI 891065 for Part B will be 
≤75% of the highest tolerated dose of Part A. Dose escalation in Part B will be guided by a 
BLRM with overdose control. Escalation of BI 891065 will be restricted to a maximum of 
100% from the previous dose. Successive cohorts of patients will receive increasing or 
decreasing doses of BI 891065 in combination with BI 754091 until the MTD of the 
combination is reached. The maximum dose level of BI 891065 in Part B is the highest 
tolerated dose from Part A. For any combination dose-escalation cohort, at least 3 patients 
will be required (refer to Section 7). However, in the case that only 2 patients are evaluable 
for the MTD and neither has experienced a DLT within the MTD evaluation period, then 
dose-escalation can occur based on these 2 patients. Based on the model and on additional 
information (patient profiles, cumulative safety outputs), the members of the SRC will reach 
a joint recommendation on the next dose level of BI 891065 and of the dose combination to 
be investigated and the size for the next dose-escalation cohort.
In both Parts A and B, the SRC will recommend and decide on the size for the next dose 
escalation cohort. After all patients in a cohort in Part A and Part B have either experienced a 


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DLT or have been observed for at least the MTD evaluation period without experiencing a 
DLT, the BLRM will be updated with the newly accumulated data. The overdose risk will 
then be calculated for each dose, and escalation will be permitted to all doses (dose 
combinations in Part B) which fulfil the EWOC criterion and the additional maximum 100%
escalation rule. Based on the model and on additional information (e.g., PK, PDc, patient 
profiles, cumulative safety outputs), the members of the SRC will reach a joint decision on 
the next dose level to be investigated.
For dose levels above 15 mg, if DLTs are observed in the first two consecutive patients of a 
previously untested dose level, subsequent enrolment to that cohort will be stopped. The 
BLRM will be re-run to confirm that the dose level still fulfils the EWOC principle. Based on 
this information, the SRC will evaluate whether the next patients will be enrolled at the same 
dose level, or if they will be enrolled at a lower dose level.
The SRC may recommend stopping the dose-finding phase after the criterion for MTD (see 
Section 7) is fulfilled. Further patients may be included to confirm this MTD estimate (i.e., to 
confirm that the EWOC criterion is still fulfilled). If no DLT is observed at a dose of which 
the efficacy is considered sufficient, the SRC may decide to include an additional number of 
patients at the same dose level and to declare this dose as the recommended dose for further 
development. The SRC can declare any dose fulfilling the EWOC criterion as recommended 
dose for further development, independent of the MTD estimate.
Once the combination dose is determined (to be confirmed by the Sponsor), the Part C 
expansion cohort will be initiated in patients with NSCLC who failed an anti-PD-1/anti-PD-
L1 treatment as a first-line therapy, either by itself or in combination with platinum-based 
therapy (see Section 3.3.2). In Part C, the SRC will assess the safety data and trial conduct in 
regular intervals as described in the SRC documentation. In addition, Part C will further 
evaluate the efficacy of the combined compounds. The trial design is displayed in Figure 3.1: 
1.


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Figure 3.1: 1 Design of trial 1379.1 including 2 dose-escalation parts and 1 expansion 
cohort
Patients will continue treatment as long as they are deriving clinical benefit in the opinion of 
the Investigator, or until withdrawal of consent, occurrence of unacceptable toxicity, or for 
additional reasons detailed in Section 3.3.4.1.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The primary objective of this trial is to determine the MTD and/or the dose for later 
development of BI 891065 monotherapy as well as of BI 891065 in combination with 
BI 754091 and to confirm the selected combination dose for an expansion cohort. The open 
dose-escalation design will allow an assessment of the safety of BI 891065 monotherapy as 
well as in combination with BI 754091 in this first-in-human trial. Given the objectives of 
this trial, a placebo treatment group is not included.
Dose escalation and cohort size will be determined based on the recommendation of the SRC, 
guided by BLRMs with overdose control (one for monotherapy and one for combination 
therapy). An escalation with overdose control design will increase the chance of treating 
patients at efficacious doses while reducing the risk of overdosing. This design is based on 
practical experience and is an efficient method due to its ability to identify the dose with a 
desired toxicity rate and its allocation of a greater proportion of patients to doses at, or close 
to, that desired dose (R13-4802; R13-4804; R13-4805). The use of BLRMs for Phase I 


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studies has also been advocated by the EMA guideline on small populations (R07-4856) and 
by the FDA (R13-4881).
Part A will be focused on BI 891065 monotherapy to provide the first safety data that can be 
implemented in Part B of the trial where BI 891065 will be combined with BI 754091. 
Observations from Part A and Part B then can be integrated in Part C where patients in an 
expansion cohort will be treated with the combination of BI 891065 plus BI 754091. An SRC
will also evaluate safety aspects in all expansion cohorts.
3.3
SELECTION OF TRIAL POPULATION
Approximately 60 patients (total) are planned to be included in the dose-escalation parts
(Part A and Part B), and approximately 44 patients are planned in the dose-expansion cohort
(Part C) of this international multi-centre trial.
A log of all patients enrolled into the trial (i.e., who have signed an informed consent form 
[ICF]) will be maintained in the Investigator site file (ISF) at the investigational site 
irrespective of whether or not they have been treated with investigational drug. Relevant data 
for all patients enrolled in the trial will be entered in the electronic Case Report Form 
(eCRF).
3.3.1
Main diagnosis for trial entry
Part A: Patients with a confirmed diagnosis of advanced, unresectable and/or metastatic solid 
tumours, who have failed standard treatment, or for whom no therapy of proven efficacy 
exists, or who are not amenable to standard therapies.
Part B: Patients with a confirmed diagnosis of advanced, unresectable and/or metastatic
cancers who have failed standard treatment, or for whom no therapy of proven efficacy 
exists, or who are not amenable to standard therapies. Eligibility is limited to patients with 
the following cancer types: bladder, colon, breast, NSCLC, ovarian, pancreatic, renal, 
esophagogastric, sarcoma, prostate, and melanoma.
Part C (NSCLC): Patients with metastatic NSCLC who developed disease progression (per 
RECIST v1.1) after the first scan (where SD, PR, or CR was demonstrated at the first scan), 
and require new anti-cancer therapy after first-line treatment with an anti PD-1/anti PD-L1 
mAb (given either as single agent therapy or in combination with a platinum-based 
chemotherapy regimen).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1. Provision of signed and dated, written ICF in accordance with ICH-GCP and local 
legislation prior to any trial-specific procedures, sampling, or analyses
2. Patients ≥18 years-of-age at the time of signature of the ICF


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3. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to 
father a child must be ready and able to use highly effective methods of birth control (that 
result in a low failure rate of less than 1% per year when used consistently and correctly) 
during trial participation and for at least 6 months after the last administration of trial 
medication. A list of contraception methods meeting these criteria is provided in the 
patient information.
4. Eastern Cooperative Oncology Group (ECOG) score: 0 or 1
5. Life expectancy of at least 12 weeks after the start of the treatment according to the
Investigator’s judgement
6. For Parts A and B: Patients with a confirmed diagnosis of advanced, unresectable and/or 
metastatic solid tumours, who have failed standard treatment, or for whom no therapy of 
proven efficacy exists, or who are not amenable to standard therapies. Measurable lesions 
according to RECIST Version 1.1 must be present. Eligibility is limited to the following 
tumour subtypes in Part B: bladder, colon, breast, NSCLC, ovarian, pancreatic, renal, 
esophagogastric, sarcoma, prostate, and melanoma.
7. For Parts B and C: Patients must have measurable disease per RECIST v1.1, must have at 
least 1 tumour lesion amenable to biopsy, and must be willing to undergo a biopsy prior 
to first treatment and another biopsy while on therapy unless clinically contraindicated.
8. For Part C: Patients with metastatic NSCLC who developed disease progression (per 
RECIST v1.1) after the first scan (where SD, PR, or CR was demonstrated at the first 
scan), and require new anti-cancer therapy after first-line treatment with an anti PD-1/anti 
PD-L1 mAb (given either as single agent therapy or in combination with a platinum-
based chemotherapy regimen).
3.3.3
Exclusion criteria
1. Major surgery (major according to the Investigator’s and/or Medical Monitor’s
assessment) performed within 12 weeks prior to randomization or planned within 12 
months after screening (e.g., hip replacement)
2. Presence of other active invasive cancers other than the one treated in this trial within 
5 years prior to screening, except appropriately treated basal cell carcinoma of the skin, or 
in situ carcinoma of uterine cervix, or other local tumours considered cured by local
treatment
3. Patients who must or wish to continue the intake of restricted medications (see 
Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the 
trial
4. Previous administration of BI 891065 or BI 754091
5. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s), or receiving other 
investigational treatments.
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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6. Patients who have been treated with any other anticancer drug within 4 weeks or within 
5 half-life periods (whichever come earlier) prior to first administration of BI 891065. At 
least 7 days must have elapsed between the last dose of such agent and the first dose of 
study drug.
7. Persistent toxicity from previous treatments that has not resolved to ≤Grade 1 (except for 
alopecia and Grade 2 neuropathy due to prior platinum-based therapy)
8. Active, known or suspected autoimmune disease except vitiligo or resolved asthma/atopy
9. Interstitial lung disease
10. Any of the following cardiac criteria:
-
Mean resting corrected QT interval (QTcF) >470 msec
-
Any clinically important abnormalities (as assessed by the investigator) in rhythm, 
conduction, or morphology of resting ECGs, e.g., complete left bundle branch 
block, third degree heart block
-
Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, congenital long QT syndrome, family history 
of long QT syndrome or unexplained sudden death under 40 years-of-age, or any 
concomitant medication with known or possible risk of QT interval prolongation
-
Patients with an ejection fraction (EF) <55% or the lower limit of normal of the 
institutional standard will be excluded. Only in cases where the Investigator (or 
the treating physician or both) suspects cardiac disease with negative effect on the 
EF, will the EF be measured during screening using an appropriate method 
according to local standards to confirm eligibility (e.g., echocardiogram [ECHO],
multi-gated acquisition scan [MUGA]). A historic measurement of EF no older 
than 6 months prior to first administration of study drug can be accepted provided 
that there is clinical evidence that the EF value has not worsened since this 
measurement in the opinion of the Investigator or of the treating physician or both.
11. Out of range laboratory values are defined as:
-
Alanine transaminase (ALT) and aspartate amino transferase (AST) >3 times the
ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver 
metastases
-
Total bilirubin >1.5 times ULN, except for patients with Gilbert's syndrome who 
are excluded if total bilirubin >3.0 times ULN or direct bilirubin >1.5 times ULN
12. Human immunodeficiency virus (HIV) infection, acute or chronic viral hepatitis
13. Known hypersensitivity to the trial drugs or their excipients
14. Serious concomitant disease or medical condition affecting compliance with trial 
requirements or which are considered relevant for the evaluation of the efficacy or safety 
of the trial drug, such as cardiac, neurologic, psychiatric, infectious disease or active 
ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk 
associated with trial participation or trial drug administration, and in the judgment of the 
Investigator and/or Medical Monitor would make the patient inappropriate for entry into 
the trial.
15. Chronic alcohol or drug abuse or any condition that, in the Investigator’s and/or Medical 
Monitor’s opinion, makes them an unreliable trial patient or unlikely to complete the trial
16. Women who are pregnant, nursing, or who plan to become pregnant while in the trial and 
for at least 6 months after the last administration of trial medication.


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17. Men who plan to father a child while in the trial and for at least 6 months after the last 
administration of trial medication.
18. Known presence of symptomatic central nervous system (CNS) metastases, unless 
asymptomatic and off corticosteroids and/or anti-convulsant therapy for at least 2 weeks 
prior start of treatment. Patients with asymptomatic CNS metastases may be enrolled 
following a 2-week washout period. 
19. Patients receiving systemic treatment with any immunosuppressive medication within 
1 week prior treatment start (steroids of max. 10 mg prednisolone equivalent per day are 
allowed, topical and inhaled steroids are not considered as immunosuppressive).
20. For Parts A and B: Patients with known epidermal growth factor receptor (EGFR), known 
anaplastic lymphoma kinase (ALK), or known ROS Proto-Oncogene 1 (ROS1) genomic 
tumour aberrations, unless disease has progressed following available EGFR or ALK 
targeted therapy (including osimertinib for EGFR T790M-mutated NSCLC)
21. Out of range lab values as defined:
-
Absolute neutrophil count (ANC) <1.5 x 109/L (<1500/mm3)
-
Platelet (PLT) count <100 x 109/L
-
Haemoglobin <90 g/L (<9 g/dL)
-
Creatinine >1.5 times ULN (patients may enter if creatinine is >1.5 x ULN and 
estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m2) (Chronic 
Kidney Disease Epidemiology [CKD-EPI] Collaboration equation); confirmation 
of eGFR is only required when creatinine is >1.5 X ULN.
22. For Part C: Patients with EGFR, ALK, or (if known) ROS1 genomic tumour aberrations
23. For Part C: Patients with any CTLA-4 therapy
24. For Part C: One or more lines of anti-cancer therapy between previous anti-PD-1/anti-
PD-L1 mAb therapy and study entry.
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different ramifications. Please see Section 3.3.4.1 and 
Section 3.3.4.2, respectively.
Every effort should be made to keep the entered patients in the trial: if possible on treatment, 
or at least to collect important trial data. Measures to control the withdrawal rate include 
careful patient selection, appropriate explanation of the trial requirements and procedures
prior to entering the trial, as well as the explanation of the consequences of withdrawal. The 
decision to withdraw from trial treatment or from the whole trial as well as the reason must 
be documented in the patient files and CRF.
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment(s) if:

The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication.


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
The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy [see Section 5.2.6.8]).

The patient has been non-compliant with important trial procedures and, in the opinion of 
both, the Investigator and Sponsor representative, is not willing or able to stick to the trial
requirements in the future.

Recurring radiologic progression. Note: In the case of initial radiological PD, patients will 
be allowed to stay on treatment if the following criteria are met:
-
The Investigator feels that it is in the patient’s best interest
-
The patient signed an informed consent form specific for this circumstance after 
acknowledging that this practice is not considered standard in the treatment of 
cancer. The specific informed consent process for this circumstance includes 
discussion of alternative treatment options, including any available approved 
therapies (if applicable) and participation in alternative clinical trials.
-
Absence of clinical symptoms or signs indicating clinically significant PD
-
No decline in performance status
-
Absence of rapid PD or threat to vital organs or critical anatomical sites (e.g., 
central nervous system metastasis, respiratory failure due to tumour compression, 
spinal cord compression) requiring urgent alternative medical intervention
-
No significant, unacceptable, or irreversible toxicities related to study treatment.

A pause of treatment or delayed start of treatment of more than 12 weeks due to 
SAEs/AEs

The following adverse event(s) occur:
-
Cytokine release syndrome CTCAE Version 5.0 (R18-1357) Grade 3 or 4
-
Immune related AEs requiring permanent study drug discontinuation as described 
in Guidelines for Management of Immune-Related AEs (Appendix 10.2):
-
Grade 3 to 4 pneumonitis
-
Grade 3 to 4 adrenal insufficiency
-
Grade 4 diabetes mellitus
-
Any grade encephalitis
-
Grade 4 hypophysitis
-
Grade 4 rash
-
Grade 3 to 4 colitis or recurrent colitis of any grade
-
Any recurrent Grade 3 to 4 AE
-
Transaminase increases >5 times ULN or total bilirubin >3 times ULN
-
Inability to taper steroids to 10 mg or less prednisone or equivalent 
within 12 weeks
-
SAEs/AEs of Grade ≥2 deemed intolerable by the patient or the 
treating physician and not responding to medical management and any 
SAEs/AEs of ≥Grade 3 that do not recover to Grade 1 or less within 12 
weeks
-
Persistent Grade 2-3 AEs that do not recover to Grade 1 or less within 
12 weeks
-
Grade 3 to 4 AEs that are classified as immune-related by the 
Investigator but are not listed in Appendix 10.1 if they do not resolve 
to Grade ≤ 1 or baseline with immunosuppressive therapy within 
2 weeks.


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-
≥Grade 4 drug-related AEs.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and will be followed up as outlined in Part A Flow Chart, Part B Flow Chart, 
Part C Lung Flow Chart, and Section 6.2.3.1. For all patients the reason for withdrawal from 
trial treatment (e.g., adverse events) must be recorded in the CRF. These data will be 
included in the trial database and reported.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision. This will however mean that no further information may be collected for 
the purpose of the trial and negative implications for the scientific value may be the 
consequence. Furthermore it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the Investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment (see Section 3.3.4.1).
3.3.4.3
Discontinuation of the trial by the Sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site

Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial

Violation of Good Clinical Practice (GCP), the trial protocol, or the contract, impairing 
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).
3.3.4.4
Replacement of patients who have received at least one dose of BI 891065 or BI 
754091
Replaced patients will not be evaluated for the MTD determination, and an additional patient 
will be entered at the same dose level. The following patients may be replaced:

Patients who permanently discontinue treatment during treatment Cycle 1 of Part A or 
Part B for reasons other than a DLT, unless they develop a DLT.

Patients who have missed more than 5 doses of BI 891065 in the first treatment cycle of 
Part A or Part B, unless they develop a DLT.

Patients who have reduced BI 891065 dose level during treatment Cycle 1 Part A or Part 
B, unless they develop a DLT.

Patients who have taken less than 80% of the BI 891065 overall dose during treatment 
Cycle 1 of Part B, unless they develop DLT.


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
Patients who have received less than 50% of a BI 754091 initial dose of Part B, unless 
they develop a DLT.

Patients who miss 2 or more partial or complete visits of the first cycle of Part A or Part B 
and (after discussion between the Sponsor and the Investigator) if the information needed 
to assess PK/PDc and safety parameters (including evaluation for DLTs), unless they 
develop a DLT.
Patients who permanently discontinue treatment because of a DLT will not be replaced.
Patients in the NSCLC expansion cohort (Part C) will not be replaced unless it becomes 
apparent that probably less than 40 patients will be evaluable for the assessment of the 
primary endpoint. In such a case, patients of the NSCLC expansion cohort concerned may be 
replaced only after confirmation of the Sponsor in writing.
3.3.4.5
Trial enrolment stopping rules in case of unacceptable toxicities
All AEs, including SAEs, AESIs, and deaths will be carefully analysed by the Sponsor. This 
data will also be taken into consideration by the SRC. Unacceptable toxicity will be defined 
as:

Clinically relevant adverse events that are:
-
unexpected considering the mode of action, and are not manifestations of 
underlying disease or background events typical of the trial population 
-
and/or are debilitating, non-reversible, not manageable
-
or lead to a fatal outcome
-
where evidence suggests that there was a reasonable possibility that the drug 
caused the adverse event.

Higher than expected frequency of specific events (such as known consequences of the 
underlying disease or other events that commonly occur in the trial population 
independent of drug therapy) that indicates those events occur more frequently in the drug 
treatment group than would be expected in the trial population.
If one or both of the above criteria are met, the enrolment to the trial will be stopped to allow 
for in-depth analysis of the safety profile of BI 891065 (in combination with BI 754091). The 
risk-benefit profile of BI 891065 (in combination with BI 754091) will be re-assessed by the 
SRC. The outcome of the analysis and the recommendations will be shared with all involved 
regulatory health authorities prior to a possible re-start of enrolment. In case the benefit/risk 
assessment is no longer considered to be positive, the trial will be discontinued.
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Patients will receive either BI 891065 monotherapy or BI 891065 in combination with 
BI 754091 (see Table 4.1.1: 1 and Table 4.1.1: 2).


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Table 4.1.1: 1
BI 891065
Substance:
BI 891065
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
5 mg, 20 mg, 50 mg, 100 mg tablets
Posology
Once daily (q.d.) or twice daily (b.i.d.), individual 
dose depending on dose escalation
Route of administration:
Oral
Table 4.1.1: 2
BI 754091
Substance:
BI 754091
Pharmaceutical formulation:
Solution for infusion after dilution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
20 mg/mL (vial with 15 mL filling volume)
Posology
Infusion on day 1 of 21-day cycles
Route of administration:
Intravenous infusion
4.1.2
Selection of doses in the trial
4.1.2.1
Starting dose of BI 891065
Based on the toxicities and exposures in the GLP-compliant dog study (the more sensitive 
species), a starting dose of 5 mg BI 891065 once daily has been chosen. To minimize the 
number of patients exposed to doses of BI 891065 presumed to be below the threshold of 
activity, an adapted dose-escalation approach (see Section 4.1.3) will be used for doses of BI 
891065 below 25 mg. For details please refer to the Investigator’s Brochure (c14463420-03).
4.1.2.2
Starting dose of BI 754091
A fixed dose of BI 754091 once every 3 weeks will be administered. The anticipated starting 
dose is 240 mg (i.e., the dose currently selected in the Phase I Trial 1381.1 of BI 754091 
monotherapy for expansion cohort patients and 1381.2). Based on further data for BI 754091, 
the starting dose may be adapted by the SRC (informed by a BLRM with overdose control 
design).


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4.1.3
Dose-escalation scheme
4.1.3.1
Cohorts at dose levels <25 mg BI 891065 daily
Enrolment into the first cohort at 5 mg BI 891065 daily will begin with 1 patient. If no drug-
related AE ≥Grade 2 (CTCAE Version 5.0) and no DLT is observed for the single patient
(observation period is 3 weeks), a 15 mg daily single patient cohort will be initiated, unless 
the SRC recommends another dose or another cohort size for the second cohort. If no drug-
related AE ≥ Grade 2 (CTCAE Version 5.0) and no DLT is observed for the single patient on 
15 mg BI 891065 (observation period is 3 weeks), the 25-mg cohort will be initiated as 
described in Section 4.1.3.2, unless the SRC recommends another dose. Therefore, dose 
escalation to the second cohort will NOT be restricted to a maximum of 100% from the 
previous dose as in cohorts that follow the 15 mg cohort.
If drug-related AEs ≥ Grade 2 are observed in the above described single-patient cohorts (5 
and 15 mg), the cohort and subsequent cohorts will be expanded to at least 3 patients.
The SRC will meet at the end of each of these treatment cohorts to decide on the next dose 
level based on available safety data and the BLRM recommendation.
4.1.3.2
Cohorts at dose levels ≥25 mg BI 891065 daily
The dose of BI 891065 is planned to be escalated in the Part A cohorts ≥25 mg daily at pre-
defined provisional dose levels based on a maximum escalation of 100%. The provisional 
dose levels ≥25 mg daily to be assigned to separate cohorts of patients are listed in Table 
4.1.3.2: 1. Intermediate or lower dose levels, depending on the number of DLTs observed in 
the trial may be investigated as long as they fulfil the EWOC criterion if agreed upon by the 
SRC.
Table 4.1.3.2: 1 Provisional dose levels for dose escalation of BI 891065 in Part A
Dose level
Proposed dose
Increase from previous dose
1
5 mg
Starting dose (fixed)
2
15 mg
300%
3
25 mg
67%
4
50 mg
100%
5
100 mg
100%
6
200 mg
100%
7
400 mg
100%
At the end of each treatment cohort, BI will convene a meeting with the SRC members. At 
the dose escalation meeting the clinical course (safety information including both DLTs and 


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all Common Terminology Criteria for Adverse Events [CTCAE; R18-1357] ≥ Grade 2 
toxicity data during the MTD evaluation period and additional data if needed) for each patient 
in the current dose cohort will be described in detail. Updated safety data on other ongoing 
patients, including data in later cycles, as well as cIAP degradation in PBMCs (for dose 
cohorts ≥25 mg BI 891065), will be discussed as well. Based on that, a decision on the next 
dose level to be tested will be made.
For Part B (combination therapy), the dose of BI 891065 is planned to be escalated in cohorts 
at dose levels which will be determined based on the results of Part A. However, the starting 
dose of BI 891065 in Part B will be maximally 75% of the highest tolerated dose from
Part A. Both q.d. and b.i.d. dose escalations may be performed in Part B. It is planned that a 
fixed dose of 240 mg BI 754091 will be used as determined in Trial 1381.1 (the dose chosen 
for the expansion cohorts). Based on emerging safety information in the 1381.1 and 1381.2 
studies, the SRC may amend the dose of BI 754091 used in this trial. The SRC will determine 
the selected dose of BI 754091 for each combination cohort of this trial and communicate it 
to the investigators.
The dose and regimen of BI 891065 in combination with BI 754091 to be used in Part C will 
be determined based on the safety and PK/PDc data of Parts A and B, including data of target 
engagement in tumour tissue. The dose of BI 891065 might be changed during conduct of 
Part C, if needed.
4.1.4
Method of assigning patients to treatment groups
There will be no randomisation in this trial, as each part is single-arm and open-label. 
Patients will be assigned into escalating dose groups by order of admission into the trial.
Recruitment into the trial will be conducted in a controlled manner. Patient numbers will be 
assigned as enrolment (screening) occurs. No patient will be enrolled without prior 
authorisation from 
 to ensure adherence with eligibility criteria, the escalation 
recruitment design and subsequent allocation to expansion cohorts. If a patient withdraws 
from the trial, then the enrolment code cannot be reused.
After assessment of all inclusion and exclusion criteria, each eligible patient entering Part A 
(monotherapy) will be assigned a dose of BI 891065 and each eligible patient entering Part B 
(combination therapy) will be assigned a q.d. or b.i.d. dose of BI 891065 and a dose of 
BI 754091, as determined by the SRC.
To determine the dose or doses for subsequent cohorts, the available safety data (including 
DLTs, AEs that are not DLTs, and AE information), target engagement, as well as the 
recommendations from the BLRM, will be evaluated by the SRC members at the dose-
decision meeting.


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The SRC must reach a consensus on whether to declare the MTD, escalate the dose any 
further, or de-escalate and/or expand recruitment into particular cohorts. Minutes from these 
meetings will be prepared and circulated to the trial team and each Investigator for comment 
prior to finalisation. Dose escalation will continue until at least one dose level higher than the 
estimated human therapeutic dose (maximum 400 mg daily dose of BI 891065) or until the 
trial is terminated for other reasons.
To further characterise the safety (e.g., specific suspected treatment-related AEs) or PK/PDc 
profiles of the BI 891065 plus BI 754091 combination, one or several doses may be 
expanded. Dose escalation may be terminated at any time based on emerging safety concerns 
without establishing the recommended expansion dose or the MTD.
In Part C (dose expansion), all patients will be treated with the doses determined by the 
assessment of DLTs, available PK, and available biomarker results from Parts A and B of the 
trial.
4.1.5
Administration of doses for each patient
4.1.5.1
Administration of BI 891065
BI 891065 may be taken in either a q.d. or b.i.d. dosing, depending on the assigned treatment 
regimen.
BI 891065 film-coated tablets were developed in four dosage strengths: 5, 20, 50, and 100 mg 
and will be provided in polypropylene bottles with screw-cap closures. The different tablet 
strengths should not be combined in the same bottle at any time. BI 891065 film-coated 
tablets must be stored in the containers provided and handled according to the labelled 
storage instructions and shelf life. Labels will be prepared in accordance with Good 
Manufacturing Practice (GMP) and local regulatory guidelines.
Patients need to be instructed to return any unused BI 891065 in the dispensed bottles, in 
addition to returning any empty bottles.
All patients will be required to complete a Dosing Diary, which must be returned to the clinic 
for review at each clinic visit. For applicable cohorts, the fasting status and all meals on the 
PK days should be recorded in the patient diary.
Refer to Part A Flow Chart, Part B Flow Chart, Part C Lung Flow Chart, and Appendix 10.3
for information about sampling that is required prior to dose administration.
BI 891065 doses should be taken orally at approximately the same time each morning (and 
evening for patients with b.i.d. dosing).  Exceptions are noted in the flowchart:

Part A patients will skip a dose on Cycle 1 Day 2

Part B patients assigned to a b.i.d. regimen will skip the evening dose on Cycle 1 Day 1 
and Day 15 (in preparation for PK testing on Cycle 1 Day 2 and Day 16).


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Patients will be asked to fast overnight (minimum of 10 hours) prior to the following 
intensive PK days:
Part A: Cycle 1 Day 1, 15
Part B: Cycle 1 Day 1, 15, 16
Refer to Section 10.3 for details.
When BI 891065 and BI 754091 are to be administered on the same day, BI 891065 will be 
administered approximately 30 minutes following the end of infusion of BI 754091, based on 
the safety assessments made by the Investigator.
Whenever possible, all doses of BI 891065 should be taken with water, limited to a maximum 
of 240 mL (approximately 8 US ounces). Additional information about the food-interaction 
assessments in Part B are presented in Section 6.2.2.1.
Missed doses should not be made up if more than 6 hours have passed since scheduled dosing 
time. Missed doses must be recorded in the patient’s Dosing Diary, and then should be 
recorded in the eCRF.
4.1.5.2
Administration of BI 754091
Vials of BI 754091 will be diluted and administered via infusion according to the details in 
the Pharmacy Manual in the ISF.
4.1.6
Continuation of treatment
Patients may start the next cycle of therapy if criteria for continuation of therapy as outlined 
in Section 4.1.7 are met.
4.1.7
Dose reductions and dose delays
AEs that are immune related should be managed according to the Guidelines for irAE 
management (as outlined in Appendix 10.2).    
For Grade 4 AE/SAEs that are not immune related, study drug should be withdrawn. 
However, if it can be excluded with high certainty that the event was related to study 
medication, study drug should be paused, and resumption of study drug may be allowed after 
discussion with the Medical Monitor and the Sponsor.
For Grade 3 AE/SAEs that are not immune related, study drug should be paused. 
For Grade 2 AEs/SAEs that are not immune related but are deemed intolerable by the patient 
or the treating physician and not responding to appropriate medical management, the 
physician should decide if a pause of treatment is warranted considering relevant variables 
such as perceived relatedness to study drug.  


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If, after a treatment pause of ≤12 weeks, the non-immune related SAE/AE resolves to 
baseline or Grade 1 and the physician thinks it is clinically appropriate to restart study drug, 
then the physician may choose to restart BI 891065 at one dose lower than the dose 
administered before the pause, and BI 754091 at the same fixed dose of BI 754091. If the 
AE/SAE prompting interruption has unequivocally been excluded to be drug related, 
reintroduction of BI 891065 at the same dose as prior to the pause may be considered.
There will be no dose reductions or escalations of BI 754091 in any one patient.  However, in 
the event of an infusion-related reaction ≤ Grade 2, the infusion rate of BI 754091 may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion. In patients experiencing infusion-related reactions 
≤ Grade 2, subsequent infusions may be administered at 50% of the initial rate. If an infusion-
related reaction is Grade 3 or higher in severity at any point during the study, treatment with 
BI 891065 and BI 754091 will be permanently discontinued (see Section 5.2.6.4.2).
As a general rule for Part B and Part C, both drugs (BI 891065 and BI 754091) will be 
stopped, paused, or re-exposed together. Exemptions have to be justified and aligned with the 
Sponsor in writing.  Up to two dose reductions are allowed per patient. For q.d. dosing 
regimens, dose reductions of BI 891065 are allowed only to doses previously explored in 
earlier cohorts. If a patient on a b.i.d. dosing regimen has a dose reduction, the dose should be 
reduced as follows: 200 mg b.i.d reduced to 100 mg b.i.d; 100 mg b.i.d reduced to 50 mg 
b.i.d.  
Criteria leading to permanent discontinuation of BI 891065 and BI 754091 are presented in 
Section 3.3.4.1.
A schematic of dose delays and reductions is presented in Figure 4.1.7: 1.


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-
Figure 4.1.7: 1Schematic of dose delays and reductions for non-immune related AEs/SAEs*
4.1.8
Definition of dose-limiting toxicity
Dose-limiting toxicities (DLTs) will be recorded throughout the trial. Any DLT must be 
reported to the 
 Medical Monitor by the Investigator or designee within 24 
hours of first knowledge, and to the 
as an SAE 
when appropriate. All DLTs will be agreed upon between the Sponsor, the Study Chair, the 
 Medical Monitor, and the Investigators after review of the data from each 
cohort. Only DLTs starting in the first cycle of monotherapy during Part A or during the first 
cycle of BI 891065 in combination with BI 754091 during Part B are necessary for dose-
escalation decisions made by the SRC. DLT information from later cycles will be taken into 
consideration if available.


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All relevant safety information (including DLTs) together with data on target engagement
will be considered when selecting the recommended doses for the expansion cohorts.
Severity of AEs will be graded according to CTCAE Version 5.0. Any of the following AEs
will be classified as DLTs following review by the Investigators and the 
 
Medical Monitor unless unequivocally due to underlying malignancy or an extraneous cause.
Haematologic toxicities:

For patients with solid tumours:
-
Any Grade 5 toxicity
-
Neutropenia ≥ Grade 4 lasting for >5 days
-
Febrile neutropenia of any duration (ANC <1.0 X 109 cells/L and fever ≥38.5°C)
-
Neutropenia Grade 3 with documented infection
-
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding or a 
requirement for platelet transfusions
-
Grade 4 anaemia unexplained by underlying disease.
Non-haematological toxicities:

AST or ALT >3 times ULN and concurrent total bilirubin >2 times ULN without initial 
findings of cholestasis (e.g., findings consistent with Hy's law or the FDA definition of 
potential DILI)

≥Grade 4 AST or ALT of any duration

Any ≥Grade 3 non-haematologic toxicity with the following exceptions:
-
Grade 3 irAE that resolves to ≤ Grade 1 or to baseline with immunosuppressive 
therapy within 2 weeks
-
Grade 3 fatigue that persists <7 days
-
Grade 3 rash that resolves to ≤ Grade 1 within 2 weeks
-
Grade 3 or 4 elevation in serum amylase and/or lipase that is not associated with 
clinical or radiographic evidence of pancreatitis
-
Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical intervention
-
Grade 3 nausea or vomiting that lasts <48 hours, and resolves to ≤ Grade 1 either 
spontaneously or with conventional medical intervention
-
Alopecia
-
Grade 3 endocrine disorders (thyroid, pituitary, and/or adrenal insufficiency) that 
are managed with or without systemic corticosteroid therapy and/or hormone 
replacement therapy, and the patient is asymptomatic.
-
Grade 3 tumour flare syndrome

Any Grade 2 pneumonitis of any duration

Any Grade 2 related uveitis, eye pain, or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within 2 weeks or requires systemic 
treatment

Any treatment-related ≥ Grade 2 toxicity that persists and results in an inability to 
administer BI 754091 on Cycle 2 Day 1.


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The frequency, time to onset, and severity of toxicities, as well as the success of standard 
medical management and dosing interruptions/delays, will be analysed to determine if a 
given toxicity should be considered a DLT for dose escalation purposes.
Late immune-related DLTs are irAEs that meet the same grading criteria as DLT criteria but 
occur after the first cycle of BI 891065 in combination with BI 754091, but during the first 
90-day assessment period. At the end of the escalation parts, the BLRM will be rerun using 
all DLTs.
4.1.9
Definition of maximum-tolerated dose
Please refer to Section 7.
4.1.10
Definition of evaluable patient
Patients that are evaluable for MTD are those who do not fulfil criteria for replacement as 
outlined in Section 3.3.4.4.
4.1.11
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion by the Sponsor throughout, i.e., also for 
the purpose of data cleaning and preparation of the analysis. The CRF will contain 
information on the treatment and the dose.
4.1.12
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be
packaged and labelled in accordance with the principles of Good Manufacturing Practice
(GMP). Each site will be provided with an initial shipment of trial drug supply. Further 
medication will be automatically delivered depending on the recruitment on site using an 
Interactive Response Technology system.
For details of packaging and the description of the label, refer to the ISF.
4.1.13
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation. If the storage conditions are found to 
be outside the specified range, the 
clinical monitor (as provided in the list of 
contacts) must be contacted immediately.
4.1.14
Drug accountability
The Investigator, or designee, will receive the investigational drugs delivered by the Sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol and informed consent form (ICF) by the 
Institutional Review Board (IRB) / ethics committee


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
Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site

Approval/notification of the regulatory authority (e.g., competent authority)

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the Principal Investigator

Availability of FDA Form 1572.
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 Investigator, or designee, must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the Sponsor or alternative 
disposal of unused products.
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator, or designee, will maintain records that document adequately that the patients 
were provided the doses specified by the clinical trial protocol (CTP) and reconcile all 
investigational products received from the Sponsor. Unused or partially used drug supplies 
will be destroyed on site at the end of the trial (after relevant reconciliations have been 
completed and records reviewed by the clinical monitor).
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no other mandatory treatments to be used in this trial or special emergency 
procedures to be followed. Recommendations for the management of immune-related AEs 
can be found in Appendix 10.2.
Rescue medications to reverse the actions of BI 891065 or BI 754091 are not available.
Therefore, potential side effects of BI 891065 or BI 754091 have to be treated 
symptomatically.
Blood transfusions are allowed at any time during the trial, except to meet inclusion criteria.  
There must be at least 4 weeks between a patient’s last transfusion and the screening 
laboratory assessment.  Exceptions to this will be considered by the Sponsor on a case-by-
case basis.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Concomitant therapy, with reasons for the treatment, must be recorded in the case report form 
(CRF) during the screening and treatment periods, starting at the date of signature of 
informed consent and ending after the residual effect period (REP). After REP, only 
concomitant therapy indicated for treatment of a related AE has to be reported. If a new anti-
cancer treatment is started, it will be documented in the CRF, on a separate page of follow-up 
therapy, different from the concomitant therapies pages.
BI 891065 was found to be an inhibitor of various CYP450 enzymes in vitro, with Ki values 
in the range of 0.84 to 12 μM (see Section 1.2.1). A drug-drug interaction with other 
medications metabolized by these enzymes cannot be excluded. Caution should be exercised 
when combining BI 891065 with substrate drugs of CYP450 enzymes (1A2, 2C8, 2C9, 2C19, 
2D6, 3A4). Table 4.2.2.1:1 provides a list of restricted and permitted medications.
Alternatives with less potential for CYP450 based interactions should be considered, where 
available. Close monitoring for potential adverse reactions is warranted and patients should 
be informed about potential signs and symptoms of such adverse reactions (e.g., muscle 
pain). BI 891065 was also found to be an inhibitor of the drug transporters P-glycoprotein 
and BCRP in vitro, with IC50 values of 0.034 uM and 0.18-0.59 μM, respectively (see 
Section 1.2.1). Caution should be exercised when combining BI 891065 with P-gp and BCRP 
substrates. Table 4.2.2.1:1 provides a list of restricted and permitted medications.


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Table 4.2.2.1:1
Restricted medication when coadministered with BI 891065
Sensitive CYP1A2, CYP2C8, 
CYP2C9 and CYP2C19, 
CYP2D6, CYP3A4 substrates 
with a high probability of 
exposure increase in combination 
with BI891065
Permitted if strictly indicated and 
with judicious dosing
Buspirone, Lovastatin, 
Simvastatin and Nisoldipine
Sensitive CYP1A2, CYP2C8, 
CYP2C9 and CYP2C19, 
CYP2D6, CYP3A4 substrates 
with a medium probability of 
exposure increase in combination 
with BI891065
Permitted if strictly indicated and 
with judicious dosing
Atorvastatin, Tacrolimus, 
Cisapride, Terfenadine, 
Midazolam, Saquinavir, Rifabutin, 
and Sertraline
Sensitive CYP1A2, CYP2C8, 
CYP2C9 and CYP2C19, 
CYP2D6, CYP3A4 substrates 
with a low probability of exposure 
increase in combination with 
BI891065
Permitted if strictly indicated and 
with judicious dosing
Alfentanil, Amodiaquine, 
Felodipine, Loperamide, 
Maraviroc, Methadone, 
Montelukast, Nifedipine, 
Nimodipine, Pioglitazone , 
Repaglinide, Trazodone, 
Triazolam, Verapamil and  
Zolpidem.
Pgp substrates (partly with narrow 
therapeutic margin)
Not Permitted 
Dabigatran etexilate
Digoxin
Pgp substrates and in addition 
involvement of CYP3A4 with 
narrow therapeutic margin
Permitted if strictly indicated and 
with judicious dosing
Apixaban
Rivaroxaban
Pgp and BCRP substrates with 
a probability of exposure 
increase in combination with 
BI891065
Permitted if strictly indicated and 
with judicious dosing
Fexofenadine, Verapamil and 
Rosuvastatin
Immunosuppressive medications*
at doses exceeding 10 mg/day; 
TNFα blockers
Not Permitted*
Prednisone or equivalent, 
Methotrexate, Azathioprine
Live attenuated vaccines
Not Permitted during the trial 
through 30 days after the last dose 
of investigational product
Herbal preparations/medications
Not Permitted from 7 days prior 
to first dose of study treatment
St. John’s wort, Kava, Ephedra 
(ma huang), Gingko biloba, 
Dehydroepiandrosterone (DHEA), 
Yohimbe, Saw palmetto, and 
Ginseng
*The following caveat applies for immunosuppressive medications:


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
Use of immunosuppressive medications for the management of investigational product-
related AEs or in patients with contrast allergies is acceptable, and does not necessarily 
warrant immediate treatment discontinuation. In addition, use of inhaled, topical,
intranasal corticosteroids or local steroid injections (e.g., intra-articular injection) is 
permitted. Temporary uses of corticosteroids for concurrent illnesses (e.g., food allergies, 
computed tomography [CT] scan contrast hypersensitivity) are acceptable upon 
discussion with the 
 Medical Monitor.

For the treatment of CRS, supportive therapy including steroids and / or interleukin 
6 receptor (IL6R) antagonists (R15-0031) may be used as clinically indicated.
4.2.2.2
Restrictions on diet and life style
Patients should be instructed to avoid exposure to direct sunlight (including sunlamps), to use 
a sunblock (minimum sun-protection factor 30), and to wear clothing and sunglasses that 
protect against sun exposure during treatment and for 4 weeks after the last administration of 
BI 891065.
The usual restrictions on diet and life style that were already applicable for a given patient 
before entry into the trial, according to his/her medical condition, have to be continued, if 
feasible with the following caveats:

Fasting requirements on PK days are described in Section 4.1.5.1

Part B patients will be asked to eat a specific meal per Section 6.2.2.1.
4.2.2.3
Contraception requirements
Women of childbearing potential and men able to father a child must use the contraception 
methods described in the patient information.
4.3
TREATMENT COMPLIANCE
The investigational products should only be used as directed in this protocol. For BI 754091 
administration days, BI 891065 will be administered orally approximately 30 minutes after 
the end of the infusion of BI 754091, and only if considered safe by the Investigator.
4.3.1
BI 891065
Patients are requested to bring all remaining BI 891065 including empty package material 
with them when attending visits. Details of treatment with investigational product for each 
patient will be recorded in the eCRF.
The trial personnel at the investigational site will account for all drugs dispensed and for 
appropriate destruction. Certificates of delivery and destruction should be signed.


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Based on counts, treatment compliance will be calculated as shown in the formula below. 
Compliance will be verified by the CRA authorised by the Sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
     Number of tablets that should have been taken
If the number of doses taken is not between 80% to 100%, site staff will explain to the patient
the importance of treatment compliance. Different tablet strengths need to be taken into 
consideration for computation.
4.3.2
BI 754091
BI 754091 will be administered by i.v. infusion at the sites by the Investigator and/or trained 
site personnel, and dosing will be recorded in the eCRF. Therefore, actual dosing is expected 
to precisely follow the dose, as determined from the previous monotherapy study (Trial 
BI 1381.1). Missed or interrupted doses will be recorded in the eCRF with the associated 
reasons. The method of collecting dosing information assures that total exposure can be 
calculated programmatically taking into account any missing doses.
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
NSCLC tumour assessment and solid tumour assessment
Tumour response will be evaluated at the site according to RECIST Version 1.1 (R09-0262) 
and/or iRECIST (R17-0923 and Appendix 10.6). 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). Duplicates of the images will be collected and stored 
by a BI-appointed representative, and may be used for future independent central 
RECIST/iRECIST review, if deemed appropriate. In addition, the images may be used for 
further analysis to explore the potential for enhanced and improved baseline and on-treatment 
markers/patterns of early efficacy based on comprehensive quantitative CT metrics (i.e., 
radiomics features, assessed in standard-of-care medical imaging data).
The patients will be re-evaluated every 6 weeks for the first 6 months and then every 9 weeks 
thereafter until the earliest of PD, death, or last evaluable tumour assessment before start of 
subsequent anti-cancer therapy or until the end of the trial. The baseline scan(s) (CT scan
and/or MRI according to Investigator’s decision) from screening must have been performed
within 4 weeks prior to treatment with the trial drug(s) and the Investigator will record the
target (5 target lesions in total and maximum 2 per organ) and non-target lesions at baseline 
in the patient’s medical records and in the CRF before the start of treatment. 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 at baseline unless the lesions occurred after irradiation. Tumour
assessment will be performed at screening (as close as possible to the treatment start and no


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more than 28 days before the start of trial treatment), every 6 weeks for the first 6 months and 
every 9 weeks thereafter, and at the EOT visit (if not performed within the last 4 weeks).
If the patient stops with the trial medication for a reason other than progression, the tumour
assessment according to RECIST v1.1 and iRECIST will be performed according to standard 
of care until the last follow-up needed according to the protocol (progression, death, lost to 
follow-up, end of the trial). Patients will be allowed to stay on treatment in the case of initial 
radiological PD, if the Investigator feels that it is in the patient’s best interest, the patient 
signs an informed consent form specific for this circumstance, and the criteria listed in
Section 3.3.4.1 are met.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in Part A 
Flow Chart, Part B Flow Chart, and Part C Lung Flow Chart. It includes at a minimum
general appearance, neck, lungs, cardiovascular system, abdomen, extremities, and skin. 
Motoric functionally will be examined with an additional focus on the function of the cranial 
nerve VII. Any signs of facial nerve palsy have to be monitored closely until resolution.
Measurement of height and body weight will be performed at the time points specified in Part 
A Flow Chart, Part B Flow Chart, and Part C Lung Flow Chart.
During the physical examination, the patient should be assessed for possible adverse events.
The results must be included in the source documents available at the site.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in Part A Flow Chart, Part B Flow 
Chart, and Part C Lung Flow Chart prior to blood sampling and trial treatment administration. 
This includes body temperature, systolic and diastolic blood pressure and pulse rate 
(electronically or by palpation count for 1 minute). All except body temperature need to be 
taken in a seated position after 5 minutes of rest. Oxygen saturation will be measured, if 
needed.
Blood pressure and heart rate may also be measured after infusion of BI 754091 or at any 
time that the Investigator deems it is necessary.
5.2.3
Safety laboratory parameters
For the sampling time points please see Part A Flow Chart, Part B Flow Chart, and Part C 
Lung Flow Chart for each part. All analyses will be performed locally. Patients do not have to 
be fasted for the blood sampling for the safety laboratory tests.
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF.


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Clinically relevant abnormal findings as judged by the Investigator will be reported as 
adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.4.5 and the Potential DILI Checklist provided in the ISF). 
The amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
Safety laboratory tests will include the following parameters:
Haematology
The standard haematology panel will consist of: haemoglobin, red blood cell count, 
haematocrit, mean corpuscular volume, white blood cell count, differential blood count
(preferably expressed in absolute values), platelets, haptoglobin and reticulocytes.
Biochemistry
The standard biochemistry panel will consist of glucose, sodium, potassium, chloride, 
calcium, phosphate, venous bicarbonate HCO3, creatinine, AST, ALT, alkaline phosphatase, 
lactate dehydrogenase, total, direct and indirect bilirubin, total protein, albumin, urea nitrogen
(or urea in lieu of urea nitrogen), uric acid and creatinine kinase (CK). If CK is elevated, then 
CK-MB [cardiac], Troponin I/Troponin T, and myoglobin should be reactively tested.
A thyroid panel (TSH, free T4, and free T3) will be done during Parts B and C at the time of 
each standard biochemistry panel.
If symptoms of pancreatitis are observed, amylase and lipase should be tested at the 
discretion of the Investigator.
Coagulation
Activated partial thromboplastin time (aPTT) and prothrombin time (PT) (expressed either in 
seconds or as percentage) will be tested according to the timing in Part A Flow Chart, Part B 
Flow Chart, and Part C Lung Flow Chart.
Urine
Urine (pH, glucose, erythrocytes, leukocytes, protein, and nitrite) will be analysed by dipstick
(semi-quantitative measurements).
Pregnancy test
A beta human chorionic gonadotropin (β-HCG) pregnancy test in serum will be performed 
for women of childbearing potential at screening. Thereafter, this test may be done in serum 
or urine on Day 1 of each cycle, at the EOT visit, and at the 30-day safety follow-up visit.


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Virology
At screening, tests according to local standards for HIV infection and hepatitis B (and if 
positive, anti-HBs, anti-HBc antibodies, and HBV DNA) and hepatitis C should not be older 
than 28 days.
Alpha-1 acid glycoprotein
One plasma sample will be taken for alpha-1 acid glycoprotein (AGP) analysis at the 
beginning of Cycles 1 and 2 at the time of the safety laboratory tests (prior to BI 891065 
administration).
If laboratory safety investigations have been performed >72 hours prior to the first trial
treatment, the results of the new safety laboratory investigations performed within 72 hours 
of first treatment must be available to reconfirm eligibility.
5.2.4
Electrocardiogram
Standard 12-lead (I, II, III, aVR, aVL, aVF, V1 - V6) resting electrocardiograms (ECGs) will 
be digitally recorded at various time points throughout the trial. The Part A Flow Chart, Part 
B Flow Chart, and Part C Lung Flow Chart outline which visits will require ECGs, and 
Appendix 10.3 outlines which time points require triplicate ECGs to be done along with 
certain PK samples.
All ECGs will be obtained after the patient has been resting supine for at least 10 minutes 
prior to the indicated times. All ECGs should be recorded with the patient in the same 
physical position.
Electrocardiogram machines will be provided to facilitate central readings. Before study start, 
the study sites will be trained for the proper use of the equipment and transfer of the 
electronic data to the vendor. While all ECGs will be transmitted to the central vendor, only 
the baseline, 6-hour, 8-hour, and 24-hour readings will be reviewed directly. The other 
readings would be analyzed only if the PK analysis points to a tmax deviating from the 
predicted tmax.
ECGs may be repeated for quality reasons and the repeated recording used for analysis. If 
necessary, additional ECGs may be recorded for safety reasons. In Part C, triplicate readings 
are required with pharmacokinetic sample collection as indicated in Table 10.3: 3.  When 
triplicate ECGs are not done, single readings will be done for safety purposes as indicated in 
Part C Lung Flow Chart.
The ECG recordings must also be analysed and checked for abnormality by the Investigator
(or designated physician) who will also calculate the QTcF value for each time point as the 
mean of the 3 ECGs. Particular attention must be paid to T wave inversions. It is not 
mandatory to wait for central evaluation of ECGs to make clinical decisions. Clinically 
relevant abnormal findings will be reported either as baseline condition (if identified at the 
screening visit) or otherwise as adverse events and will be followed up and/or treated as 


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medically appropriate. CTCAE Version 5.0 will be used for the grading of prolonged QTcF 
intervals.
In case of related ECG changes and whenever the Investigator deems necessary, additional 
ECG monitoring will be performed in the respective and later courses of treatment. The 
ECGs will be recorded using dedicated equipment provided by a vendor. The ECGs will be 
sent for evaluation by a central vendor. Data from this central review will be taken for 
retrospective data analysis. 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).
In case of QTcF prolongation to >500 ms (mean of 3 ECGs) AFTER receiving therapy, the 
Investigator will initiate further ECG monitoring and diagnostics (e.g., check electrolytes and 
check concomitant therapy that may be contributing to QTcF prolongation) and if required 
provide adequate treatment according to medical standards. The patient will be discharged 
from the investigational site only after resolution of ECG findings as assessed by the 
Investigator.
In case of occurrence of symptoms suggestive of arrhythmia related to QTcF prolongation, a 
cardiologic evaluation will be performed, and treatment will be provided according to 
medical standards at the discretion of the Investigator.
In order not to confuse an ECG recording, PK samples should be taken after performing the
ECG.
The centralised ECG evaluation will include the semi-automatic determination of the RR, PR
interval, QRS complexes, and QT intervals.
All interval measurements in one patient will be performed on the same lead. The intervals 
will be measured from four cardiac cycles (beats) in lead II. If lead II shows a flat T wave or 
is not measurable for any reason, lead V5 will be used, or if that lead is not measurable, then 
lead I will be used.
Central morphological analyses of the ECGs (cardiologic assessments) will be performed by 
a board-certified cardiologist or equivalent. The cardiologist will interpret one ECG per time 
point. In case of triplicate ECG recordings per time point, this ECG will be selected 
randomly. In case additional (unscheduled) ECGs due to safety reasons are recorded at the 
study site, all ECGs of this time point including the additional ECGs will undergo 
interpretation. The ECG interpretation will include an overall assessment (normal, abnormal, 
not assessable) as well as assessments concerning rhythm, conduction, presence of 
myocardial infarction, ST segment deviations, T wave morphology, and U wave morphology 
findings.
Abnormalities detected during centralised ECG evaluation will not necessarily qualify as 
AEs. In case of clinically relevant abnormalities (e.g., heart blocks or large changes in 
interval duration) the ECG core laboratory may contact the Investigator and vice versa.


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Centrally assessed ECGs will comply with the ICH E14 guidance document and supplements 
(R05-2311, R13-0801, R13-4095) as well as the FDA requirements for annotated digital 
ECGs (R09-4830).
5.2.5
Other safety parameters
Not applicable.
5.2.6
Assessment of adverse events
5.2.6.1
Definition of adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
5.2.6.2
Definition of serious adverse event
An SAE is defined as any AE which fulfils at least one of the following criteria:

results in death

is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.

requires inpatient hospitalisation or

requires prolongation of existing hospitalisation

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect
or

is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgement which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse.
Patients may be hospitalised for administrative reasons during the trial, including 
hospitalisation for respite care. These as well as hospitalisations/surgical procedures which 
were planned before the patient signed informed consent need not be reported as SAEs if they 
have been documented at or before signing of the informed consent and have been performed 
as planned (the condition requiring hospitalisation/surgical procedure has not 
changed/worsened after signing the informed consent).


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5.2.6.3
Adverse events considered “Always Serious”
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the duration between discontinuation of the trial medication and must be 
reported as described in Section 5.2.6.7, subsections “AE collection” and “AE reporting to 
Sponsor and timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the Study Reference Manual in the 
ISF. These events should always be reported as SAEs as described above.
5.2.6.4
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial
(e.g., the potential for AEs based on knowledge from other compounds in the same class). 
AESIs need to be reported within the same time frame that applies to SAEs and according to 
the information in Section 5.2.6.7.
5.2.6.4.1
Dose-limiting toxicities
DLTs are considered to be AESIs, and must be reported as such. The definition of DLTs is 
presented in Section 0.
5.2.6.4.2
BI 754091 infusion-related reactions
Infusion-related reactions CTCAE Version 5.0 Grade ≥2 are defined as AESIs.
The following terms describe those events that are to be considered potential infusion-related 
AEs. These events are considered as AESIs and must be reported to the 
 
 Safety group within 24 hours of the event:

Allergic reaction

Anaphylaxis

CRS

Serum sickness

Infusion reactions

Infusion-like reactions
If the Investigator determines that another event (not on the list) may be a potential infusion-
related AE, the Investigator may also report that event as an AESI.
In the event of an infusion-related reaction ≤ Grade 2, the infusion rate of BI 754091 may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 


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initial rate until completion of the infusion. In patients experiencing infusion-related reactions 
≤ Grade 2, subsequent infusions may be administered at 50% of the initial rate.
If a patient experiences an infusion-related reaction, acetaminophen and/or an antihistamine 
(e.g., diphenhydramine) and/or corticosteroid or equivalent medication per institutional 
standard may be administered prior to subsequent infusions at the discretion of the 
Investigator for secondary prophylaxis of infusion-related reactions. If an infusion-related 
reaction is Grade 3 or higher in severity at any point during the trial, treatment with 
BI 754091 will be permanently discontinued.
As with any mAb, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, 
and trial personnel must be trained to recognise and treat anaphylaxis. All trial sites will have 
emergency resuscitation services and access to intensive care available.
5.2.6.4.3
Cytokine release syndrome
Events of CRS CTCAE Version 5.0 Grade ≥2 are defined as AESIs. Patients will be closely 
monitored for CRS and, in case of suspected or confirmed CRS, appropriate treated 
according to best medical judgement based on institutional standards and/or publications 
(e.g., Lee at al. 2016 [R16-2323]). For the treatment of CRS, supportive therapy including 
steroids and / or interleukin 6 receptor (IL6R) antagonists (R15-0031) may be used as 
clinically indicated.
For Part A:

Patients will remain under surveillance for 10 hours after first administration of 
BI 891065

Patients will remain under surveillance for at least 8 hours after the second and third 
administrations of BI 891065.
For Part B:

Patients will remain under surveillance after the administration of BI 891065 
 in combination with BI 754091 
during Cycles 1 and 2.

Duration of surveillance will be for 8 hours after the first dose of BI 891065 during Cycle 
1, and for 6 hours after the first dose of BI 891065 in Cycle 2
For Part C:

Patients will remain under surveillance after the administration of BI 891065 
 in combination with BI 754091 
 during Cycles 1 and 2.

Duration of surveillance will be for 4 hours after the first dose of BI 891065 during 
Cycles 1 and 2.
Although patients will not be required to stay overnight on the first day of monotherapy or 
combination therapy treatments, they should be advised to remain close to the study site 
where medical coverage will be ready to support them, if required. Thereafter, patients will 


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be monitored with regular safety visits. All trial sites will have emergency resuscitation 
services and access to intensive care available.
Monitoring will include measurement of body temperature, heart rate, and blood pressure at 
regular intervals as presented in Part A Flow Chart, Part B Flow Chart, and Part C Lung Flow 
Chart. Patients will be assessed for signs or symptoms of CRS (e.g., hypotension, hypoxia, 
tachycardia, fever, nausea, fatigue, headache, myalgias, and malaise).
Patients will be informed about possible signs and symptoms of CRS, and the need to 
immediately contact or present to the investigational site if symptoms occur after discharge.
The following recommendations for the management of CRS regarding administration of 
BI 754091 and BI 891065 should be considered by the Investigator as guidance:

In the case of a CRS CTCAE Version 5.0 Grade 2, the intake of BI 891065 and infusion 
of BI 754091 should be temporarily interrupted. BI 891065 maybe resumed as soon as 
symptoms of CRS have completely resolved to baseline for at least 48 hours.
In case less than 50% of a BI 754091 dose was administered due to CRS, a dose of 50% 
of the intended dose may be administered on the day when BI 891065 is re-started to 
ensure the patient receives an adequate dose of BI 754091. Please see Section 3.3.4.4
regarding replacement of patients.

In the case of a CRS CTCAE Version 5.0 Grade 2, patients should be under close 
surveillance during the first 2 re-exposure administrations of BI 891065 and (if the CRS 
occurred during the or shortly after the infusion of BI 754091) during the first re-exposure 
administration of BI 754091 to ensure appropriate surveillance.

In the case of CRS CTCAE Version 5.0 Grade 3 or 4, the patient must not be re-exposed 
to BI 891065 and BI 754091. Please refer to Section 3.3.4 for details.
5.2.6.4.4
Immune-related adverse events (irAE)
Immune-related AEs are AEs associated with immunotherapy treatments that appear to be 
associated with the immune therapy’s mechanism of action. These adverse reactions, which 
can be severe, may involve the gastrointestinal, skin, liver, endocrine, respiratory, renal, or 
other organ systems. The Sponsor has defined a list of potential irAEs in Table 10.1: 1 in 
Appendix 10.1. These irAEs must be reported as AESIs. If an Investigator determines another 
event (not on the list) should be a potential irAE, the Investigator may also report that event 
as an AESI. Immune-related AEs should be reported as AESIs only for patients who received 
immunotherapy. 
Recommendations for the management of irAEs are presented in Appendix 10.2.
5.2.6.4.5
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN


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These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “Potential DILI checklist” provided in 
the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the Potential DILI checklist should be 
followed.
Lab values meeting this definition of hepatic injury will need to be reported as an AESI. 
Please follow the flowchart below (Figure 5.2.6.4.5: 1) for reporting hepatic injury / potential 
DILI cases.
Figure 5.2.6.4.5: 1
Processing Potential DILI cases in oncology
Hy’s Law cases have the following 3 components:

The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold or 
greater elevations above the ULN of ALT or AST

Among trial subjects showing such aminotransferase elevations, often with elevations 
much greater than 3 times ULN, one or more also show elevation of serum total bilirubin 
to >2 times ULN, without initial findings of cholestasis (elevated serum ALP)


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
No other reason can be found to explain the combination of increased aminotransferase 
and total bilirubin, such as viral hepatitis A, B, or C; pre-existing or acute liver disease; or 
another drug capable of causing the observed injury.
5.2.6.5
Severity of adverse events
The severity of AEs should be classified and recorded in the eCRF according to the CTCAE
Version 5.0 (R18-1357).
5.2.6.6
Causal relationship of adverse events
Medical judgement 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.
Examples of arguments that may suggest that there is a reasonable possibility of a causal 
relationship could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g., pre-existing
or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g., Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Examples of arguments that may suggest that there is no reasonable possibility of a causal
relationship could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g., pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g., after 5 half-lives). Of note, this 
criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g.,
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.


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5.2.6.7
Adverse event collection and reporting
5.2.6.7.1
Adverse event collection
The adverse event reporting scheme is presented in Figure 5.2.6.7.1: 1. The Investigator shall 
maintain and keep detailed records of all AEs in the patient files. The following must be 
collected and documented on the appropriate eCRF by the Investigator:

From signing the informed consent onward until the end of treatment including residual 
effect period (REP):
-
all AEs (non-serious and serious) and all AESIs.

After the end of treatment including REP until the individual patient’s end of trial:
-
all related SAEs and all related AESIs.

After the individual patient’s end of the trial:
-
the Investigator does not need to actively monitor the patient for new AEs but 
should only report related SAEs and related AESIs of which the Investigator may 
become aware of by any means of communication (e.g., phone call). Those AEs 
should however, not be reported in the CRF.
The rules for Adverse Event Reporting exemptions still apply.
Figure 5.2.6.7.1: 1
Adverse event reporting scheme
The REP is defined as 30 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment. Events which occurred after the REP will be considered as post treatment events.
5.2.6.7.2
Adverse event reporting to Sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via secure e-mail connection or via fax 
immediately (within 24 hours ) to the

Secure email (Innovations SAE mailbox: 
) or 

Fax (SCRI Innovations safety fax number): 


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The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the 
upfront via telephone by calling the Central 
 SAE reporting phone number 
(
). This does not replace the requirement to complete and fax the BI SAE 
form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
5.2.6.7.3
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, if applicable. The Investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):

Worsening of 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 and should be collected in the eCRF only. All AEs/SAEs, including those 
persisting after individual patient’s end of trial must be followed up until they have resolved, 
have been assessed as “chronic” or “stable” , or no further information can be obtained.
5.2.6.8
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the Investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the Sponsor’s unique entry point. 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). Similarly, potential drug exposure during pregnancy must be reported if a 
partner of a male trial participant becomes pregnant. This requires a written consent of the 
pregnant partner. Reporting and consenting must be in line with local regulations. The ISF 
will contain the trial specific information and consent for the pregnant partner.
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (the form consists of 
Parts A and 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 to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.


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5.2.6.9
Exemptions to AE/SAE reporting
Progressive disease is a trial endpoint for analysis of efficacy and as such is exempted from 
reporting as an AE/SAE. Progression of the patient’s underlying malignancy will be recorded 
on the appropriate pages of the eCRF as part of efficacy data collection only and will not be 
reported on the SAE Form. Death due to disease progression is also to be recorded on the 
appropriate eCRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the trial drug or 
trial drugs and the progression of the underlying malignancy (PD), the event must be reported 
as an SAE on the SAE Form and on the eCRF.
Exempted events include:
Progression of underlying malignancy
Hospitalisation / procedures due solely to the progression of the underlying malignancy
Clinical symptoms and/or signs of PD (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.
Exempted events are collected and tracked following a protocol specified monitoring plan. 
Exempted events are monitored at appropriate intervals throughout the study at SRC 
meetings.
Lab values meeting the hepatic injury definition as defined in Section 5.2.6.4.5 will need to 
be reported as an AESI. PD reporting exemption does not apply to hepatic injury.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Standard pharmacokinetic parameters of BI 891065 will be determined from plasma and 
urine analyses after a single oral dose and after repeated dosing, at steady state. After 
multiple dose administration, the influence of food intake on the PK of BI 891065 will be 
investigated by comparison of Cmax,ss and AUC0-τ,ss, if feasible (for further details see 
Section 7.3.5).
Dose proportionality of the single and multiple dose pharmacokinetic parameters Cmax,ss, 
AUCτ,ss and AUC0-24(,ss) of BI 891065 in Cycle 1 of Part A will be assessed as described in 
Section 7.3.5.
If data allow, the PK parameters of BI 754091 will be evaluated using noncompartmental
analysis methods according to BI internal SOP (001-MCS-36-472_RD-01 [actual version]).
Food interaction analyses are described in Section 6.2.2.1.


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5.3.2
Methods of sample collection
The planned PK analyses will require blood and urine sampling at the time points indicated in
Part A Flow Chart, Part B Flow Chart, and Part C Lung Flow Chart. Correct, complete and 
legible documentation of drug administrations and blood sampling times, as well as adequate 
handling and identification of PK samples, are mandatory to obtain data of adequate quality 
for the PK analysis.
Pharmacokinetic sampling times and periods may be adapted by the Sponsor during the trial 
based on information obtained during trial conduct (e.g., preliminary PK data). Such changes 
would be implemented via non-substantial Clinical Trial Protocol Amendments.
Details on sample characteristics, collection, processing, handling, and shipment are provided 
in the Laboratory Manual in the ISF.
5.3.2.1
Plasma sampling for BI 891065 pharmacokinetics
For quantification of analyte plasma concentrations, blood will be taken from an antecubital 
or forearm vein at the times indicated in Part A Flow Chart, Part B Flow Chart, and Part C 
Lung Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter 
or by venipuncture.
After completion of the trial, the plasma samples may be used for further methodological 
investigations, e.g., for stability testing, assessment of metabolites. However, only data 
related to the analyte and/or its metabolites will be generated by these additional 
investigations. The trial samples will be discarded after completion of the additional 
investigations, but not later than 5 years following signature of the final trial report.
5.3.2.2
Plasma sampling for BI 754091 pharmacokinetics
For quantification of analyte plasma concentrations, samples will be drawn at the time points 
listed in Part A Flow Chart, Part B Flow Chart, Part C Lung Flow Chart and specified in PK 
time schedules in Appendix 10.3.
For Parts B and C, if collected from an arm, it is essential to collect blood from the arm that is 
opposite to the arm used for infusion in order to avoid artificially high or low drug 
concentration determinations.
After completion of the trial, plasma samples may be used for further methodological
investigations (e.g., stability testing). However, only data related to the analyte or 
bioanalytical assay will be generated by these additional investigations. The trial samples will 
be discarded after completion of the additional investigations, but not later than 5 years after 
the final trial report has been signed.


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5.3.2.3
Plasma sampling for metabolism analysis of BI 891065
Backup samples for PK analysis might be investigated for the identification of drug 
metabolites beginning with the first cohort of BI 891065 monotherapy. Based on the 
knowledge gained during the trial conduct, e.g., from preliminary PK results, the dose group 
for analysis will be determined.
The blood samples will be drawn together with the PK samples on Days 1, 15, and 16 (see
Part A Flow Chart). Details on sample processing, shipment and handling are provided in the 
Laboratory Manual in the ISF.
Only data related to the parent compound and its metabolites will be acquired. Evaluation of 
the drug metabolism will be reported separately and not included in the clinical trial report of 
this trial. The trial samples will be discarded after completion of the assessments, but not later 
than 5 years after the final trial report has been signed.
5.3.2.5
Urine sampling and analysis for pharmacokinetics of BI 891065 (Part A only)
A background urine sample will be collected before administration of trial medication (within 
2 hours before drug dosing) and aliquots will be retained to check for analytical interference.
All urine voided during the sampling intervals indicated in Table 10.3: 1 will be collected and 
stored. Subjects will be told to empty their bladders at the end of each sampling interval:
Cycle 1 Day 1:

Spot urine pre-dose

Pool 0 to 3 hours

Pool 3 to 8 hours

Pool 8 to 10 hours

Pool 10 to 24 hours

Pool 24 to 48 hours
Cycle 1 Day 15

Spot urine pre-dose

Pool 0 to 3 hours

Pool 3 to 8 hours

Pool 8 to 10 hours

Pool 10 to 24 hours


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In order to facilitate urine sampling, subjects will be advised to drink at least 100 mL water 
before the end of each urine sampling interval. Details on urine sample characteristics, 
processing, handling, and shipment are provided in the Laboratory Manual in the ISF.
After completion of the trial, the urine samples may be used for further methodological 
investigations, e.g., for stability testing, assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) will be generated by these additional 
investigations. The trial samples will be discarded after completion of the additional 
investigations but not later than 5 years upon the final trial report has been signed.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
No formal analysis of a PK/PDc relationship is planned.


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5.4
5.4.1
Methods of sample collection
Details about tumour tissue and blood sample collection, plasma/serum preparation, required 
tubes, labelling of tubes, storage and shipment (frequency and addresses) will be provided in 
the Laboratory Manual in the ISF.


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5.4.3
Biobanking (solid tumours)
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will be realised only after a separate biobanking informed consent has been given 
in accordance with local ethical and regulatory requirements. Banked samples may be 
analysed in the future for scientific evaluations or to further explore, for example, the 
mechanistic understanding of drug effects and/or to identify genetic or other factors
associated with response to therapy or the risk of adverse drug reactions.


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The leftovers of the following biomarker samples as specified in Section 5.4.2 will be
banked:

FFPE blocks of pre- and on-treatment biopsies.
5.5
OTHER ASSESSMENTS
5.6
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are in accordance with measurements in Phase I 
oncology trials and will be performed in order to monitor safety aspects and to determine 
efficacy and PK parameters in an appropriate way.
6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients meeting the inclusion and exclusion criteria for the part they are participating in and 
who have signed a written ICF, are eligible for participation in the trial. Patients will visit the 
clinical site at the time points specified in Part A Flow Chart, Part B Flow Chart, and Part C 
Lung Flow Chart specific to each part. If a patient misses a scheduled visit, and reports to the 
Investigator between the missed visit and the next scheduled visit, the assessments for the
missed visit must be done with the actual date and the reason must be given for the delayed 
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.


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Once the decision for any reason is made for a patient to stop the treatment with BI 891065 or 
the combination of BI 891065 plus BI 754091, an EOT visit must occur as soon as possible 
(preferably within 7 days and no later than 14 days after stopping treatment). After the EOT 
visit, the patient must undergo a follow-up safety evaluation 30 (+7) days after the last 
administration of trial therapy.
Additional PD follow-up visits after the 30-day safety follow-up visit will only be performed 
for patients who did not progress on treatment (see Section 6.2.3.3) with the exception of 
those who may continue treatment for a time after initial radiologic progression.
The trial will be conducted according to the principles of GCP.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The procedures required at each trial visit in all portions of the trial are presented in Part A 
Flow Chart, Part B Flow Chart, and Part C Lung Flow Chart at the beginning of this protocol. 
The key procedures required include:

PK samples throughout the trial

Reporting of all AEs occurring after the ICF has been signed

Baseline and on-treatment blood biomarker and immunogenicity assessments

Tumour biopsy biomarker assessments (Parts B and C only)

Tumour assessments (based on CT/positron emission tomography [PET]/ and/or magnetic 
resonance imaging [MRI] scan) according to RECIST Version 1.1 and/or iRECIST must
be performed once every 2 cycles (meaning every 6 weeks if there are no delays in cycles 
but as close as possible to the end of the second of the 2 cycles of treatment if there was a 
delay) after the start of BI 891065 for the first 6 months, and then every 3 cycles 
(9 weeks) thereafter.
6.2.1
Screening
At enrolment, each potential patient will provide written informed consent prior to starting 
any trial specific procedures. Upon signature of the informed consent, patients will be 
assigned a unique patient number as enrolment (screening) occurs.
6.2.1.1
Screening period
Screening (Visit 1) will take place 1 to 28 days prior to first administration of trial 
medication. The screening period can be extended for up to a total of 12 weeks, if deemed 
clinically justified by the Investigator. The following given situations are examples that might 
trigger an extension of the screening period, e.g., an intermittent disease, or adverse event or 
an exacerbation of a concomitant disease that needs to be recovered before administration of 
trial medication, or a single episode of an abnormal laboratory value that needs to be repeated 
for proper evaluation. Investigations during the screening period, such as laboratory 
examinations, can be repeated during extended screening to meet the time period allowed 
between a respective examination and the first treatment with the trial medication. Patients 


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who do not meet all inclusion/exclusion criteria for eligibility at the end of the extended 
screening period are not allowed to be re-screened.
If the required baseline imaging is older than 28 days due to extended screening, imaging 
needs to be repeated.
6.2.1.2
Baseline conditions
Demographics (sex, birth date, race, and ethnicity where allowed), information on tobacco 
and alcohol use, and baseline conditions will be collected during the screening visit.
6.2.1.3
Medical history
History of the patient’s cancer will be obtained. 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, and metastasis (TNM) classification will be provided as obtained at diagnosis and at 
trial screening. Previous surgeries will be reported.
Previously administered chemotherapy, tyrosine kinase inhibitor 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 
neoadjuvant, adjuvant, or palliative therapy. The date of tumour progression after previous 
lines of treatment will be recorded, if known.
6.2.1.4
Concomitant therapies
Relevant concomitant diagnoses and/or therapies present at trial entry and/or during 
screening and relevant to the patient’s safety during the trial as judged by the Investigator 
will be recorded in the eCRF (see Section 4.2.2.1 for details on concomitant medications). 
Post-trial therapy for advanced or metastatic disease will also be documented.
6.2.2
Treatment period
Patients will remain on treatment as long as, in the opinion of the Investigator, they are 
deriving benefit and the criteria listed in Section 3.3.4.1 are not met. Please refer to Part A 
Flow Chart, Part B Flow Chart, and Part C Lung Flow Chart for detailed presentations of 
each visit during the treatment period for each part of the trial.
6.2.2.1
Food-interaction assessment
An explorative food effect will be assessed for q.d. patients in Part B. Patients will fast for at 
least 10 hours prior to Cycle 1 Day 15 then receive BI 891065 together with approximately 
240 mL water. Patients will remain fasted until at least 2 hours after drug intake. Water will 
be allowed except 30 minutes before and 1 hour after administration of BI 891065.


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Patients will fast for at least 10 hours prior to Cycle 1 Day 16. At this visit, within 30 minutes 
of planned BI 891065 dose administration time, patients will be given a standard continental 
breakfast (see below) which they should consume within the 30 minutes prior to drug 
administration. Then patients will receive BI 891065 with approximately 240 mL water 
within 5 minutes of consuming the standard meal. If the patients are not able to eat or eat 
almost nothing, the information should be recorded on the eCRF.
The following definition of the standard continental breakfast is given in order to standardise 
the food intake prior to assessing food effects on BI 891065 (rough approximation): 2 bread 
rolls, 20 g butter, 25 g cheese, 25 g ham, 25 g jam, and 1 cup (~250 mL) of decaffeinated tea 
or coffee (average energy value per breakfast: ~688 kcal or 2880 kJ). Note: Alternative food 
components/quantity can be proposed by the Investigator, but it should be ensured that the 
caloric breakdown of the test meal is roughly in line with the breakfast indicated above.
6.2.3
Follow up periods and trial completion
6.2.3.1
End-of-treatment (EOT) visit
The EOT visit will be performed after permanent discontinuation of trial treatment for any 
reason, as soon as possible (preferably within 7 days but no later than 14 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 at the next planned visit. 
If the patient finishes active treatment without having PD, tumour assessment/imaging must 
be performed at the time of treatment discontinuation, unless it has been done within the past 
4 weeks.
6.2.3.2
30-day safety follow-up visit (end of residual-effect period)
The safety follow-up visit is performed 30 (+7) days after permanent discontinuation of the 
trial medication. The information collected at this visit must include all new AEs that 
occurred after the EOT visit, and a follow-up of AEs ongoing at EOT.
A patient will be considered as having completed the trial if he/she discontinues because of 
PD and has performed the safety follow-up 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.
6.2.3.3
Extended follow-up period
Additional follow-up visits after the 30-day safety follow-up visit will be performed every 
6 weeks if the patient has withdrawn prior to completing 6 months of treatment and/or every 
9 weeks following 6 months of treatment until PD or another withdrawal criterion is met. The 
last follow-up visit will be considered the “end-of-follow-up” visit.


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The follow-up for progression period will end at the time that one of the following events is
met:

Disease progression based on RECIST v1.1 and iRECIST

Start of a new anti–cancer therapy

Lost to follow-up

Death

6 months after the last patient completed the 30-day safety follow-up visit in Parts A and 
B, and 12 months after the last patient completed the 30-day safety follow-up in Part C

End of whole trial as specified in Section 8.6.
The following will be obtained and/or performed during the follow-up visits for progression.

For each reportable SAE/AESI, the Investigator should provide the information with 
regard to concomitant medication and the medication administered to treat the AE on the 
appropriate CRF pages and the SAE form including trade name, indication and dates of 
administration

Record performance score/status (e.g., ECOG)

Perform tumour assessment and imaging

Treatment and date with any subsequent anti-cancer drug / therapy including the name
and type of the anti-cancer drug and/or best supportive care (if applicable)

Home care information

Outcome (date of and reason for death [if applicable], in case the patient had PD the
actual date of PD shall be recorded).
These visits may also be performed by telephone interview or via written correspondence in 
case the patient is unable to visit the Investigator.
6.2.3.4
Trial completion for an individual patient
A patient is considered to have completed the trial in case any of the following applies:

Completion of planned follow-up period

Lost to follow-up

Refusal to be followed-up

Death.
7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
7.1.1
Part A
The trial will be performed as an open-label study. The objective of the design is to determine 
the MTD of BI 891065 defined as the highest dose with less than 25% risk of the true DLT 
rate being equal or above 33% (EWOC criterion). The dose-finding in Part A will be guided 
by a Bayesian 2-parameter logistic regression model with overdose control (R13-4803; R13-
4806).


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The model is given as follows:
logit(πd) = log(α) + β*log(d/d*), 
where logit(π) = log(π/(1-π)).
πd represents the probability of having a DLT in the MTD evaluation period at dose d, d* = 
200 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.
The estimated probability of a DLT at each dose level from the model will be summarised 
using the following intervals:
Under dosing: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over toxicity: [0.33, 1.00]
The BLRM recommended dose for the next dose level is the level with the highest posterior 
probability of the DLT rate falling in the target interval [0.16, 0.33) among the doses 
fulfilling EWOC. Applying the EWOC criterion it should be unlikely (<25% posterior 
probability) that the DLT rate at that dose will be ≥0.33. In addition, for dose levels ≥25 mg 
BI 891065, the maximum allowable dose increment for the subsequent cohort will be no 
more that 100% from cohort to cohort. 
The MTD may be considered reached if one of the following criteria is fulfilled:

The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of the 
MTD is above 0.5, or

At least 18 patients have been treated in the dose escalation phase of the trial, of which at 
least 6 at the MTD.
The SRC may recommend stopping the dose finding phase after the criterion for MTD is 
fulfilled. Further patients may be included to confirm this MTD estimate. If no DLT is 
observed at a dose of which the efficacy is considered sufficient, the SRC may decide to 
include additional number of patients at this dose level and to declare this dose as the dose 
recommended for further testing.
Since a Bayesian approach is applied, a prior distribution f(θ) for the unknown parameter 
vector θ needs to be specified.
This prior distribution will be specified as a mixture of three multivariate normal 
distributions, i.e.
а(θ) = a1f1(θ) + a2f2(θ) + a3f3(θ)
with
ai, i = 1, 2, 3 the prior mixture weights (a1+ a2+ a3 = 1)
and
fi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where 


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Σ = 
	
,
 , ,		
 , ,		
	
,		

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
Prior derivation:
For the current trial, no relevant information in the form of human data was available, since 
no trial in a comparable population with comparable dosing schedule has been conducted. 
Therefore, the three mixture components were established as follows:

A weakly informative prior was derived reflecting the a priori assumption that the median 
DLT rate at the dose of 25 mg would equal 0.01, and the median DLT rate at the highest 
dose of 400 mg would equal 0.10. This yields μ1 = (-2.787, -0.145). 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 a1 for the first component was chosen as 0.9.

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 dose of 25 mg would equal 0.10, and the median 
DLT at the highest dose of 400 mg would equal 0.60. These assumptions yield μ2 = 
(-0.245, -0.063). The standard deviations and correlations were set identical to the weakly 
informative prior, i.e. σ2,11 = 2, σ2,22 = 1 and ρ2 = 0, respectively. The prior weight a2 for 
the second component was chosen as 0.05.

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 dose of 25 mg would equal 0.001, and the 
median DLT at the highest dose of 400 mg would equal 0.05. These assumptions yield μ3
= (-3.935, 0.357), i.e. basically a flat curve. The standard deviations and correlations were 
set to σ3,11 = 5, σ3,22 = 0.01, therefore almost fixing the slope parameter to its mean. The 
correlation was set to 0, i.e. ρ3 = 0. The prior weight a3 for the third component was 
chosen as 0.05.
A summary of the prior distribution is provided in Table 7.1.1: 1. Additionally, the prior 
probabilities of DLTs at different doses, as well as the corresponding probability of under-, 
targeted and overdosing, are shown in Table 7.1.1: 2. Graphically, the prior medians with 
accompanying 95% credible intervals are shown in Figure 7.1.1: 1. As can be seen from both, 
the table and the figure, the prior medians of the DLT probabilities are in-line with the prior 
medians derived from the weakly informative prior, and the uncertainty around the medians 
is large, showing the low amount of information this prior provides. This is also supported by 
the prior sample size, i.e., the information contained in the prior. This is approximately equal 
to 1.8 patients. Furthermore, it can be seen that the overdose prior probability of the starting 
dose of 5 mg is 0.029 and therefore well below the EWOC boundary of 0.25. A detailed
evaluation of the model using hypothetical data scenarios and operating characteristics is 
provided in the statistical appendix (see Appendix 10.5).


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Table 7.1.1: 1 Summary of prior distribution
Prior Component
Mixture Weight
Mean Vector
SD Vector
1: Weakly inf.
0.900
(-2.797, -0.145)
(2, 1, 0)
2: High Tox.
0.050
(-0.245, -0.063)
(2, 1, 0)
3: Low Tox.
0.050
(-3.935, 0.357)
(5, 0.01, 0)
Table 7.1.1: 2 Prior probabilities of DLTs 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%
5 mg
0.939
0.032
0.029
0.035
0.106
0.000
0.002
0.370
15 mg
0.912
0.045
0.042
0.050
0.128
0.000
0.004
0.470
25 mg
0.894
0.055
0.051
0.059
0.140
0.000
0.007
0.537
50 mg
0.859
0.072
0.069
0.078
0.159
0.000
0.013
0.631
100 mg
0.803
0.096
0.101
0.107
0.158
0.000
0.026
0.732
200 mg
0.691
0.135
0.174
0.164
0.224
0.001
0.061
0.847
400 mg
0.530
0.157
0.313
0.269
0.296
0.001
0.138
0.972


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Figure 7.1.1: 1 Prior medians and 95% credible intervals
7.1.2
Part B
The primary objective of this part is to determine the MTD of BI 891065 in combination with 
BI 754091. To determine the MTD, patients are entered sequentially into escalating dose 
cohorts. The dose finding will be guided by a Bayesian 5-parameter logistic regression model 
with overdose control (R15-4233, Chapter 6).
This logistic regression model is defined as follows. Let π1,d1 be the probability of having a 
DLT when giving dose d1 of BI 891065 as monotherapy, and π2,d2 the probability of having a 
DLT when giving dose d2 of the combination partner BI 754091 as monotherapy, 
respectively. A logistic regression is used to model the dose-toxicity relationship for each of 
these drugs individually:
BI 891065:
logit(π1,d1) =log(α1) + β1log(d1/d1*)
BI 754091:
logit(π2,d2) =log(α2) + β2log(d2/d2*)
Here, the doses d1* = 200 mg and d2* = 3200 mg represent the reference doses for BI 891065
and BI 754091, respectively. 
Assuming no toxicity interaction between the two compounds, the probability of a DLT when 
giving the combination dose d1, d2 is obtained as 
π0
12,d1,d2 = π1,d1 + π2,d2 - π1,d1π2,d2
with corresponding odds 
odds(π0
12,d1,d2)= π0
12,d1,d2 /(1- π0
12,d1,d2)


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In order to account for a potential positive (higher toxicity than expected under 
independence) or negative (lower toxicity than expected under independence) interaction 
between BI 891065 and BI 754091, a dose-dependent interaction term -∞<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.
The prior distributions for θk (k=1, 2) will be specified as a mixture of two bivariate normal 
distributions, 
f(θk) = a1,k f1(θk) + a2,k f2(θk)
with 
a1,k, a2,k the prior mixture weights (a1,k + a2,k = 1), k = 1,2 and
fi(θk) = MVN(µik, ∑ik) a bivariate normal distribution with mean vector µik and covariance 
matrix ∑ik where
Σ = 
	
,
 , ,		
 , ,		
	
,		

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
The priors for θk (k=1, 2) will be derived using the meta-analytic predictive approach. They 
will take into account available data from Part A of this trial and available data from the 
monotherapy dose escalation part of BI trial 1379.6 for the prior of BI 891065 and available 
data from the BI trial 1381.1 that aims to determine the MTD of BI 754091.
A weakly informative normal prior distribution will be used for η.
The derivation of these prior distributions is described in Appendix 10.5.
The estimated probability of DLT π12,d1,d2 at each dose combination d1, d2 from the model 
will be summarised using the following intervals:
Under dosing: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over dosing: [0.33, 1.00]
The BLRM recommended dose combination for the next cohort is the combination 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 be ≥0.33.


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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:

The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of the 
MTD is above 0.50, or

At least 12 patients have been treated in the trial, of which at least 6 at the MTD.
The BLRM is set up for a fixed dosing schedule of once daily (q.d.) across dose levels of 
BI 891065. For the purpose of dose-toxicity modelling, a b.i.d. regimen will be converted in 
the BLRM to an equivalent q.d. regimen that has a similar Cmax at steady state. This 
conversion is based on the assumption that safety events are triggered by Cmax at steady state. 
For example, based on Table 7.1.2: 1, the 200 mg b.i.d. regimen will be modelled as 
equivalent to a 300 mg q.d regimen. For any other b.i.d. doses considered, their conversions 
will be specified in the TSAP. 
The posterior probabilities of over toxicity are evaluated based on historical data for BI 
891065 in Table 7.1.2: 2 and Table 7.1.2: 3, historical data for BI 754091 in Table 7.1.2: 4
and current data for the combination therapy of BI 891065 and BI 754091 in Table 7.1.2: 5. 
For example, as seen in Table 7.1.2: 6, the dose combination of 200 mg b.i.d. BI 891065 and 
240 mg BI 754091 has a posterior probability of over toxicity below 25% and would 
therefore be suitable as a dose combination to select.
If multiple b.i.d. doses are tested, appropriate modifications to the BLRM to account for the 
heterogeneity of different dosing schedules might be considered. Details will be specified in 
the TSAP if needed.
Table 7.1.2: 1 Simulated Cmax at steady state with 95% confidence intervals. 
Possible Regimen
Cmax (nmol/L)
200 mg q.d.
2457.12 (771.53 - 6835.05)
300 mg q.d.
3421.69 (1286.11 - 9653.55)
400 mg q.d.
4357.98 (1672.88 - 12541.8)
200 mg b.i.d.
3502.75 (1458.73 - 10986.75)
Table 7.1.2: 2 Historical data for BI 891065 from Part A (status as of 16 Dec 2019)
Dose
N of patients with DLTs during MTD evaluation 
period / N of evaluable patients
5 mg q.d.
0/2
15 mg q.d.
0/1
25 mg q.d.
0/3
50 mg q.d.
0/4
100 mg q.d.
0/3


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200 mg q.d.
0/3
400 mg q.d.
0/6
Table 7.1.2: 3 Historical data for BI 891065 from BI trial 1379.6 (status as of 16 Dec 2019)
Dose
N of patients with DLTs during MTD evaluation 
period / N of evaluable patients
100 mg q.d.
1/2
Table 7.1.2: 4 Historical data for BI 754091 from BI trial 1381.1 (status as of 30 Sep 2019)
Dose
N of patients with DLTs during MTD evaluation 
period / N of evaluable patients
80 mg
0/3
240 mg
0/71
400 mg
0/3
Table 7.1.2: 5 Data for combination of BI 891065 and BI 754091 from Part B (status as of 13 
Nov 2019)
Dose BI 891065
Dose  BI 754091
N of patients with DLTs during MTD evaluation 
period / N of evaluable patients
50 mg q.d.
240 mg
0/6
200 mg q.d.
240 mg
0/8
400 mg q.d.
240 mg
1/5
Table 7.1.2: 6 Posterior probabilities of DLTs
Dose BI 
891065
Dose BI 
754091
Probability of true DLT rate in 
Quantiles
[0,0.16)
[0.16,0.
33)
[0.33,1]
Mea
n
StD
2.5
%
50%
97.5%
50 mg q.d.
240 mg
0.977
0.023
0.000
0.071
0.036
0.01
9
0.065
0.158
200 mg q.d.
240 mg
0.853
0.147
0.000
0.110
0.050
0.03
5
0.102
0.229
200 mg b.i.d. [1]
240 mg
0.708
0.274
0.018
0.132
0.073
0.03
1
0.118
0.313
400 mg q.d.
240 mg
0.615
0.313
0.072
0.154
0.105
0.02
0.130
0.423


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3
[1] The 200 mg b.i.d. dose is modeled as equivalent to a 300 mg q.d. dose in terms of dose-toxicity relationship 
in the BLRM.
7.1.3
Part C
The analysis in this trial is descriptive in nature. No statistical model will be used.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory. No formal statistical test will be 
performed.
7.3
PLANNED ANALYSES
No per protocol set will be used in the analysis. However, important protocol violations will 
be summarised. The TSAP will specify the important protocol violations in detail.
In Parts A and B, for the determination of the MTD, only MTD evaluable patients will be 
considered. For the analysis of secondary and further endpoints in Parts A and B and for all 
analyses in Part C, all patients in the treated set (i.e., patients treated with at least one dose of 
trial medication) will be included in the analysis. Any other analysis sets will be defined in 
the TSAP.
7.3.1
Primary endpoint analyses
Part A:

In order to identify the MTD of BI 891065, the number of evaluable patients with DLTs 
during the MTD evaluation period at each dose level must be presented. Patients who are 
replaced during the MTD evaluation period will be excluded from the determination of 
MTD.
For the analysis of tolerability and safety, please refer to Section 7.3.4.
Part B:

In order to identify the MTD of BI 891065 in combination with BI 754091, the number of 
evaluable patients with DLTs during the MTD evaluation period at each dose level must 
be presented. Patients who are replaced during the MTD evaluation period will be 
excluded from the determination of MTD.
For the analysis of tolerability and safety, please refer to Section 7.3.4.
Part C:

The OR by Investigator assessment will be analysed descriptively in terms of objective 
response rate (ORR), defined as the proportion of patients with best overall response of 


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CR or PR. The primary analysis of Part C will take place after the last patient was treated 
for at least 18 weeks.
7.3.2
Secondary endpoint analyses
Part A:

The number of patients with DLTs during the entire on-treatment period will be presented 
in a summary table.

PK parameters will be analysed as described in Section 7.3.5.

OR based on RECIST v1.1 will be analysed descriptively in terms of objective response 
rate, defined as the proportion of patients with objective response.
Part B:

The number of patients with DLTs during the entire on-treatment period will be presented 
in a summary table.

PK parameters will be analysed as described in Section 7.3.5.

OR will be analysed descriptively in terms of ORR, defined as the proportion of patients 
with OR based on RECIST v1.1.
Part C:

Duration of OR (based on RECIST v1.1) will analysed descriptively.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 


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with an onset between start of treatment and end of the residual effect period (REP), a period 
of 30 days after the last dose of trial medication, will be assigned to the on-treatment period 
for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
residual effect period. Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA
at the database lock.
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 summarised. 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.
Analyses of the centrally evaluated ECG data will be specified in the TSAP.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
The pharmacokinetic parameters listed in Section 5.3.1 and Appendix 10.4 will be calculated
according to the relevant BI internal procedures.
Only concentration values within the validated concentration range and actual sampling times
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the
pharmacokinetic calculations will be in the same format provided in the bioanalytical report,
(that is, to the same number of decimal places provided in the bioanalytical report).
The following descriptive statistics will be calculated for plasma concentrations and PK
parameters: number (N), arithmetic mean, standard deviation, minimum, median, maximum,
arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation.
The exception to this is tmax, where only median, minimum and maximum will be calculated. 
The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. Thereafter, the individual values, as well as the descriptive
statistics, will be reported with three significant digits in the clinical trial report.


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For handling of missing data, please refer to Section 7.5.
Analyses will be carried out using Phoenix® WinNonlin® 6.3 (or later) and/or SAS® 
software, Version 9.4 (or later).
7.4
INTERIM ANALYSES
The Sponsor will continuously monitor the safety. The dose escalation design in parts A and 
B foresees that the Sponsor and the SRC perform regular safety evaluations. These
evaluations will be unblinded to dose.
If considered necessary, as soon as the MTDs in Part A and Part B are determined or when 
the highest dose levels are reached, evaluations of the safety and other relevant aspects will 
be performed. Results of these evaluations will be documented and archived. If needed, each 
part will be analysed and reported in separate clinical trial reports. If applicable, such 
analyses will be defined in more detail in the TSAP.
An interim futility analysis will be performed by the SRC in Part C after 20 patients have 
been treated for at least 18 weeks. Until a decision from this futility analysis is made, the 
enrolment for that trial part will not be stopped. Enrolment will only be stopped if the defined 
efficacy boundary (see Table 7.7: 1) is not met. The SRC will document the decision, 
whether the futility bound is met or not in the SRC meeting minutes.
7.5
HANDLING OF MISSING DATA
No imputation will be performed on missing efficacy data. Missing baseline laboratory 
values will be imputed by the respective values from the screening visit. No other 
imputations will be performed on missing data although every effort will be made to obtain 
complete information on all adverse events, with particular emphasis on potential DLTs.
Plasma concentration - time profiles
Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not 
analyzed), and BLQ (below the limit of quantification) will be ignored and not replaced by 
zero at any time point (applies also to the lag phase). 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 are included).
Pharmacokinetic parameters
In the non-compartmental analysis, concentration data identified with NOS, NOR, and NOA 
will not be considered. BLQ 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 values of the profile will be ignored.


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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 tables in 
Section 15 of 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 is not 
recorded or is missing for a certain time point, the planned time will generally be used for this 
time point instead. Pharmacokinetic parameters which cannot be determined will be 
identified by "not calculated" (NC).
7.6
RANDOMISATION
No randomisation will be performed. In Part A and Part B, patients will be assigned to 
escalating dose groups by order of admission into the trial. In Part C, patients will be assigned 
to the expansion cohorts according to their diagnosis.
7.7
DETERMINATION OF SAMPLE SIZE
The number of patients to be enrolled in Part A and B cannot be predicted. Only estimation is 
provided in this section.
Part A:
No formal statistical power calculations to determine sample size were performed for this
trial part. Approximately 30 patients (including patients at the MTD) are expected to be 
enrolled into Part A of this trial based on the number of dose levels/cohorts that are tested. 
Fewer patients might be needed based on the recommendation of the SRC and the criteria 
specified (see Section 8.7). However, the actual number of patients will depend on the 
number of dose cohorts tested. Based on the simulation study to evaluate operating 
characteristics of the BLRM (see statistical appendix), at least 20 evaluable patients (where 
evaluable patients refer to patients not fulfilling the criteria for replacement [Section 3.3.4.4])
are expected to be treated in the dose escalation part for the model to have reasonable 
operating characteristics relating to its MTD recommendation.
Part B:
No formal statistical power calculations to determine sample size were performed for this
trial part. Approximately 31-37 patients (including patients at the MTD) will be expected for 
this part based on the number of dose levels/cohorts that are tested. Fewer patients might be 
needed based on the recommendation of the SRC and the criteria specified (see Section 8.7). 
However, the actual number of patients will depend on the number of dose cohorts tested.


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Part C NSCLC:
A justification of the cohort size for this expansion cohort is based on assumed OR rates.
A futility check will be performed by the SRC when 20 evaluable patients have been treated 
for at least 18 weeks. If an efficacy signal, i.e. at least 2 patients with OR, is observed out of 
20 evaluable patients, the total intended 40 evaluable patients will be recruited into this trial 
part. If this efficacy signal cannot be observed, enrolment into the trial will be stopped.
Table 7.7: 1 summarises the probabilities to stop the trial after the futility analysis assuming 
different true underlying OR rates.
Table 7.7: 1 Probabilities to stop the trial at the futility analysis
Assumed true OR 
rate (%)
Cohort size
P(< 2 patients with 
OR)
P(≥2 patients with 
OR)
10
20
0.39
0.61
30
20
0.01
0.99
45
20
<0.01
>0.99
Table 7.7: 2 displays the probability of observing at least 2 patients with OR in the first 20 
evaluable patients and then observing a certain number of patients with OR out of a total of 
40 evaluable patients given different assumed true underlying OR rates. For example, 
assuming a true underlying OR rate of 10%, the probability to observe 2 or more patients 
with OR out of 20 evaluable patients is 0.61. This means that the probability to stop the trial 
is 0.39 in this scenario. Overall, the probability to observe 4 patients with OR out of 40 
patients, given that at least 2 patients with OR had been seen already in the first 20 patients, is 
only 0.473 which is considered as acceptable for this trial. 
Assuming a true underlying OR rate of 45%, the probability to observe 2 or more patients 
with OR out of 20 patients is almost 1. Overall, the probability to observe 18 patients with 
OR out of 40 patients, given that at least 2 patients with OR had been seen already in the first 
20 patients, is 0.561 which is considered satisfactory for this trial.


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Table 7.7: 2 Probabilities for objective response rates of the expansion cohort under different 
assumptions given the trial has not been stopped at the futility 
analysis
Assumed 
true OR 
rate (%)
Cohort 
size
At least 2 patients with OR in the first 20 patients and probability 
to observe at least 18 patients with OR in total
4
8
10
12
14
16
18
10
40
0.473
0.041
0.005
< 
0.001
< 
0.001
< 
0.001
< 
0.001
30
40
0.992
0.942
0.803
0.559
0.297
0.115
0.032
45
40
>0.999
>0.999
0.997
0.982
0.925
0.786
0.561
Probabilities in Table 7.7: 2 are calculated as P(n1 + n2 ≥c AND n1 ≥2), where n1 is the 
number of patients with OR out of the first 20 patients, n2 is the number of additional patients 
with OR after more patients are enrolled after the futility check. c is the required minimum 
number of patients with OR displayed in Table 7.7: 2 (i.e. 4, 8, 10, 12, 14, 16, or 18 
respectively). The calculations in this section were performed using R version 3.5.1.
It is assumed that 44 patients need to be enrolled in order to end up with 40 evaluable patients 
for the primary analysis.
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), and 
other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the Investigator and of the Sponsor with 
regard to publication of the results of this trial are described in the investigator contract. As a 
rule, no trial results should be published prior to finalization of the Clinical Trial Report.


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8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB and competent authority according to national and 
international regulations. The same applies for the implementation of changes introduced by 
amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The Investigator or delegate must give a full explanation to trial patients based on the patient 
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible.
The patient must be given sufficient time to consider participation in the trial. The 
Investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
Investigator or his/her delegate must sign (or place a seal on) and date the informed consent 
form. If a trial collaborator has given a supplementary explanation, the trial collaborator also 
signs (or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the Sponsor’s instructions. The consent and re-consenting 
process should be properly documented in the source documentation.
Following the initial radiologic progression, patients may be allowed to continue on treatment 
if, in the opinion of the Investigator, they are experiencing clinical benefit and criteria for 
withdrawal are not met (see Section 3.3.4.1). In this case, an additional informed consent 
form specific for this circumstance will be signed by the patient prior to treatment 
continuation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by an IRB or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the Investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
8.3
RECORDS
Electronic CRFs for individual patients will be provided by 
 


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8.3.1
Source documents
In accordance with regulatory requirements, the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails, a verbal history from the patient, documented in their 
medical records, will be acceptable.
Before providing any copy of patients’ source documents to the Sponsor, the Investigator
must ensure that all patient identifiers (e.g., patient’s name, initials, address, phone number, 
social security number) have properly been removed or redacted from any copy of the 
patients’ source documents before sending them to the Sponsor.
Copies of tumour assessments scans may be collected by the Sponsor upon request. This 
could include CT scans of the chest and abdomen and/or imaging of any other known or 
suspected sites of disease (e.g., pelvis, brain) using an appropriate method (CT scan or MRI).
If the patient is not compliant with the protocol, any corrective action (e.g., re-training) must 
be documented in the patient file.
For the eCRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

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

Adverse events and outcome events (onset date [mandatory], and end date [if available])

Serious adverse events (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

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 


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meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.

Technical information collected on PK sampling days (e.g., PK sampling times, 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 the eCRF and are considered part of the 
ISF.
8.3.2
Direct access to source data and documents
will monitor the conduct of the trial by regular on-
site monitoring visits and in-house data quality reviews. The frequency of on-site monitoring 
will be determined by assessing all characteristics of the trial, including its nature, objective, 
methodology and the degree of any deviations of the intervention from normal clinical 
practice.
The Investigator /institution will allow site trial-related monitoring, audits, IRB review and 
regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the monitor, auditor, and regulatory inspector
(e.g., FDA). The monitor and auditor may review all eCRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The Sponsor will also monitor compliance with the protocol and 
ICH GCP.
8.3.3
Storage period of records
Trial sites: The trial sites must retain the source and essential documents (including the ISF) 
according to contract or the local requirements valid at the time of the end of the trial
(whatever is longer).
Sponsor: The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
will retain 
trial documents according to contractual agreements with the Sponsor.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. Exemptions from expedited reporting are described in
Section 5.2.6.9, if applicable.


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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit (including all follow-up visits) of
the last patient in the whole trial (“Last Subject Completed” = 6 months after the last patient 
completed the 30-day safety follow-up visit in Parts A and B, and 12 months after the last 
patient completed the 30-day safety follow-up in Part C).
The “Last Subject Last Treatment” date is defined as the date on which the last patient at 
an individual trial site ends trial medication (as scheduled per protocol or prematurely). 
Individual Investigators will be notified of SUSARs occurring with the trial medication until 
30 days after this date at their site.
The “Last Patient Last Visit Primary Endpoint (LPLV PE)” is defined as the date at 
which the last patient was examined or received an intervention for the purposes of final 
collection of data for the primary endpoint (according to the protocol specified schedule or 
after premature discontinuation) for each part of the trial. Patient treatment and follow up 
may continue after this time point. For Parts A and B, this is the last visit in the first cycle of 
the last patient in the respective part. A CSR will be considered at these time points. For Part 
C, this is the date when the last subject was treated for at least 18 weeks. At this time, the 
CSR will report the analysis of all primary and secondary endpoints. The CSR will be revised 
after “last subject completed”.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
Sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.


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The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report. The 
Sponsor will submit to the EU database a summary of the final trial results within one year 
from the end of a clinical trial as a whole, regardless of the country of the last patient (EU or 
non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A contract research organisation,
, is responsible for 
project management, medical management, site management, data management, site 
regulatory document management, management of the Trial Master File, some aspects of 
safety management and reporting, medical writing, and medical monitoring.
A Safety Review Committee (SRC) will be established. Members of the SRC will include:

Medical Monitor for the trial, or delegate

Principal Investigators, or delegates, from each investigational site

BI Safety Physician, or delegate

BI Clinical Program Leader, or delegate, responsible for the project.
The BI Safety Physician (or delegate), BI Clinical Program Leader (or delegate) should 
always attend the SRC to discuss safety issues.
Medical Monitor, or delegate, should always be 
present at the SRC. Other BI and non-BI subject matter experts may also be invited, as 
appropriate. The SRC documentation for this trial will define the exact membership and who 
should be present for decisions to be made.
The SRC will be responsible for assessing the progress of the clinical trial, including making 
safety and efficacy assessments at specified intervals, making dose-escalation decisions for 
BI 891065, making dose selection decisions for BI 754091, making decisions on the next 
cohort size, and recommending to the Sponsor whether to continue, modify, or stop the trial. 
To support their decision making, the SRC will have unblinded access to data from this trial 
and the ongoing studies, BI 1381.1 and BI 1381.2, which evaluate BI 754091. Minutes from 
these meetings will be prepared and circulated to the trial team and each investigator for 
comment prior to finalisation.
The tasks and responsibilities of the SRC will be documented. The SRC will maintain written 
records of all its meetings.


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Relevant documentation on the participating investigators and other important participants, 
including their curricula vitae, will be filed in an Investigator Site File (ISF).
The statistical analysis will be done by BI according to BI Standard Operating Procedures 
(SOPs).
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs and 
 SOPs as agreed upon and 
documented. A list of responsible persons and relevant local information can be found in the 
ISF.
An Interactive Response Technology (IRT) vendor will be used in this trial for development 
of shipment orders and assignment of trial medication.
 Study Chair is responsible for coordinating investigators at the different 
sites participating in this trial. Tasks and responsibilities are defined in a contract.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 

manage the trial in accordance with applicable regulations and internal SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial.
The organisation of the trial in the participating countries will be performed by 
 
with which the responsibilities and tasks will have been agreed and 
a written contract filed before initiation of the clinical trial.
A central laboratory service will be used in this trial. Details will be provided in the Central 
Laboratory Manual, available in the ISF.


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9.
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9.2
UNPUBLISHED REFERENCES
c07895878
 Investigator’s Brochure: BI 754091; Indication: Solid tumors 
1381.P1. 11 August 2016.
c14463420-03
Investigator’s Brochure: BI 891065; Indication: Various 
malignancies 1379.P1. Version 3, 14 July 2017.


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10.
APPENDICES
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST
Table 10.1: 1 Immune-related adverse events of special interest*
Immune-related adverse events of special interest
Pneumonitis (reported as an irAE if ≥Grade 2)

Acute interstitial pneumonitis

Interstitial lung disease

Pneumonitis
Colitis (reported as an irAE if ≥Grade 2 or any grade resulting in dose modification or use 
of systemic steroids to treat the AE)

Intestinal obstruction

Colitis

Colitis microscopic

Enterocolitis

Enterocolitis haemorrhagic

Gastrointestinal perforation

Necrotizing colitis

Diarrhea
Endocrine (reported as an irAE if ≥Grade 3 or ≥Grade 2 and resulting in dose modification 
or use of systemic steroids to treat the AE)

Adrenal insufficiency

Hyperthyroidism

Hypophysitis

Hypopituitarism

Hypothyroidism

Thyroid disorder

Thyroiditis

Hyperglycaemia, if ≥ Grade 3 and associated with ketosis or metabolic acidosis
Endocrine (reported as an irAE)

Type 1 diabetes mellitus (if new onset)


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Table 10.1: 1 Immune-related adverse events of special interest (continued)
Hematologic (reported as an irAE if ≥Grade 3 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE)

Autoimmune haemolytic anaemia

Aplastic anaemia

Thrombotic thrombocytopenic purpura

Idiopathic (or immune) thrombocytopenia purpura

Disseminated intravascular coagulation

Haemolytic-uraemic syndrome

Any Grade 4 anaemia regardless of underlying mechanism
Hepatic (reported as an irAE if ≥Grade 2, or any grade resulting in dose modification or use 
of systemic steroids to treat the AE)

Hepatitis

Autoimmune hepatitis

Transaminase elevations (ALT and/or AST)
Infusion Reactions (reported as an irAE for any grade)

Allergic reaction

Anaphylaxis

Cytokine release syndrome

Serum sickness

Infusion reactions

Infusion-like reactions
Neurologic (reported as an irAE for any grade)

Autoimmune neuropathy

Guillain-Barre syndrome

Demyelinating polyneuropathy

Myasthenic syndrome
Ocular (report as an irAE if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE)

Uveitis

Iritis


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Table 10.1: 1 Immune-related adverse events of special interest (continued)
Renal (reported as an irAE if ≥ Grade 2)

Nephritis

Nephritis autoimmune

Renal failure

Renal failure acute

Creatinine elevations (report as an irAE if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE)
Skin (reported as an irAE for any grade)

Dermatitis exfoliative

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis
Skin (reported as an irAE if ≥ Grade 3)

Pruritus

Rash

Rash generalized

Rash maculopapular

Any rash considered clinically significant in the physician’s judgment
Other (reported as an irAE for any grade)

Myocarditis

Pancreatitis

Pericarditis

Any other Grade 3 event that is considered immune-related by the physician
*Immune-related AEs should be reported as AESIs only for patients who received 
immunotherapy. 


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10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS
Regarding diagnosis, grading and therapeutic management of immune-related adverse events, 
grading and treatment, up-to-date published guidelines should be considered (e.g. P19-
00269). Only limited guidance on management of specific irAEs can be given here.
Please refer to published guidelines (e.g. ASCO guideline, Brahmer [P19-00269]) for details. 
In general, 
-
BI 754091 and BI 891065 should be continued with close monitoring in case of grade 
1 irAEs, with the exception of irAEs that may rapidly evolve into severe or fatal 
conditions (encephalitis of any grade, myocarditis of any grade, pneumonitis that is 
grade 1 but shows radiographic evidence of worsening – see detailed guidance 
below).
-
For most Grade 2 irAEs, BI 754091 and BI 891065 should be withheld and treatment 
with corticosteroids is commonly warranted, usually with an initial dose of 0.5 to 1 
mg/kg prednisone / prednisone equivalent daily. Restart of therapy is commonly 
possible once symptoms and/or laboratory values have resolved to grade 1 or less, and 
on ≤ 10 mg prednisone / prednisone equivalent per day.
-
For Grade 3 irAEs, BI 754091 and BI 891065 has to be withheld, and treatment with 
high-dose corticosteroids (1-2mg/kg/d prednisone / prednisone equivalent) is usually 
warranted. Upon improvement, steroids should be tapered slowly over 4-6 weeks. 
Non-steroidal immunosuppressives (e.g. infliximab, mycophonlate mofetil) should be 
considered if no improvement or worsening occurs within the initial 48 to 72 hours. 
Upon recovery to grade 1 or less, and on ≤ 10 mg prednisone / prednisone equivalent 
per day, restarting  BI 754091 and BI 891065 may be considered for selected irAEs, 
but caution is advised, in particular in patients with early-onset irAEs. Expert 
consultancy and agreement with medical monitor is recommended prior to restart of 
therapy.
-
Most Grade 4 irAEs warrant permanent discontinuation of BI 754091 and BI 891065. 
-
Restart of therapy is commonly possible for endocrine irAEs regardless of grade once 
stable hormone replacement has been instituted and symptoms have recovered. In 
case of multiple hormone deficiencies, corticosteroid replacement has to precede 
thyroid hormone replacement therapy by several days in order to avoid adrenal crisis. 
In case of prolonged steroid therapy or treatment with immunosuppressives consider the 
possibility of opportunistic infections and tuberculosis reactivation. Careful monitoring 
andconsideration of administration of prophylactic antibiotics where appropriate are 
warranted. 
Commonly, referral to experts in the management of organ-specific conditions is highly 
recommended, especially for irAEs grade 3 or grade 4, or irAEs where management is 
complex. 
BI 754091 and BI 891065 should be permanently discontinued for immune related


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
encephalitis, aseptic meningitis, transverse myelitis, or Guillain-Barre syndrome of 
any grade 

acquired thrombotic thrombocytopenic purpura of any grade

myocarditis of any grade

myasthenia gravis, peripheral neuropathy or autonomic neuropathy of grade ≥3

myositis grade 2 with objective findings (see below), any myositis grade ≥3   

hepatitis grade ≥3  (transaminase >5 times ULN or total bilirubin >3 times ULN), 
recurrent hepatitis grade ≥2

nephritis grade ≥3, persisting grade 2 nephritis unresponsive to initial steroid therapy 
or worsening, and recurrent nephritis grade ≥2 

pneumonitis grade ≥3

rash, bullous dermatoses, severe cutaneous adverse reaction, Stevens Johnson 
Syndrome, toxic epidermal necrolysis of grade 4, and recurrent rash grade ≥3 

colitis grade 4, and recurrent colitis of any grade 

uveitis, iritis, episcleritis of grade ≥3

autoimmune-hemolytic anemia grade ≥2

haemolytic uremic syndrome grade ≥3

immune thrombocytopenia grade 4

any recurrent irAE grade ≥3, 

inability to taper steroids to 10 mg or less prednisone or equivalent within 12 weeks, 
or

persistent Grade 2-3 AEs that do not recover to Grade 1 or less within 12 weeks. 
Dose adjustment of BI 754091 and BI 891065 besides interrupting or permanently 
discontinuing BI 754091 and BI 891065 are not allowed. 
In rare situations when benefit and risk assessment is considered positive for a patient to 
continue BI 754091 and BI 891065 treatment despite guidance to permanently discontinue 
(e.g. in case no alternative anti-cancer therapy is available), it should be discussed with the 
sponsor.  
Pneumonitis:

For Grade 1 pneumonitis with radiographic evidence of worsening, withhold BI 
754091 and BI 891065 until improvement or resolution; BI 754091 and BI 891065
may be reintroduced upon radiographic improvement. In the absence of radiographic 
improvement within 3-4 weeks, follow guidance as for grade 2 event. 

For Grade 2 pneumonitis, hold BI 754091 and BI 891065 until resolution to at least 
grade 1. If not already started, initiate therapy for the event as per available 
guidelines. Follow guidance as for grade 3 pneumonitis if no clinical improvement 
after 48 -72 hr of starting therapy. 

For Grade 3-4 pneumonitis, permanently discontinue BI 754091 and BI 891065 and 
immediately initiate treatment according to available guidelines. 
Diarrhoea/Colitis:


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
For Grade 1 diarrhoea/colitis, consider interruption of BI 754091 and BI 891065
therapy.  

For Grade 2 diarrhea/colitis, withhold BI 754091 and BI 891065 until patient’s 
symptoms recovered to grade 1 or less. Consider initiating treatment with steroids. 

For Grade 3 diarrhoea/colitis, withhold BI 754091 and BI 891065 and immediately 
start treatment (steroids, non-steroidal immunosuppressents) as per available 
guidelines. 

For Grade 4 diarrhoea/colitis, permanently discontinue BI 754091 and BI 891065 and 
immediately commence adequate therapy (e.g. i.v. corticosteroids).   

For Grade 1-3 colitis, restart of BI 754091 and BI 891065 may be considered once 
symptoms improve to Grade 1 or less without need for continued steroids. After 
careful benefit risk assessment, BI 754091 and BI 891065 may also be restarted after 
recovery to grade 1 or less, and on corticosteroid ≤ 10 mg per day  

BI 754091 and BI 891065 should be permanently discontinued for recurrent 
diarrhoea/colitis of any grade.  
Diabetes

Consider withholding BI 754091 and BI 891065 in case of grade 2 hyperglycemia. 
Check for ketonuria. In case of new onset of diabetes or unexpected worsening of pre-
existing diabetes, check for new manifestation of type 1 diabetes. 

For new onset Type 1 diabetes mellitus, or Grade 3-4 hyperglycaemia associated with 
ketosis (ketonuria or metabolic acidosis)
o
Initiate insulin therapy 
o
Evaluate subjects as appropriate per available guidelines regarding presence of 
type 1 diabetes
o
BI 754091 and BI 891065 should be withheld until glucose level is controlled 
with insulin with no sign of ketoacidosis.  

BI 754091 and BI 891065 may be restarted once insulin therapy has established stable 
glycemic control 
Thyroid disorders:
For diagnosed thyroid disorders, thyroid hormone supplementation and monitoring should 
occur as per available guidelines

Primary hypothyroidism:
o
For Grade 1 hypothyroidism, BI 754091 and BI 891065 may be continued, 
with regular monitoring of thyroid values. 
o
For Grade 2 hypothyroidism, consider withholding BI 754091 and BI 891065
o
For Grade 3-4 hypothyroidism, withhold BI 754091 and BI 891065, consider 
admission and IV therapy, especially in case of myxedema 
o
BI 754091 and BI 891065 may be restarted once symptoms resolve to baseline 
with appropriate thyroid hormone supplementation

Primary hyperthyroidism
o
For Grade 1 hyperthyroidism, BI 754091 and BI 891065 may be continued , 
with regular monitoring of thyroid values. 
o
For Grade 2 hyperthyroidism, consider withholding BI 754091 and BI 891065, 
initiate therapy as per available guidelines. 


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o
For Grade 3-4 hyperthyroidism, withhold BI 754091 and BI 891065. Consider 
hospitalization, especially in case of thyreotoxicosis. 
o
BI 754091 and BI 891065 may be restarted once symptoms resolve to 
baseline.
Note: in case of concomitant adrenal dysfunction, this must be corrected first, prior to thyroid 
hormone replacement (reduced stress tolerance) 
Adrenal insufficiency

Interruption of BI 754091 and BI 891065 therapy should be considered for adrenal 
insufficiency grade 1 or 2, and is warranted for grade 3 and grade 4 adrenal insufficiency, 
until patient is stabilized on hormone replacement therapy. 

Therapy with BI 754091 and BI 891065 may be restarted once stable replacement therapy 
has been achieved.

Note: in case of concomitant hypothyroidism, steroid replacement therapy should precede 
thyroid hormone substitution to avoid adrenal crisis.
Hypophysitis:

Diagnostic workup for hypophysitis should be considered e.g. for patients with multiple 
endocrinopathies, unexplained fatigue, new severe headaches or vision changes. 

Patients should be appropriately advised regarding potentially reduced stress tolerance 
and increased substitution demands e.g. in case of infections, and to wear a medical alert 
bracelet to inform medical personnel about potentially increased hormone demands in 
situations of stress, in case of emergencies.

Interruption of BI 754091 and BI 891065 therapy should be considered for Grade 1 or 2 
hypophysitis , and is warranted for Grade 3 and higher hypophysitis, until patient is 
stabilized on hormone replacement therapy. 
Hepatitis:

Work-up for other causes of elevated liver enzymes, see also section on potential DILI.

For Grade 1 hepatitis (elevated AST/ALT < 3x ULN and/or total bilirubin <1.5x ULN), 
BI 754091 and BI 891065 may be continued, close monitoring of liver values is 
warranted.  

For Grade 2 hepatitis (AST/ALT 3–5x ULN and/or total bilirubin >1.5 to ≤ 3x ULN), BI 
754091 and BI 891065 should be suspended. Monitoring of liver values every 3 days is 
recommended. Initiate treatment according to available guidelines. Restarting of BI 
754091 and BI 891065 may be considered upon recovery to grade 1 or less, and on 
corticosteroid ≤ 10 mg per day .

For Grade 3 or higher hepatitis, BI 754091 and BI 891065 has to be permanently 
discontinued. 
Nephritis:

For Grade 1 nephritis, consider temporarily withholding BI 754091 and BI 891065.

For Grade 2 nephritis, withhold BI 754091 and BI 891065. Consult nephrology. Initiate 
treatment according to guidelines. In case of no improvement or worsening, permanently 
discontinue BI 754091 and BI 891065.BI 754091 and BI 891065 may only be re-started 
upon recovery to grade 1 or less , and on corticosteroid ≤ 10 mg per day.


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
For Grade 3 or higher nephritis, permanently discontinue BI 754091 and BI 891065. 
Consult nephrology. Treat with steroids 1-2 mg/kg prednisone or equivalent. If improved 
to grade 1 or less, taper corticosteroids over no less than 4-6 weeks.

BI 754091 and BI 891065 should also be permanently discontinued for recurrent nephritis 
grade 2 or higher.
Rash

For Grade 1 rash, continue BI 754091 and BI 891065. Initiate topical treatment.  

For Grade 2 rash, BI 754091 and BI 891065 may be continued, in case of no 
improvement upon weekly monitoring, consider interruption of BI 754091 and BI 891065
therapy. Treat topically, add systemic corticosteroid therapies as clinically appropriate. 

For Grade 3 rash, withhold BI 754091 and BI 891065. Initiate topical and systemic 
therapy as per available guidelines. Upon improvement of event to grade 1 or less, and on 
corticosteroid ≤ 10 mg per day, consult with dermatology whether therapy with BI 
754091 and BI 891065 might be restarted, especially in case no alternative anti-neoplastic 
therapy is available. 

For Grade 4 rash, BI 754091 and BI 891065 should be permanently discontinued.

BI 754091 and BI 891065 should also be discontinued for recurrent rash grade 3 or 
higher.
Bullous dermatosis

For Grade 1 bullous dermatosis, use local wound care and observation. BI 754091 and BI 
891065 can be continued. 

For Grade 2 bullous dermatosis, withhold BI 754091 and BI 891065. Administer topical 
therapy, add systemic therapy as clinically adequate. 

For Grade 3 bullous dermatosis, withhold BI 754091 and BI 891065, initiate topical and 
systemic therapy as per available guidelines. Restarting of BI 754091 and BI 891065
may be considered after dermatology consultation. 

For Grade 4 bullous dermatosis, permanently discontinue BI 754091 and BI 891065.
Severe cutaneous adverse reaction (SCAR), Stevens Johnson Syndrome (SJS), Toxic 
Epidermal Necrolysis (TEN)

For Grade 2 events, withhold BI 754091 and BI 891065, initiate treatment as per 
available guidelines. Closely monitor for improvement or worsening. 

For Grade 3 events, withhold BI 754091 and BI 891065. Initiate treatment as per 
available guidelines. In case mucous membranes are affected, involve appropriate 
disciplines in management to prevent sequelae from scarring (e.g. ophthalmology). 

For Grade 4 events, permanently discontinue BI 754091 and BI 891065, immediately 
administer adequate therapy. Immediate admission to burn center or intensive care with 
dermatology and wound care is recommended, involve appropriate other disciplines as 
needed in management of mucosal involvement. 
In case of Grade 2 or Grade 3 events, BI 754091 and BI 891065 may only be re-started upon 
event recovered to Grade 1 or less, on corticosteroid ≤ 10 mg per day, and after consultation 
with dermatology. 
Encephalitis/Aseptic meningitis


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
BI 754091 and BI 891065 should be permanently discontinued for any grade.
  
Myasthenia gravis

For Grade 2 myasthenia gravis, withhold BI 754091 and BI 891065, 

For Grade 3 or 4 myasthernia gravis, permanently discontinue BI 754091 and BI 891065  
Guillain Barré Syndrome (GBS)

Discontinue BI 754091 and BI 891065 permanently for any grade GBS. 
Transverse Myelitis

Discontinue BI 754091 and BI 891065 permanently for any grade transverse myelitis. 
Peripheral neuropathy, autonomic neuropathy

For Grade 1 events, may continue BI 754091 and BI 891065, but with low threshold to 
discontinue while monitoring closely for worsening. 

For Grade 2 events, withhold BI 754091 and BI 891065 until resolution to grade 1 or 
less, and on corticosteroid ≤ 10 mg per day. Initiate therapy as appropriate per available 
guidelines. 

For Grade 3 or grade 4 events, permanently discontinue BI 754091 and BI 891065. 
Inflammatory Arthritis

For Grade 1 arthritis, BI 754091 and BI 891065 can be continued. Administer analgetic 
treatment (acetaminophen, NSAID). 

For Grade 2-4 arthritis, withhold BI 754091 and BI 891065. Initiate treatment as per 
available guidelines, cave regarding reactivation of tuberculosis/opportunistic infections 
in case of prolonged immunosuppressive/DMARD therapy. 
BI 754091 and BI 891065 may be restarted after consultancy with rheumatology once 
recovery to grade 1 or less, and on corticosteroid ≤ 10 mg per day. 
Myositis
Diagnostic workup should consider the need to also evaluate myocardial involvement.   

For Grade 1 myositis, BI 754091 and BI 891065 may be continued. Initiate adequate 
therapy as clinically warranted. In case of elevated CK or muscle weakness, treat as 
grade 2. 

For Grade 2 myositis, withhold BI 754091 and BI 891065, discontinue permanently in 
patients with objective findings (elevated enzymes, abnormal EMG, abnormal muscle 
MRI or biopsy). Initiate therapy as per available guidelines. Resuming BI 754091 and BI 
891065 may be considered in patients without objective findings, symptoms have 
resolved to grade 1 or less without any immunosuppressive therapy, and after 
consultation with rheumatology/neurology. 

For Grade 3 or  4 myositis, permanently discontinue BI 754091 and BI 891065. 

BI 754091 and BI 891065 should be permanently discontinued if there is any evidence of 
myocardial involvement.
Polymyalgia-like syndrome

For Grade 1 event, BI 754091 and BI 891065 can be continued.   


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
For Grade 2 event, withhold BI 754091 and BI 891065 and promptly initiate adequate 
therapy. If no improvement, treat as grade 3.

For Grade 3 or G4 event, withhold BI 754091 and BI 891065, promptly initiate adequate 
therapy Rheumatology consultancy is highly recommended. 
BI 754091 and BI 891065 may be resumed after careful assessment of risks and benefits, 
rheumatology consultancy highly recommended prior to reinitiation. BI 754091 and BI 
891065 may only be re-started upon recovery to grade 1 or less and on corticosteroid ≤ 10 mg 
per day. 
Myocarditis

Discontinue BI 754091 and BI 891065 permanently for any grade of myocarditis. 
Uveitis/Iritis, Episcleritis

For Grade 1 events, treatment with BI 754091 and BI 891065 can continue. Treat
topically as needed.

For Gade 2 events, withhold therapy with BI 754091 and BI 891065, urgent 
ophthalomology referral is recommended. Initiate topical treatment, consider systemic 
therapy if needed. Restart of BI 754091 and BI 891065 is permitted once resolved to 
grade 1 or less, and off systemic steroids (for the ocular condition, if steroids needed for 
other irAEs, up to 10 mg prednisone or equivalent are permitted). Continuation of 
topical/ocular steroids is permitted and does not prohibit resuming BI 754091 and BI 
891065 therapy. 

For Grade 3 or 4 events, permanently discontinue BI 754091 and BI 891065 therapy. 
Seek emergent ophthalmology consultation.. Initiate adequate local and systemic 
treatment.   
Autoimmune-hemolytic anemia (AIHA)

For Grade 1 AIHA, continue treatment with BI 754091 and BI 891065. Close follow-up 
of anemia and other lab values. 

For Grade 2-4 AIHA, discontinue BI 754091 and BI 891065 permanently. Initiate 
systemic therapy as per guideline. Consult Hermatology.
Acquired thrombotic thrombocytopenic purpura (TTP), haemolytic uremic syndrome. 
Timely recognition upon suggestive findings is essential, timely/immediate involvement of 
hematology consultancy may be beneficial. 

For any grade TTP, permanently discontinue BI 754091 and BI 891065. 

For HUS (TTP excluded), withhold BI 754091 and BI 891065 for grade 1 and grade 2, 
provide supportive care. Upon full recovery, BI 754091 and BI 891065 may be restarted 
after carefuly weighing of risks and benefits. 

For Grade 3 or Grade 4 HUS, discontinue BI 754091 and BI 891065 permanently. 
Immune thrombocytopenia (ITP)

In case of Grade 1 ITP, BI 754091 and BI 891065 can be continued. 

For Grade 2 or Grade 3 ITP, withhold BI 754091 and BI 891065 and initiate systemic 
therapy. BI 754091 and BI 891065 may be restarted upon resolution to at least grade 1. 

For Grade 4 ITP, permanently discontinue BI 754091 and BI 891065. 


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10.3
TIME SCHEDULES FOR PHARMACOKINETIC (PK) 
 
SAMPLING
Table 10.3: 1
Time schedule for PK blood and urine samplings, 
 
, and ECG measurements - Part A BI 891065 Monotherapy
Blood samples
Urine 
samples
c
Cycl
e
Visit Day
Time 
Point 
[hh:min]/ 
event
CRF 
Time
/PTM
Sampl
e No.
Triplicat
e
ECGs*
Plasma 
for BI 
891065b
 
 
1
2
1
-1:00 
(+/-10min
-1:00
X
-30 min 
(+/-15min)
-30 
min
X
Predose 
(within 15 
min)
Predos
e
X
Just before 
drug intake
-0:05a
1
X
X
X
X
BI 891065 
intake
0:00
---
0:30
0:30
2
X
X
1:00
1:00
3
X**
X
2:00
2:00
4
X**
X
3:00
3:00
5
X**
X
X
5:00
5:00
6
X**
X
6:00
6:00
7
X
X
7:00
7:00
8
X**
X
8:00
8:00
9
X
X
X
10:00
10:00
10
X**
X
3
2
No drug 
intake
24:00
11
X
X
X
X
36:00
36:00
12
X
4
3
Just before 
drug intake
47:55
13
X
BI 891065 
intake
48:00
---
5
8
Just before 
drug intake
167:55
14
X
X
X
BI 891065 
intake
168:00
---
BI = Boehringer Ingelheim; CRF = Case Report Form; ECG = electrocardiogram; IAP = inhibitor of apoptosis; PBMC = Peripheral blood 
mononuclear cells; PTM = planned time
a PK to be taken following an overnight fast (minimum 10 hours) on this day


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b The following windows of time are allowed for PK sampling:

Predose samples (PTM -0:05, 47:55, 167:55, etc.): within 1 hour before drug intake

On Day 1 (PTM 1:00 through PTM 3:00): within ±10 minutes of designated time

On Day 1 (PTM 5:00, 6:00, 7:00, 8:00, and 10:00): within ±15 minutes of designated time

Days 2 and beyond post first drug intake (PTM 24:00, 47:55, 167.55, etc.): ±1 hour.
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of samples from data 
evaluation. The new PK and urine schedule will be implemented upon availability of updated lab kits.
c A spot urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be collected 
over the post-dose intervals indicated between the arrows (◄––│––│––►) 0-3, 3-8, 8-10, 10-24 (Cycle 1 Days 1 and 15) 
and 24-48 h (Cycle 1 Day 1 only) and detailed in Section 5.3.2.5.
* In order not to confuse an ECG recording, all PK samples should be taken after performing the ECG. 
** ECGs will be taken throughout, as it is possible that time of maximum concentration is not accurately estimated; for 
safety, time of maximum concentration is one of the most relevant time points, so should not be missed. As such, some 
ECGs may only be evaluated at later points or, if deemed unnecessary, not at all.


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Table 10.3: 1
Time schedule for PK blood and urine samplings, 
 
and ECG measurements - Part A BI 891065 Monotherapy 
(continued)
Blood samples
Urine 
sampl
esd
Cycl
e
Visit Day
Time Point 
[hh:min]/ 
event
CRF 
Time
/PTM
Sampl
e No.
Triplicat
e
ECGs*
Plasma 
for BI
891065b,c
 
 
1
6
12
Just before 
drug intake
263:55
15
X
BI 891065 
intake
264:00
7
15
Just before 
drug intake
335:55 a
16
X
X
X
X
X
BI 891065 
intake
336:00
---
0:30
336:30
17
X
X
1:00
337:00
18
X**
X
2:00
338:00
19
X**
X
3:00
339:00
20
X**
X
5:00
341:00
21
X**
X
6:00
342:00
22
X
X
7:00
343:00
23
X**
X
8:00
344:00
24
X
X
10:00
346:00
25
X**
X
8
16
Just before 
drug intake
359:55
26
X
X
BI 891065 
intake
360:00
---
2
9
1
Just before 
drug intake
-0:05
27
X
EOT
X
X
BI = Boehringer Ingelheim; CRF = Case Report Form; ECG = electrocardiogram; EOT = end of treatment; IAP = inhibitor 
of apoptosis; PBMC = Peripheral blood mononuclear cells; PTM = planned time
a PK to be taken following an overnight fast (minimum 10 hours) on this day
b The following windows of time are allowed for PK sampling:

Predose samples (PTM 335:55, 359:55, etc.): within 1 hour before drug intake

Day 15 (PTM 336:30 through PTM 339:00): within ±10 minutes of the designated time

Day 15 (PTM 341:00 through 346:00):within ±15 minutes of the designated time
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of samples from data 
evaluation.
c Serum aliquot B samples for PK might be used for identification of metabolites on Days 1 (prior to treatment), 15, and 16 
at the same time points as the PK samples.
d A spot urine sample (X) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the post-dose intervals indicated between the arrows (◄––│––│––►) 0-3, 3-8, 8-10, and 10-24 (Cycle 1 
Days 1 and 15) and detailed in Section 5.3.2.5.
* In order not to confuse an ECG recording, all PK samples should be taken after performing the ECGs.
** ECGs will be taken throughout, as it is possible that time of maximum concentration is not accurately estimated; for 
safety, this is one of the most relevant time points, so should not be missed. As such, some ECGs may only be evaluated at 
later points or, if deemed unnecessary, not at all.


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Table 10.3: 2
Time schedule for PK blood, 
during Part B including food effect in q.d. treatment group
Samples
Cycle
Visi
t
Day
Time Point 
[hh:min]/ event
CRF 
Time
/PTM
Tripli
cate
ECG*
Plasmab
BI 
891065
Plasmab
BI 
754091
Biopsyc
1
2
1
Predose (between screening 
and C1D1 dosing)
X
-30 min 
(+/-15min)
-30 min
X
1
2
1
Just before drug 
admin
Predosea
X
X
X
X
BI 754091 admin
0:00
Just before 
infusion end 
1:00
X
1:25
1:25
X**
X
X
BI 891065 admin
1:30
2:00
2:00
X
X
2:30
2:30
X**
X
X
3:30
3:30
X**
X
X
4:30
4:30
X**
X
X
X
6:30
6:30
X**
X
X
7:30
7:30
X
X
X
8:30
8:30
X**
X
X
9:30
9:30
X
X
X
X
11:30
11:30
X**
X
X
3
2
Just before drug 
intake
25:25
X
X
X
X
BI 891065 intake
25:30
4
8
Just before drug 
intake
167:55
X
X
X
BI 891065 intake
168:00
5
12
Just before drug 
intake
263:55
X
X
BI 891065 intake
264:00
ADA = anti-drug antibodies; BI = Boehringer Ingelheim; CRF = Case Report Form; IAP = inhibitor of apoptosis;
PTM = planned time
a PK to be taken following an overnight fast (minimum 10 hours) on this day
b The following windows of time are allowed for PK and ECG sampling (ECGs should be performed PRIOR to PK 
sampling):

Predose samples (PTM -0:05, 25:25, 167:55, etc.): within 1 hour before drug intake

One hour to 4:30 hours post first drug intake (PTM 1:00 through PTM 4:30): within ±10 minutes of designated time

6:30 to 11:30 hours post first drug intake (PTM 6:30 through 11:30): within ±15 minutes of designated time
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of samples from data 
evaluation.
c Biopsy for IAP degradation to be taken as noted in Part B Flow Chart.
* In order not to confuse an ECG recording, all PK samples should be taken after performing the ECG(s).
** ECGs will be taken throughout, as it is possible that time of maximum concentration is not accurately estimated; for 
safety, this is one of the most relevant time points, so should not be missed. As such, some ECGs may only be evaluated at 
later points or, if deemed unnecessary, not at all.


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Table 10.3: 2
Time schedule for PK blood,
 during Part B including food effect in q.d. treatment group
(continued)
Samples
Cycle
Visit Day
Time Point 
[hh:min]/ event
CRF 
Time
/PTM
Tripli
cate
ECGs
*
Plasma
b BI 
891065
Plasma
b BI 
754091
Biopsy
c
1
6
15
Just before drug 
admin
335:55a
X
X
X
BI 891065 intake
336:00
0:30
336:30
X
X
1:00
337:00
X**
X
2:00
338:00
X**
X
3:00
339:00
X**
X
5:00
341:00
X**
X
6:00
342:00
X
X
7:00
343:00
X**
X
8:00
344:00
X
X
10:00
346:00
X**
X
7
16
-0:30
Breakfast
359:30a
X
X
X
BI 891065 intake
360:00
0:30
360:30
X
1:00
361:00
X
2:00
362:00
X
3:00
363:00
X
5:00
365:00
X
6:00
366:00
X
7:00
367:00
X
8:00
368:00
X
10:00
370:00
X
8
17
Just before drug 
admin
383:55
X
X
BI 891065 intake
384:00
2-5, then 
every 2nd
cycle
9-12 
then 
ever
y 2nd
cycle
1
Just before drug 
admin
-0:05
X (C2 
only)
X
X 
X
Just before infusion 
end
1:00
X
EOT
X
X
X
30-Day FU
X
X
ADA = anti-drug antibodies; BI = Boehringer Ingelheim; CRF = Case Report Form; ECG = electrocardiogram; EOT = end 
of treatment; FU = follow up; IAP = inhibitor of apoptosis; PTM = planned time
a PK to be taken following an overnight fast (minimum 10 hours) on this day
b The following windows of time are allowed for PK and ECG sampling (ECGs should be performed PRIOR to PK 
sampling):

Predose samples (PTM 335:55 [Day 15], 359:30 [Day 16], 383:55 [Day 17], etc.): within 1 hour before drug intake

On Day 15 (PTM 336:30 through 339:00) and Day 16 (PTM 360:30 to 363:00): within ±10 minutes of designated time


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
On Day 15 (PTM 341:00 through 346:00) and Day 16 (PTM 365:00 through 370:00): within ±15 minutes of designated 
time
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of samples from data 
evaluation.
c Biopsy for IAP degradation to be taken as noted in Part B Flow Chart.
* In order not to confuse an ECG recording, all PK samples should be taken after performing the ECGs.
** ECGs will be taken throughout, as it is possible that time of maximum concentration is not accurately estimated; for 
safety, this is one of the most relevant time points, so should not be missed. As such, some ECGs may only be evaluated at 
later points or, if deemed unnecessary, not at all.


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Table 10.3: 3
Time schedule for PK blood, 
 
 during Part B excluding food effect in b.i.d. treatment group 
Samples
Cycle
Visi
t
Day
Time Point 
[hh:min]/ event
CRF 
Time
/PTM
Triplica
te
ECG*
Plasmab
BI 
891065
Plasmab
BI 
754091
Biopsyc
1
2
1
Predose (between screening 
and C1D1 dosing)
X
-30 min 
(+/-15min)
-30 min
X
1
2
1
Just before drug 
admin
Predosea
X
X
X
X
BI 754091 admin
0:00
Just before 
infusion end 
1:00
X
1:25
1:25
X**
X
X
BI 891065 admin
1:30
2:00
2:00
X
X
2:30
2:30
X**
X
X
3:30
3:30
X**
X
X
4:30
4:30
X**
X
X
X
6:30
6:30
X**
X
X
7:30
7:30
X
X
X
8:30
8:30
X**
X
X
9:30
9:30
X
X
X
X
11:30
11:30
X**
X
X
No drug intake
13:30
3
2
Just before drug 
intake
25:25
X
X
X
X
BI 891065 intake
25:30
4
8
Just before drug 
intake
167:55
X
X
X
BI 891065 intake
168:00
5
12
Just before drug 
intake
263:55
X
X
BI 891065 intake
264:00
ADA = anti-drug antibodies; BI = Boehringer Ingelheim; CRF = Case Report Form; IAP = inhibitor of apoptosis; 
PTM = planned time
a PK to be taken following an overnight fast (minimum 10 hours) on this day
b The following windows of time are allowed for PK and ECG sampling (ECGs should be performed PRIOR to PK 
sampling):

Predose samples (PTM -0:05, 25:25, 167:55, etc.): within 1 hour before drug intake

One hour to 4:30 hours post first drug intake (PTM 1:00 through PTM 4:30): within ±10 minutes of designated time

6:30 to 11:30 hours post first drug intake (PTM 6:30 through 11:30): within ±15 minutes of designated time
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of samples from data 
evaluation.
c Biopsy for IAP degradation to be taken as noted in Part B Flow Chart.
* In order not to confuse an ECG recording, all PK samples should be taken after performing the ECGs.
** ECGs will be taken throughout, as it is possible that time of maximum concentration is not accurately estimated; for 
safety, this is one of the most relevant time points, so should not be missed. As such, some ECGs may only be evaluated at 
later points or, if deemed unnecessary, not at all.


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Table 10.3: 3
Time schedule for PK blood, 
 
 during Part B excluding food effect in b.i.d. treatment group 
(continued)
Samples
Cycle
Visit
Day
Time Point 
[hh:min]/ event
CRF 
Time
/PTM
Triplica
te 
ECGs*
Plasmab 
BI 
891065
Plasmab
BI 
754091
Biopsyc
1
6
15
Just before drug 
admin
335:55a
X
X
X
BI 891065 intake
336:00
0:30
336:30
X
X
1:00
337:00
X**
X
2:00
338:00
X**
X
3:00
339:00
X**
X
5:00
341:00
X**
X
6:00
342:00
X
X
7:00
343:00
X**
X
8:00
344:00
X
X
10:00
346:00
X**
X
No drug intake
348:00
7
16
Just before drug 
intake
359:30*
**
X
X
X
BI 891065 intake
360:00
2-5, then 
every 2nd
cycle
9-12 
then 
every 
2nd
cycle
1
Just before drug 
admin
-0:05
X (C2 
only)
X
X 
X
Just before 
infusion end
1:00
X
EOT
X
X
X
30-Day FU
X
X
ADA = anti-drug antibodies; BI = Boehringer Ingelheim; CRF = Case Report Form; ECG = electrocardiogram; EOT = end 
of treatment; FU = follow up; IAP = inhibitor of apoptosis; PTM = planned time
a PK to be taken following an overnight fast (minimum 10 hours) on this day
b The following windows of time are allowed for PK and ECG sampling (ECGs should be performed PRIOR to PK 
sampling):

Predose samples (PTM 335:55 [Day 15]): within 1 hour before drug intake

On Day 15 (PTM 336:30 through 339:00): within ±10 minutes of designated time

On Day 15 (PTM 341:00 through 346:00): within ±15 minutes of designated time

On Day16 (PTM 359:30): within 30 min before drug intake
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of samples from data 
evaluation.
c Biopsy for IAP degradation to be taken as noted in Part B Flow Chart.
* In order not to confuse an ECG recording, all PK samples should be taken after performing the ECGs.
** ECGs will be taken throughout, as it is possible that time of maximum concentration is not accurately estimated; for 
safety, this is one of the most relevant time points, so should not be missed. As such, some ECGs may only be evaluated at 
later points or, if deemed unnecessary, not at all.
***Central lab kits provided will contain extra tubes (for post-dose timepoints 360:30-370:00 on Day 16 and 383:55 on Day
17).  These tubes should not be used for b.i.d patients.


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Table 10.3: 4
Time schedule for PK blood,
 during Part C – NSCLC
Samples
Cycl
e
Visi
t
Da
y
Time 
Point 
[hh:min]
/ event
CRF 
Time
/PTM
Triplica
te ECGs
*
Plasmab
BI 8910
65
Plasmab
BI 7540
91
 
Biopsie
s
Scr
1
X
1
2
1
-30 min 
(±15min)
-0:30
X
Just 
before 
drug 
admin
-0:05a
X
X
X
X
X
X
BI 
754091 
admin
0:00
Just 
before 
infusion 
end 
1:00
X
1:25
1:25
X
X
BI 
891065 
intake
1:30
2:00
2:00
X
X
2:30
2:30
X
X
3:30
3:30
X
X
4:30
4:30
X
X
6:30
6:30
X
X
7:30
7:30
X
X
3
2
24:00
24:00
X
X
X
X
4
8
Just 
before 
drug 
intake
167:55
X
X
X
X
BI 
891065 
intake
168:00


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Table 10.3: 4 Time schedule for PK blood, 
 sampling during 
Part C – NSCLC (continued)
Samples
Cycl
e
Visi
t
Da
y
Time 
Point 
[hh:min]
/ event
CRF 
Time
/PTM
Triplica
te ECGs
*
Plasmab
BI 8910
65
Plasmab
BI 7540
91
 
Biopsie
s
1
5
15
Just 
before 
drug 
intake
335:55
X
X
X
X
BI 
891065 
intake
336:00
0:30
336:30
X
X
1:00
337:00
X
X
2:00
338:00
X
X
3:00
339:00
X
X
5:00
341:00
X
X
6:00
342:00
X
X
6
16
24:00
360:00
X
X
X
2-5, 
then 
every 
2nd
cycle
7-10 
then 
ever
y 2nd
cycl
e
1
Just 
before 
drug 
admin
(both)
-0:05
X (only 
cycle 2)
X
X 
(only 
cycle 
2,4)
X (only 
cycle 
2.4)
X (only 
cycle 3)
X
Just 
before 
infusion 
end
1:00
X
EOT
X
(X)
X
30-Day FU
X
X
ADA = anti-drug antibodies; BI = Boehringer Ingelheim; CRF = Case Report Form; PTM = planned time; EOT = end of 
treatment; FU = follow up; MDSC = myeloid-derived suppressor cells; PBMC = Peripheral blood mononuclear cells; 
PTM = planned time
a PK to be taken following an overnight fast (minimum 10 hrs) on this day
b The following windows of time are allowed for PK and ECG sampling (ECGs should be performed PRIOR to PK 
sampling):

Predose samples (PTM -0:05, 167:55, etc.): within 1 hour before drug intake

Just before end of infusion (PTM 1:00): within ±10 minutes of designated time

On Day 1 (PTM 1:25 through 8:30) and on Day 15 (PTM 336:30 through 339:00): within ±10 minutes of designated 
time

On Day 1 (PTM 0:30 through 6:00) and on Day 15 (PTM 341:00 through 342:00): within ±15 minutes of designated 
time
Time windows are specified for procedural reasons; deviations do not automatically lead to exclusion of samples from data 
evaluation.
* In order not to confuse an ECG recording, all PK samples should be taken after performing the ECGs.
Optional assessments are noted in parentheses. Please refer to the footnotes in Part C Lung Flow Chart for details.


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10.5
STATISTICAL APPENDIX
Part A:
A BLRM with overdose control will be used to guide dose escalation in this part of the trial. 
The BLRM is introduced in Section 7, which also specifies the prior for the model. After 
patients in each cohort have completed at least one cycle of treatment, the prior distribution 
will be updated through Gibbs sampling procedures with the accumulated DLT data from the 
MTD evaluation period. Posterior probabilities for the rate of DLTs will be summarised from 
BLRM. Selection of the next dose will be based on these probabilities as well as on other 
safety and laboratory data.
The purpose of this statistical appendix is to present performance metrics (operating 
characteristics) that illustrate the precision of the design in estimating the MTD under various 
dose-toxicity relationships through computer simulation. These results are summarised in 
Table 10.5: 3. In addition, recommendations of the next dose level by the BLRM with 
overdose control principle are also provided under various hypothetical outcome scenarios in 
early cohorts to show how it facilitates on-trial dose-escalation decisions (see Table 10.5: 1).
For simplicity reasons, a cohort size of 3 patients who are all evaluable starting at 25 mg is 
assumed for calculation of the operating characteristics.
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.5: 1. These scenarios reflect potential on-
trial data constellations and related escalation as allowed by the model and the 100%
escalation limit. It is assumed that each cohort has exactly three patients who are all evaluable. 
For each scenario, the probability of overdose for the current dose, as well as the next 
potential dose and related probabilities of under-dosing, target dose and over-dosing are 
shown.
For example, Scenario 1 represents the case where 1 patient has been treated at the starting 
dose of 5 mg and did not experience a DLT. Then, the BLRM would recommend escalating 
to 200 mg as the next dose. Since escalation is only allowed up to 15 mg per protocol, the 
next dose to be tested in the trial would be 15 mg.
Similarly, Scenario 4 represents the case where 1 patient has been treated at 5 mg and 1 at 15 
mg, none of them with a DLT. In this case, the model recommends escalating to 200 mg. As 
this exceeds the per protocol margin, the next dose to be tested would be 25 mg.
Scenario 3 shows the case that already the starting dose level is quite toxic, with 2 out of 3 
treated patients experiencing DLTs. The overdose control implemented in the model then 
does not allow going to any of the pre-specified doses.
Finally, Scenario 14 and 15 illustrate a case where escalation has proceeded up to the highest 
dose of 400 mg. Scenario 15 represents a scenario where the MTD could be declared at 
400 mg.


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Table 10.5: 1 
Hypothetical data scenarios
Scenario
Dose  
(mg)
# 
Patients
# 
DLT
Current 
Dose: 
P(OD)
Next 
recommended 
dose 
Next recommended 
dose:
P(UD)
P(TD)
P(OD)
1
5
1
0
0.012
200* [15]
0.701
0.143
0.156
2
5
3
1
0.161
5
0.592
0.246
0.161
3
5
3
2
0.607
NA
NA
NA
NA
4
5
15
1
1
0
0
0.012
200* [25]
0.724
0.137
0.140
5
5
15
1
3
0
1
0.131
25
0.540
0.273
0.186
6
5
15
25
1
1
3
0
0
0
0.003
200* [50]
0.769
0.127
0.104
7
5
15
25
1
1
3
0
0
1
0.095
50
0.522
0.281
0.196
8
5
15
25
1
1
3
0
0
2
0.415
5
0.571
0.282
0.147
9
5
15
25
50
1
1
3
3
0
0
0
0
0.002
400*[100]
0.626
0.148
0.226
10
5
15
25
50
1
1
3
3
0
0
0
1
0.055
100
0.550
0.280
0.170
11
5
15
25
50
100
1
1
3
3
3
0
0
0
0
0
0.003
400*[200]
0.674
0.124
0.202


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Table 10.5: 1 
Hypothetical data scenarios (continued)
12
5
15
25
50
100
1
1
3
3
3
0
0
0
0
2
0.290
50
0.654
0.284
0.062
13
5
15
25
50
100
200
1
1
3
3
3
3
0
0
0
0
0
0
0.011
400
0.760
0.111
0.129
14
5
15
25
50
100
200
400
1
1
3
3
3
3
3
0
0
0
0
0
0
0
0.021
400
0.899
0.080
0.021
15
5
15
25
50
100
200
400
1
1
3
3
3
3
6
0
0
0
0
0
1
1
0.158
400
0.450
0.392
0.158
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of the design in estimating the MTD. 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 10.5: 2 describes 4 assumed true dose-
toxicity scenarios which were used to assess the operating characteristics of the model. These 
scenarios reflect a wide range of possible cases as follows:

Scenario 1: aligned with prior means

Scenario 2: high-toxicity scenario

Scenario 3: low-toxicity scenario

Scenario 4: non-logistic dose-toxicity scenario


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Table 10.5: 2 
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
25
50
100
200
400
1: Prior
P(DLT)
0.059
0.078
0.107
0.164
0.269
2: High Tox
0.259
0.278
0.307
0.364
0.469
3: Low Tox
0.009
0.028
0.057
0.114
0.219
4: Non-
Logistic
0.048
0.147
0.193
0.312
0.348
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the following rules:

Escalate to the dose which maximises the probability of the targeted toxicity region and 
satisfies the overdose criterion if it is ≤100% increase from the current dose

If the recommended dose satisfying the overdose criterion is >100% increase in dose, 
then escalate to the highest dose level which is ≤100% increase from the current dose.
The MTD was considered reached if at least 6 patients have been evaluated at a dose level 
which is the model’s recommendation for the next dose cohort and for which the posterior 
probability of targeted toxicity was at least 50%, or if at least 18 patients have been treated in 
the trial, of which at least 6 at the MTD. 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 10.5: 3.
Table 10.5: 3 
Simulated operating characteristics
Scenario
% of trials declaring a MTD with true DLT rate in
# Patients
# DLTs
underdose
target dose
overdose
Stopped
Mean 
(Min-Max)
Mean
(Min-
Max)
1
20.8
77.6
0.0
1.6
20.350
(3 - 42)
2.669
(1 - 8)
2
0.0
44.7
8.9
46.4
13.250
(3 - 30)
3.816
(1 - 9)
3
46.2
53.7
0.0
0.1
20.830
(6 - 39)
2.179
(1 - 6)
4
19.4
68.5
10.4
1.7
19.250
(3 - 33)
3.612
(1 - 9)
In Scenario 1 which reflects the case that the true dose-toxicity is aligned with prior means
almost 78% of trials have found a MTD with true DLT rate in the target interval. 412 trials 


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declared 400 mg as the MTD, 364 trials declared 200 mg as the MTD. In Scenario 2 (high-
toxicity scenario), almost as many trials declared a MTD with true DLT rate in the target 
interval, as trials that were stopped without declaring a MTD since all dose levels were too 
toxic. The high number of prematurely stopped trials is an expected situation for such a high 
toxicity scenario. Only few trials declared MTDs with true DLT rates in the overdose interval.
Scenario 3 (low-toxicity scenario) shows that more than 50% of trials (537 of 1000) declared 
MTDs with true DLT rate in the target interval although only one dose level (400 mg) has 
assumed true DLT rate in the target interval. The majority of the rest of the trials (393 trials) 
declared 200 mg as the MTD. Only one trial has been stopped prematurely due to too toxic 
doses. Scenario 4 represents a case where the assumed true dose-toxicity curve does not 
follow a logistic shape. In this scenario, more than 60% of trials determined MTDs with true 
DLT rate in the target interval an only a few trials declared MTDs with true DLT rate in the 
overdose interval. The mean patient numbers range from 13.25 patients (Scenario 2) to 20.83
patients (Scenario 3) and the maximum number of patients was 39. Therefore, the patient 
numbers are as expected and increase when moving away from the high-toxicity scenario.
By reviewing the metrics presented in Table 10.5: 3, it can be seen that the model is not 
sensitive to different scenarios of truth, even under misspecification results are satisfactory. 
In general, this model is conservative due to the overdose control criteria. In all scenarios, the 
probabilities of recommending a dose with true P(DLT) ≥33% as MTD are much smaller 
than probabilities of recommending a dose with true P(DLT) between 16% and 33% as MTD.
On-trial recommendations based on the model are consistent with the clinical decision 
making process, and should be considered in conjunction with other available clinical 
information by the BI clinical trial team and trial Investigators in deciding the dose levels to 
be tested in order to determine the MTD estimate. R Version 3.2.2 was used for data 
scenarios and simulations.
Part B:
Dose finding in Part B of the trial will be guided by a Bayesian 5-parameter logistic 
regression model with overdose control. For a description of the model refer to Section 7.1.2.
To determine the prior distributions for θ1 and θ2, a meta-analytic predictive approach will be 
used. Toxicity information on BI 891065 from Part A of the trial and toxicity information on 
BI 754091 from the Trial 1381.1 will be incorporated.
Data of the 400 mg cohort of Part A was not completely available by the time of the 
finalisation of this version of the CTP. Therefore, two possible scenarios of how the prior to 
be used for Part B could be defined are presented. The first scenario represents the case that 
none of the patients treated with 400 mg in Part A experiences a DLT. The second scenario 
represents that case that one of the 6 patients treated with 400 mg in Part A experiences a 
DLT.
The historical data for BI 891065 can be found in Table 10.5: 4 for Scenario 1 and in Table 
10.5: 5 for Scenario 2. 


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Table 10.5: 4 Historical data for BI 891065 assuming no DLTs happen at 400 mg (status as of 
17 Oct 2018)
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of evaluable 
patients
5 mg
0/2
15 mg
0/1
25 mg
0/3
50 mg
0/4
100 mg
0/3
200 mg
0/3
400 mg
0/6
Table 10.5: 5 Historical data for BI 891065 assuming one patient has a DLT at 400 mg (status 
as of 17 Oct 2018)
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of evaluable 
patients
5 mg
0/2
15 mg
0/1
25 mg
0/3
50 mg
0/4
100 mg
0/3
200 mg
0/3
400 mg
1/6


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The following steps were used to derive the prior distributions for all parameters:
1. θ1: 
1.
The meta-analytic-predictive prior was derived using the information in Table 
10.5: 4 (for Scenario 2 information is in Table 10.5: 5), allowing for small to 
moderate between-trial heterogeneity. This mixture component was assigned 
90% mixture weight.
2.
A second, weakly-informative component was added with 10% mixture 
weight.
2. θ2: 
1.
The meta-analytic-predictive prior was derived using the information in Table 
10.5: 6, allowing for moderate to substantial between-trial heterogeneity. This 
mixture component was assigned 90% mixture weight.
2.
A second, weakly-informative component was added with 10% mixture 
weight.
3. η: based on the a priori assumption of no interaction between the two compounds, a 
normal distribution with mean 0 and standard deviation 0.56 was chosen. At the 
starting dose combination, the corresponding 95% credible interval covers an up to 
1.4-fold increase (or decrease) in the odds of a DLT over no interaction.
The prior distributions for both scenarios are given in Table 10.5: 7 and Table 10.5: 8. The 
corresponding prior probabilities of a DLT at different dose combinations and the 
corresponding probabilities of under toxicity, targeted toxicity and over toxicity are shown in 
Table 10.5: 9 and Table 10.5: 10.


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Table 10.5: 7 Prior distributions for Scenario 1 (no DLTs at 400 mg in Part A)
Parameter
means, standard deviations, correlation
mixture 
weight
log(α1), log(β1): component 1
(-2.404, -0.364), (0.679, 0.737), -0.036
0.9
log(α1), log(β1): component 2
(-2.404, -0.364), (2, 1), 0
0.1
log(α2), log(β2): component 1
(-2.946, -0.193), (0.690, 0.884), -0.037
0.9
log(α2), log(β2): component 2
(-2.946, -0.193), (2, 1), 0
0.1
η
0, 0.56
N/A
Table 10.5: 8 Prior distributions for Scenario 2 (one DLT at 400 mg in Part A)
Parameter
means, standard deviations, correlation
mixture weight
log(α1), log(β1): component 1
(-2.040, -0.093), (0.644, 0.716), -0.095
0.9
log(α1), log(β1): component 2
(-2.040, -0.093), (2, 1), 0
0.1
log(α2), log(β2): component 1
(-2.946, -0.193), (0.690, 0.884), -0.037
0.9
log(α2), log(β2): component 2
(-2.946, -0.193), (2, 1), 0
0.1
η
0, 0.56
N/A
Table 10.5: 9 Prior probabilities of DLTs for Scenario 1 (no DLTs at 400 mg in Part A)
Dose BI 
891065
Dose BI 
754091
Probability of true DLT rate in 
Quantiles
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
50 mg
240 mg
0.831
0.140
0.030
0.113
0.097
0.023
0.089
0.357
100 mg
240 mg
0.743
0.214
0.043
0.134
0.107
0.029
0.108
0.417
200 mg
240 mg
0.565
0.324
0.110
0.179
0.135
0.032
0.143
0.544
400 mg
240 mg
0.408
0.274
0.318
0.274
0.225
0.018
0.207
0.839


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Table 10.5: 10 Prior probabilities of DLTs for Scenario 2 (one DLT at 400 mg in Part A)
Dose BI 
891065
Dose BI 
754091
Probability of true DLT rate in 
Quantiles
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
50 mg
240 mg
0.804
0.162
0.033
0.118
0.102
0.022
0.093
0.376
100 mg
240 mg
0.684
0.263
0.053
0.147
0.113
0.030
0.119
0.451
200 mg
240 mg
0.450
0.387
0.162
0.211
0.147
0.040
0.174
0.600
400 mg
240 mg
0.297
0.268
0.435
0.342
0.248
0.026
0.282
0.905
As can be seen from Table 10.5: 9 and Table 10.5: 10, the dose combinations 50 mg BI 
891065 and 240 mg BI 754091, 100 mg BI 891065 and 240 mg BI 754091, and 200 mg BI 
890165 and 240 mg BI 754091 have prior probabilities of over toxicity below 25% in both 
scenarios. They fulfill the overdose criterion and are therefore suitable starting dose 
combinations.
Since prior probabilities for both scenarios shown above are similar, only Scenario 2 with a 
starting dose combination 100 mg BI 891065 and 240 mg BI 754091 will be used to evaluate 
the model in terms of performance metrics and data scenarios.
Performance metrics (operating characteristics) illustrate the precision of the design in 
estimating the MTD under various dose-toxicity relationships through computer simulation. 
These results are summarized in Table 10.5: 13. In addition, recommendations of the next 
dose combination by the BLRM with overdose control principle are also provided under 
various hypothetical outcome scenarios in early cohorts to show how it facilitates on-trial
dose-escalation decisions (see Table 10.5: 11). For simplicity reasons, a cohort size of 3 
patients who are all evaluable is assumed.
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.5: 11. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model and the 100%
escalation limit. For each scenario, the probability of overdose for the current dose 
combination, as well as the next potential dose combination and related probabilities of 
under-dosing, target dose, and over-dosing are shown.
Scenario 1 represents the case that 3 patients are treated at the starting dose combination 100 /
240 and none of these patients experiences a DLT. The model recommendation then is to 
escalate to the combination 200 / 240. Even if one of these 3 patients experiences a DLT, the 
model still recommends to escalate to 200 / 240 (see Scenario 2).
Scenario 3 describes a case where de-escalation to 50 / 240 would be required. In case 2 of 3 
patients at 100 / 240 experience DLTs, the overdose probability at 100 / 240 exceeds 25%, 
which implies that 100 / 240 cannot be tested without further data at lower dose levels.


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Scenarios 4 and 5 illustrate that when 3 patients have been treated at 100 / 240 without DLT 
and then additional 3 patients have been treated at 200 / 240 without DLT, the model would 
still recommend to treat the next patient with 200 / 240. Only in the case 4 or more patients 
are treated with 200 / 240 without experiencing a DLT, the model recommends to escalate to 
400 / 240. Scenarios 9 and 10 show that in case one patient experiences a DLT at 200 / 240, 
the model requires 9 additional patients without DLT to allow escalating to 400 / 240.
Scenarios 11 and 12 illustrate possible ways to declare 400 / 240 as the MTD.


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Table 10.5: 11
Hypothetical data scenarios
Sce
nari
o
Dose 
[combi-
nation] 
(mg)
# 
Patients
# DLT
Current 
Dose 
[combi-
nation]: P 
(OD)
Next 
recom-
mended 
dose 
[combi-
nation]
Next dose [combination]:
P (UD)
P (TD)
P (OD)
1
100 / 240
3
0
0.012
200 / 240
0.548
0.369
0.083
2
100 / 240
3
1
0.066
200 / 240
0.335
0.453
0.212
3
100 / 240
3
2
0.256
50 / 240
0.444
0.381
0.175
4
100 / 240
200 / 240
3
3
0
0
0.027
200 / 240
0.691
0.282
0.027
5
100 / 240
200 / 240
3
4
0
0
0.021
400 / 240
0.488
0.277
0.234
6
100 / 240
200 / 240
3
3
0
1
0.117
200 / 240
0.420
0.463
0.117
7
100 / 240
200 / 240
3
3
0
2
0.308
100 / 240
0.534
0.412
0.054
8
100 / 240
200 / 240
3
6
0
1
0.048
200 / 240
0.547
0.405
0.048
9
100 / 240
200 / 240
3
10
0
1
0.014
400 / 240
0.434
0.318
0.249
10
100 / 240
200 / 240
400 / 240
3
4
6
0
0
0
0.017
400 / 240
0.819
0.164
0.017
11
100 / 240
200 / 240
400 / 240
3
4
6
0
0
1
0.101
400 / 240
0.522
0.377
0.101
12
100 / 240
200 / 240
400 / 240
3
10
6
0
1
1
0.107
400 / 240
0.488
0.405
0.107
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of the design in estimating the MTD. Under an assumed true dose-toxicity curve, 
metrics such as the probability of recommending a dose combination with true DLT rate in 
the target interval can be approximated via simulation. Table 10.5: 12 describes 4 assumed 


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true dose-toxicity scenarios that were used to assess the operating characteristics of the model. 
These scenarios reflect a wide range of possible cases as follows:

Scenario 1: aligned with prior means

Scenario 2: high-toxicity scenario

Scenario 3: low-toxicity scenario

Scenario 4: non-logistic dose-toxicity scenario
Table 10.5: 12 
Assumed true dose-toxicity scenarios
Scenario
Dose combination (mg/mg)
50 / 240
100 / 240
200 / 240
400 / 240
1: Prior
P(DLT)
0.118
0.147
0.211
0.342
2: High 
Tox
0.156
0.298
0.379
0.514
3: Low 
Tox
0.051
0.092
0.137
0.254
4: Non-
Logistic
0.098
0.112
0.317
0.675
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the following rules:
1. Escalate to the dose combination which maximises the probability of the targeted toxicity 
region and satisfies the overdose criterion if it is ≤100% increase from the current 
dose of BI 891065
2. If the recommended dose combination satisfying the overdose criterion is >100% increase 
in dose of BI 891065, then escalate to the highest dose combination which is ≤100% 
increase from the current dose of BI 891065.
The MTD was considered reached if at least 6 patients have been evaluated at a dose level 
which is the model’s recommendation for the next dose cohort and if in total at least 12 
patients have been included in the trial or if the posterior probability of targeted toxicity was 
at least 50% for the dose combination which is the model’s recommendation for the next dose 
cohort and if in total at least 12 patients have been included in the trial.
It was then assessed how often a dose combination was declared as MTD with true DLT rate 
in the under-dose, targeted dose, 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 10.5: 13.


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Table 10.5: 13 
Simulated operating characteristics
% of trials declaring a MTD with true DLT rate in
# Patients
# DLTs
Underdose
Target dose
Overdose
Stopped
Mean 
(Min-Max)
Mean
(Min-Max)
1
19.4
70.4
9.3
0.9
12.711 (3 - 30)
2.601 (1 - 8)
2
6.9
51.1
35.5
6.5
11.538 (3 - 30)
3.648 (1 - 12)
3
76.2
23.1
0.0
0.7
13.752 (6 - 30)
2.048 (0 - 7)
4
34.5
64.9
0.2
0.4
12.414 (6 - 27)
3.007 (1 - 9)
In Scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
70.4% of the simulated trials declared the combination 200 / 240 mg as MTD. Only 9.3% of 
the simulated trials declared the dose combination 400 / 240 mg as MTD, which has an 
assumed true toxicity probability in the overdose interval.
In Scenario 2 (high-toxicity scenario), more than 50% of simulated trials declared a dose as 
MTD with assumed true toxicity probability in the target interval. 35.2% of simulated trials 
declared 200 / 240 as MTD which has a true toxicity probability of 0.379 which is close to 
boundary between target dose interval and overdose interval. The high-toxicity scenario has 
the biggest number of stopped trials (6.5%). This is expected for such a scenario.
In Scenario 3 (low-toxicity scenario) the MTD was more often chosen as a dose combination 
with true toxicity probability in under-dose interval than in the target dose interval. In the 
majority of simulated trials (70.4%) the MTD was chosen as 200 / 240, which has an 
assumed true toxicity probability of 0.137 which is close to the boundary of the target dose 
interval.
Scenario 4 (non-logistic scenario) illustrates that even if the model assumption of a logistic 
dose-toxicity relationship is not fulfilled, the model still selects doses with true toxicity 
probability in the target interval as MTD in almost 65% of simulated trials. This illustrates 
that the model is not sensitive to model misspecification.
The mean patient numbers range from 11.5 patients (Scenario 2) to 13.8 patients (Scenario 3) 
and the maximum number of patients was 30. Therefore, the patient numbers are as expected 
and increase when moving away from the high-toxicity scenario.
By reviewing the metrics presented in Table 10.5: 13, it can be seen that the model is not 
sensitive to different scenarios of truth. In general, this model is conservative due to the 
overdose control criteria. In all scenarios, the probabilities of recommending a dose
combination with true P(DLT) ≥33% as MTD are much smaller than probabilities of 
recommending a dose combination with true P(DLT) between 16% and 33% as MTD.


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On-study recommendations based on the model are consistent with the clinical decision 
making process, and should be considered in conjunction with other available clinical 
information by the BI clinical trial team and trial investigators in deciding the dose levels to 
be tested in order to determine the MTD estimate.
R version 3.5.1 and JAGS version 4.3.0 were used for data scenarios and simulations for Part 
B.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global 
amendment
1
Date of CTP revision
27 July 2017
EudraCT number
2017-000465-74
BI Trial number
1379.1
BI Investigational Products
BI 891065 and BI 754091
Title of protocol
An open-label Phase I dose finding trial with 
BI 891065 alone and in combination with BI 754091 
to characterise safety, tolerability, pharmacokinetics, 
pharmacodynamics, and efficacy in patients with 
advanced and/or metastatic malignancies
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as 
changes involve logistical or 
administrative aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of 
sections with changes are presented. Please note that formatting changes and minor changes 
to punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be changed
All sections, tables, etc. pertaining to Part C Cohort 2 
(Multiple Myeloma) have been removed. Details are 
not provided in this description. In addition, the 
NSCLC portion is no longer designated Cohort 1, 
because it is the only Part C cohort currently planned. 
This change is also not detailed here.


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Rationale for change
The FDA requested that the multiple myeloma cohort 
planned for Part C be removed from this protocol at 
this time and be submitted as a stand-alone protocol
at the discretion of the Sponsor.
Section to be changed
Title page
Description of change
Trial Medical Monitor changed to:
Phone: 
Fax: 
Rationale for change
Logistical change due to the location of the trial sites.
Section to be changed
Synopsis, Section 1.2.2 BI 754091, and Section 4.1.2 
Selection of doses in the trial (changes to Sections 
1.2.2 and 4.1.2 are presented here)
Description of change
1.2.2 BI 754091
BI 754091 is currently being tested in patients in the 
BI 1381.1 BI 1381.2 clinical trials and will be closely 
monitored during the conduct of this trial. The dose 
of 240 mg BI 754091 once every 3 weeks was taken 
forward into the expansion portion of the 
BI 1381.1 trial and will be the starting dose of 
BI 754091 used in this trial.
Rationale for change
Based on recommendations of the FDA, the starting 
dose of BI 754091 has been set at 240 mg.
Section to be changed
4.1.2.1 Starting dose of BI 891065
Description of change
A dose Based on the toxicities and exposures in the 
GLP-compliant dog study (the more sensitive 
species), a starting dose of 255 mg BI 891065 daily 
is expected to be a safe first-in-human starting dose 
for has been chosen. To minimize the number of
patients in Part A, which is supported by the low 
overdose prior probability of 0.051exposed to doses 
of BI 891065 presumed to be below the threshold 
of activity, an adapted dose-escalation approach 
(see Section 4.1.3) will be used for doses of BI 
891065 below 25 mg. For details please refer to the 


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Investigator’s Brochure (c14463420).
Rationale for change
Based on the toxicities and exposures in the GLP-
compliant dog study, a starting dose of 5 mg BI 
891065 daily has been chosen. Because of the 
lowering of the original planned starting dose, the 
dose escalation plan has been adjusted for cohorts 
using doses <25 mg BI 891065.
Section to be changed
4.1.2.2 Starting dose of BI 754091
Description of change
A fixed dose of BI 754091 once every 3 weeks will 
be administered. The anticipated starting dose of 
BI 754091 is 240 mg (i.e., the dose currently 
selected in this trial will be determined by the SRC 
using the most recent safety information from another 
ongoing trial, BIPhase I Trial 1381.1. In the BI of 
BI 754091 monotherapy for expansion cohort 
patients and 1381.1 trial, 80 mg was2). Based on 
further data for BI 754091, the starting dose of BI 
754091 the dose of 240 mg has been cleared. 
Escalating doses are selected may be adapted by the 
SRC (informed by a BLRM with overdose control 
design).
The dosing schedule of BI 754091 will be once every 
3 weeks (q3w) and is not anticipated to change.
Rationale for change
Based on recommendations of the FDA, the starting 
dose of BI 754091 has been set at 240 mg.
Section to be changed
All flow charts
Description of change
A row for virology testing at screening was added to 
all flow charts.
Rationale for change
To clarify that if recent virology tests (≤28 days) are 
not available, virology testing must be done at 
screening.
Description of change
A row for cardiac testing (only if cardiac disease 
suspected) was added to all flow charts. In addition, a 
new Footnote f was added for this row.
All subsequent footnotes were reordered.


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Rationale for change
To clarify the criteria for cardiac testing at screening 
by adding a link to the exclusion criteria.
Description of change
A row for reviewing patient diaries was added.
Rationale for change
To reinforce compliance during study conduct.
Description of change
All charts follow-up for PD visits footnotes: tumour 
assessment by imaging […] should be performed 
every 6 weeks (±-5 days) for the first 6 months […]
Rationale for change
Corrected from -5 days to ±5 days
Section to be changed
Part A flow chart
Description of change
Blood, urine sampling for pharmacokinetics
Rationale for change
To clarify that blood and urine samples are taken 
during Part A.
Section to be changed
Part B flow chart
Description of change
This row was added to the Part B Flow Chart:  Food 
administration for Food Interaction Assessment
Rationale for change
To clarify for the sites exactly when the meal is 
administered during the food interaction assessment.
Section to be changed
Flow chart footnotes
Description of change
All charts Footnote a: Treatment cycles (C) are 21 
days (3 weeks). Patients maywill continue treatment 
with BI 891065 as long as they are deriving clinical 
benefit or until undue drug toxicity (both according to 
the Investigator’s judgment) or withdrawal of 
consent, whichever occurs first. All circumstances 
for withdrawal of trial treatment are presented in 
Sections 3.3.4.1.
Rationale for change
To provide consistency throughout the protocol 
concerning withdrawal of patients from treatment.
Description of change
The following was added to Part A Footnote l, Part B 
Footnote n: Patients will be observed after their 
first 3 doses of BI 891065 as outlined in Section 


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5.2.6.4.3. Patients will fast a minimum of 10 hours 
prior to select visits as outlined in Section 4.1.5.1. 
Patients should not take BI 891065 prior to certain 
visits that require pre-dose blood sampling as 
detailed in Table 10.3: 1.
The following was added to Part C Footnote m: 
Patients will be observed after their first 3 doses of 
BI 891065 as outlined in Section 5.2.6.4.3. Patients 
should not take BI 891065 prior to certain visits 
that require pre-dose blood sampling as detailed 
in Table 10.3: 1.
Rationale for change
To clarify intense observation during the first doses 
of BI 891065 and the timing of doses for PK 
sampling days.
Description of change
Parts A and C Footnote m and Part B Footnote o:  An 
EOT visit should be performed for all patients who 
permanently discontinued trial medication. If the 
decision to permanently discontinue treatment is 
taken at a scheduled visit, the EOT visit should be 
performed instead of the scheduled visit (preferably 
within 7 days and no later than 14 days after the last 
treatment). Please note that a patient with an initial 
radiologic PD does not have to be automatically 
withdrawn from treatment (see Sections 3.3.4.1).
Rationale for change
To clarify that patients will be allowed to continue 
treatment following the first radiologic progression 
and details are provided in Section 3.3.4.1.
Section to be changed
Part A Flow Chart Footnote l
Description of change
Added: Patients will be observed after their first 
3 doses of BI 891065 as outlined in Section 
5.2.6.4.3. Patients will fast a minimum of 10 hours 
prior to select visits as outlined in Section 4.1.5.1. 
Patients should not take BI 891065 prior to certain 
visits that require pre-dose blood sampling as 
detailed in Table 10.3: 1.
Rationale for change
To reinforce the extent of fasting and add links to 
sections describing patient observation and drug 
dosing details.
Section to be changed
2.1.2 Primary endpoints


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2.1.2.1 Part A
Description of change
[…] For doses below 25 mg, single patient cohorts 
will be treated at 5 mg and 15 mg if not specified 
otherwise by the SRC. For doses above 25 mg, aA
BLRM employing the escalation with overdose 
control (EWOC) principle will be used during the 
escalation phase for selection of doses to investigate 
and for estimation of the MTD. Cohorts of patients 
will receive escalating doses of BI 891065 until the 
MTD is reached or the highest possible dose has been 
tested. Each cohort will consist of newly enrolled 
patients. Estimation of the MTD during the escalation 
phase of the trial will be based upon the estimation of 
the probability of a DLT in Cycle 1 in the set of 
evaluable patients (where evaluable patients refer 
to patients not fulfilling the criteria for 
replacement [Section 3.3.4.4]) for MTD.
Another BLRM employing the EWOC principle will 
be used during the escalation phase for selection of 
dose combinations and for estimation of the MTD. It 
is planned that cCohorts of patients will receive 
escalating doses of BI 891065 in combination with a 
stable dose of BI 754091 (at the dose pre-specified 
by the SRC) until the MTD is reached or the highest 
tolerated dose of BI 891065 determined in Part A has 
been tested.
Rationale for change
Based on the recommendation by the FDA, doses 
<25 mg BI 891065 will be tested.
Description of evaluable patient was moved forward 
in the protocol for this section and for Section 7.7.
Clarified that the SRC can change the dose of 
BI 754091, if needed.
Section to be changed
2.1.2 Primary Endpoints
2.1.2.2 Part B Last paragraph
Description of change
Another BLRM employing the EWOC principle will 
be used during the escalation phase for selection of 
dose combinations and for estimation of the MTD. It 
is planned that Ccohorts of patients will receive 
escalating doses of BI 891065 in combination with a 
stable dose of BI 754091 (at the dose pre-specified 


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by the SRC) until the MTD is reached or the highest 
tolerated dose of BI 891065 determined in Part A has 
been tested.
Rationale for change
To clarify that the fixed dose of BI 754091 may be 
changed for future cohorts if deemed necessary by the 
SRC.  Dosing of BI 754091 will not change within an 
individual patient’s study participation.
Section to be changed
2.1.2 Primary endpoints
2.1.2.3 Part C
Description of change
The dose of each of the study drugs used for Part 
C will be determined from the data of Parts A and 
B. […]
Rationale for change
To clarify this point under primary endpoints
Section to be changed
Description of change
Rationale for change
Section to be changed
3.1 Overall trial design and plan
Description of change
[…] Dose-escalation will in addition be restricted to a 
maximum of 100% from the previous dose for any 
dose ≥15 mg BI 891065 (see Section 4.1.3). 
Successive cohorts of patients will receive increasing 
or decreasing doses of BI 891065 until the MTD is 
reached; the maximum dose level planned is 400 mg. 
For any dose-escalation cohort >15 mg BI 891065, at 
least 3 patients will be required (refer to Section 7). 


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[…]
[…]Part B will be a dose escalation of BI 891065 in 
combination with a dose of 240 mg BI 754091 once 
every 3 weeks (the dose used for the expansion 
portion of Trial 1381.1.at the biologically relevant 
dose as determined in the BI 754091 development 
program (Trials 1381.1 and 1381.2). The dose of 
BI 754091 will be kept stable during this part of the 
trial while escalating the dose of BI 891065. Should 
it be decided that a higher starting dose of BI 
754091 is warranted in the combination with BI 
891065, this BI 754091 dose is not to exceed the 
highest dose assessed as safe for BI 754091 
monotherapy, and in any case must not exceed 
2000 mg for the single dose (technical limit). […]
[…] For dose levels above 25 mg, iIf DLTs are 
observed in the first two consecutive patients of a 
previously untested dose level, subsequent enrolment 
to that cohort will be stopped. The BLRM will be re-
run to confirm that the dose level still fulfils the 
EWOC principle. Based on this information, the SRC 
will evaluate whether the next patients will be 
enrolled at the same dose level, or if they will be 
enrolled at a lower dose level. In the unlikely event 
that the initial dose of 25 mg once daily is considered 
as not tolerated by the SRC, cohorts on lower dose 
level(s) may be initiated based on the decision of the 
SRC. […]
[…]Patients will continue treatment as long as they 
are deriving clinical benefit in the opinion of the 
Investigator, or until withdrawal of consent, 
oroccurrence of unacceptable toxicity, whichever 
occurs first. Patients will be allowed to stay on 
treatmentor for additional reasons detailed in 
Section 3.3.4.1the case of initial radiological PD, if 
the Investigator feels that it is in the patient’s best 
interest.
Rationale for change
Based on recommendations of the FDA, the starting 
dose of BI 891065 has been set at 5 mg, the starting 
dose of BI 754091 has been set at 240 mg, and it is 
clarified that the dose of BI 754091 cannot exceed 
2000 mg.


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Because of the lowering of the original planned 
starting dose, the dose escalation plan has been 
adjusted for cohorts using doses <25 mg BI 891065.
Section to be changed
3.3.3 Exclusion criteria
Description of change
10
Any of the following cardiac criteria:
[…]

Patients with an eEjection fraction <55% or the 
lower limit of normal of the institutional standard
will be excluded. Only in cases where the 
Investigator or the treating physician or both 
suspects cardiac disease with negative effect on 
the ejection fraction, the ejection fraction will 
be measured during screening using an 
appropriate method according to local 
standards to confirm eligibility (e.g., 
echocardiogram [ECHO)], multi-gated 
acquisition scan [MUGA]). A historic 
measurement of EF no older than 6 months 
prior to first administration of study drug can 
be accepted provided that there is clinical 
evidence that the EF value has not worsened 
since this measurement in the opinion of the 
Investigator or of the treating physician or 
both.
Rationale for change
To clarify that echocardiograms or MUGAs need not 
be done for all patients at screening and to detail the 
circumstances for doing them.
Description of change
14
Serious concomitant disease or medical 
condition affecting compliance with trial 
requirements or which are considered relevant for the 
evaluation of the efficacy or safety of the trial drug, 
such as cardiac, neurologic, psychiatric, infectious 
disease or active ulcers (gastro-intestinal tract, skin) 
or laboratory abnormality that may increase the risk 
associated with trial participation or trial drug 
administration, and in the judgment of the 
Investigator would make the patient inappropriate for 
entry into the trial.
Rationale for change
To clarify that echocardiograms are only done at 
screening if the Investigator suspects cardiac disease 
and therefore patients with know cardiac disease must 


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be excluded.
Description of change
19
Patients receiving systemic treatment with any 
immunosuppressive medication within 1 week prior 
treatment start (steroids of max. 10 mg prednisolone 
equivalent per day are allowed, topical [e.g.,and
inhaled] steroids are not considered as 
immunosuppressive) within 1 week prior treatment 
start.).
Rationale for change
To clarify details for pre-study steroid use and to 
refine the definition of steroids not considered to be 
immunosuppressive.
Description of change
20
For Parts A and B: Patients with known
epidermal growth factor receptor (EGFR) or), known
anaplastic lymphoma kinase (ALK), or known ROS 
Proto-Oncogene 1 (ROS1) genomic tumour 
aberrations, unless disease has progressed following 
available EGFR or ALK targeted therapy (including 
osimertinib for EGFR T790M-mutated NSCLC)
22
For Part C: Patients with EGFR, ALK, or (if 
known) ROS1 genomic tumor aberrations
Rationale for change
At the request of the FDA, ROS1 genomic tumour 
aberrations were added to the relevant exclusion 
criteria.
Section to be changed
3.3.4.1 Withdrawal from trial treatment
Description of change
An individual patient is to be withdrawn from trial 
treatment(s) if:
[…]

Recurring radiologic progression. Note: In the 
case of initial radiological PD, patients will be 
allowed to stay on treatment if the following 
criteria are met:
-
The Investigator feels that it is in the 
patient’s best interest
-
The patient signed an informed consent 
form specific for this circumstance after 
acknowledging that this practice is not 
considered standard in the treatment of 
cancer. The specific informed consent 
process for this circumstance includes 


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discussion of alternative treatment 
options, including any available 
approved therapies (if applicable) and 
participation in alternative clinical 
trials.
-
Absence of clinical symptoms or signs 
indicating clinically significant PD
-
No decline in performance status
-
Absence of rapid PD or threat to vital 
organs or critical anatomical sites (e.g., 
central nervous system metastasis, 
respiratory failure due to tumor 
compression, spinal cord compression) 
requiring urgent alternative medical 
intervention
-
No significant, unacceptable, or 
irreversible toxicities related to study 
treatment.

A pause of treatment or delayed start of 
treatment of more than 12 weeks due to 
SAEs/AEs

The following adverse event(s) occur:
-
Cytokine release syndrome CTCAE 
Version 4.03 Grade 3 or 4
-
Immune related AEs requiring permanent 
study drug discontinuation as described in 
Guidelines for Management of Immune-
Related AEs (Appendix 10.2):
-
Grade 3 to 4 pneumonitis
-
Grade 3 to 4 adrenal 
insufficiency
-
Grade 4 diabetes mellitus
-
Any grade encephalitis
-
Grade 4 hypophysitis
-
Grade 4 rash
-
Grade 3 to 4 colitis or 
recurrent colitis of any grade
-
Any recurrent Grade 3 to 4 
AE
-
Transaminase increases >5 
times ULN or total bilirubin 
>3 times ULN
-
Inability to taper steroids to 
10 mg or less prednisone or 
equivalent within 12 weeks
-
SAEs/AEs of Grade ≥2 
deemed intolerable by the 


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patient or the treating 
physician and not responding 
to medical management and 
any SAEs/AEs of ≥ Grade 3 
that do not recover to 
Grade 1 or less within 12 
weeks
-
Persistent Grade 2-3 AEs 
that do not recover to Grade 
1 or less within 12 weeks
-
Grade 3 to 4 AEs that are 
classified as immune-related 
by the Investigator but are 
not listed in Appendix 10.1 if 
they do not resolve to Grade 
≤ 1 or baseline with 
immunosuppressive therapy 
within 2 weeks.
-
≥Grade 4 drug-related AEs.
Rationale for change
To consolidate all circumstances for withdrawal in 
one section.
Based on recommendations of the FDA, specifics 
were added for circumstances where a patient will be 
allowed to stay on treatment after initial radiologic 
progression. It is also clarified that these patients 
must sign an additional informed consent in order to 
do so.
Section to be changed
4.1.3.1 Cohorts at dose levels <25 mg BI 891065 
daily
Description of change
Enrolment into the first cohort at 5 mg BI 891065 
daily will begin with 1 patient. If no drug-related 
AE ≥ Grade 2 (CTCAE Version 4.03) is observed 
for the single patient (observation period is 
3 weeks), a 15 mg daily single patient cohort will 
be initiated, unless the SRC recommends another 
dose for the second cohort. If no drug-related AE 
≥ Grade 2 (CTCAE Version 4.03) is observed for 
the single patient on 15 mg BI 891065 (observation 
period is 3 weeks), the 25-mg cohort will be 
initiated as described in Section 4.1.3.2, unless the 
SRC recommends another dose. Therefore, dose 
escalation to the second cohort will NOT be 


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restricted to a maximum of 100% from the 
previous dose as in cohorts that follow the 15 mg 
cohort.
If drug-related AEs ≥ Grade 2 are observed in the 
above described single-patient cohorts (5 and 
15 mg), the cohort and subsequent cohorts will be 
expanded to at least 3 patients.
The SRC will meet at the end of each of these 
treatment cohorts to decide on the next dose level 
based on available safety data.
Rationale for change
Based on recommendations of the FDA, the starting 
dose of BI 891065 has been set at 5 mg. Because of 
the lowering of the original planned starting dose, the 
dose escalation plan has been adjusted for cohorts 
using doses <25 mg BI 891065.
Section to be changed
4.1.3.2 Cohorts at dose levels ≥25 mg BI 891065 
daily
Description of change
The dose of BI 891065 is planned to be escalated in 
the Part A cohorts ≥25 mg daily at pre-defined 
provisional dose levels based on a maximum 
escalation of 100%. The provisional dose levels 
≥25 mg daily to be assigned to separate cohorts of 
patients are listed in Table 4.1.3: 1. Intermediate or 
lower dose levels, depending on the number of DLTs 
observed in the trial may be investigated as long as 
they fulfil the EWOC criterion if agreed upon by the 
SRC.
Table 4.1.3: 1 was updated by the addition of the
5 mg and 15 mg dose levels as Doses 1 and 2.  The 
rest of the table items were subsequently shifted.
At the end of each treatment cohort, BI will convene 
a meeting with the SRC members. At the dose 
escalation meeting the clinical course (safety 
information including both DLTs and all Common 
Terminology Criteria for Adverse Events [CTCAE; 
R18-1357] ≥ Grade 2 toxicity data during the MTD 
evaluation period and additional data if needed) for 
each patient in the current dose cohort will be 
described in detail. Updated safety data on other 


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ongoing patients, including data in later cycles, as 
well as cIAP degradation in PBMCs (for dose 
cohorts above 25 mg BI 891065), will be discussed 
as well. Based on that, a decision on the next dose 
level to be tested will be made.
For Part B (combination therapy), the dose of BI 
891065 is planned to be escalated in cohorts at dose 
levels which will be determined based on the results 
of Part A. However, the starting dose of BI 891065 in 
Part B will be maximally 75% of the highest tolerated 
dose from Part A. It is planned thatThe a fixed dose 
of 240 mg BI 754091 will be used as determined in
tTrial 1381.1 (the dose chosen for the expansion 
cohortsand possibly Trial 1381.2). Based on 
emerging safety information in the 1381.1 and 1381.2 
studies, the SRC may amend the dose of BI 754091 
used in this trial. The SRC will determine the selected 
dose of BI 754091 for each combination cohort of 
this trial and communicate it to the investigators.
The dose of BI 891065 in combination with 
BI 754091 to be used in Part C will be determined 
based on the safety and PK/PDc data of Parts A and 
B including data of target engagement in tumour 
tissue. The fixed dose of BI 754091 will be used as 
determined in trial 1381.1 (and possibly trial 1381.2).
The dose of BI 891065 might be changed during 
conduct of Part C, if needed. In Part C Cohort 2 
(MM), the dose of BI 891065 will be assessed by the 
SRC and confirmed after the number of patients 
specified in the SRC documentation have been 
treated for at least one cycle.
Rationale for change
Based on recommendations of the FDA, the starting 
dose of BI 891065 has been set at 5 mg. Because of 
the lowering of the original planned starting dose, the 
dose escalation plan has been adjusted for cohorts 
using doses <25 mg BI 891065.
Section to be changed
4.1.5.1 Administration of BI 891065
Description of change
[…] Patients need to be advisedinstructed to return 
any unused BI 891065 in the dispensed bottles, in 
addition to returning any empty bottles.


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All patients will be required to complete a Dosing 
Diary, which must be returned to the clinic for review 
at each clinic visit. The fasting status and all meals 
on the PK days should be recorded in the patient 
diary.
Refer to flowcharts and Appendix 10.3 for 
information about sampling that is required prior 
to dose administration.
BI 891065 doses should be taken orally at 
approximately the same time each morning with the 
exception of certain trial visit days. For clinic visits 
on PK days following a single dose of BI 891065 
(prior to Part A Cycle 1 Day 1) and for the food 
effect assessment in Part B (see the flow charts and 
tables in Section ), patients2 where study drug is not 
taken. 
Patients will be asked to fast overnight (minimum of 
10 hours) prior to the following intensive PK days: 
Part A: Cycle 1 Day 1, 15 
Part B: Cycle 1 Day 1,15, 16
Refer to Section 10.3visit. Pre-dose laboratory 
samples will be collected prior to receiving the single 
morning dose. for details.
When BI 891065 and BI 754091 are to be 
administered on the same day, BI 891065 will be 
administered approximately 30 minutes following the 
end of infusion of BI 754091, based on the safety 
assessments made by the Investigator.
Whenever possible, all doses of BI 891065 should be 
taken with water, limited to a maximum of 240 mL 
(approximately 8 US ounces). The fasting status and 
all meals on the PK days should be recorded in the 
patient diary. Additional information about the food-
interaction assessments in Part B are presented in 
Section 6.2.2.1.
For clinic visits on non-PK days, patients will be 
asked to fast overnight (minimum of 10 hours) prior 
to the visit. Pre-dose laboratory samples will be 
collected prior to receiving the single morning dose. 
The fasting status on non-PK days should be recorded 
in the patient diary.


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Missed doses should not be made up if more than 6 
hours have passed since scheduled dosing time. 
Missed doses must be recorded in the patient’s 
Dosing Diary, and then should be recorded in the 
eCRF.
Rationale for change
Increased detail on fasting requirements and timing in 
relation to PK sampling to add clarity.
Section to be changed
4.1.7 Dose reductions and dose delays
Description of change
If the treatment pause is ≤126 weeks, the patient can 
be re-exposed to BI 891065 at one dose level lower 
than the dose administered before the pause (except 
for the 5 mg monotherapy dose) and the same fixed 
dose of BI 754091 (applicable for Part A 
monotherapy and Part B combination therapy) as 
long as the re-exposure is considered clinically 
indicated by the Investigator.
Figure 4.1.7: 1 was updated to reflect the new timing.
BI 891065 and BI 754091 should be permanently 
discontinued together for Grade 3 to 4 pneumonitis, 
Grade 3 to 4 adrenal insufficiency, Grade 4 diabetes 
mellitus, any grade encephalitis, Grade 4 
hypophysitis, Grade 4 rash, Grade 3 to 4 colitis or 
recurrent colitis of any grade, any recurrent 
Grade 3 to 4 AE, transaminase increases >5 times 
ULN or total bilirubin >3 times ULN, inability to 
taper steroids to 10 mg or less prednisone or 
equivalent within 12 weeks, or persistent Grade 2 to 3 
AEs that do not recover to Grade 1 or less within 12 
weeks. BI 754091 and BI 891065 should be 
permanently discontinued together for Grade 3 to 4 
AEs that are classified as immune-related by the 
Investigator that are not listed in Appendix .Please 
see Appendix for guidelines for management of 
immune-related adverse events.
[…]
Criteria leading to permanent discontinuation of 
BI 891065 and BI 754091 are presented in 
Section 3.3.4.1.
Section 4.1.7.1 Permanent discontinuation of 


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BI 891065 and BI 754091 was removed and included 
in Section 3.3.4.1.
Rationale for change
!" #$%&'() 
*+,%'$- "( &+.+/0"-1&+ ," 23 456789 
("$$":';< % 0%1-+ "( =6> :++?-@
!A+ 0%&%<&%0A *+-#&'B';< 0+&C%;+;, *'-#";,';1%,'"; 
"( ,A+ -,1*) ,&+%,C+;,- :%- C"D+* ," E+#,'"; F@F@G@6 
-" ,A%, %$$ 
*'-#";,';1%,'"; 
#&',+&'% 
:"1$* B+ '; ,A+ 
-%C+ -+#,'";@
Section to be changed
G@6@67 H+(';','"; "(+D%$1%B$+ 
0%,'+;,
Description of change
Please refer to Section 7.2.
Patients that are evaluable for MTD are those who 
do not fulfil criteria for replacement as outlined in 
Section 3.3.4.4.
Rationale for change
!" %** ,A+ *+(';','"; 
&%,A+& 
,A%; ";$) 0&+-+;,';<% 
$';?@
Section to be changed
G@>@>@> I+-,&'#,'";- "; *'+, %;* $'(+ -,)$+
Description of change
[…] The usual restrictions on diet and life style that 
were already applicable for a given patient before 
entry into the trial, according to his/her medical 
condition, have to be continued, if feasible with the 
following caveats:

Fasting requirements on PK days are 
described in Section 4.1.5.1

Part B patients will be asked to eat a specific 
meal per Section 6.2.2.1.
Rationale for change
A link was added to the fasting requirements and 
details around the fed portion of the food interaction 
assessment.
Section to be changed
G@F 
!&+%,C+;, #"C0$'%;#+
Description of change
The investigational products should only be used as 
directed in this protocol. For BI 754091 
administration days, BI 891065 will be 
administered orally approximately 30 minutes after 
the end of the infusion of BI 754091, and only if 
considered safe by the Investigator.
Rationale for change
JA%;<+* ," %** #$%&',)@


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Section to be changed
9@6K--+--C+;, "( +(('#%#)
Description of change
Copies of scans maywill be collected by the Sponsor 
upon request.
Rationale for change
!" +C0A%-'L+ ,A%, ,A+ E0";-"& :'$$ #"$$+#, #"0'+- "( 
+(('#%#) %--+--C+;, -#%;-@
Section to be changed
5.1.1 NSCLC tumour assessment and solid tumour 
assessment
Description of change
[…]
If the patient stops with the trial medication for 
another reason other than progression, the tumour 
assessment according to RECIST v1.1 and iRECIST 
will be performed according to standard of care until 
the last follow-up needed according to the protocol 
(progression, death, lost to follow-up, end of the 
trial). Patients will be allowed to stay on treatment 
in the case of initial radiological PD, if the 
Investigator feels that it is in the patient’s best 
interest, the patient signs an informed consent 
form specific for this circumstance, and the 
criteria listed in Section 3.3.4.1 are met.
Rationale for change
Based on recommendations of the FDA, specifics are 
added for circumstances where a patient will be 
allowed to stay on treatment after initial radiologic 
progression.  It is also clarified that these patients 
must sign an additional informed consent in order to 
do so.
Section to be changed
5.2.3 Safety laboratory parameters
Description of change
Biochemistry
The standard biochemistry panel will consist of 
glucose, sodium, potassium, chloride, calcium, 
phosphate, venous bicarbonate HCO3, urea, 
creatinine, AST, ALT, alkaline phosphatase, lactate 
dehydrogenase, bilirubin (direct and indirect bilirubin 
in case of elevated total bilirubin values), total 
protein, albumin, urea nitrogen, uric acid and 
creatinine kinase (CK; if). If CK is elevated, then 
CK-MB [cardiac], Troponin I, and myoglobin should 
be reactively tested).
C-peptide , serum cholesterol, serum triglycerides 


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will be done at baseline only.
Rationale for change
To clarify C-peptide, cholesterol, and triglycerides 
testing.
Description of change
Virology
At screening, tests according to local standards for 
HIV infection (PCR) and hepatitis B (HBs-Ag, and if 
positive, anti-HBs, anti-HBc antibodies, and HBV 
DNA) and hepatitis C (PCR) should not be older than 
28 days.
Rationale for change
To clarify that virology testing should be according to 
local standards, and therefore specific types of testing 
are not mandated.
Section to be changed
5.2.4 Electrocardiograms
Description of change
Electrocardiogram machines will be provided for 
Part A to facilitate central readings. Before study 
start, the study sites will be trained for the proper use 
of the equipment and transfer of the electronic data to 
the vendor. While all ECGs will be transmitted to the 
central vendor, only the baseline, 6-hour, 8-hour, and 
24-hour readings will be reviewed directly. The other 
readings wouldwill be analyzed only ifafter the PK 
analysis points to a tmax deviate from the predicted 
tmax.
Rationale for change
To clarify when additional ECG reading time points 
might be read by the central vendor.
Section to be changed
5.2.6.3 Adverse events considered “Always Serious”
Description of change
[…]
The latest list of “Always Serious AEs” can be found 
in the Study Reference Manualelectronic document 
system. These events should always be reported as 
SAEs as described above.
Rationale for change
Clarification that the latest list of “Always Serious 
AEs” will be located in the Study Reference Manual.
Section to be changed
5.2.6.4.3 Cytokine release syndrome


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Description of change

[…] In the case of a CRS CTCAE Version 4.03 
Grade 2, the intake of BI 891065 and infusion of 
BI 754091 should be temporarily interrupted. 
BI 891065 maybe resumed as soon as symptoms 
of CRS have completely resolved to baseline for 
at least 48 hours.
In case less than 50% of a BI 754091 dose was 
administered due to CRS, a dose of 50% of the 
intended dose may be administered on the day 
when BI 891065 is re-started to ensure the 
patient receives an adequate dose of BI 754091. 
Please see Section 3.3.4.4 regarding replacement 
of patients.
Rationale for change
To clarify the intention of the 50% dose of BI 754091 
when BI 891065 is being restarted.
Section to be changed
5.3.2 Methods of sample collection
Description of change
[…]
Pharmacokinetic sampling times and periods may 
be adapted by the Sponsor during the trial based 
on information obtained during trial conduct (e.g., 
preliminary PK data). Such changes would be 
implemented via non-substantial Clinical Trial 
Protocol Amendments.
[…]
Rationale for change
To clarify that PK sampling times may be changed 
based on new data.
Section to be changed
6.1 Visit schedule
Description of change
Additional PD follow-up visits after the 30-day safety 
follow-up visit will only be performed for patients 
who did not progress on treatment (see Section 
6.2.3.3) with the exception of those who may 
continue treatment for a time after initial 
radiologic progression.
Rationale for change
To clarify that patients will be allowed to continue 
treatment following the first radiologic progression if 
deemed appropriate by the Investigator


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Section to be changed
6.2.2 Treatment period
Description of change
Patients will remain on treatment as long as, in the 
opinion of the Investigator, they are deriving benefit 
and the criteria listed in Section 3.3.4.1 are not 
met. Please refer to the respective flow charts for 
detailed presentations of each visit during the 
treatment period for each part of the trial.
Rationale for change
To provide a link for the reviewer to new criteria 
specified in Section 3.3.4.1 explaining the criteria for 
patients to continue on treatment after the initial 
radiologic progression.
Section to be changed
6.2.2.1 Food-interaction assessment
Description of change
At all dose levels in Part B, an explorative food effect 
will be assessed. Consecutive patientsPatients will be 
assignedfast for at least 10 hours prior to a fixed 
sequence of a fasted treatment followed by a fed 
treatment the next day. For the fasted condition 
(Cycle 1 Day 15), patients willthen receive BI 
891065 after an overnight fast of at least 10 hours, 
together with approximately 240 mL water. Patients 
will remain fasted until at least 2 hours after drug 
intake. Water will be allowed except 30 minutes 
before and 1 hour after administration of BI 891065.
The fed condition Patients will occur on Day 16; 
after an overnight fast offor at least 10 hours and 
followingprior to Cycle 1 Day 16. At this visit, 
within 30 minutes of planned BI 891065 dose 
administration time, patients will be given a 
standard continental breakfast (see below) which 
they should consume within the 30 minutes prior 
to drug administration. Then patients will receive 
BI 891065together with approximately 240 mL 
water within 5 minutes of consuming the standard 
meal. Patients should start and consume the breakfast 
within the 30 minutes prior to administration of 
BI 891065. If the patients are not able to eat or eat 
almost nothing, the information should be recorded 
on the eCRF.
The following definition of the standard continental 
breakfast is given in order to standardise the food 


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intake prior to assessing food effects on BI 891065 
(rough approximation): 2 bread rolls, 20 g butter, 
25 g cheese, 25 g ham, 25 g jam, and 1 cup (~250 
mL) of decaffeinated tea or coffee (average energy 
value per breakfast: ~688 kcal or 2880 kJ. Note: 
Alternative food components/quantity can be 
proposed by the Investigator, but it should be 
ensured that the caloric breakdown of the test 
meal is roughly in line with the breakfast indicated 
above.
Rationale for change
Additional details are added for the sites to increase 
compliance with the food interaction assessment part 
of the study.
Section to be changed
7.1 Statistical design model
7.1.1 Part A
Description of change
The BLRM recommended dose for the next dose 
level is the level with the highest posterior probability 
of the DLT rate falling in the target interval [0.16, 
0.33) among the doses fulfilling EWOC. Applying 
the EWOC criterion it should be unlikely (<25% 
posterior probability) that the DLT rate at that dose 
will be ≥0.33. HoweverIn addition, for dose levels 
≥25 mg BI 891065, the maximum allowable dose 
increment for the subsequent cohort will be no more 
that 100% from cohort to cohort.
[…]
A summary of the prior distribution is provided in 
Table 7.1.1: 1. Additionally, the prior probabilities of 
DLTs at different doses, as well as the corresponding 
probability of under-, targeted and overdosing, are 
shown in Table 7.1.1:2. Graphically, the prior 
medians with accompanying 95% credible intervals 
are shown in Figure 7.1.1:1. As can be seen from 
both, the table and the figure, the prior medians of the 
DLT probabilities are in-line with the prior medians 
derived from the weakly informative prior, and the 
uncertainty around the medians is large, showing the 
low amount of information this prior provides. This is 
also supported by the prior sample size, i.e., the 
information contained in the prior. This is 
approximately equal to 1.8 patients. Furthermore, it 
can be seen that the overdose prior probability of 


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the starting dose of 5 mg is 0.029 and therefore 
well below the EWOC boundary of 0.25. A detailed 
evaluation of the model using hypothetical data 
scenarios and operating characteristics is provided in 
the statistical appendix (see Appendix 10.5).
In the following paragraphs of this section, it was 
clarified that the starting dose was no longer 25 mg.
Table 7.1.1: 2 and Figure 7.1.1:1 were updated to add 
the 5 mg and 15 mg doses as dose levels 1 and 2.
Rationale for change
To clarify that there will be new dose levels at 5 and 
15 mg and that the BLRM will be initiated for doses 
≥25 mg BI 891065.
Section to be changed
7.7 DETERMINATION OF SAMPLE SIZE
Description of change
Part A:
No formal statistical power calculations to determine 
sample size were performed for this trial part. 
Approximately 30 patients (including patients at the 
MTD) are expected to be enrolled into Part A of this 
trial based on the number of dose levels/cohorts that 
are tested. Fewer patients might be needed based on 
the recommendation of the SRC and the criteria 
specified (see Section 8.7). However, the actual 
number of patients will depend on the number of dose 
cohorts tested. Based on the simulation study to 
evaluate operating characteristics of the BLRM (see 
statistical appendix), at least 20 evaluable patients
(where evaluable patients refer to patients not 
fulfilling the criteria for replacement 
[Section 3.3.4.4]) are expected to be treated in the 
dose escalation part for the model to have reasonable 
operating characteristics relating to its MTD 
recommendation.
Part C
[…]
With only 20 evaluable patients (at least one post-
baseline response assessment is available), the 
probability of observing 7 ORs assuming a true 
underlying response rate of 30% is only 39%.


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Rationale for change
Descriptions of evaluable patients are moved forward 
in the protocol for this section and for Section 7.7, 
and the differences in definitions are highlighted 
between Parts A and C.
Section to be changed
8.1 TRIAL APPROVAL, PATIENT 
INFORMATION, INFORMED CONSENT
Description of change
[…]
Following the initial radiologic progression, 
patients may be allowed to continue on treatment 
if, in the opinion of the Investigator, they are 
experiencing clinical benefit. In this case, an 
additional informed consent form specific for this 
circumstance will be signed by the patient prior to 
treatment continuation.
Rationale for change
Based on recommendations of the FDA, it is clarified 
that patients staying on treatment after initial 
radiologic progression must sign an additional 
informed consent in order to do so.
Section to be changed
References
Description of change
Reference to the BI 891065 Investigator’s Brochure 
was updated to Edition 3.
All references used in the multiple myeloma sections 
were removed.
Rationale for change
The BI 891065 Investigator’s Brochure has been 
updated.
The multiple myeloma cohort has been removed from 
the protocol.
Section to be changed
Table 10.3: 1
Description of change
Footnote c A spot urine sample (x) is to be obtained 
prior to administration of trial medication. Other 
urine samples are to be collected over the post-
dose intervals indicated between the arrows (◄––
│––│––►) 0-4, 4-8, 8-12, 12-24 (Cycle 1 Days 1 
and 15) and 24-48 h (Cycle 1 Day 1 only) and 
detailed in Section 5.3.2.4.


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Rationale for change
The table was updated by adding Footnote c and by 
making it clear that the pre-dose sampling is a spot 
urine sample and not a pool.
Description of change
It was confirmed that overnight fasting is required 
before the first PK sampling on Day 15.
Rationale for change
Correction: the footnote was mistakenly not added to 
the table.
Section to be changed
10.5 Statistical Appendix
Description of change
This appendix has been updated to include the 2 new 
doses <25 mg.
Rationale for change
Based on recommendations of the FDA, the starting 
dose of BI 891065 has been set at 5 mg. Because of 
the lowering of the original planned starting dose, the 
dose escalation plan has been adjusted for cohorts 
using doses <25 mg BI 891065.


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Number of global amendment
2
Date of CTP revision
27 February 2018
EudraCT number
2017-000465-74
BI Trial number
1379.1
BI Investigational Products
BI 891065 and BI 754091
Title of protocol
An open-label Phase I dose finding trial with 
BI 891065 alone and in combination with BI 
754091 to characterise safety, tolerability, 
pharmacokinetics, pharmacodynamics, and efficacy 
in patients with advanced and/or metastatic 
malignancies
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of 
sections with changes are presented. Please note that formatting changes and minor changes 
to punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be changed
All flow charts Footnote c
Description of change
[…]clinical chemistry (sodium, potassium, 
phosphate, chloride, creatinine, calcium, venous 
bicarbonate HCO3, albumin, total protein, aspartate 
aminotransferase [AST], alanine aminotransferase 
[ALT], alkaline phosphatase, bilirubin, lactate 
dehydrogenase, serum glucose, c-peptide [baseline 
only], serum cholesterol [baseline only], serum 
triglycerides [baseline only], creatinine kinase [CK: 


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if CK is elevated, then CK-MB, Troponin I, and 
myoglobin should be reactively tested, with further 
follow-up as clinically warranted], serum urea 
nitrogen, serum uric acid, and thyroid panel [TSH, 
free T4, and free T3]), […]
Rationale for change
It has been determined that these tests are not 
needed.
Section to be changed
Part A flow chart Footnote c
Description of change
[…] and single/triplicate ECGs required prior to 
first trial doseas outlined in Section 5.2.4 and 
Table 10.3: 1.[…]
Rationale for change
To clarify that single or triplicate ECGs are taken in 
relation to specific PK sampling times as presented
in the Section 10 tables.
Section to be changed
Part A flow chart Footnote e
Description of change
Triplicate or single 12-lead electrocardiograms 
(ECGs) will be done at the time points as outlined 
in Section 5.2.4 and Table 10.3: 1in triplicate 
before blood work or other procedures after 10 
minutes of rest at screening, during Cycle 1 on 
Days 1, 2, 15, and 16 at every PK sampling point, 
and pre-treatment on Cycle 2 Day 1, Cycle 3 Day 1, 
and Day 1 of every third cycle thereafter (Cycles 6, 
9, 12, etc.), at the EOT visit, and whenever […]
Rationale for change
To clarify that not all ECGs taken in Part A will be 
triplicate ECGs.  Triplicate ECGs are taken in 
relation to specifc PK sampling times as defined in 
the Section 10 tables.
Section to be changed
Part A flow chart Footnotes h and p
Description of change
Tumour assessments should be done according to 
RECIST v1.1 and iRECIST […]
Rationale for change
To clarify that there are iRECIST parameters in Part 
A in addition to Parts B and C.
Section to be changed
Part B flow chart Footnote c
Description of change
[…] and single/triplicate ECGs as outlined in 
Section  5.2.4 and Table 10.3: 2 required prior to 


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first administrations of trial treatments. […]
Rationale for change
To clarify that not all ECGs taken in Part B will be 
single ECGs.  Some triplicate ECGs are taken in 
relation to specific PK sampling times as defined in 
Section 5.2.4 and the Section 10 tables.
Section to be changed
Part B flow chart Footnote e
Description of change
Triplicate or Ssingle 12-lead electrocardiograms 
(ECGs) will be done at time points as outlined in 
Section 5.2.4 and Table 10.3: 2 before blood work 
or other procedures after 10 minutes of rest at 
screening, and pre-treatment during Cycle 1 on 
Days 1, 2, 15, and 16, single ECGs will be done 
during Cycle 2 on Day 1, during Cycle 3 on Day 1, 
and on Day 1 of every third cycle thereafter (Cycles 
6, 9, 12, etc.), at the EOT visit, and whenever the 
Investigator deems it necessary (see Section 5.2.4 
and Table 10.3: 2 Table 10.3.1). ECG machines 
will be provided for Part B to facilitate central 
readings. While all ECGs will be transmitted to 
the central vendor, only the baseline, 6-hour, 8-
hour, and 24-hour readings will be reviewed 
directly. The other readings will be analysed 
only after the PK analysis points to a tmax.
Rationale for change
To clarify that not all ECGs taken in Part B will be 
single ECGs. Some triplicate ECGs are taken in 
relation to specific PK sampling times as defined in 
the Section 10 tables.
Section to be changed
Part B flow chart Footnote l
Description of change
Blood samples for biomarkers - samples for the 
quantification of cytokines will be taken during 
Cycle 1 on Day 1 pre-treatment and at 5.5 and 9.5 
hours post treatment, on Day 2 (no treatment day) at 
24 hours after first drug intake on the previous day, 
pre-treatment on Day 8, and at the EOT visit (see 
Section 5.4.2 and Appendix 10.3).
Rationale for change
Correction


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Section to be changed
Section 1.3 Rationale for conducting the trial
Description of change
[…]
Parts A and B of the trial will be undertaken in 
patients with advanced/refractory solid tumours. 
Part A will determine the MTD and/or the 
recommended dose for Part B as well as 
investigate the safety, PK, and 
pharmacodynamics (PDc) of BI 891065 
monotherapy. Target engagement will be 
determined in peripheral blood (cIAP 
degradation in peripheral blood mononuclear 
cells [PBMCs]). Dose escalation in Part A will be 
guided by a BLRM with overdose control. The 
data obtained from the trial will determine the 
MTD estimate based on a BLRM employing an 
escalation with overdose control (EWOC) 
principle (R13-4803). The BLRM estimates the 
MTD by updating estimates of the probability of 
observing a DLT in the MTD evaluation period 
(first treatment cycle) for each dose level in the 
trial as patient information becomes available. 
At any time in the trial, it will not be permitted 
to escalate to a dose which does not fulfil the 
EWOC criterion (refer to Section 7).
In both Parts A and B, the Safety Review 
Committee (SRC) will recommend and decide on 
the size for the next dose escalation cohort. After 
all patients in a cohort in Part A and Part B have 
either experienced a DLT or have been observed 
for at least the MTD evaluation period without 
experiencing a DLT, the BLRM will be updated 
with the newly accumulated data.
Parts A and B will be undertaken in patients with 
advanced/refractory solid tumours to determine the 
MTD and/or the recommended dose for later 
development (Part C). Part C will be in the selected 
indication (NSCLC) in order to assess efficacy 
(objective response [OR]) and reconfirm safety and 
tolerability at the combination doses determined 
in Part B.
[…]
Rationale for change
Clarification of the BLRM estimates.


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Section to be changed
Section 1.4 Benefit Risk Assessment
Description of change
[…]
Since this is the first-in-human trial for BI 891065, 
patients in Part A will remain under surveillance for 
1012 hours after first administrations of BI 891065 
and for at least 8 hours after administration of the 
second and third administrations of BI 891065. For 
Parts B and C, patients will remain under 
surveillance for 1012 hours after the administration 
of BI 891065 in combination with BI 754091 in 
Cycles 1 and 2, and for at least 8 hours after the 
second and third administrations of BI 891065 in 
Cycle 1 (see Section 5.2.6.4.3). All trial sites will 
have emergency resuscitation services and access to 
intensive care available.
[…]
Rationale for change
Preliminary data supports the shortening of the 
length of required surveillance following the first 
administration of BI 891065 to make it easier for 
the patients.
Section to be changed
Section 2.1.2.1 Part A (Primary endpoints)
Description of change
[…]
For doses below 25 mg, single patient cohorts will 
be treated at 5 mg and 15 mg if not specified 
otherwise by the SRC. For doses above 25 mg, a A
BLRM employing the escalation with overdose 
control (EWOC) principle will be used during the 
escalation phase for selection of doses to investigate 
and for estimation of the MTD.
[…]
Rationale for change
Clarification of when the BLRM will be used in 
Part A.
Section to be changed
Section 2.1.2.3 Part C (NSCLC)
Description of change
[…]
Tumor imaging will be performed at baseline and 
then every 6 weeks for the first 6 months and then 
every 9 weeks thereafter as required by RECIST / 
iRECIST (R17-0923) until the earliest of PD, death 
or the last evaluable tumour assessment before start 
of subsequent anti-cancer therapy or until the end of 


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the trial as defined in Section 8.6.
Rationale for change
To clarify that the requirements of RECIST and 
iRECIST will be followed for continued tumour 
imaging.
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
[…]
In both Parts A and B, the SRC will recommend 
and decide on the size for the next dose escalation 
cohort. After all patients in a cohort in Part A and 
Part B have either experienced a DLT or have been 
observed for at least the MTD evaluation period 
without experiencing a DLT, the BLRM will be 
updated with the newly accumulated data. […]
For dose levels above 2515 mg, if DLTs are 
observed in the first two consecutive patients of a 
previously untested dose level, subsequent 
enrolment to that cohort will be stopped. The 
BLRM will be re-run to confirm that the dose level 
still fulfils the EWOC principle. Based on this 
information, the SRC will evaluate whether the next 
patients will be enrolled at the same dose level, or if 
they will be enrolled at a lower dose level.
Rationale for change
To clarify that the BRLM will be run for both Parts 
A and B, and for all dose levels above 15 mg.


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Section to be changed
Section 4.1.3.1 Cohorts at dose levels <25 mg 
BI 891065 daily
Description of change
Enrolment into the first cohort at 5 mg BI 891065 
daily will begin with 1 patient. If no drug-related 
AE ≥ Grade 2 (CTCAE Version 4.03) and no DLT
is observed for the single patient (observation 
period is 3 weeks), a 15 mg daily single patient 
cohort will be initiated, unless the SRC 
recommends another dose or another cohort size 
for the second cohort. If no drug-related AE ≥ 
Grade 2 (CTCAE Version 4.03) and no DLT is 
observed for the single patient on 15 mg BI 891065 
(observation period is 3 weeks), the 25-mg cohort 
will be initiated as described in Section 4.1.3.2, 
unless the SRC recommends another dose.
[…]
The SRC will meet at the end of each of these 
treatment cohorts to decide on the next dose level 
based on available safety data and the BLRM 
recommendation.
Rationale for change
To clarify the method of dose escalation in Part A 
and to clarify that a BLRM will be used in Part A.
Section to be changed
Table 4.1.3: 1 Provisional dose levels for dose 
escalation of BI 891065 in Part A
Description of change
Increase of Dose Level 2 over Dose Level 1 is 
corrected to 300%.
Rationale for change
Correction
Section to be changed
Section 4.1.5.1 Administration of BI 891065
Description of change
[…]
Patients will be asked to fast overnight (minimum 
of 10 hours) prior to the following intensive PK 
days:
Part A: Cycle 1 Day 1, 15
Part B: Cycle 1 Day 1, 15, 16
Rationale for change
Correction
Section to be changed
Section 4.1.8 Definition of dose-limiting toxicity
Description of change
Dose-limiting toxicities (DLTs) will be recorded 


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throughout the trial. Any DLT must be reported to 
the 
 Medical Monitor by the 
Investigator or designee within 24 hours of first 
knowledge, and to the 
 
as an SAE when appropriate. All 
DLTs will be agreed upon between the Sponsor, the 
Study Chair, the 
 Medical Monitor, 
and the Investigators after review of the data from 
each cohort. […]
[…]
Severity of AEs will be graded according to 
CTCAE Version 4.03. Any of the following AEs
that are not equivocally due to underlying 
malignancy or an extraneous cause will be 
classified as DLTs following review by the 
Investigators and the 
Medical 
Monitor unless unequivocally due to underlying 
malignancy or an extraneous cause.
[…]
Rationale for change
To clarify which Medical Monitor should be 
notified. In addition, the sentence was rewritten for 
better clarity.
Section to be changed
Section 4.2.2.1 Restrictions regarding concomitant
treatments
Description of change
[…]
BI 891065 was found to be an inhibitor of 
various CYP450 enzymes in vitro, with Ki values 
in the range of 0.84 to 12 μM (see Section 1.2.1). 
A drug-drug interaction with other medications 
metabolized by these enzymes cannot be 
excluded. Caution should be exercised when 
combining BI 891065 with substrate drugs of 
CYP450 enzymes (1A2, 2C8, 2C9, 2C19, 2D6, 
3A4). Table 4.2.2.1: 1 provides a list of restricted 
and permitted medications. Alternatives with 
less potential for CYP450 based interactions 
should be considered, where available. Close 
monitoring for potential adverse reactions is 
warranted and patients should be informed 
about potential signs and symptoms of such 
adverse reactions (e.g., muscle pain). BI 891065 
was also found to be an inhibitor of the drug 
transporters P-glycoprotein and BCRP in vitro, 
with IC50 values of 0.034 uM and 0.18-0.59 μM, 


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respectively (see Section 1.2.1). Caution should 
be exercised when combining BI 891065 with P-
gp and BCRP substrates. Table 4.2.2.1: 1
provides a list of restricted and permitted 
medications.
Table 4.2.2.1: 1 was added.
BI 891065 is an in vitro inhibitor of various 
CYP450 enzymes, with Ki values in the range of 
0.84 to 12 μM (see Section 1.2.1). A drug-drug 
interaction with other medications metabolized by 
these enzymes cannot be excluded. Caution should 
be exercised when combining BI 891065 with 
substrate drugs of CYP450 enzymes. In particular, 
concomitant administration of BI 891065 and drugs 
metabolized by CYP3A4, e.g., HMG CoA-
reductase inhibitors (such as lovastatin, simvastatin, 
and atorvastatin) or calcium antagonists (such as 
nisoldipine, less for verapamil or nifedipine), could 
result in increased exposure of the concomitant 
drug, depending on the currently yet 
uncharacterized bioavailability of BI 891065. 
Concomitant treatment with such drugs while the 
patient is receiving BI 891065 should occur only if 
strictly indicated, and with judicious dosing. 
Alternatives with less potential for CYP450 based 
interactions should be considered, where available. 
Close monitoring for potential adverse reactions is 
warranted, and patients should be informed about 
potential signs and symptoms of such adverse 
reactions (e.g., muscle pain).
*The following caveat applies for concomitant 
medications immunosuppressive medications are 
prohibited:

Immunosuppressive medications including, but 
not limited to systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
TNFα blockers are prohibited. Use of 
immunosuppressive medications for the 
management of investigational product-related 
AEs or in patients with contrast allergies is 
acceptable, and does not necessarily warrant 
immediate treatment discontinuation. In 
addition, use of inhaled, topical, intranasal 


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corticosteroids or local steroid injections (e.g., 
intra-articular injection) is permitted. 
Temporary uses of corticosteroids for 
concurrent illnesses (e.g., food allergies, 
computed tomography [CT] scan contrast 
hypersensitivity) are acceptable upon discussion 
with the 
 Medical Monitor. For 
the treatment of CRS, supportive therapy 
including steroids and / or interleukin 6 receptor 
(IL6R) antagonists (R15-0031) may be used as 
clinically indicated.

Live attenuated vaccines are prohibited during 
the trial through 30 days after the last dose of 
investigational product.

Herbal preparations/medications are not allowed 
throughout the trial. These herbal medications 
include, but are not limited to: St. John’s wort, 
kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng. Patients should stop 
using these herbal medications 7 days prior to 
first dose of study treatment.
Rationale for change
In response to comments from the FDA, further 
restrictions were applied for concomitant 
medications.  In addition, clarification of which 
Medical Monitor to contact was added.


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Section to be changed
Section 5.1.1 NSCLC tumour assessment and solid 
tumour assessment
Description of change
Tumour response will be evaluated at the site 
according to RECIST Version 1.1 (R09-0262) 
and/or iRECIST (R17-0923 and Appendix 10.6)
(relevant during combination therapy). 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). Duplicates of the images will 
be collected and stored by a BI-appointed 
representative, and may be usedcould be sent for 
future independent central RECIST/iRECIST
review, if deemed appropriate. In addition, the 
images may be used for further future 
investigations (e.g., Radiomics).
[…]
Rationale for change
To clarify that iRECIST applies to Part A in 
addition to Parts B and C, and to introduce that 
images collected may be used in future Radiomics 
investigations.
Section to be changed
Section 5.2.3 Safety laboratory parameters
Description of change
Biochemistry
[…]
C-peptide , serum cholesterol, serum triglycerides 
will be done at baseline only.
[…]
Rationale for change
The Medical Monitors and Investigators have 
determined that these tests are not needed.
Section to be changed
Section 5.2.4 Electrocardiograms
Description of change
Standard 12-lead (I, II, III, aVR, aVL, aVF, V1 -
V6) resting electrocardiograms (ECGs) will be 
digitally recorded in triplicate (3 single ECGs 
within a maximum period of 5 minutes) and 
performed for each patient at various time points 
throughout the trial. during Part A of the trial 
according to The Part A Flow Chart and the Part 
B Flow Chart and Appendix 10.3 outline which 
visits will require ECGs, and Appendix 10.3 
outlines which time points (during Parts A and 


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B) require triplicate ECGs to be done along with 
certain PK samples. This will include triplicate 
readings during Part A at every PK sampling time 
point during Cycle 1 on Days 1, 2, 15, and 16.
[…]
Electrocardiogram machines will be provided for 
Parts A and B to facilitate central readings.[…]
ECGs may be repeated for quality reasons and the 
repeated recording used for analysis. If necessary, 
additional ECGs may be recorded for safety 
reasons. In Parts B and C, single ECGs will 
typically be taken unless additional readings are 
indicated.
The ECG recordings must also be analysed and 
checked for abnormality by the Investigator (or 
designated physician) who will also calculate the 
QTcF value for each time point as the mean of the 3 
ECGs.  Particular attention must be paid to T 
wave inversions. It is not mandatory to wait for 
central evaluation of ECGs to make clinical 
decisions. Clinically relevant abnormal findings 
will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as 
adverse events and will be followed up and/or 
treated as medically appropriate. CTCAE Version 
4.03 will be used for the grading of prolonged 
QTcF intervals.
During the BI 891065 monotherapy dose escalation, 
ECGs will be done at screening, specified visits and 
at EOT.
[…]
In Parts B and C, single 12-lead ECGs will be done 
as outlined in the flow charts and will be assessed 
by the sites locally; particular attention must be paid 
to T wave inversions. Clinically relevant abnormal 
findings will be reported either as baseline 
condition (if identified at the screening visit) or 
otherwise as AEs and will be followed up and/or 
treated as medically appropriate.
Rationale for change
To clarify that not all ECGs taken in Part A will be 
triplicate ECGs.  Triplicate ECGs are taken in 
relation to PK sampling as defined in the Section 10 
tables, while single ECGs are taken for safety 


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reasons on non-PK days.
Section to be changed
Section 5.2.6.4.3 Cytokine release syndrome
Description of change
[…]
For Part A:

Patients will remain under surveillance for 
1012 hours after first administration of 
BI 891065 
[…]
For Parts B and C:

Patients will remain under surveillance for 
1012 hours after the administration of 
BI 891065 
 in combination 
with BI 754091 
 during Cycles 1 and 
2.
[…]
Rationale for change
Preliminary data supports the shortening of the 
length of required surveillance following the first 
administration of BI 891065 to make it easier for 
the patients.
Section to be changed
Section 5.3.2.4 Urine sampling and analysis for 
pharmacokinetics of BI 891065 (Part A only)
Description of change
[…]
Cycle 1 Day 1:

Spot urine pre-dose

Pool 0 to 34 hours

Pool 34 to 8 hours

Pool 8 to 1210 hours

Pool 1210 to 24 hours

Pool 24 to 48 hours
Cycle 1 Day 15

Spot urine pre-dose

Pool 0 to 34 hours

Pool 34 to 8 hours

Pool 8 to 1210 hours

Pool 1210 to 24 hours
[…]
Rationale for change
To shorten the length of the PK testing days to 
make it easier for the patients.


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Section to be changed
Description of change
Rationale for change
Section to be changed
Section 5.4 Assessment of biomarkers
Description of change
[…]
As medical knowledge in this field is constantly 
evolving, other tissue/blood biomarkers that may 
become relevant as predictive markers of treatment 
response (e.g., 4β-OH cholesterol) may also be 
explored via available tissues/blood or acquisition 
of additional tumour tissues/blood. […]
Rationale for change
To clarify that 4β-OH cholesterol may likely be 
explored in the future.
Section to be changed
Section 8.7 Administrative structure of the trial
Description of change
[…]
A Safety Review Committee (SRC) will be 
established. Members of the SRC will include:

 
Medical Monitor for the trial, or delegate
[…]
The BI Safety Physician (or delegate) and the BI 
Clinical Program Leader (or delegate) should 
always attend the SRC to discuss safety issues.
Rationale for change
To clarify attendance at the SRC meetings.
Section to be changed
Tables 10.3: 1 and 10.3: 2
Description of change
Each of these tables was edited to add a separate 
column for ECGs clearly showing which ECGs are 
to be done in triplicate.
Note to Footnote b was edited to:
Time windows have been specified for procedural 
reasons; deviations do not automatically lead to 
exclusion of samples from data evaluation. The 
new PK and urine schedule will be implemented 
upon availability of updated lab kits.


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Footnote c (urine collections was edited to reflect 
the new timings as presented in the table and 
Section 5.3.2.4.
The ECG footnote was edited to add:
In order not to confuse an ECG recording, PK 
samples should be taken after performing the 
ECG.
Rationale for changes
To clarify that not all ECGs taken in Parts A and B 
will be triplicate ECGs.  Triplicate ECGs are taken 
in relation to specific PK sampling times.
Urine sampling has been changed to coincide with 
PK blood sampling. 
To clarify for the sites when PK samples should be 
taken in relation to ECGs.


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Number of global amendment
3
Date of CTP revision
12 November 2018
EudraCT number
2017-000465-74
BI Trial number
1379.1
BI Investigational Products
BI 891065 and BI 754091
Title of protocol
An open-label Phase I dose finding trial with 
BI 891065 alone and in combination with BI 
754091 to characterise safety, tolerability, 
pharmacokinetics, pharmacodynamics, and 
efficacy in patients with advanced and/or 
metastatic malignancies
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of 
sections with changes are presented. Please note that formatting changes and minor changes 
to punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be changed
Section 3.1 Overall trial design and plan
Description of change
Patients with select advanced/refractory solid 
tumours  without established treatment options will 
be entered in order to determine the MTD and/or 
recommended dose for the expansion cohort in Part 
C of BI 891065 in combination with BI 754091, to 
assess safety and tolerability, and to explore 
PK/PDc.
Rationale for change
Amended to restricted eligibility for Part B


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Section to be changed
Figure 3.1: 1 Design of trial 1379.1 including 2 
dose-escalation parts and 1 expansion cohort
Description of change
Part B: solid select tumours
Rationale for change
Amended to restricted eligibility for Part B
Section to be changed
Section 3.3.1 Main diagnosis for trial entry 
Description of change
Part A and B: Patients with a confirmed diagnosis 
of advanced, unresectable and/or metastatic solid 
tumours, who have failed standard treatment, or for 
whom no therapy of proven efficacy exists, or who 
are not amenable to standard therapies.
Part B: Patients with a confirmed diagnosis of 
advanced, unresectable and/or metastatic 
cancers who have failed standard treatment, or 
for whom no therapy of proven efficacy exists, 
or who are not amenable to standard therapies.  
Eligibility is limited to patients with the 
following cancer types: bladder, colon, breast, 
NSCLC, ovarian, pancreatic, renal, 
esophagogastric, sarcoma, prostate and 
melanoma.
Rationale for change
Specify tumour types that are eligible for Part B
Section to be changed
Section 3.3.2 Inclusion criteria
Description of change
6.  For Parts A and B: Patients with a confirmed 
diagnosis of advanced, unresectable and/or 
metastatic solid tumours, who have failed standard 
treatment, or for whom no therapy of proven 
efficacy exists, or who are not amenable to 
standard therapies. Measurable lesions according 
to RECIST Version 1.1 must be present. Eligibility 
is limited to the following tumour subtypes in 
Part B: bladder, colon, breast, NSCLC, ovarian, 
pancreatic, renal, esophagogastric, sarcoma, 
prostate and melanoma.
Rationale for change
Specify tumour types that are eligible for Part B
Section to be changed
Figure 4.1.7: 1 Schematic of dose delays and 
reductions
Description of change
Must Restart at one dose level lower (unless at 


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Cohort 1 dose, then restart at Cohort 1 dose)*
*The following caveat applies for restart of BI 
891065:
•
If at Cohort 1 dose, then restart at 
Cohort 1 dose
•
If deemed in the best interest of the 
patient, may restart at the original 
assigned dose.  If dose is lowered, may 
escalate from lower dose to the 
maximum of the originally assigned dose 
when deemed clinically appropriate.
Rationale for change
To include option to restart BI 891065 at original 
dose
Section to be changed
Section 4.1.7 Dose reductions and dose delays
Description of change
As a general rule, serious related AEs/AEs of ≥ 
Grade 2 deemed intolerable by the patient or the 
treating physician and not responding to 
appropriate medical management and any 
SAEs/AEs of ≥ Grade 3 will result in a pause of 
treatment with BI 891065 (in Part A) and with 
BI 891065 and BI 754091 (Part B and C) until 
resolution to baseline or Grade 1.
[…]
A maximum of 2 dose reductions of BI 891065 are 
allowed, if lower tested dose levels are available. 
Dose reductions will be only to doses previously 
explored in earlier cohorts. In case of BI 891065 
dose reductions, all future dose administrations 
will also be at the reduced dose. If a reduced dose
is intolerable (as previously described), the 
treatment of that patient should be discontinued.  
Where deemed in the best interest of the 
patient, the investigator may restart at the 
originally assigned dose of BI 891065.  If dose is 
lowered, the investigator may also escalate from 
the lower dose to the maximum of the originally 
assigned dose of BI 891065 as soon as deemed 
clinically appropriate (note: study treatment 


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can be restarted during tapering of 
immunosuppressive medications.  See Table 
4.2.2.1:1 for more information).
Rationale for change
To provide further information regarding dosing 
options after dose reductions.
Section to be changed
Section 4.2.1 Other treatments and emergency 
procedures
Description of change
Blood transfusions are allowed at any time 
during the trial, except to meet inclusion 
criteria. There must be at least 4 weeks between 
a patient’s last transfusion and the screening 
laboratory assessment. Exceptions to this will be 
considered by the Sponsor on a case-by-case 
basis.
Rationale for change
To clarify guidance regarding blood transfusions
Section to be changed
Table 4.2.2.1:1 Restricted medication when 
coadministered with BI 891065
Description of change
An asterisk was added in the 2nd column for 
Immunosuppressive medications* at doses 
exceeding 10 mg/day; TNFα blockers
Rationale for change
To draw further attention to the footnote below the 
table
Section to be changed
Section 5.1 Assessment of efficacy
Description of change
In addition, the images may be used for further 
analysis future investigations (e.g., Radiomics). to 
explore the potential for enhanced and 
improved baseline and on-treatment 
markers/patterns of early efficacy based on 
comprehensive quantitative CT metrics (i.e., 
radiomics features, assessed in standard-of-care 
medical imaging data).
Rationale for change
To clarify the purpose of radiomics assessments


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Section to be changed
Throughout
Description of change
Updated all references to CTCAE from Version 
4.03 to Version 5.0
Rationale for change
CTCAE has been updated to Version 5.0
Section to be changed
7.1.2 Part B
Description of change
[…]
The derivation of these prior distributions will be 
given in the TSAP and if applicable in the minutes 
of the SRC meetings. is described in Appendix 
10.5.
Rationale for change
The statistical methods for Part B were updated.
Section to be changed
7.3.2 Secondary endpoint analyses
Description of change
Part B
[…]

OR will be analysed descriptively in terms of 
ORR, defined as the proportion of patients with 
OR based on RECIST v1.1.
Rationale for change
To clarify that RECIST V1.1 criteria will be used 
for OR.
Section to be changed
8.1 Trial approval, patient information, informed 
consent
Description of change
[…]
The investigator or delegate must give a full 
explanation to trial patients based on the patient 
information form. A language understandable 
to the patient should be chosen, technical terms 
and expressions avoided, if possible.
The patient must be given sufficient time to 
consider participation in the trial. The Investigator 
or delegate obtains written consent of the patient’s 
own free will with the informed consent form after 
confirming that the patient understands the 
contents. The Investigator or his/her delegate
must sign (or place a seal on) and date the 


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informed consent form. If a trial collaborator has 
given a supplementary explanation, the trial 
collaborator also signs (or places a seal on) and 
dates the informed consent.
Rationale for change
To clarify that investigators may delegate the 
responsibility of consenting patients (where locally 
allowable).
Section to be changed
10.3 Time schedules for PK and biomarker 
sampling
Table 10.3.2 Part B Food effect
Description of change
Visit column: 9-12 then every 2nd cycle
Rationale for change
To clarify visit numbers for Cycles 2-5 and every 
2nd cycle
Section to be changed
10.3 Time schedules for PK and biomarker 
sampling
Table 10.3.3 Part C
Description of change
Visit column: 5-8 then every 2nd cycle
Rationale for change
To clarify visit numbers for Cycles 2-5 and every 
2nd cycle
Section to be changed
10.5 Statistical Appendix
Description of change
[…]
Part B:
Operating characteristics and data scenarios for the 
BLRM used in Part B of the trial will be provided 
in the TSAP.
Thereafter, the operating characteristics and data 
scenarios for the BLRM used in Part B were 
added.
Rationale for change
The statistical methods for Part B were updated.


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Number of 
global 
amendment
4
Date of CTP 
revision
08 May 2019
EudraCT 
number
2017-000465-74
BI Trial 
number
1379.1
BI 
Investigation
al Products
BI 891065 and BI 754091
Title of 
protocol
An open-label Phase I dose finding trial with BI 891065 alone and in 
combination with BI 754091 to characterise safety, tolerability, 
pharmacokinetics, pharmacodynamics, and efficacy in patients with 
advanced and/or metastatic malignancies
To be 
implemented 
only after 
approval of 
the IRB / 
IEC / 
Competent 
Authorities
X
To be 
implemented 
immediately 
in order to 
eliminate 
hazard –
IRB / IEC / 
Competent 
Authority to 
be notified of 
change with 
request for 
approval
Can be 
implemented 
without IRB 
/ IEC / 
Competent 
Authority 
approval as 
changes 
involve 


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logistical or 
administrati
ve aspects 
only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of 
sections with changes are presented. Please note that formatting changes and minor changes 
to punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be 
changed
Part A, B, and C Flow chart footnote c and Section 5.2.3 Safety 
laboratory parameters
Description 
of change
[…] total, direct and indirect bilirubin (direct and indirect bilirubin in 
case of elevated total bilirubin values) […]
Rationale for 
change
To clarify that fractionated bilirubin needs to be collected in addition to 
total bilirubin as part of each clinical chemistry assessment.
Section to be 
changed
Section 3.3.1 Main diagnosis for trial entry and Synopsis
Description 
of change
Part C (NSCLC): Patients with metastatic NSCLC who developed 
disease progression (per RECIST v1.1) after the first scan (where SD, 
PR, or CR was demonstrated at the first scan), and require new anti-
cancer therapy after first line treatment with an anti PD-1/anti PD-
L1 mAb (given either as single agent therapy or in combination with 
a platinum-based chemotherapy regimen) advanced NSCLC who have 
been treated with platinum-based chemotherapy as first-line therapy, and 
who are not responding to an anti-PD-1/anti-PD-L1 mAb therapy as 
second-line therapy.
Rationale for 
change
To update the NSCLC patient population for Part C
Section to be 
changed
Part C Flowchart
Description 
of change
The following tumour biopsies will be mandatory for all patients in Part C 
of the trial:
-
The equivalent of two 2 fine-14-16G needle biopsies must be 
freshly taken between screening and the day before the first trial drug 
treatment. If archival formalin-fixed paraffin-embedded (FFPE) tumour 
material is available that is not older than 6 months, 20 26 4-5µm sections 
would be acceptable as well.
-
The equivalent of two 2 fine-14-16G needle biopsies on treatment 
at the beginning of Cycle 3 (i.e., after 6 weeks of treatment) if possible 
from the same lesion as the pre-treatment biopsies.
Rationale for 
change
To update the requirements for needle size in Part C (to obtain sufficient 
material for transciptomic and genomic analyses) and the number of 
sections collected from archival FFPE block.  Further details are provided 


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in the lab manual.
Section to be 
changed
Section 3.3.2 Inclusion Criteria
Description 
of change
8. For Part C: Patients with metastatic NSCLC who developed disease 
progression (per RECIST v1.1) after the first scan (where SD, PR, or 
CR was demonstrated at the first scan), and require new anti-cancer 
therapy after first line treatment with an anti PD-1/anti PD-L1 mAb 
(given either as single agent therapy or in combination with a 
platinum-based chemotherapy regimen). Patients with a confirmed 
diagnosis of advanced NSCLC who have been treated with combination 
of platinum-based chemotherapy as first-line therapy.
9. For Part C: Patients within 6 to 16 weeks are not responding to 
treatment with an anti PD-1/anti PD-L1 mAb second line therapy, and 
who are no longer benefitting from the previous therapy in the opinion of 
the Investigator.
Rationale for 
change
To update the NSCLC patient population for Part C
Section to be 
changed
Section 3.3.4 1 Withdrawal from trial treatment
Section 4.1.5.1 Administration of BI 891065
Section 5.2.1 Physical examination
Section 5.2.2 Vital Signs
Section 5.2.3 Safety laboratory parameters
Section 5.2.6.4.3 Cytokine release syndrome
Section 5.3.2 Methods of sample collection
Section 5.3.2.1 Plasma sampling for BI 891065 pharmacokinetics
Section 5.3.2.2 Plasma sampling for BI 754091 pharmacokinetics 
Section 5.5.1 Immunogenicity testing
Section 6.1 Visit Schedule
Section 6.2 Details of Trial Procedures at Selected Visits
Section 6.2.2 Treatment period
Description 
of change
[…] the respective flow charts Part A Flow Chart, Part B Flow Chart, 
Part C Lung Flow Chart […]
Rationale for 
change
To link the reader to the appropriate flow chart.
Section to be 
changed
Section 3.3.4.4 Replacement of patients who have received at least one 
dose of BI 891065 or BI 754091
Description 
of change
Patients in the NSCLC expansion cohort (Part C) will not be replaced 
unless it becomes apparent that probably less than 30 40 patients will be 
evaluable for the assessment of the primary endpoint.
Rationale for 
change
To clarify the number of NSCLC patients for Part C


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Section to be 
changed
Section 4.1.5.2 Administration of BI 754091
Section 5.2.6.3 Adverse events considered “Always Serious”
Section 5.3.2 Methods of sample collection
Section 5.3.2.3 Plasma sampling for metabolism analysis of BI 891065
Section  5.3.2.4 Urine sampling and analysis for pharmacokinetics of BI 
891065 (Part A only)
Section 5.3.3.2 BI 754091 plasma concentration
Section 5.4.1 Methods of sample collection 
Section 5.5.1 Immunogenicity testing
Description 
of change
[…] manual in the ISF[…]
Rationale for 
change
To align terminology for ISF
Section to be 
changed
Section 4.1.7  Dose reductions and dose delays
Description 
of change
In the event of an infusion-related reaction ≤ Grade 2, the infusion rate of 
BI 754091 may be decreased by 50% or interrupted until resolution of the 
event and re-initiated at 50% of the initial rate until completion of the 
infusion. In patients experiencing infusion-related reactions ≤ Grade 2, 
subsequent infusions may be administered at 50% of the initial rate. If an 
infusion-related reaction is Grade 3 or higher in severity at any point 
during the study, treatment with BI 754111 891065 and BI 754091 will be 
permanently discontinued (see Section 5.2.6.4.2).
Rationale for 
change
Correction of typo
Section to be 
changed
Figure 4.1.7: 1 Schematic of dose delays and reductions
Description 
of change
Restart at original dose or at one dose level lower*
*The following caveat applies for restart of BI 891065:
•
[…]
•
If deemed Investigator to decided based on what is in the best 
interest of the patient, may restart at the original assigned dose.  If 
dose is lowered, may escalate from lower dose to the maximum of 
the originally assigned dose when deemed clinically appropriate.
Rationale for 
change
To clarify option to restart BI 891065 at original dose
Section to be 
changed
Section 5.2.3 Safety laboratory parameters and Section 5.2.6.4.5 Hepatic 
injury
Description 
[…] Potential DILI checklist […]


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of change
Rationale for 
change
To clarify information around potential DILI requirements.
Section to be 
changed
Section 5.2.6.4.3 Cytokine release syndrome
Description 
of change
For Parts B and C:

Patients will remain under surveillance for at least 8 hours after 
the first second and second third administrations of BI 891065 
during Cycle 1.
Rationale for 
change
To clarify surveillance time for Part B and C patients.
Section to be 
changed
Section 5.2.6.4.5 Hepatic injury
Description 
of change
Lab values meeting this definition of hepatic injury will need to be 
reported as an AESI. Please follow the flowchart below (Figure 
5.2.6.4.5: 1) for reporting hepatic injury / potential DILI cases.
Hy’s Law cases have the following 3 components:

The drug causes hepatocellular injury, generally shown by a 
higher incidence of 3-fold or greater elevations above the ULN of 
ALT or AST

Among trial subjects showing such aminotransferase elevations, 
often with elevations much greater than 3 times ULN, one or 
more also show elevation of serum total bilirubin to >2 times 
ULN, without initial findings of cholestasis (elevated serum ALP)

No other reason can be found to explain the combination of 
increased aminotransferase and total bilirubin, such as viral 
hepatitis A, B, or C; pre-existing or acute liver disease; or another 
drug capable of causing the observed injury.
Rationale for 
change
To clarify  the lab values that prompt the use of the Potential DILI 
Checklist.
Section to be 
changed
5.2.6.7.1 Adverse event collection
Description 
of change
[…]

After the individual patient’s end of the trial:
-
the Investigator does not need to actively monitor the patient 
for new AEs but should only report related SAEs and related 
AESIs of which the Investigator may become aware of by any 
means of communication (e.g., phone call). Those AEs should 
however, not be reported in the CRF.
Rationale for 
change
To clarify AE collection process after the patient ends the trial.


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Section to be 
changed
Section 5.2.6.8 Pregnancy
Description 
of change
[…] Similarly, potential drug exposure during pregnancy must be 
reported if a partner of a male trial participant becomes pregnant. 
This requires a written consent of the pregnant partner. Reporting 
and consenting must be in line with local regulations. The ISF will 
contain the trial specific information and consent for the pregnant 
partner. […]
Rationale for 
change
To update information on pregnant partner with current template.
Section to be 
changed
Section 5.2.6.9 Exemptions to AE/SAE reporting
Description 
of change
[…] Lab values meeting the hepatic injury definition as defined in 
Section 5.2.6.4.5 will need to be reported as an AESI. PD reporting 
exemption does not apply to hepatic injury.
Rationale for 
change
To clarify that the lab values meeting hepatic injury definition need to be 
reported as an AESI. 
Section to be 
changed
Description 
of change
Rationale for 
change
Section to be 
changed
Section 7.7 Determination of Sample Size and Synopsis
Part C NSCLC
Description 
of change
A futility check will be performed by the SRC when 20 evaluable 
patients have been treated for at least 18 weeks. If an efficacy signal, 
i.e. at least two patients with OR, is observed out of 20 evaluable 
patients, the total intended 40 evaluable patients will be recruited into 
this trial part. If this efficacy signal cannot be observed, enrolment 
into the trial will be stopped.
Table 7.7: 1 summarizes the probabilities to stop the trial after the 
futility analysis assuming different true underlying OR rates.


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Table 7.7: 1 Probabilities to stop the trial at the futility analysis
Assumed true 
OR rate (%)
Cohort size
P(< 2 patients 
with OR)
P(≥ 2 patients 
with OR)
10
20
0.39
0.61
30
20
0.01
0.99
45
20
<0.01
>0.99
Table 7.7: 2 displays the probability of observing at least 2 patients 
with OR in the first 20 evaluable patients and then observing a 
certain number of patients with OR out of a total of 40 evaluable 
patients given different assumed true underlying OR rates. For 
example, assuming a true underlying OR rate of 10%, the probability 
to observe 2 or more patients with OR out of 20 evaluable patients is 
0.61. This means that the probability to stop the trial is 0.39 in this 
scenario. Overall, the probability to observe 4 patients with OR out of 
40 patients, given that at least 2 patients with OR had been seen 
already in the first 20 patients, is only 0.473 which is considered as 
acceptable for this trial. 
Assuming a true underlying OR rate of 45%, the probability to 
observe 2 or more patients with OR out of 20 patients is almost 1. 
Overall, the probability to observe 18 patients with OR out of 40 
patients, given that at least 2 patients with OR had been seen already 
in the first 20 patients, is 0.561 which is considered satisfactory for 
this trial.
Table 7.7: 2 Probabilities for objective response rates of the 
expansion cohort under different assumptions given the trial has not 
been stopped at the futility analysis
Assume
d true 
OR 
rate 
(%)
Coho
rt size
At least 2 patients with OR in the first 20 
patients and probability to observe at least 18 
patients with OR in total
4
8
10
12
14
16
18
10
40
0.473
0.041
0.00
5
< 
0.00
1
< 
0.00
1
< 
0.00
1
< 
0.00
1
30
40
0.992
0.942
0.80
3
0.55
9
0.29
7
0.11
5
0.03
2
45
40
>0.99
9
>0.99
9
0.99
7
0.98
2
0.92
5
0.78
6
0.56
1


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Probabilities in Table 7.7: 2 are calculated as P(n1 + n2 ≥ c AND n1 ≥ 
2), where n1 is the number of patients with OR out of the first 20 
patients, n2 is the number of additional patients with OR after more 
patients are enrolled after the futility check. c is the required 
minimum number of patients with OR displayed in Table 7.7: 2 (i.e. 
4, 8, 10, 12, 14, 16, or 18 respectively). The calculations in this section 
were performed using R version 3.5.1.
It is assumed that 44 patients need to be enrolled in order to end up 
with 40 evaluable patients for the primary analysis.
Table 7.7: 1 summarises the probabilities of observing certain OR 
rates based on different assumptions on sample size and on 
underlying OR rates. Assuming a true objective response rate of 
30%, a sample size of 30 evaluable patients (where evaluable patients 
refer to patients having at least one post-baseline response 
assessment) leads to a probability of 84% of observing at least 7 ORs. 
If the true OR rate is higher, i.e. 45%, the probability of observing at 
least 7 ORs out of 30 evaluable patients is higher than 99%. The 
probability of observing a false positive signal, i.e. to observe at least 
7 ORs if the underlying true OR rate is 10%, is only 7%.
With only 20 evaluable patients (at least one post-baseline response 
assessment is available), the probability of observing 7 ORs assuming 
a true underlying response rate of 30% is only 39%.
With a higher number of evaluable patients, the probabilities of 
observing responses increase, however the probabilities determined 
for 30 evaluable patients are considered satisfactory. Therefore, a 
sample size of 30 evaluable patients per cohort is deemed sufficient 
for Part C. It is assumed that 33 patients need to be enrolled to end 
up with 30 evaluable patients.
Table 7.7: 1 Probabilities for objective response rates of NSCLC 
expansion cohort under different assumptions
Tru
e 
OR 
rate
Patient
s
Probability to observe at least
6 
event
s
7 
event
s
8 
event
s
9 
event
s
10 
event
s
11 
event
s
10%
20
0.01
<0.01
<0.01
<0.01
<0.01
<0.01


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30%
20
0.58
0.39
0.23
0.11
0.05
0.02
45%
20
0.94
0.87
0.75
0.56
0.41
0.25
10%
30
0.07
0.03
0.01
<0.01
<0.01
<0.01
30%
30
0.92
0.84
0.72
0.57
0.41
0.27
45%
30
>0.99
>0.99
0.99
0.97
0.93
0.86
10%
40
0.21
0.10
0.04
0.02
0.01
<0.01
30%
40
0.99
0.98
0.94
0.89
0.80
0.69
45%
40
>0.99
>0.99
>0.99
>0.99
>0.99
0.99
The calculations in this section were performed using R version 3.2.2.
Rationale for 
change
To clarify the sample size for Part C NSCLC
Section to be 
changed
Section 10.3 Time schedules for PK and biomarker sampling
Table 10.3.3 Part C
Description 
of change
Added column for Triplicate ECGs and additional PK time points during 
Cycle 1
Day 1 
-30 min (±15min) (pre dose)
[…] 1:25 post dose […]
[…] 2:00 
2:30 
3:30 
4:30 
6:30 
7:30 
Day 15
0:30 post dose, 336:30
1:00, 337:00
2:00, 338:00
3:00, 339:00
5:00, 341:00
6:00, 342:00
b The following windows of time are allowed for PK sampling:

Predose samples (PTM -0:05, 167:55, 335:55, etc.): within 1 hour before drug 
intake

Just before end of infusion (PTM 1:00): within ±10 minutes of designated time

On Day 1 (PTM 1:25 through 8:30) and on Day 15 (PTM 336:30 through 
339:00): within ±10 minutes of designated time


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
On Day 1 (PTM 0:30 through 6:00) and on Day 15 (PTM 341:00 through 
342:00): within ±15 minutes of designated time
The following text was also added at the bottom of the table: 
* In order not to confuse an ECG recording, all PK samples should be 
taken after performing the ECGs.
Optional assessments are noted in parentheses. Please refer to the 
footnotes in Part C Lung Flow Chart for details.
Rationale for 
change
To clarify Part C ECG/PK sample time points and provide clarifications


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Number of global amendment
5
Date of CTP revision
26 July 2019
EudraCT number
2017-000465-74
BI Trial number
1379.1
BI Investigational Products
BI 891065 and BI 754091
Title of protocol
An open-label Phase I dose finding trial with 
BI 891065 alone and in combination with BI 
754091 to characterise safety, tolerability, 
pharmacokinetics, pharmacodynamics, and 
efficacy in patients with advanced and/or 
metastatic malignancies
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of 
sections with changes are presented. Please note that formatting changes and minor changes 
to punctuation, spelling, and abbreviations that do not affect meaning are not noted in this 
summary.
Section to be changed
Part B Flowchart
Description of change
Removed (C3) from Tumour biopsy assessment 
row
Rationale for change
To allow flexibility for the timing of on-treatment 
biopsy collection and ensure that the necessary 
prerequisites for time on treatment are met prior to 
biopsy collection
Section to be changed
Part B Flowchart footnote m


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Description of change
One fine needle biopsy from the same lesion on 
treatment as soon as possible after the 21-day 
observation period is completed and the patient 
has been on the uninterrupted and unchanged 
dose of BI 891065 for at least two continuous 
weeksat the beginning of Cycle 3 (i.e., after 6 
weeks of treatment). Biopsy collection should be 
delayed until these conditions are met.
Rationale for change
To allow flexibility for the timing of on-treatment 
biopsy collection and ensure that the necessary 
prerequisites for time on treatment are met prior to 
biopsy collection
Section to be changed
Part B Flowchart footnote n
Description of change
[…] Patients will be observed after their first 3
doses of BI 891065 and BI 754091 given at Cycle 
1 Day 1 (for 8 hours) and Cycle 2 Day 1 (for 6 
hours) as outlined […].
Rationale for change
To clarify surveillance period after administration 
of BI 891065 with BI 754091.
Section to be changed
Part C Flowchart
Description of change
Added (single/triplicate), and footnote c
Added “X” to Electrocardiograms row for the 
following time points:

Cycle 1 Day 15
Added “(single)” to Electrocardiograms row for 
the following time points:

Screening

Cycle 1 Day 8

Cycle 2+ Day 1

EOT
Rationale for change
To clarify timing for single and triplicate ECG 
collections.
Section to be changed
Part C Flowchart footnote e
Description of change
Triplicate electrocardiograms (ECGs) are 
required in connection with pharmacokinetic 
sample collection as outlined in Table 10.3: 3.
SWhen triplicate ECGs are not done, single 12-
lead ECGs electrocardiograms (ECGs) will be 


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done per the flow chart above for safety 
purposes before blood work or other procedures 
after 10 minutes of rest at screening, , and pre-
treatment during Cycle 1 on Cycle 1 Day 8, on 
Day 1 of each additional cycle, on Days 1 and 8, 
during Cycle 2 on Day 1, during Cycle 3 on Day 1, 
on Day 1 of every third cycle thereafter (Cycles 6, 
9, 12, etc.), at the EOT visit, and whenever the 
Investigator deems it necessary (see Section 5.2.4).
Rationale for change
To clarify timing of single and triplicate ECG 
collections.
Section to be changed
Part C Flowchart footnote l
Description of change
[…]. Iif possible the biopsy should be collected
from the same lesion as the pre-treatment biopsies.  
In case study drug was interrupted for 3 weeks 
or longer, consult with the Sponsor regarding 
whether or not to delay the biopsy.  
Rationale for change
To clarify biopsy collection procedure
Section to be changed
Part C Flowchart footnote m
Description of change
[…] Patients will be observed after their first 3
doses of BI 891065 during on Day 1 of Cycles 1 
and 2 as outlined in Section 5.2.6.4.3
Rationale for change
Revised for consistency with Section 5.2.6.4.3
Section to be changed
Section 1.4 Benefit – Risk Assessment
Description of change
For Parts B and C, patients will remain under 
surveillance for 10 hours after the administration of 
BI 891065 in combination with BI 754091 in 
Cycles 1 and 2, and for at least for 8 hours after the 
second and third first administrationdoses of BI 
891065 in Cycle 1, and then for 6 hours after the 
first dose of BI 891065 in Cycle 2
Rationale for change
To reduce the patient burden of a surveillance 
period after BI 891065 administration with BI 
754091 based on emerging data from Part B.
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
Once the combination dose is determined (to be 
confirmed by the Sponsor), the Part C expansion 
cohort will be initiated in patients with NSCLC 
who failed previous treatment with an anti-PD-
1/anti-PD-L1 treatment as a first-line therapy, 
either by itself or in combination with platinum-
based therapy


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Rationale for change
To clarify Part C expansion cohort
Section to be changed
Section 3.3.2 Inclusion criteria
Description of change
7.   For Parts B and C: Patients must have 
measurable disease per RECIST v1.1, must have at 
least 1 tumour lesion amenable to biopsy, and must 
be willing to undergo a biopsy prior to first 
treatment and after 6 weeks another biopsy while
on therapy.
Rationale for change
To allow flexibility for the timing of on-treatment 
biopsy collection in Part B and ensure that the 
necessary prerequisites for time on treatment are 
met prior to biopsy collection
Section to be changed
Section 4.1. Investigational Treatments
Description of change
Added BI 891065 tablet strength of 100 mg in 
Table 4.1.1:1 and in Section 4.1.5.1 
(Administration of BI 891065) text
Rationale for change
Update BI 891065 tablet strengths in this study 
because 100 mg tablet will become available.  It 
will not be distributed to countries until all local 
regulatory requirements for adding a new dose 
strength are met.
Section to be changed
Figure 4.1.7: 1 Schematic of dose delays and 
reductions
Description of change
Modified box BI 891065: Restart at original dose 
or at one dose level lower*
Figure footnote: If deemed Investigator to decide 
based on what is in the best interest of the patient, 
may restart at original assigned dose.
Rationale for change
To clarify criteria for restarting at original or a 
lower dose after a dose interruption
Section to be changed
Figure 4.1.7 Dose reduction and dose delays
Description of change
A maximum of 2 dDose reductions of BI 891065 
are allowed, if lower tested dose levels are 
available. Dose reductions will be only to doses 
previously explored in earlier cohorts if the 
Investigator anticipates a lower dose would be 
better tolerated.
Rationale for change
To clarify criteria for dose reduction of BI 891065
Section to be changed
Section 5.2.3 Safety laboratory parameters
Description of change
The standard haematology panel will consist of: 


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haemoglobin, red blood cell count, haematocrit, 
mean corpuscular volume, white blood cell count, 
and differential blood count (preferably expressed 
in absolute values), and platelets, haptoglobin and 
reticulocytes.
Rationale for change
To investigate the reason for isolated bilirubin 
increases observed. 
Section to be changed
Section 5.2.4 Electrocardiogram
Description of change
In Part C, single ECGs will typically be taken 
unless additional triplicate readings are required 
with pharmacokinetic sample collection as
indicated in Table 10.3: 3.  When triplicate 
ECGs are not done, single readings will be done 
for safety purposes as indicated in Part C Lung 
Flow Chart.
Rationale for change
To clarify timing of single and triplicate ECG 
collections in Part C.
Section to be changed
Section 5.2.6.4.3 Cytokine release syndrome
Description of change
For Parts B and C:

Patients will remain under surveillance for 
10 hours after the administration of BI 
891065 
 in combination 
with BI 754091 
 during Cycles 
1 and 2.

Patients will remain under surveillance for 
about 8 hours after the first dose of 
BI 891065 at least 8 hours after the first 
and second administrations of BI891065
during Cycle 1, and for about 6 hours 
after the first dose of BI 891065 in Cycle 
2
Rationale for change
To reduce the patient burden of a surveillance 
period after BI 891065 administration with BI 
754091 based on emerging data from Part B.
Section to be changed
Table 10.3:2 Time schedule for PK blood, 
biomarker, and immunogenicity sampling during 
Part B including food effect


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Description of change
Removed (C 3 only) from mandatory biopsy 
during study treatment
Rationale for change
To allow flexibility for the timing of on-treatment 
biopsy collection in Part B
Section to be changed
Table 10.3:2 footnote c
Description of change
Biopsy for IAP degradation to be taken as noted 
in Part B Flow Chart
Rationale for change
To clarify the timing of biopsy collection in Part B
Number of global 
amendment
6
Date of CTP revision
12 February 2020
EudraCT number
2017-000465-74
BI Trial number
1379.1
BI Investigational Products
BI 891065 and BI 754091
Title of protocol
An open-label Phase I dose finding trial with BI 891065 alone 
and in combination with BI 754091 to characterise safety, 
tolerability, pharmacokinetics, pharmacodynamics, and efficacy 
in patients with advanced and/or metastatic malignancies
To be implemented only 
after approval of the IRB / 
IEC / Competent 
Authorities
X
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Additions to the text are bolded and deletions from the text are crossed-off. Only the parts of 
sections with changes are presented. Please note that formatting changes and minor changes to 
punctuation, spelling, and abbreviations that do not affect meaning are not noted in this summary.


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Section to be changed
Synopsis_Number of patients on each treatment and 
Section 7.7 Determination of Sample Size
Description of change
Part B (dose escalation BI 891065 in combination with 
BI 754091): approximately 3031-37 patients
Rationale for change
The number of patients was updated to include additional patients 
to be enrolled in Part B. 
Section to be changed
Flow Chart Part B
Description of change
Tumour biopsy was moved from Cycle 3 to Cycle 2
C2
C3
X
X
Rationale for change
To align the Flow Chart B table with the edits made to the 
footnotes in the previous amendment.
Section to be changed
Flow Chart Part B and Part C footnote c
Description of change
The safety laboratory assessments listed in footnote c was 
amended to: Troponin I/Troponin T
Rationale for change
To allow flexibility to sites for collection of Troponin at sites 
where local labs do not report Troponin I.
Section to be changed
Flow Chart Part B footnote j
Description of change
The effect of food will be tested in this part of the study until 
sufficient data is obtained. Only q.d. patients enrolled in Part 
B will participate in the food effect study.
Rationale for change
To clarify that food effects will only be tested on q.d. dosed 
patients. 
Section to be changed
Flow Chart Part B footnote n
Description of change
Dosing amounts, dosing frequency (e.g. b.i.d or q.d.) and 
escalations…… Patients should not take BI 891065 prior to 
certain visits that require pre-dose blood sampling as detailed in 
Table 10.3: 2 and Table 10.3: 3. For patients taking b.i.d. 
dosing, the evening dose should be skipped (Day 1 and Day 15 
of Cycle 1).  For all patients, the morning dose on Day 2 and 
Day 16 should be taken in the clinic (after pre-dose blood 
sampling is taken).
Rationale for change
To clarify when doses should be skipped on PK analysis days. 
Section to be changed
Flow Chart Part C
Description of change
Columns for Day 2 and Day 16 of Cycle 1 were added. 
Rationale for change
To better indicate that patients have assessments to be collected 
on Days 2 and 16 of Cycle 1. 
Section to be changed
Flow Chart Part C Blood sampling for BI 891064 
pharmacokinetics
Description of change
X (C2 only)
Rationale for change
To clarify that the last blood sampling for BI 891064 
pharmacokinetics will be at Cycle 2


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Section to be changed
Flow Chart Part C Blood sampling for biomarkers (cytokines) 
and footnote k
and 
Table 10.3: 4 Time schedule for PK blood, biomarker, and 
immunogenicity sampling during Part C-NSCLC
Description of change
Blood sampling for biomarkers (cytokines) was added to Cycle 1 
Day 2. 
Rationale for change
To allow for collection of blood sampling for cytokines on Cycle 
1 Day 2 for patients in Part C. 
Section to be changed
Flow Chart Part C Blood sampling for biomarkers 
(PBMC/MDSC) and Blood sampling for biomarkers (cytokines) 
and 
Table 10.3: 4 Time schedule for PK blood, biomarker, and 
immunogenicity sampling during Part C-NSCLC
Description of change
C2+
EOT
X (C2, 4 only)
X
Rationale for change
To change the final biomarker blood sample collection from EOT 
to Cycle 4 Day 1. 
Section to be changed
Flow Chart Part C footnote k
Description of change
Blood samples for biomarkers - samples for the quantification of 
cytokines will be taken pre-treatment during Cycle 1 on Days 1, 
8, and 15, Cycle 2 on Day 1, and Cycle 4 on Day 1 at the EOT
visit (see Section 5.4.2 and Table 10.3: 3). Blood samples for 
biomarker peripheral blood mononuclear cells (PBMC)/ myeloid-
derived suppressor cells (MDSCs) will be taken pre-treatment 
during Cycle 1 on Days 1, 8, and 15, Cycle 2 on Day 1, and 
Cycle 4 on Day 1 at the EOT visit.
Rationale for change
Section to be changed
Flow Chart Part C footnote m
Description of change
Patients should not take BI 891065 prior to certain visits that 
require pre-dose blood sampling as detailed in Table 10.3: 4. 
Patients could be assigned q.d. or b.i.d. dosing. For patients 
taking b.i.d. dosing, the evening dose on infusion days should 
be skipped (Day 1 and Day 15 of Cycle 1). For all patients, the 
morning dose on Day 2 and Day 16 should be taken in the 
clinic (after pre-dose blood sampling is taken). On BI 754091 
infusion days, BI 891065 will be administered approximately 30 
minutes after the end of the BI 754091 infusion.. Patients will be 
observed after their first dose of BI 891065 on Cycle 1 Day 1 (for 
8 hours) and Cycle 2 Day 2 (for 64 hours) as outlined in Section 
5.2.6.4.3.
Rationale for change
To clarify that in the regimen for patients in Part C could be q.d. 
or b.i.d. and that the evening dose on Cycle 1 Days 1 and 15 
should be skipped and the morning dose on Cycle 1 Days 2 and 
16 should be taken in the clinic after the pre-dose blood sampling


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is taken.
Section to be changed
Abbreviations
Description of change
b.i.d (twice a day) and q.d. (once a day) were added to the table. 
Rationale for change
q.d. and b.i.d. abbreviations have been added to the table 
abbreviations since these have been added to the text in this 
amendment. 
Section to be changed
Section 1.1 Medical Background
Description of change
The 2nd line treatment of NSCLC has also been markedly 
transformed by the introduction of PD-1/PD-L1 immune 
checkpoint inhibitor monoclonal antibodies (mAbs) (nivolumab, 
durvalumab and atezolizumab in addition to pembrolizumab).
Rationale for change
Durvalumab was added to the list of 2nd-line NSCLC PD-1/PD-
L1 mAb treatments since it has been approved by the FDA. 
Section to be changed
Section 1.4 Benefit-Risk Assessment
Description of change
For Parts B and C, patients will remain under surveillance after 
the administration of BI 891065 in combination with BI 754091 
for 8 hours after the first dose of BI 891065 in Cycle 1, and then 
for 6 hours after the first dose of BI 891065 in Cycle 2. For Part 
C, patients will remain under surveillance for 4 hours after 
the first dose of BI 891065 in both Cycle 1 and Cycle 2 (see 
Section 5.2.6.4.3).
Rationale for change
The surveillance time has been reduced for patients in Part C. 
Section to be changed
Section 2.1.2.2 Part B
Description of change
Q.D. and b.i.d. dosing schedules may be explored in Part B.
Rationale for change
To identify that a b.i.d. cohort may be explored in Part B. 
Section to be changed
Figure 3.1.: 1 Design of trial 1379.1 including 2 dose-escalation 
parts and 1 expansion cohort
Description of change
Patients in Parts B and C may receive either q.d. or b.i.d. 
BI 891065
Rationale for change
To identify that a b.i.d. cohort may be explored in Part B and Part 
C.
Section to be changed
Section 3.3.2 Inclusion criteria 4
Description of change
Eastern Cooperative Oncology Group (ECOG) score: 0 to or 1
Rationale for change
The inclusion criteria text was clarified. 
Section to be changed
Section 3.3.3 Exclusion criteria 1, 14, 15
Description of change
(major according to the Investigator’s and/or Medical Monitor’s 
assessment)
Rationale for change
Medical monitor’s input has been added to the exclusion criteria. 
Section to be changed
Section 3.3.3 Exclusion criteria 6
Description of change
At least 7 days must have elapsed between the last dose of 
such agent and the first dose of study drug.
Rationale for change
The drug washout period has been clarified. 


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Section to be changed
Section 3.3.3 Exclusion criteria 7
Description of change
Persistent toxicity from previous treatments that has not resolved 
to ≤ Grade 1 (except for alopecia and Grade 2 neuropathy due 
to prior platinum-based therapy)
Rationale for change
The prior toxicity exclusion criteria has been clarified. 
Section to be changed
Section 3.3.3 Exclusion criteria 10
Description of change
Any factors that increase the risk of QTc prolongation or risk of 
arrhythmic events such as heart failure, hypokalaemia, congenital 
long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years-of-age, or any 
concomitant medication with known to prolong the or possible 
risk of QT interval prolongation
Rationale for change
The cardiac risk exclusion criteria has been clarified
Section to be changed
Section 3.3.3 Exclusion criteria 18
Description of change
Patients with asymptomatic CNS metastases may be enrolled 
following a 2-week washout period.
Rationale for change
The CNS metastases exclusion criteria has been clarified. 
Section to be changed
Table 4.1.1:1 BI 891065
Description of change
Once daily, (q.d.) or twice daily (b.i.d.), individual dose 
depending on dose escalation
Rationale for change
Both the q.d. and b.i.d. dosing schedule was added to the table. 
Section to be changed
Section 4.1.2.1 Starting dose of BI 891065
Description of change
Based on the toxicities and exposures in the GLP-compliant dog 
study (the more sensitive species), a starting dose of 5 mg 
BI 891065 once daily has been chosen.
Rationale for change
To identify this text as describing the q.d. dosing. 
Section to be changed
Section 4.1.3.2 Cohorts at dose levels ≥25 mg BI 891065 daily
Description of change
Both q.d. and b.i.d. dose escalations may be performed in 
Part B.
Rationale for change
To clarify both q.d. and b.i.d. dosing will used in Part B. 
Section to be changed
Section 4.1.3.2 Cohorts at dose levels ≥25 mg BI 891065 daily
Description of change
The dose and regimen of BI 891065 in combination with BI 
754091 to be used in Part C will be determined based on the 
safety and PK/PDc data of Parts A and B, including data of target 
engagement in tumour tissue.
Rationale for change
To clarify that both the dose and regimen of the drug combination 
to be used in Part C will be based on safety and PK/PDc data 
from Parts A and B. 
Section to be changed
Section 4.1.4 Method of assigning patients to treatment groups
Description of change
Part B (combination therapy) will be assigned a q.d. or b.i.d.
dose of BI 891065 and a dose of BI 754091, as determined by the 
SRC.


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Rationale for change
To clarify both q.d. and b.i.d. dosing will used in Part B.
Section to be changed
Section 4.1.4 Method of assigning patients to treatment groups
Description of change
(maximum 400 mg daily dose of BI 891065)
Rationale for change
To identify this text as describing the q.d. dosing. 
Section to be changed
4.1.5.1 Administration of BI 891065
Description of change
BI 891065 may be taken in either a q.d. or b.i.d. dosing, 
depending on the assigned treatment regimen. …… The For 
applicable cohorts, the fasting status and all meals on the PK 
days should be recorded in the patient diary….
BI 891065 doses should be taken orally at approximately the 
same time each morning (and evening for patients with b.i.d. 
dosing).  Exceptions are noted in the exception of prior to
flowchart:
•
Part A patients will skip a dose on Cycle 1 Day 2 where 
study drug is not taken.
•
Part B patients assigned to a b.i.d. regimen will skip 
the evening dose on Cycle 1 Day 1 and Day 15 (in preparation 
for PK testing on Cycle 1 Day 2 and Day 16).
Rationale for change
To clarify both q.d. and b.i.d. dosing will used in Part B.
Section to be changed
Section 4.1.7 Dose reductions and dose delays
Description of change
AEs that are immune related should be managed according to 
the Guidelines for irAE management (as outlined in 
Appendix 10.2).    
For Grade 4 AE/SAEs that are not immune related, study 
drug should be withdrawn. However, if it can be excluded 
with high certainty that the event was related to study 
medication, study drug should be paused, and resumption of 
study drug may be allowed after discussion with the Medical 
Monitor and the Sponsor.
For Grade 3 AE/SAEs that are not immune related, study 
drug should be paused. 
For Grade 2 AEs/SAEs that are not immune related but are 
deemed intolerable by the patient or the treating physician 
and not responding to appropriate medical management, the 
physician should decide if a pause of treatment is warranted 
considering relevant variables such as perceived relatedness 
to study drug.  
If, after a treatment pause of ≤12 weeks, the non-immune 
related SAE/AE resolves to baseline or Grade 1 and the 
physician thinks it is clinically appropriate to restart study 
drug, then the physician may choose to restart BI 891065 at 
one dose lower than the dose administered before the pause, 
and BI 754091 at the same fixed dose of BI 754091. If the 
AE/SAE prompting interruption has unequivocally been 


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excluded to be drug related, reintroduction of BI 891065 at 
the same dose as prior to the pause may be considered.
There will be no dose reductions or escalations of BI 754091 
in any one patient.  However, in the event of an infusion-
related reaction ≤ Grade 2, the infusion rate of BI 754091 
may be decreased by 50% or interrupted until resolution of 
the event and re-initiated at 50% of the initial rate until 
completion of the infusion. In patients experiencing infusion-
related reactions ≤ Grade 2, subsequent infusions may be 
administered at 50% of the initial rate. If an infusion-related 
reaction is Grade 3 or higher in severity at any point during 
the study, treatment with BI 891065 and BI 754091 will be 
permanently discontinued (see Section 5.2.6.4.2).
As a general rule for Part B and Part C, both drugs (BI 
891065 and BI 754091) will be stopped, paused, or re-exposed 
together. Exemptions have to be justified and aligned with the 
Sponsor in writing.  Up to two dose reductions are allowed 
per patient. For q.d. dosing regimens, dose reductions of BI 
891065 are allowed only to doses previously explored in 
earlier cohorts. If a patient on a b.i.d. dosing regimen has a 
dose reduction, the dose should be reduced as follows: 200 mg
b.i.d reduced to 100 mg b.i.d; 100 mg b.i.d reduced to 50 mg 
b.i.d.  
Criteria leading to permanent discontinuation of BI 891065 
and BI 754091 are presented in Section 3.3.4.1.
A schematic of dose delays and reductions is presented in Figure 
4.1.7: 1.


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Figure 4.1.7: 1
Schematic of dose delays and reductions 
for non-immune related AEs/SAEs*
As a general rule, related serious AEs/AEs of ≥ Grade 2 deemed 
intolerable by the patient or the treating physician and not 
responding to appropriate medical management and any 
SAEs/AEs of ≥ Grade 3 will result in a pause of treatment with 
BI 891065 (in Part A) and with BI 891065 and BI 754091 (Part B 
and C) until resolution to baseline or Grade 1.
If the treatment pause is ≤12 weeks, the patient can be re-exposed
to BI 891065 at one dose level lower than the dose administered 
before the pause (except for the 5 mg monotherapy dose) and the 
same fixed dose of BI 754091 as long as the re-exposure is 
considered clinically indicated by the Investigator.  
As a general rule (relevant for Part B and Part C), both drugs (BI 
891065 and BI 754091) will be stopped, paused, or re-exposed 
together. Exemptions have to be justified and aligned with the 
Sponsor in writing.
In the event of an infusion-related reaction ≤ Grade 2, the 
infusion rate of BI 754091 may be decreased by 50% or 
interrupted until resolution of the event and re-initiated at 50% of 
the initial rate until completion of the infusion. In patients 
experiencing infusion-related reactions ≤ Grade 2, subsequent 


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infusions may be administered at 50% of the initial rate. If an 
infusion-related reaction is Grade 3 or higher in severity at any 
point during the study, treatment with BI 891065 and BI 754091 
will be permanently discontinued (see Section 5.2.6.4.2).
Dose reductions of BI 891065 are allowed to doses previously 
explored in earlier cohorts if the Investigator anticipates a lower 
dose would be better tolerated. If a reduced dose is intolerable (as 
previously described), the treatment of that patient should be 
discontinued.  Where deemed in the best interest of the patient, 
the investigator may restart at the originally assigned dose of BI 
891065.  If dose is lowered, the investigator may also escalate 
from the lower dose to the maximum of the originally assigned 
dose of BI 891065 as soon as deemed clinically appropriate 
(note: study treatment can be restarted during tapering of 
immunosuppressive medications.  See Table 4.2.2.1:1 for more 
information).
There will be no dose reductions or escalations of BI 754091 in 
any one patient.
Criteria leading to permanent discontinuation of BI 891065 and 
BI 754091 are presented in Section 3.3.4.1.
Rationale for change
Dose reductions and dose delay text was clarified and aligned 
with the other edits made to the trial protocol.
Section to be changed
Section 5.2.3 Safety laboratory parameters n  
Description of change
The standard biochemistry panel will consist of glucose, sodium, 
potassium, chloride, calcium, phosphate, venous bicarbonate 
HCO3, urea, creatinine, AST, ALT, alkaline phosphatase, lactate 
dehydrogenase, total, direct and indirect bilirubin, total protein,
albumin, urea nitrogen (or urea in lieu of urea nitrogen), uric 
acid and creatinine kinase (CK). If CK is elevated, then CK-MB 
[cardiac], Troponin I/Troponin T, and myoglobin should be 
reactively tested.
Rationale for change
The collection parameters for blood urea and Troponin were 
clarified. 
Section to be changed
Section 5.2.6.4.3 Cytokine release syndrome
Description of change
For Parts B and C:
•
Patients will remain under surveillance after the 
administration of BI 891065 
 in combination 
with BI 754091 
 during Cycles 1 and 2.
•
Patients will remain under Duration of surveillance will 
be for 8 hours after the first dose of BI 891065 during Cycle 1, 
and for 6 hours after the first dose of BI 891065 in Cycle 2
For Part C:
•
Patients will remain under surveillance after the 
administration of BI 891065 
 in combination 


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with BI 754091 
 during Cycles 1 and 2.
•
Duration of surveillance will be for 4 hours after the 
first dose of BI 891065 during Cycles 1 and 2.
Rationale for change
The surveillance time has been reduced for patients in Part C. 
Section to be changed
Section 5.2.6.4.4 Immune-related adverse events (irAE) and 
Table 10.1: 1 Immune-related adverse events of special interest
Description of change
Immune-related AEs should be reported as AESIs only for 
patients who received immunotherapy. 
Rationale for change
To clarify when irAEs are reported as AESIs. 
Section to be changed
Section 5.3.2.4 Plasma sampling for coprophyrin
Description of change
Section 5.3.2.4 Plasma sampling for coprophyrin
Backup samples for PK analysis might be used for 
coproporphyrin analysis. Coproporphyrin is an exploratory 
plasma biomarker to investigate the potential of BI 891065 to 
inhibit OATP1B1/B3. Assays are under development. 
Measurement will be done when feasible assays have been 
developed and validated.
Rationale for change
Coprophyrin analysis has been added to the trial protocol.
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 6.2.2.1 Food-interaction assessment
Description of change
At all dose levels in Part B, aAn explorative food effect will be 
assessed for q.d. patients in Part B.
Rationale for change
To clarify that food analysis PK will conducted for only q.d. 
patients in Part B. 
Section to be changed
Section 7.1.2 Part B
Description of change
They will take into account available data from Part A of this 
trial and available data from the monotherapy dose 
escalation part of BI trial 1379.6 for the prior of BI 891065 and 
available data from the BI trial 1381.1 that aims to determine the 
MTD of BI 754091.
Rationale for change
To clarify data to be used for the baseline statistical analysis for 
Part B. 
Section to be changed
Section 7.1.2 Part B
Description of change
The BLRM is set up for a fixed dosing schedule of once daily 
(q.d.) across dose levels of BI 891065. For the purpose of 
dose-toxicity modelling, a b.i.d. regimen will be converted in 
the BLRM to an equivalent q.d. regimen that has a similar 
Cmax at steady state. This conversion is based on the 
assumption that safety events are triggered by Cmax at steady 
state. For example, based on Table 7.1.2: 1, the 200 mg b.i.d. 


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regimen will be modelled as equivalent to a 300 mg q.d 
regimen. For any other b.i.d. doses considered, their 
conversions will be specified in the TSAP. 
The posterior probabilities of over toxicity are evaluated
based on historical data for BI 891065 in Tables 7.1.2: 2 and 
7.1.2: 3, historical data for BI 754091 in Table 7.1.2: 4 and 
current data for the combination therapy of BI 891065 and 
BI 754091 in Table 7.1.2: 5. For example, as seen in Table 
7.1.2: 6, the dose combination of 200 mg b.i.d. BI 891065 and 
240 mg BI 754091 has a posterior probability of over toxicity 
below 25% and would therefore be suitable as a dose 
combination to select.
If multiple b.i.d. doses are tested, appropriate modifications 
to the BLRM to account for the heterogeneity of different 
dosing schedules might be considered. Details will be specified 
in the TSAP if needed.
Table 7.1.2: 1 Simulated Cmax at steady state with 95% 
confidence intervals. 
Possible 
Regimen
Cmax (nmol/L)
200 mg q.d.
2457.12 (771.53 - 6835.05)
300 mg q.d.
3421.69 (1286.11 - 9653.55)
400 mg q.d.
4357.98 (1672.88 - 12541.8)
200 mg b.i.d.
3502.75 (1458.73 - 10986.75)
Table 7.1.2: 2 Historical data for BI 891065 from Part A 
(status as of 16 Dec 2019)
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of evaluable 
patients
5 mg q.d.
0/2
15 mg q.d.
0/1
25 mg q.d.
0/3
50 mg q.d.
0/4
100 mg q.d.
0/3
200 mg q.d.
0/3
400 mg q.d.
0/6
Table 7.1.2: 3 Historical data for BI 891065 from BI trial 
1379.6 (status as of 16 Dec 2019)
Dose
N of patients with DLTs 
during MTD evaluation 


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period / N of evaluable 
patients
100 mg q.d.
1/2
Table 7.1.2: 4 Historical data for BI 754091 from BI trial 
1381.1 (status as of 30 Sep 2019)
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of evaluable 
patients
80 mg
0/3
240 mg
0/71
400 mg
0/3
Table 7.1.2: 5 Data for combination of BI 891065 and BI 
754091 from Part B (status as of 13 Nov 2019)
Dose BI 
891065
Dose  BI 
754091
N of patients with DLTs 
during MTD evaluation 
period / N of evaluable 
patients
50 mg q.d.
240 mg
0/6
200 mg q.d.
240 mg
0/8
400 mg q.d.
240 mg
1/5
Table 7.1.2: 6 Posterior probabilities of DLTs
Dose 
BI 
891065
Dos
e BI 
754
091
Probability of 
true DLT rate 
in 
Quantiles
[0,
0.1
6)
[0.
16,
0.3
3)
[0.
33,
1]
M
ea
n
St
D
2.
5
%
50
%
97.
5
%
50 mg 
q.d.
240 
mg
0.9
77
0.0
23
0.0
00
0.
07
1
0.
03
6
0.
0
1
9
0.0
65
0.1
58
200 mg 
q.d.
240 
mg
0.8
53
0.1
47
0.0
00
0.
11
0
0.
05
0
0.
0
3
5
0.1
02
0.2
29
200 mg 
b.i.d. [1]
240 
mg
0.7
08
0.2
74
0.0
18
0.
13
0.
07
0.
0
0.1
18
0.3
13


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2
3
3
1
400 mg 
q.d.
240 
mg
0.6
15
0.3
13
0.0
72
0.
15
4
0.
10
5
0.
0
2
3
0.1
30
0.4
23
[1] The 200 mg b.i.d. dose is modeled as equivalent to a 300 
mg q.d. dose in terms of dose-toxicity relationship in the 
BLRM.
Rationale for change
To revise clarify the BLRM statistical analysis for Part B. 
Section to be changed
Section 9.1 Published References
Description of change
P19-00269
Brahmer JR, Lacchetti C, Schneider BJ, Atkins 
MB, Brassil KJ, Caterino JM, et al. Management of Immune-
Related Adverse Events in Patients Treated With Immune 
Checkpoint Inhibitor Therapy: American Society of Clinical 
Oncology Clinical Practice Guideline.J Clin Oncol. Jun 
10;36(17):1714-68.
Rationale for change
A new reference was added to the text.
Section to be changed
Section 10.2 Management of Immune-Related Adverse Events
Description of change
Regarding diagnosis, grading and therapeutic management of 
immune-related adverse events, grading and treatment, up-
to-date published guidelines should be considered (e.g. P19-
00269). Only limited guidance on management of specific 
irAEs can be given here.
Please refer to published guidelines (e.g. ASCO guideline, 
Brahmer [P19-00269]) for details. 
In general, 
-
BI 754091 and BI 891065 should be continued with 
close monitoring in case of grade 1 irAEs, with the 
exception of irAEs that may rapidly evolve into severe 
or fatal conditions (encephalitis of any grade, 
myocarditis of any grade, pneumonitis that is grade 1 
but shows radiographic evidence of worsening – see 
detailed guidance below).
-
For most Grade 2 irAEs, BI 754091 and BI 891065 
should be withheld and treatment with corticosteroids 
is commonly warranted, usually with an initial dose of 
0.5 to 1 mg/kg prednisone / prednisone equivalent 
daily. Restart of therapy is commonly possible once 
symptoms and/or laboratory values have resolved to 
grade 1 or less, and on ≤ 10 mg prednisone / 
prednisone equivalent per day.
-
For Grade 3 irAEs, BI 754091 and BI 891065 has to 
be withheld, and treatment with high-dose 
corticosteroids (1-2mg/kg/d prednisone / prednisone 
equivalent) is usually warranted. Upon improvement, 


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steroids should be tapered slowly over 4-6 weeks. 
Non-steroidal immunosuppressives (e.g. infliximab, 
mycophonlate mofetil) should be considered if no 
improvement or worsening occurs within the initial 48 
to 72 hours. Upon recovery to grade 1 or less, and on 
≤ 10 mg prednisone / prednisone equivalent per day,
restarting  BI 754091 and BI 891065 may be 
considered for selected irAEs, but caution is advised, 
in particular in patients with early-onset irAEs. 
Expert consultancy and agreement with medical 
monitor is recommended prior to restart of therapy.
-
Most Grade 4 irAEs warrant permanent 
discontinuation of BI 754091 and BI 891065. 
-
Restart of therapy is commonly possible for endocrine 
irAEs regardless of grade once stable hormone 
replacement has been instituted and symptoms have 
recovered. In case of multiple hormone deficiencies, 
corticosteroid replacement has to precede thyroid 
hormone replacement therapy by several days in 
order to avoid adrenal crisis. 
In case of prolonged steroid therapy or treatment with 
immunosuppressives consider the possibility of opportunistic 
infections and tuberculosis reactivation. Careful monitoring 
andconsideration of administration of prophylactic 
antibiotics where appropriate are warranted. 
Commonly, referral to experts in the management of organ-
specific conditions is highly recommended, especially for 
irAEs grade 3 or grade 4, or irAEs where management is 
complex. 
BI 754091 and BI 891065 should be permanently 
discontinued for immune related

encephalitis, aseptic meningitis, transverse myelitis, 
or Guillain-Barre syndrome of any grade 

acquired thrombotic thrombocytopenic purpura of 
any grade

myocarditis of any grade

myasthenia gravis, peripheral neuropathy or 
autonomic neuropathy of grade ≥3

myositis grade 2 with objective findings (see below), 
any myositis grade ≥3   

hepatitis grade ≥3  (transaminase >5 times ULN or 
total bilirubin >3 times ULN), recurrent hepatitis 
grade ≥2

nephritis grade ≥3, persisting grade 2 nephritis 
unresponsive to initial steroid therapy or worsening, 
and recurrent nephritis grade ≥2 

pneumonitis grade ≥3, 


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
rash, bullous dermatoses, severe cutaneous adverse 
reaction, Stevens Johnson Syndrome, toxic epidermal 
necrolysis of grade 4, and recurrent rash grade ≥3 

colitis grade 4, and recurrent colitis of any grade 

uveitis, iritis, episcleritis of grade ≥3

autoimmune-hemolytic anemia grade ≥2

haemolytic uremic syndrome grade ≥3

immune thrombocytopenia grade 4

any recurrent irAE grade ≥3, 

inability to taper steroids to 10 mg or less prednisone 
or equivalent within 12 weeks, or

persistent Grade 2-3 AEs that do not recover to 
Grade 1 or less within 12 weeks. 
Dose adjustment of BI 754091 and BI 891065 besides 
interrupting or permanently discontinuing BI 754091 and BI 
891065 are not allowed. 
In rare situations when benefit and risk assessment is 
considered positive for a patient to continue BI 754091 and BI 
891065 treatment despite guidance to permanently 
discontinue (e.g. in case no alternative anti-cancer therapy is 
available), it should be discussed with the sponsor.  
Pneumonitis:

For Grade 1 pneumonitis with radiographic evidence 
of worsening, withhold BI 754091 and BI 891065 until 
improvement or resolution; BI 754091 and BI 891065 
may be reintroduced upon radiographic 
improvement. In the absence of radiographic 
improvement within 3-4 weeks, follow guidance as for 
grade 2 event. 

For Grade 2 pneumonitis, hold BI 754091 and BI 
891065 until resolution to at least grade 1. If not 
already started, initiate therapy for the event as per 
available guidelines. Follow guidance as for grade 3 
pneumonitis if no clinical improvement after 48 -72 hr 
of starting therapy. 

For Grade 3-4 pneumonitis, permanently discontinue 
BI 754091 and BI 891065 and immediately initiate 
treatment according to available guidelines. 
Diarrhoea/Colitis:

For Grade 1 diarrhoea/colitis, consider interruption 
of BI 754091 and BI 891065 therapy.  

For Grade 2 diarrhea/colitis, withhold BI 754091 and 
BI 891065 until patient’s symptoms recovered to 
grade 1 or less. Consider initiating treatment with 
steroids. 

For Grade 3 diarrhoea/colitis, withhold BI 754091 
and BI 891065 and immediately start treatment 


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(steroids, non-steroidal immunosuppressents) as per 
available guidelines. 

For Grade 4 diarrhoea/colitis, permanently 
discontinue BI 754091 and BI 891065 and 
immediately commence adequate therapy (e.g. i.v. 
corticosteroids).   

For Grade 1-3 colitis, restart of BI 754091 and BI 
891065 may be considered once symptoms improve to 
Grade 1 or less without need for continued steroids. 
After careful benefit risk assessment, BI 754091 and 
BI 891065 may also be restarted after recovery to 
grade 1 or less, and on corticosteroid ≤ 10 mg per day  

BI 754091 and BI 891065 should be permanently 
discontinued for recurrent diarrhoea/colitis of any 
grade.  
Diabetes

Consider withholding BI 754091 and BI 891065 in 
case of grade 2 hyperglycemia. Check for ketonuria. 
In case of new onset of diabetes or unexpected 
worsening of pre-existing diabetes, check for new 
manifestation of type 1 diabetes. 

For new onset Type 1 diabetes mellitus, or Grade 3-4 
hyperglycaemia associated with ketosis (ketonuria or 
metabolic acidosis)
o
Initiate insulin therapy 
o
Evaluate subjects as appropriate per available 
guidelines regarding presence of type 1 
diabetes
o
BI 754091 and BI 891065 should be withheld 
until glucose level is controlled with insulin 
with no sign of ketoacidosis.  

BI 754091 and BI 891065 may be restarted once 
insulin therapy has established stable glycemic 
control 
Thyroid disorders:
For diagnosed thyroid disorders, thyroid hormone 
supplementation and monitoring should occur as per 
available guidelines

Primary hypothyroidism:
o
For Grade 1 hypothyroidism, BI 754091 and 
BI 891065 may be continued, with regular 
monitoring of thyroid values. 
o
For Grade 2 hypothyroidism, consider 
withholding BI 754091 and BI 891065
o
For Grade 3-4 hypothyroidism, withhold BI 
754091 and BI 891065, consider admission 
and IV therapy, especially in case of 
myxedema 
o
BI 754091 and BI 891065 may be restarted 


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once symptoms resolve to baseline with 
appropriate thyroid hormone 
supplementation

Primary hyperthyroidism
o
For Grade 1 hyperthyroidism, BI 754091 and 
BI 891065 may be continued , with regular 
monitoring of thyroid values. 
o
For Grade 2 hyperthyroidism, consider 
withholding BI 754091 and BI 891065, initiate 
therapy as per available guidelines. 
o
For Grade 3-4 hyperthyroidism, withhold BI 
754091 and BI 891065. Consider 
hospitalization, especially in case of 
thyreotoxicosis. 
o
BI 754091 and BI 891065 may be restarted 
once symptoms resolve to baseline.
Note: in case of concomitant adrenal dysfunction, this must 
be corrected first, prior to thyroid hormone replacement 
(reduced stress tolerance) 
Adrenal insufficiency

Interruption of BI 754091 and BI 891065 therapy should 
be considered for adrenal insufficiency grade 1 or 2, and 
is warranted for grade 3 and grade 4 adrenal 
insufficiency, until patient is stabilized on hormone 
replacement therapy. 

Therapy with BI 754091 and BI 891065 may be restarted 
once stable replacement therapy has been achieved.

Note: in case of concomitant hypothyroidism, steroid 
replacement therapy should precede thyroid hormone 
substitution to avoid adrenal crisis.
Hypophysitis:

Diagnostic workup for hypophysitis should be considered 
e.g. for patients with multiple endocrinopathies, 
unexplained fatigue, new severe headaches or vision 
changes. 

Patients should be appropriately advised regarding 
potentially reduced stress tolerance and increased 
substitution demands e.g. in case of infections, and to 
wear a medical alert bracelet to inform medical personnel 
about potentially increased hormone demands in 
situations of stress, in case of emergencies.

Interruption of BI 754091 and BI 891065 therapy should 
be considered for Grade 1 or 2 hypophysitis , and is 
warranted for Grade 3 and higher hypophysitis, until 
patient is stabilized on hormone replacement therapy. 
Hepatitis:

Work-up for other causes of elevated liver enzymes, see 
also section on potential DILI.


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
For Grade 1 hepatitis (elevated AST/ALT < 3x ULN 
and/or total bilirubin <1.5x ULN), BI 754091 and BI 
891065 may be continued, close monitoring of liver values 
is warranted.  

For Grade 2 hepatitis (AST/ALT 3–5x ULN and/or total 
bilirubin >1.5 to ≤3x ULN), BI 754091 and BI 891065 
should be suspended. Monitoring of liver values every 3 
days is recommended. Initiate treatment according to 
available guidelines. Restarting of BI 754091 and BI 
891065 may be considered upon recovery to grade 1 or 
less, and on corticosteroid ≤ 10 mg per day.

For Grade 3 or higher hepatitis, BI 754091 and BI 891065 
has to be permanently discontinued. 
Nephritis:

For Grade 1 nephritis, consider temporarily withholding 
BI 754091 and BI 891065.

For Grade 2 nephritis, withhold BI 754091 and BI 
891065. Consult nephrology. Initiate treatment according 
to guidelines. In case of no improvement or worsening, 
permanently discontinue BI 754091 and BI 891065.BI 
754091 and BI 891065 may only be re-started upon 
recovery to grade 1 or less , and on corticosteroid ≤ 10 mg 
per day.

For Grade 3 or higher nephritis, permanently discontinue 
BI 754091 and BI 891065. Consult nephrology. Treat with 
steroids 1-2 mg/kg prednisone or equivalent. If improved 
to grade 1 or less, taper corticosteroids over no less than 
4-6 weeks.

BI 754091 and BI 891065 should also be permanently 
discontinued for recurrent nephritis grade 2 or higher.
Rash

For Grade 1 rash, continue BI 754091 and BI 891065. 
Initiate topical treatment.  

For Grade 2 rash, BI 754091 and BI 891065 may be 
continued, in case of no improvement upon weekly 
monitoring, consider interruption of BI 754091 and BI 
891065 therapy. Treat topically, add systemic 
corticosteroid therapies as clinically appropriate. 

For Grade 3 rash, withhold BI 754091 and BI 891065. 
Initiate topical and systemic therapy as per available 
guidelines. Upon improvement of event to grade 1 or less, 
and on corticosteroid ≤ 10 mg per day, consult with 
dermatology whether therapy with BI 754091 and BI 
891065 might be restarted, especially in case no 
alternative anti-neoplastic therapy is available. 

For Grade 4 rash, BI 754091 and BI 891065 should be 
permanently discontinued.

BI 754091 and BI 891065 should also be discontinued for 
recurrent rash grade 3 or higher.


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Bullous dermatosis

For Grade 1 bullous dermatosis, use local wound care 
and observation. BI 754091 and BI 891065 can be 
continued. 

For Grade 2 bullous dermatosis, withhold BI 754091 and 
BI 891065. Administer topical therapy, add systemic 
therapy as clinically adequate. 

For Grade 3 bullous dermatosis, withhold BI 754091 and 
BI 891065, initiate topical and systemic therapy as per 
available guidelines. Restarting of BI 754091 and BI 
891065 may be considered after dermatology 
consultation. 

For Grade 4 bullous dermatosis, permanently 
discontinue BI 754091 and BI 891065.
Severe cutaneous adverse reaction (SCAR), Stevens Johnson 
Syndrome (SJS), Toxic Epidermal Necrolysis (TEN)

For Grade 2 events, withhold BI 754091 and BI 891065, 
initiate treatment as per available guidelines. Closely 
monitor for improvement or worsening. 

For Grade 3 events, withhold BI 754091 and BI 891065. 
Initiate treatment as per available guidelines. In case 
mucous membranes are affected, involve appropriate 
disciplines in management to prevent sequelae from 
scarring (e.g. ophthalmology). 

For Grade 4 events, permanently discontinue BI 754091 
and BI 891065, immediately administer adequate 
therapy. Immediate admission to burn center or 
intensive care with dermatology and wound care is 
recommended, involve appropriate other disciplines as 
needed in management of mucosal involvement. 
In case of Grade 2 or Grade 3 events, BI 754091 and BI 
891065 may only be re-started upon event recovered to Grade 
1 or less, on corticosteroid ≤ 10 mg per day, and after 
consultation with dermatology. 
Encephalitis/Aseptic meningitis

BI 754091 and BI 891065 should be permanently 
discontinued for any grade.
  
Myasthenia gravis

For Grade 2 myasthenia gravis, withhold BI 754091 and 
BI 891065, 

For Grade 3 or 4 myasthernia gravis, permanently 
discontinue BI 754091 and BI 891065  
Guillain Barré Syndrome (GBS)

Discontinue BI 754091 and BI 891065 permanently for 
any grade GBS. 


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Transverse Myelitis

Discontinue BI 754091 and BI 891065 permanently for 
any grade transverse myelitis. 
Peripheral neuropathy, autonomic neuropathy

For Grade 1 events, may continue BI 754091 and BI 
891065, but with low threshold to discontinue while 
monitoring closely for worsening. 

For Grade 2 events, withhold BI 754091 and BI 891065 
until resolution to grade 1 or less, and on corticosteroid ≤ 
10 mg per day. Initiate therapy as appropriate per 
available guidelines. 

For Grade 3 or grade 4 events, permanently discontinue 
BI 754091 and BI 891065. 
Inflammatory Arthritis

For Grade 1 arthritis, BI 754091 and BI 891065 can be 
continued. Administer analgetic treatment 
(acetaminophen, NSAID). 

For Grade 2-4 arthritis, withhold BI 754091 and BI 
891065. Initiate treatment as per available guidelines, 
cave regarding reactivation of tuberculosis/opportunistic 
infections in case of prolonged 
immunosuppressive/DMARD therapy. 
BI 754091 and BI 891065 may be restarted after consultancy 
with rheumatology once recovery to grade 1 or less, and on 
corticosteroid ≤ 10 mg per day. 
Myositis
Diagnostic workup should consider the need to also evaluate 
myocardial involvement.   

For Grade 1 myositis, BI 754091 and BI 891065 may be 
continued. Initiate adequate therapy as clinically 
warranted. In case of elevated CK or muscle weakness, 
treat as grade 2. 

For Grade 2 myositis, withhold BI 754091 and BI 
891065, discontinue permanently in patients with 
objective findings (elevated enzymes, abnormal EMG, 
abnormal muscle MRI or biopsy). Initiate therapy as per 
available guidelines. Resuming BI 754091 and BI 891065 
may be considered in patients without objective findings, 
symptoms have resolved to grade 1 or less without any 
immunosuppressive therapy, and after consultation with 
rheumatology/neurology. 

For Grade 3 or  4 myositis, permanently discontinue BI 
754091 and BI 891065. 

BI 754091 and BI 891065 should be permanently 
discontinued if there is any evidence of myocardial 
involvement.
Polymyalgia-like syndrome


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
For Grade 1 event, BI 754091 and BI 891065 can be 
continued.   

For Grade 2 event, withhold BI 754091 and BI 891065 
and promptly initiate adequate therapy. If no 
improvement, treat as grade 3.

For Grade 3 or G4 event, withhold BI 754091 and BI 
891065, promptly initiate adequate therapy 
Rheumatology consultancy is highly recommended. 
BI 754091 and BI 891065 may be resumed after careful 
assessment of risks and benefits, rheumatology consultancy 
highly recommended prior to reinitiation. BI 754091 and BI 
891065 may only be re-started upon recovery to grade 1 or 
less and on corticosteroid ≤ 10 mg per day. 
Myocarditis

Discontinue BI 754091 and BI 891065 permanently for 
any grade of myocarditis. 
Uveitis/Iritis, Episcleritis

For Grade 1 events, treatment with BI 754091 and BI 
891065 can continue. Treat topically as needed.

For Gade 2 events, withhold therapy with BI 754091 and 
BI 891065, urgent ophthalomology referral is 
recommended. Initiate topical treatment, consider 
systemic therapy if needed. Restart of BI 754091 and BI 
891065 is permitted once resolved to grade 1 or less, and 
off systemic steroids (for the ocular condition, if steroids 
needed for other irAEs, up to 10 mg prednisone or 
equivalent are permitted). Continuation of topical/ocular 
steroids is permitted and does not prohibit resuming BI 
754091 and BI 891065 therapy. 

For Grade 3 or 4 events, permanently discontinue BI 
754091 and BI 891065 therapy. Seek emergent 
ophthalmology consultation.. Initiate adequate local and 
systemic treatment.   
Autoimmune-hemolytic anemia (AIHA)

For Grade 1 AIHA, continue treatment with BI 754091 
and BI 891065. Close follow-up of anemia and other lab 
values. 

For Grade 2-4 AIHA, discontinue BI 754091 and BI 
891065 permanently. Initiate systemic therapy as per 
guideline. Consult Hermatology.
Acquired thrombotic thrombocytopenic purpura (TTP), 
haemolytic uremic syndrome. 
Timely recognition upon suggestive findings is essential, 
timely/immediate involvement of hematology consultancy 
may be beneficial. 

For any grade TTP, permanently discontinue BI 754091 
and BI 891065. 


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
For HUS (TTP excluded), withhold BI 754091 and BI 
891065 for grade 1 and grade 2, provide supportive care. 
Upon full recovery, BI 754091 and BI 891065 may be 
restarted after carefuly weighing of risks and benefits. 

For Grade 3 or Grade 4 HUS, discontinue BI 754091 and 
BI 891065 permanently. 
Immune thrombocytopenia (ITP)

In case of Grade 1 ITP, BI 754091 and BI 891065 can be 
continued. 

For Grade 2 or Grade 3 ITP, withhold BI 754091 and BI 
891065 and initiate systemic therapy. BI 754091 and BI 
891065 may be restarted upon resolution to at least grade 
1. 

For Grade 4 ITP, permanently discontinue BI 754091 
and BI 891065. 
Management of immune-related event toxicities associated with 
anti-PD-1 mAbs are presented below. BI 754091 should be 
permanently discontinued for Grade 3-4 pneumonitis, Grade 3-4 
adrenal insufficiency, Grade 4 diabetes mellitus, any grade 
encephalitis, Grade 4 hypophysitis, Grade 4 rash, Grade 3-4 or 
recurrent colitis of any grade, any recurrent Grade 3-4 AE, 
transaminase >5 times ULN or total bilirubin >3 times ULN, 
inability to taper steroids to 10 mg or less prednisone or 
equivalent within 12 weeks, or persistent Grade 2-3 AEs that do 
not recover to Grade 1 or less within 12 weeks.
Pneumonitis:

For Grade 2 events, treat with systemic corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 28 days.

Add prophylactic antibiotics for opportunistic infections in 
the case of prolonged steroid administration.
-
For Grade 3-4 events immediately treat with i.v. 
steroids. Administer additional anti-inflammatory 
measures, as needed.

BI 754091 should be permanently discontinued for Grade 
3-4 pneumonitis, inability to taper steroids to 10 mg or 
less prednisone or equivalent within 12 weeks, or 
persistent Grade 2 AEs that do not recover to Grade 1 or 
less within 12 weeks.
Diarrhoea/Colitis:
Subjects should be carefully monitored for signs and symptoms 
of enterocolitis (such as diarrhoea, abdominal pain, blood or 
mucus in stool, with or without fever) and of bowel perforation 
(such as peritoneal signs and ileus).

All subjects who experience diarrhoea/colitis should be 
advised to drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and electrolytes should 


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be substituted via i.v. infusion. For Grade 2 or higher 
diarrhoea, consider GI consultation and endoscopy to confirm 
or rule out colitis.

For Grade 2 diarrhoea/colitis that persists greater than 3 days, 
administer oral corticosteroids.

For Grade 3 or 4 diarrhoea that persists >1 week, treat with 
i.v. steroids followed by high-dose oral steroids.

For Grade 3 or 4 colitis, or recurrent colitis of any grade, 
permanently discontinue BI 754091 and immediately treat 
with i.v. steroids followed by high-dose oral steroids.

When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 28 
days.

BI 754091 should be permanently discontinued for Grade 3-4 
or recurrent colitis of any grade, inability to taper steroids to 
10 mg or less prednisone or equivalent within 12 weeks, or 
persistent Grade 2-3 AEs that do not recover to Grade 1 or 
less within 12 weeks.
Type I diabetes mellitus (if new onset, including diabetic 
ketoacidosis) Grade 3, or ≥Grade 3 hyperglycaemia, if associated 
with ketosis (ketonuria) or metabolic acidosis

For Type I diabetes mellitus Grade 3-4 or Grade 3-4 
hyperglycaemia

Insulin replacement therapy is recommended for Type I 
diabetes mellitus and for Grade 3-4 hyperglycaemia 
associated with metabolic acidosis or ketonuria.

Evaluate subjects with serum glucose and a metabolic panel, 
urine ketones, glycosylated haemoglobin, and C-peptide.
-
BI 754091 should be permanently discontinued for 
Grade 4 diabetes mellitus, any recurrent Grade 3 AE 
or persistent Grade 2-3 AE that does not recover to 
Grade 1 or less within 12 weeks.
Hypophysitis:

For Grade 2 events, treat with corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 28 days. Replacement 
of appropriate hormones may be required as the steroid dose 
is tapered.

For Grade 3 events, treat with an initial dose of i.v. 
corticosteroids followed by oral corticosteroids.  When 
symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 28 days. Replacement 
of appropriate hormones may be required as the steroid dose 
is tapered.

For Grade 4 events, permanently discontinue BI 754091, and 
treat with an initial dose of i.v. corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no 
less than 28 days. Replacement of appropriate hormones may 


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be required as the steroid dose is tapered.

BI 754091 should be permanently discontinued for Grade 4 
hypophysitis, any recurrent Grade 3 AE, inability to taper 
steroids to 10 mg or less prednisone or equivalent within 12 
weeks, or persistent Grade 2-3 AEs that do not recover to 
Grade 1 or less within 12 weeks.
Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. 
Monitor subjects for changes in thyroid function (at the start 
of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and 
symptoms of thyroid disorders.

For Grade 2 hyperthyroidism events (and Grade 3-4 
hypothyroidism):

In hyperthyroidism, nonselective beta-blockers (e.g., 
propranolol) are suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, 
with levothyroxine or liothyronine, is indicated per standard 
of care.

For Grade 3-4 hyperthyroidism

Treat with an initial dose of i.v. corticosteroid followed by 
oral corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no 
less than 28 days. Replacement of appropriate hormones may 
be required as the steroid dose is tapered.

BI 754091 should be permanently discontinued for any 
recurrent Grade 3-4 AE, inability to taper steroids to 10 mg 
or less prednisone or equivalent within 12 weeks, or 
persistent Grade 2-3 AEs that do not recover to Grade 1 or 
less within 12 weeks.
Hepatic:

For Grade 2 events, monitor liver function tests more 
frequently until returned to baseline values (consider 
weekly).

Treat with i.v. or oral corticosteroids

For Grade 3-4 events, treat with i.v. corticosteroids for 24 to 
48 hours.

When symptoms improve to Grade 1 or less, a steroid taper 
should be started and continued over no less than 28 days.

BI 754091 should be permanently discontinued for any 
recurrent Grade 3-4 AE, transaminase >5 times ULN or total 
bilirubin >3 times ULN, inability to taper steroids to 10 mg 
or less prednisone or equivalent within 12 weeks, or 
persistent Grade 2-3 AEs that do not recover to Grade 1 or 
less within 12 weeks.
Renal failure or nephritis:

For Grade 2 events, treat with corticosteroids.

For Grade 3-4 events, treat with systemic corticosteroids.


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
When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 28 days.

BI 754091 should be permanently discontinued for any 
recurrent Grade 3-4 AE, inability to taper steroids to 10 mg 
or less prednisone or equivalent within 12 weeks, or 
persistent Grade 2-3 AEs that do not recover to Grade 1 or 
less within 12 weeks.
Adrenal insufficiency

BI 754091 should be permanently discontinued for 
Grade 3 to 4 adrenal insufficiency or persistent Grade 2 AEs 
that do not recover to Grade 1 or less within 12 weeks.
Rash

BI 754091 should be permanently discontinued for Grade 4 
rash, any recurrent Grade 3 AE or persistent Grade 2 to 3 
AEs that do not recover to Grade 1 or less within 12 weeks.
Encephalitis

BI 754091 should be permanently discontinued for any grade 
encephalitis.
Infusion reactions:
Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 
hours of completion of infusion.
Rationale for change
To revise and clarify the management of immune-related adverse 
events based on more recent data. 
Section to be changed
Table 10.3: 2 Time schedule for PK blood, 
 
 sampling during Part B including food effect
Description of change
Time schedule for PK blood, 
 
 during Part B including food effect in q.d. treatment 
group
Rationale for change
To identify that the PK, 
 sample 
collections described in the table are only for q.d. patients. 
Section to be changed
Table 10.3: 2 Time schedule for PK blood, 
 
 sampling during Part B including food effect 
effect in q.d. treatment group and 
Table 10.3: 4 Time schedule for PK blood, 
 
 sampling during Part C-NSCLC
Description of change
b The following windows of time are allowed for PK and ECG
sampling: (ECGs should be performed PRIOR to PK 
sampling):
Rationale for change
To clarify when ECGs should be collected relative to PK 
collections. 
Section to be changed
Table 10.3:3 was added to the trial protocol
Description of change
Table 10.3: 3 Time schedule for PK blood, 
 
 sampling during Part B excluding food 


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effect in b.i.d. treatment group 
Samples
Cy
cle
Vi
sit
D
ay
Time 
Point 
[hh:min]/ 
event
CRF 
Tim
e
/PT
M
Trip
licat
e
EC
G*
Plas
mab
BI 
8910
65
Plas
mab
BI 
7540
91
Biop
syc
1
2
1
Predose (between 
screening and 
C1D1 dosing)
X
-30 min 
(+/-15min)
-30 
min
X
1
2
1
Just before 
drug admin
Pred
osea
X
X
X
X
BI 754091 
admin
0:00
Just before 
infusion 
end 
1:00
X
1:25
1:25
X**
X
X
BI 891065 
admin
1:30
2:00
2:00
X
X
2:30
2:30
X**
X
X
3:30
3:30
X**
X
X
4:30
4:30
X**
X
X
X
6:30
6:30
X**
X
X
7:30
7:30
X
X
X
8:30
8:30
X**
X
X
9:30
9:30
X
X
X
X
11:30
11:3
0
X**
X
X
No drug 
intake
13:3
0
3
2
Just before 
drug intake
25:2
5
X
X
X
X
BI 891065 
intake
25:3
0
4
8
Just before 
drug intake
167:
55
X
X
X
BI 891065 
intake
168:
00
5
12 Just before 
drug intake
263:
55
X
X
BI 891065 
intake
264:
00
ADA = anti-drug antibodies; BI = Boehringer Ingelheim; CRF = Case Report 
Form; IAP = inhibitor of apoptosis; PTM = planned time
a PK to be taken following an overnight fast (minimum 10 hours) on this day
b The following windows of time are allowed for PK and ECG sampling (ECGs 
should be performed PRIOR to PK sampling):

Predose samples (PTM -0:05, 25:25, 167:55, etc.): within 1 hour before 
drug intake

One hour to 4:30 hours post first drug intake (PTM 1:00 through PTM 


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4:30): within ±10 minutes of designated time

6:30 to 11:30 hours post first drug intake (PTM 6:30 through 11:30): 
within ±15 minutes of designated time
Time windows are specified for procedural reasons; deviations do not 
automatically lead to exclusion of samples from data evaluation.
c Biopsy for IAP degradation to be taken as noted in  Part B Flow Chart.
* In order not to confuse an ECG recording, all PK samples should be taken 
after performing the ECGs.
** ECGs will be taken throughout, as it is possible that time of maximum 
concentration is not accurately estimated; for safety, this is one of the most 
relevant time points, so should not be missed. As such, some ECGs may only be 
evaluated at later points or, if deemed unnecessary, not at all.
Table 10.3: 3 Time schedule for PK blood, 
 
 sampling during Part B excluding food 
effect in b.i.d. treatment group (continued)
Samples
Cycle Vi
sit
D
ay
Time 
Point 
[hh:min]/ 
event
CR
F 
Tim
e
/PT
M
Trip
licat
e 
EC
Gs*
Plas
mab 
BI 
8910
65
Plas
mab
BI 
7540
91
Bio
psyc
1
6
15 Just before 
drug admin
335:
55a
X
X
X
BI 891065 
intake
336:
00
0:30
336:
30
X
X
1:00
337:
00
X**
X
2:00
338:
00
X**
X
3:00
339:
00
X**
X
5:00
341:
00
X**
X
6:00
342:
00
X
X
7:00
343:
00
X**
X
8:00
344:
00
X
X
10:00
346:
00
X**
X
No drug 
intake
348:
00
7
16 Just before 
drug intake
359:
30**
*
X
X
X
BI 891065 
intake
360:
00


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2-5, 
then 
every 
2nd
cycle
9-
12 
the
n 
ev
ery 
2nd
cy
cle
1
Just before 
drug admin
-
0:05
X 
(C2 
only
)
X
X 
X
Just before 
infusion 
end
1:00
X
EOT
X
X
X
30-Day 
FU
X
X
ADA = anti-drug antibodies; BI = Boehringer Ingelheim; CRF = Case Report 
Form; ECG = electrocardiogram; EOT = end of treatment; FU = follow up; 
IAP = inhibitor of apoptosis; PTM = planned time
a PK to be taken following an overnight fast (minimum 10 hours) on this day
b The following windows of time are allowed for PK and ECG sampling (ECGs 
should be performed PRIOR to PK sampling):

Predose samples (PTM 335:55 [Day 15]): within 1 hour before drug intake

On Day 15 (PTM 336:30 through 339:00): within ±10 minutes of 
designated time

On Day 15 (PTM 341:00 through 346:00): within ±15 minutes of 
designated time

On Day16 (PTM 359:30): within 30 min before drug intake
Time windows are specified for procedural reasons; deviations do not 
automatically lead to exclusion of samples from data evaluation.
c Biopsy for IAP degradation to be taken as noted in Part B Flow Chart.
* In order not to confuse an ECG recording, all PK samples should be taken 
after performing the ECGs.
** ECGs will be taken throughout, as it is possible that time of maximum 
concentration is not accurately estimated; for safety, this is one of the most 
relevant time points, so should not be missed. As such, some ECGs may only be 
evaluated at later points or, if deemed unnecessary, not at all.
***Central lab kits provided will contain extra tubes (for post-dose timepoints 
360:30-370:00 on Day 16 and 383:55 on Day 17).  These tubes should not be 
used for b.i.d patients. 
Rationale for change
To describe the PK, 
 sample 
collections for Part B b.i.d. patients. 
Section to be changed
Section 10.4 Pharmacokinect Analyses
Description of change
•
Cpre,N (pre-dose concentration of the analyte in plasma 
after before the Nth dose)
Rationale for change
To correct an error in the text for the Cpre N collection time.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11957282
7.0
clinical-trial-protocol-version-07
An open-label Phase I dose finding trial with BI 891065 alone and in combination
with BI 754091 to characterise safety, tolerability, pharmacokinetics,
pharmacodynamics, and efficacy in patients with advanced and/or metastatic
malignancies
Approval-Team Member Medicine
14 Feb 2020 17:12 CET
Approval-Translational Medicine
Expert
14 Feb 2020 17:51 CET
Author-Clinical Trial Leader
14 Feb 2020 18:16 CET
Approval-Therapeutic Area
14 Feb 2020 18:52 CET
Author-Trial Statistician
14 Feb 2020 21:57 CET
Author-Trial Clinical
Pharmacokineticist
17 Feb 2020 02:10 CET
Verification-Paper Signature
Completion
18 Feb 2020 19:48 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11957282
7.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c17263334-04
BI Trial No.:
1379.1
Title:
An open-label Phase I dose finding trial with BI 891065 alone and 
in combination with BI 754091 to characterise safety, tolerability, 
pharmacokinetics, pharmacodynamics, and efficacy in patients with 
advanced and/or metastatic malignancies
Including Protocol Amendments 1, 2, 3, 4, 5 and 6 (c11957282-07)
Investigational
Product(s):
BI 891065 + BI 754091
Responsible trial 
statistician(s):
Phone: 
Date of statistical 
analysis plan:
21 DEC 2020 REVISED
Version:
Revised
Page 1 of 48
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Boehringer Ingelheim
TSAP for BI Trial No: 1379.1
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINT(S).......................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
5.4
OTHER VARIABLE(S) .....................................................................................15
5.4.1
Demographics and baseline history...................................................................15
5.4.2
Extent of Exposure..............................................................................................16
5.4.3 
ECG......................................................................................................................16
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................19
6.1
TREATMENT(S)................................................................................................19
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................19
6.3
SUBJECT SETS ANALYSED...........................................................................22
6.5
POOLING OF CENTRES .................................................................................23
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................23
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................26
7.
PLANNED ANALYSIS......................................................................................28
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........29
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................29
7.3
TREATMENT COMPLIANCE........................................................................29
7.4
PRIMARY ENDPOINT(S) ................................................................................29
7.5
SECONDARY ENDPOINT(S) ..........................................................................30
7.5.1
Key secondary endpoint(s).................................................................................30
7.5.2
(Other) Secondary endpoint(s) ..........................................................................30
7.7
EXTENT OF EXPOSURE.................................................................................31
7.8
SAFETY ANALYSIS..........................................................................................32
7.8.1
Adverse events.....................................................................................................32
7.8.2
Laboratory data ..................................................................................................33
7.8.3
Vital signs.............................................................................................................36
7.8.4
ECG......................................................................................................................36
7.8.5
Others...................................................................................................................40


Boehringer Ingelheim
TSAP for BI Trial No: 1379.1
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8.
REFERENCES....................................................................................................44
10.
HISTORY TABLE..............................................................................................48


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LIST OF TABLES
Table 5.2.2: 1 Censoring rules for duration of objective response according to RECIST 
v1.1...................................................................................................................10
Table 6.2: 1
Important protocol deviations ..........................................................................19
Table 6.6: 1 Interpretation of qualitative ECG findings ..........................................................25
Table 6.7: 1 
Nominal time points and windows for imaging...............................................26
Table 7.8.2: 1 Primary laboratory tests....................................................................................34
Table 7.8.2: 2 Secondary laboratory tests................................................................................35
Table 10: 1
History table .....................................................................................................48


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
BMI
Body Mass Index
cIAP
Cellular Inhibitor of Apoptosis
CR
Complete Response
CT
Concomitant Therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug-induced Liver Injury
DLT
Dose-limiting Toxicity
ECG
Electrocardiogram
ECGPCS
Electrocardiogram Pharmacokinetic Concentration Set
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ES
Enrolled Set
HR
Heart Rate
ICH
International Conference on Harmonization
iCPD
Immune Confirmed Progressive Disease
iCR
Immune Complete Response
iPR
Immune Partial Response
IPD
Important Protocol Deviation
iRECIST
modified RECIST 1.1 for immune-based therapeutics
iSD
Immune Stable Disease
iUPD
Immune Unconfirmed Progressive Disease


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MedDRA
Medical Dictionary for Regulatory Activities
ms
milliseconds
MTD
Maximum Tolerated Dose
NSCLC
Non-small Cell Lung Cancer
OR
Objective Response
ORR
Objective Response Rate
PBMCs
Peripheral Blood Mononuclear cells
PD
Progressive Disease
PFS
Progression-free Survival
PK
Pharmacokinetics
PKS
Pharmacokinetic Set
PR
Partial Response
PR interval
ECG interval from the onset of the P wave to the beginning of the QRS 
complex
PT
Preferred Term
QRS
Combination of the Q, R and S waves
QT
ECG interval from the beginning of the QRS complex to the end of the T 
wave
QTc
Generic term for QTcF and QTcB intervals
QTcB
QT interval, corrected by Bazett’s formula
QTcF
QT interval, corrected by Fridericia’s formula
RECIST
Response Evaluation Criteria In Solid Tumours
REP
Residual Effect Period
SCR
Screened Set
SD
Stable Disease 
SOC
System Organ Class
SRC
Safety Review Committee
StD
Standard Deviation
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO DD
World Health Organisation Drug Dictionary 


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3.
INTRODUCTION
As per International Conference on Harmonisation E9 (ICH E9) (1) the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the protocol, and to include detailed procedures for executing the 
statistical analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, and definition of measurements and variables.
The study is a multicentre study consisting of three study parts. Part A is an open-label, dose-
escalation of BI 891065 alone. Part B is an open-label dose-escalation of BI 891065 in 
combination with a fixed dose of BI 754091. Part C consists of an expansion cohort in non-
small cell lung cancer (NSCLC).
For the primary objective of the separate parts of the trial, refer to Section 2 of the CTP. 
In the following, study medication always refers to BI 891065 in Part A, and to BI 891065
and/or BI 754091 in Parts B and C. 
SAS® Version 9.4 or higher will be used for all analyses besides pharmacokinetic (PK)
analyses if not specified otherwise. WinNonlin Version 8.1 will be used for PK analyses. 


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in the CTP will be carried out.
Since  of BI 891065 appears to be earlier than expected, all ECG recordings collected at 
the scheduled time points listed in Tables 10:3:1, 10:3:2 and 10:3:3 of the CTP will be 
analysed.
Part C of this trial is cancelled and enrolled no patients. Hence, no planned analyses for this 
trial part will be conducted.


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT(S)
Part A:
The primary endpoints for Part A of the trial are the MTD of BI 891065 and the number of 
patients with dose-limiting toxicities (DLTs) during the MTD evaluation period (first 
treatment cycle). For definition of the MTD, refer to Section 2.1.2.1 of the CTP.
Part B:
The primary endpoints for Part B of the trial are the MTD of BI 891065 in combination with 
BI 754091 and the number of patients with DLTs during the MTD evaluation period (first 
treatment cycle). For definition of the MTD, refer to Section 2.1.2.2 of the CTP.
Part C:
The primary endpoint is OR by investigator’s assessment based on RECIST version 1.1 (2).
For definition of OR refer to CTP Sections 2.1.2.3.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
Secondary endpoint(s)
Part A:

The number of patients with DLTs observed during the entire treatment period

Cmax,ss, AUC0-tz and AUCτ,ss of BI 891065 in the first treatment cycle

OR by investigator’s assessment based on RECIST v1.1, defined in the same way as 
the primary endpoint for Part C.
Part B:

The number of patients with DLTs observed during the entire treatment period

Cmax,ss, AUC0-tz and AUCτ,ss of BI 891065 in the first treatment cycle and Cmax and 
AUC0-tz of BI 754091 in the first treatment cycle

OR by investigator’s assessment based on RECIST v1.1, defined in the same way as 
the primary endpoint for Part C.
Part C:
Secondary endpoint for Part C is the duration of OR by investigator’s assessment based on 
RECIST v1.1.
Duration of OR is defined as:
Duration of OR [days] = date of outcome – date of attaining complete response (CR) or 
partial response (PR) +1,


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for patients who achieve a CR or PR according to RECIST v1.1. Censoring rules and 
applicable dates of outcome for duration of OR according to RECIST v1.1 are specified in 
Table 5.2.2: 1.
Table 5.2.2: 1 Censoring rules for duration of objective response according to RECIST v1.1
Situation
Outcome 
(event or 
censored)
Date of outcome
No other anti-cancer therapy
Alive and not progressed according to 
RECIST v1.1, no more than one 
consecutively missed radiological 
assessment
Censored
Date of last radiological 
assessment
Alive and not progressed according to 
RECIST v1.1, two or more consecutively 
missed radiological assessments 
Censored
Date of last radiological 
assessment prior to 
missed radiological 
assessments
Progressed according to RECIST v1.1, 
zero or one missed radiological assessment 
prior to progression 
Event
Date of radiological 
assessment of 
progression
Progressed according to RECIST v1.1, two 
or more consecutively missed radiological 
assessments prior to progression
Censored
Date of last radiological 
assessment prior to 
missed assessments
Death but no progression according to 
RECIST v1.1, zero or one missed 
radiological assessment prior to death
Event
Date of death
Death without progression according to 
RECIST v1.1, but two or more 
consecutively missed radiological 
assessments prior to death
Censored
Date of last radiological 
assessment prior to 
missed assessments
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer therapy started 
before progression according to RECIST 
v1.1 or death, no more than one 
consecutively missed radiological 
assessments prior to start of subsequent 
anti-cancer therapy
Censored
Date of last radiological 
assessment before 
initiation of subsequent 
anti-cancer therapy


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5.4
OTHER VARIABLE(S)
5.4.1
Demographics and baseline history
Only derived variables are defined here. Standard demographic and baseline characteristics 
will be used as recorded in the electronic case report form (eCRF). 


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Body Mass Index (BMI):
BMI #kg
m%& =
weight [kg]
(height [m])%
5.4.2
Extent of Exposure
Duration of BI 891065 intake is defined as the time from first administration of BI 891065 
until the last administration of BI 891065 +1 day.
The duration of BI 754091 intake will be assessed in terms of number of BI 754091 courses
administered for Part B and Part C.
The time to first dose reduction of BI 891065 is defined as the time from first administration 
of BI 891065 to the first administration of the first reduced dose of BI 891065 +1 day.
Dose intensity (%) will be calculated as the total dose received by the patient divided by the 
planned total dose, where the planned total dose will be calculated as the dose that the patient 
should have received between the day of first administration and the date of last 
administration of BI 891065 (for the dose intensity of BI 891065) and BI 754091 (for the
dose intensity of BI 754091), respectively. That is, the actual dose will be divided by the 
amount of drug that would have been administered had the protocol-specified first dose been 
administered at each day according to the protocol schedule until the end of treatment.
5.4.3 
ECG
Clinically relevant electrocardiogram (ECG) findings will be analysed in terms of adverse 
events (AEs). Additionally, statistical ECG analyses will be done with variables defined as in 
the following paragraphs for all 3 trial parts.
Refer to Section 7.8.4 for a detailed description of the derivation of ECG variables. 
The generic term QTc for heart rate corrected QT intervals comprises the fixed corrections
QTcF (Fridericia’s correction) and QTcB (Bazett’s correction). Results involving the QTcB 
interval will only be presented in listings in the appendix of the CTR. For ECG analyses, the 
on-treatment period refers to all scheduled time points with centrally evaluated ECG 
recordings following the first administration of trial medication in Cycle 1.
Quantitative variables

Changes in QTcF interval between baseline and on-treatment

Absolute QTcF intervals at baseline and on-treatment
These variables will also be computed for the uncorrected QT interval, QTcB, the heart rate, 
the PR interval, and the QRS complex. Furthermore, the percentage change will be calculated 
for PR interval and QRS complex.


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Categorical variables
The following thresholds will be used for a categorization of the quantitative ECG variables 
for each patient per time point:

QTc intervals ≤450 ms, > 450 to 480 ms, > 480 to 500 ms or > 500 ms, at baseline 
and for all on-treatment values

QT intervals ≤500 ms, > 500 ms, at baseline and for all on-treatment values

Change from baseline to on-treatment value in QTc interval ≤ 30 ms, 30 ms < QTcF 
interval ≤ 60 ms, > 60 ms

Change from baseline to on-treatment value in QT interval ≤ 60 ms, > 60 ms
For the QTcF and uncorrected QT interval, the categorizations described above will be 
performed separately for the visit days where an ECG profile has been taken as well as for 
the overall on-treatment period using the maximum value per patient within the considered 
period.
A notable finding in QT/QTcF interval in any on-treatment value for a given patient is 
defined as

QTcF change from baseline to on-treatment value > 60 ms at any time on-treatment

new onset of QT/QTcF > 500 ms, where “new onset” denotes the occurrence of a 
finding on-treatment which was not present at baseline

Increase of the PR interval from baseline ≥ 25%, when the corresponding PR interval 
is > 200 ms

Increase of QRS complex from baseline ≥ 25%, when the corresponding QRS 
complex is > 110 ms
Qualitative variables

The overall interpretation of an ECG, which is classified as “normal”, “abnormal”, or 
“unable to evaluate”,

New onset of morphological findings, where “new onset” denotes the occurrence of 
an on-treatment finding, while at baseline this finding was not reported. Among these, 
new onset of the following findings are of special interest: atrial flutter, atrial 
fibrillation, any degree or type of heart block, ST-segment changes, T wave 
abnormalities, new U waves and myocardial infarction pattern.
The occurrence of notable or qualitative ECG findings will also be derived for the aggregated 
on-treatment time points of the visit days where an ECG profile has been taken as well as for 
the overall on-treatment period.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
In this Phase I trial, treatments are not randomized. In Parts A and B, different dose levels of 
BI 891065 alone (Part A) or of BI 891065 in combination with BI 754091 (Part B) are being 
administered. In the expansion part (Part C), patients will be treated with the dose 
combination that has been determined in Part B. 
The data will be presented separately for each part, if not specified otherwise. All planned 
analyses will be presented by initial treatment group, i.e. in Parts A and B for all dose cohorts 
separately and in total over all dose cohorts of that trial part. Patients where treatment group 
assignment in terms of dose cohorts within a trial part has not been followed will be handled 
on a case-by-case basis and will be agreed upon latest at the report planning meeting before 
database lock of the specific trial part.
For safety summaries events that start from the first administration of any trial medication 
until 30 days (REP) after the last administration of any trial medication will be considered as 
having occurred “on-treatment”. If not specified otherwise, all safety tables will be based on 
the on-treatment period. Adverse events that have onset during the screening or the follow-up 
period will be displayed in separate listings from those that occurred during the on-treatment 
period. The MTD evaluation period will be defined as start of cycle 1 + 21 days for all 
patients. Labels of each analysing treatment period, analysis numbers, the labels used for 
displays in the tables and listings in the CTR, as well codes, decodes, sort order and labels for 
each trial medication are provided in the TSAP technical documents. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
No per protocol set analysis will be performed for this study, hence no patient will be 
excluded from this analysis. However, patients with important protocol deviations (IPDs) will 
be documented. The following table defines the different categories of IPDs. The final list of 
IPDs will be confirmed at the last report planning meeting before database lock for the 
analysis.
Table 6.2: 1
Important protocol deviations
Category 
/ Code
Description
Comment / 
Example
Excluded 
from
Automatic 
/ Manual
A
Entrance criteria not 
met
A1
Patient has condition that 
may cause additional risk 
from study medication
IN3; EX7, EX8, 
EX9, EX10, EX12, 
EX13, EX16, EX17
None
Automatic


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Table 6.2: 1 Important protocol deviations (cont.)
Category 
/ Code
Description
Comment / Example
Excluded 
from
Automatic 
/ Manual
A2
Patient has 
laboratory 
assessment that 
may cause 
additional risk
EX11, EX21
None
Automatic
A3
Patient is 
unable to 
comply with the 
protocol
EX3, EX15
None
Automatic
A4
Patient does not 
have trial 
diagnosis or is 
not part of the 
target 
population
IN2, IN4, IN5, IN6, IN7, IN8, 
IN9
EX20, EX22, EX23, EX24
None
Automatic
A5
Patient has 
condition that 
may interfere 
with evaluation 
of safety and/or 
efficacy
EX1, EX2, EX4, EX5, EX6, 
EX14, EX18, EX19
None
Automatic
B
Informed 
consent
B1
Trial Informed 
consent not 
available, not 
done
IN1
All
Automatic
B2
Informed 
consent too late
Date of informed consent 
later than the first study 
related procedure (This does 
not include the informed 
consent for biobanking and 
the informed consent for 
treatment beyond 
progression)
None
Automatic


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Table 6.2: 1 Important protocol deviations (cont.)
Category 
/ Code
Description
Comment / Example
Excluded 
from
Automatic 
/ Manual
B3
Informed 
consent for 
treatment 
beyond 
progression not 
available or too 
late
Date of informed consent for 
treatment beyond progression 
not available although patient 
treated after progression or 
date of informed consent for 
treatment beyond progression 
later than first administration 
of trial medication after 
progression 
None (as 
long as 
patient 
has not 
withdrawn 
from the 
general 
study 
informed 
consent)
Automatic
C
Trial 
medication
C1
Incorrect 
treatment taken

Study medication 
dispensing error 
leading to change in 
actual treatment 
None
Manual
C2
Incorrect dose 
administered
E.g. reduction criteria as 
specified in CTP Section 
4.1.7 met but no dose 
reduction
None
Manual
C3
Discontinuation 
of study 
medication not 
according to 
protocol
Discontinuation criteria as 
specified in CTP Section 
4.1.7 met but study 
medication not discontinued
None
Manual
D
Concomitant 
medication
D1
Prohibited 
medication

Immunosuppressive 
medications

Live attenuated 
vaccines

Herbal preparations / 
medications
None
Automatic 
& Manual


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Table 6.2: 1 Important protocol deviations (cont.)
Category 
/ Code
Description
Comment / Example
Excluded 
from
Automatic 
/ Manual
E
Trial specific 
violations
E1
Pregnancy test 
not done
Pregnancy test not done in 
women of childbearing 
potential although indicated 
by the protocol
None
Automatic 
& Manual
6.3
SUBJECT SETS ANALYSED
The Screened Set (SCR) includes all patients who signed the informed consent form and will 
be used to summarise patient disposition.
The Enrolled Set (ES) includes all patients who have been enrolled into the study and will be 
used for demographics analyses. 
The Treated Set (TS) consists of all patients who have received at least one administration of 
any trial medication and will be used for all planned safety, efficacy and biomarker analyses
in the CTRs besides the MTD determination.
The MTD Evaluation Set includes all patients from the TS who have not been replaced for 
the MTD evaluation; patients who has no actual replacement but satisfies the replacement 
criteria per protocol thus ineligible for MTD evaluation will also be excluded form the MTD 
Evaluation set. This set will be used for the primary analyses of DLTs and MTD 
determination.
Rules for replacement of patients are defined in CTP Section 3.3.4.4. The list of patients 
replaced for MTD evaluation or ineligible for MTD evaluation will be stored in the trial 
master file. 
The Pharmacokinetic Parameter Set (PKS) consists of all patients in the TS who have at least 
one valid secondary PK endpoint available and will be used for all pharmacokinetic analyses. 
The ECG Set includes all patients in the treated set who do not have an artificial pacemaker 
and have at least one on-treatment value for at least one ECG variable.
The ECG Pharmacokinetic Concentration Set (ECGPCS) includes all patients from the ECG 
Set who provide at least one time-matched pair of valid BI 891065 plasma concentration and 
corresponding ECG variable to be used in the exposure-response analysis. 
The decision about concentration value validity needs to be made within the Clinical 
Pharmacology group. Refer to the Section 7.8.4 for the definition of the maximum acceptable 


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time deviation between PK blood sampling and ECG recording at different time points during 
the trial.
The analysis of ECG data will be based on the ECG Set, except those analyses concerning the 
relationship between plasma concentrations and ECG variables which will be based on the 
ECGPCS. Listings for patients with artificial pacemakers will be based on the TS.
6.5
POOLING OF CENTRES
This section is not applicable since there will be no inferential analyses. Thus, no statistical 
model in which centre or country is included as factor will be applied.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates are imputed according to BI standards (4). Missing data and 
outliers of PK data are also handled according to BI standards (5). Potential outliers will be 
reported and analysed as observed. In general, missing data not discussed in (4) and (5) will 
not be imputed unless required for the following analyses and definitions. Then the rules as 
described below apply.
1) Change of laboratory values from baseline
Laboratory values at baseline: For missing laboratory data at cycle 1 day 1 (before the 
first administration of any study medication) the data of preceding visits will be used 
if available. 
2) Definition of on-treatment period and actual treatment 
Date of permanent discontinuation of study medication: All reasonable efforts should 
be undertaken during the study to obtain the dates of permanent discontinuation of 
study medication. However, if the date of the very last administration is missing this 
will be imputed with:

If only month and year are given, the last day of the month will be used for 
imputation

If only the year is given, the 31st of December of this year will be used for 
imputation
If the imputed date leads to a date that is later than the date of the EOT visit, then the 
imputed date is the date of the EOT visit. If the imputed date leads to a date that is 
later than the death date, then the imputed date is the date of death.
3) Partial death dates 


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If a partial (year and month) death date is reported, the date will be imputed with the 
end of the month for the analysis of PFS. This is in line with the imputation of partial 
dates for the analysis of AEs. 
4) Partial or missing start date of subsequent anti-cancer therapy/subsequent 
radiotherapy 
If the day of the start date of subsequent systemic therapy/subsequent radiotherapy is 
missing, then the 1st of the month will be imputed unless this leads to a date before the 
stop date of study medication. In this case the stop date of study medication +1 day 
will be imputed.
If day and month, or day and month and year are missing, it will be distinguished 
whether the start date of subsequent systemic therapy/subsequent radiotherapy is 
required for censoring of PFS or for other descriptive statistics:

For censoring of PFS: If only the year is reported, the 1st of January of this 
year will be imputed unless this leads to a date before the stop date of study 
medication. In this case the stop date of study medication +1 day will be 
imputed. In case of a completely missing start date of subsequent anti-cancer 
therapy/subsequent radiotherapy and the patient did not have any post-baseline 
tumour assessment or did not progress or die, the PFS of this patient will be 
censored at the day of first administration of BI 836826. Additionally, all 
imputed start dates of subsequent anti-cancer therapy/subsequent radiotherapy 
should be before death date, if available.

For descriptive statistics: Dates will not be imputed if more than only the day 
of the date is missing.  
5) ECG analysis
Quantitative and derived categorical ECG endpoints

If single cardiac cycles are missing, the arithmetic means per single ECG will 
be computed with the reduced (1, 2 or 3) number of cardiac cycles.

If replicate ECG recordings are missing, the arithmetic means per time point 
will be computed with the reduced (1 or 2) number of recordings.

If the actual times of all triplicate pre-dose ECG recordings on Day 1 or the 
time of the first drug administration are missing, or the planned pre-dose 
ECGs are recorded after the first drug administration, they will not be used as 
baseline values and will be excluded from the analyses.

If baseline is missing, a QTcF/QT interval > 500 msec at any time on 
treatment will be a notable finding. 


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Qualitative ECG findings

In case a certain qualitative ECG finding is not reported at baseline but 
occurring on-treatment, this will be categorized as a ’new onset’ of this 
finding.

For the analysis of overall ECG interpretation values (comparison of on-
treatment with baseline results), missing values will be handled as indicated in 
the following table.
Table 6.6: 1 Interpretation of qualitative ECG findings
Condition: Overall ECG interpretation
Aggregated result 
presented in 
Table
At baseline
On treatment
(specific time interval under consideration)
Overall ECG 
interpretation
Normal, 
abnormal or 
unable to 
evaluate
Normal (all time points)
Normal
Abnormal
Abnormal (at least one time point)
Abnormal, and 
abnormal at 
baseline
Normal or 
unable to 
evaluate 
Abnormal (at least one time point)
Abnormal (new 
onset) 
Normal, 
abnormal or 
unable to 
evaluate/missing
Unable to evaluate (at least one time point), 
normal or unable to evaluate/missing at the other 
time points
Unable to 
evaluate/missing
Exposure-response analysis

Missing BI 891065 plasma concentration data which are identified by BLQ 
(below lower limit of quantification) will be replaced by zero if measured at 
baseline and by ½ LLOQ (lower limit of quantification) if measured on-
treatment.

If the actual sampling time of the blood sample or of the ECG recording is not 
available, the pair of plasma concentration and time-matched ECG endpoint 
will be excluded from the analyses at the corresponding planned time point. 
Furthermore, plasma concentration data will be excluded from the ECG 
exposure-response analyses, if it is excluded from all calculations in PK 
analysis. 


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study days and visits will be labelled according to the flowchart in the CTP. 
Unless otherwise specified baseline is defined as the time point closest to but prior to the first 
administration of any study medication. If no time is specified and the date is the same as the 
first administration date, then it will still be considered baseline if not specified otherwise. If 
there is no measurement earlier than the first administration of study medication, then no 
baseline will be derived.
Laboratory values: 
Baseline is defined as the latest time point before the very first administration of any study
medication. For laboratories where not only the examination date but also time are recorded, 
examination time has to be taken into account when defining baseline. That is, a laboratory 
value on the same date as the first administration of study medication is considered as 
baseline value if and only if the time of laboratory assessment is before or the same as the 
time of first study drug administration.
If any of these times is missing and the date of laboratory assessment is equal to the date of 
first administration of study medication, then the laboratory assessment will be considered as 
according to protocol, i.e. as prior to first study medication.
Imaging time windows:
In order to identify whether consecutive imaging time points are missing for a given patient, a 
nominal time point (6, 12, … weeks etc.) will be assigned to each and every image. This is 
achieved by creating windows for every radiological response assessment. These windows 
are defined in Table 6.7: 1.
Table 6.7: 1
Nominal time points and windows for imaging
Nominal time point 
(weeks from start of 
study medication)
Due date of scans (days)*
Window (days)
6
43
1 to ≤64
12
85
65 to ≤106
18
127
107 to ≤148
24
169
149 to ≤200
33
232
201 to ≤263 
42
295
264 to ≤326
51
358
327 to ≤389
Etc., 9 week interval
Etc.
Etc.
* the date of the first dose of study medication is Day 1


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If a patient does not have an image in one of the windows described above, he/she will be 
said to have missed an assessment for that time point.
ECG analysis: 
Baseline values will be derived from the 1-3 triplicate ECG recordings prior to the first drug 
administration on Day 1 (refer to Section 7.8.4).


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7.
PLANNED ANALYSIS
The labelling and display format of statistical parameters will follow the BI guideline (8).
All analyses are presented separately for the 3 trial parts, if not specified otherwise. Efficacy 
data are presented by dose cohort for Parts A and B and in total for Part C. Displays of safety 
data will be presented by dose cohort and in total for Parts A and B and in total for Part C, if 
not specified otherwise.
For End-of-Text 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 should be preferred to Mean, StD, Min and Max.
For time-to-event analysis tables the set of statistics is: number of patients [N(%)], number of 
patients with event [N(%)], <time to event> [months] followed by P25 (25th percentile), 
median, P75 (75th percentile) and number of patients censored [N(%)]. If not specified 
otherwise the duration as well as the time to event will be displayed in months.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (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. The 
denominator of the main categories is defined by the number of patients in the used patient 
set. The main categories define the denominators of the subcategories. Subcategories should 
be intended and “[N(%)]” will be displayed only for the main category. If a table includes 
only categorical data, “[N(%)]” is to be displayed in the column header.
Sort order for general categorical variables: If categories correspond to the collected 
categories on the eCRF and the table shells do not explicitly specify the ordering, the “default
ordering” defined by the eCRF is to be used in such cases. If categories are derived, the 
ordering as specified in the table shell document should be used; in general ordinal data (e.g. 
categorised continuous data) are to be displayed in ascending order.
Abbreviations (e.g. Wors.) should not be displayed without any explanations. They will be 
either spelled out in the table or explained in footnotes (whatever is more reasonable from the 
programming point of view).
If applicable, conversion from days to weeks, months and years will be as follows:

Weeks = Days / 7

Months = (Days * 12) / 365.25

Years = Days / 365.25


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive statistics are planned for demographic characteristics, disease history, prior 
therapies, medical history, alcohol and tobacco use, baseline eastern cooperative oncology 
group (ECOG) performance status, and baseline disease assessment.
7.2
CONCOMITANT DISEASES AND MEDICATION
Descriptive statistics are planned for this section of the report. Concomitant diseases will be 
coded similarly as adverse events based on the most current Medical Dictionary for 
Regulatory Activities (MedDRA) version. Concomitant therapies (CTs) will be coded 
according to 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 3 category will be counted more than once. Footnotes will clarify this possible 
double counting in tables.
7.3
TREATMENT COMPLIANCE
Treatment compliance will be listed in the appendix of the CTR. In general, the amount of 
and time for which BI 891065 and BI 754091 are taken will be interpreted in light of 
treatment exposure, efficacy and safety. Refer to Section 5.4.2 and Section 7.7 for further 
details on exposure analysis. 
7.4
PRIMARY ENDPOINT(S)
Part A:
The primary endpoints of Part A are the MTD of BI 891065 and the number of patients with 
DLTs in the first treatment cycle. The number of patients with DLTs at each dose level will 
be presented for the first cycle for the MTD evaluation set and for the whole on-treatment 
period for the treated set separately.
The MTD will be determined by the SRC using recommendations from a Bayesian logistic 
regression model (BLRM, see CTP Section 7 for details on the model and on the prior). 
BLRM evaluations for the CTR will be performed once using the number of patients with 
DLTs during the first cycle from the MTD evaluation set and once using the number of 
patients with DLTs during the whole on-treatment period from the treated set.
Tables and bar charts displaying the posterior probabilities of the true DLT rates being in 
either the underdosing interval, the targeted toxicity interval or the over toxicity interval will 
be produced.   
Part B:
The primary endpoints of Part B are the MTD of BI 891065 in combination with BI 754091
and the number of patients with DLTs in the first treatment cycle. The number of patients 


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with DLTs at each dose level will be presented for the first cycle for the MTD evaluation set 
and for the whole on-treatment period for the treated set separately.
The MTD will be determined by the SRC using recommendations from a BLRM (see CTP 
Section 7 for details on the model, the prior for Part B is described in Section 9.1 of this 
TSAP). BLRM evaluations for the CTR will be performed once using the number of patients 
with DLTs during the first cycle from the MTD evaluation set and once using the number of 
patients with DLTs during the whole on-treatment period from the treated set.
Tables and bar charts (per dose level of BI 754091) displaying the posterior probabilities of 
the true DLT rates being in either the underdosing interval, the targeted toxicity interval or 
the over toxicity interval will be produced.   
Part C:
The primary endpoint of Part C is OR by investigator’s assessment based on RECIST v1.1. 
OR will be analysed descriptively for the treated set in terms of objective response rate 
(ORR), defined as the proportion of patients with best overall response of CR or PR.
An interim futility analysis will be performed by the SRC after 20 patients have been treated 
for at least 18 weeks. Enrolment into Part C will be stopped if less than 2 patients with OR 
have been observed in these 20 patients. Results of this interim analysis will be documented 
in the SRC minutes. 
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
Not applicable as no key secondary endpoints have been defined in the CTP.
7.5.2
(Other) Secondary endpoint(s)
Part A:
The number of patients with DLTs observed during the on-treatment period will be analysed 
descriptively and will be displayed by dose level.  
PK endpoints will be analysed descriptively as well. Plasma (and urine) concentrations of BI 
891065 will be plotted against time. The calculation of the PK parameters, as well as the 
descriptive and comparative analysis of the PK parameters, will be based on the methods 
outlined in Section 7.3.5 of the CTP, as well as in (9). 
OR by investigator’s assessment based on RECIST v1.1 will be analysed descriptively for the 
treated set in terms of the ORR, defined as the proportion of patients with best overall 
response of CR or PR. 
Part B:
The number of patients with DLTs observed during the on-treatment period will be analysed 
descriptively and displayed by dose level.  


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PK endpoints will be analysed descriptively as well. Plasma concentrations of BI 891065 and 
of BI 754091 will be plotted against time. The calculation of the PK parameters, as well as 
the descriptive and comparative analysis of the PK parameters, will be based on the methods 
outlined in Section 7.3.5 of the CTP as well as in (9).
OR by investigator’s assessment based on RECIST v1.1 will be analysed descriptively for the 
treated set in terms of the ORR, defined as the proportion of patients with best overall 
response of CR or PR. 
Part C:
Duration of OR by investigator’s assessment based on RECIST v1.1 will be summarised by 
its median and quartiles derived using the Kaplan-Meier estimation procedure. Duration of 
OR can only be calculated for patients in the treated set that have an OR.
7.7
EXTENT OF EXPOSURE
For all 3 trial parts, duration of BI 891065 intake will be summarised descriptively.


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The number of BI 754091 courses will be assessed for Part B and Part C. 
For all 3 trial parts, the number of patients with at least one dose reduction of BI 891065 will 
be displayed and the time to first dose reduction of BI 891065 will be analysed descriptively 
as well as using Kaplan-Meier methods based on the treated set. Patients who discontinue BI 
891065 without a dose reduction will be censored at the date of the last BI 891065 intake for 
this analysis. Furthermore, dose intensity of BI 891065 will be calculated for all 3 trial parts 
and dose intensity of BI 754091 will be calculated for Part B and Part C.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS, besides the analyses of MTD determination. 
These will be performed on the MTD evaluation set. 
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature. All analyses will be based on the number 
of patients with AEs (not on the number of AEs). The analysis will be based on BI standards 
(6). AEs will be coded using the most recent version of MedDRA. According to the BI 
standards multiple overlapping or adjacent recordings (AE occurrences) of the same AE are 
collapsed into one AE event if all AE attributes are identical (lower level term, severity, 
action taken, therapy required, seriousness, reason for seriousness, relationship, outcome, AE 
of special interest (AESI) flag).
The analyses of AEs will be based on the concept of treatment-emergent AEs, where a 
treatment-emergent AE has an onset in the analysing treatment period. The AE analysis will 
be based on the on-treatment period which starts with the date of the first administration of 
study medication and ends 30 days after the last administration of study medication. AEs 
with an onset date in the screening period (time between informed consent date and date of 
the first administration of study medication) or follow-up period (time after the on-treatment 
period) will be tabulated and listed separately.
Sorting order: In AE tables, system organ classes (SOCs) will be sorted alphabetically and 
preferred terms (PTs, within SOCs) will be sorted by descending frequency.
Listings of AEs will be displayed by patient. The actual planned dose of BI 891065/dose 
combination of BI 891065 and BI 754091 will be derived and included in the listings. AEs 
will be reported with start day and end day as calculated from the first day of treatment with 
study medication. For listings displaying AEs during the screening or follow-up period, the 
start and stop day are calculated from the start of the respective analysis period. 
The incidence of AEs overall, related AEs, serious AEs (SAEs), and immune-related AEs
will be reported by severity according to common terminology criteria for adverse events 
(CTCAE) grades (CTCAE version 4.03 for Part A, CTCAE version 5.0 for Part B and Part 
C). Drug-related serious AEs will also be tabulated. Protocol-specified AESI will be analysed 
based on data reported in the eCRF.


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AEs leading to death during the on-treatment period will be tabulated by SOC and PT. 
Reported fatal AEs during the follow-up period will be listed. 
Other significant AEs are defined as serious and non-serious AEs that lead to dose reduction 
of BI 891065 (for all trial parts) or permanent discontinuation of study medication (BI 
891065 in Part A, BI 891065 and BI 754091 in Parts B and C). Their incidence will be 
reported by severity according to CTCAE grades. A listing of patients who developed other 
significant AEs will be provided and a flag for serious and non-serious will be included. In 
addition, AEs leading to treatment interruption will be reported by severity according to 
CTCAE grades. 
7.8.2
Laboratory data
The analysis of laboratory data will be descriptive in nature and will be based on BI standards 
(7). The same on-treatment period as considered for the analysis of adverse events will be 
applied for laboratory values. Patients having at least one post-baseline laboratory value will 
be displayed in the descriptive analyses. Patients with missing CTCAE grade at baseline or 
no baseline value but with post-baseline values will be displayed in a new category “missing 
CTCAE grade at baseline” for those laboratory parameters where CTCAE grading is 
applicable. CTCAE grades for applicable laboratory parameters will be calculated according 
to CTCAE v5.0.
For Primary laboratory tests listed in Table 7.8.2: 1, the following outputs will be presented:

Descriptive statistics, including changes from baseline

Shift tables in terms of:
o
CTCAE grade, for laboratory tests with CTCAE grade defined;
o
Upper and lower reference limits, for laboratory tests without CTCAE grades;
o
Multiples of upper reference limit for customized shift tables of ALP, ALT, 
AST, bilirubin and creatinine.

Frequency of patients with potential clinically significant abnormalities.
For secondary laboratory tests listed in Table 7.8.2: 2, analyses will be limited to frequency 
of patients with potential clinically significant abnormalities.
For other laboratory tests, only listing of observed values will be presented.
Analyse of descriptive statistics should use normalized lab values. Analyses of frequencies of 
patients with potential clinical significance, analyses of shift, and liver function categories 
tables should use converted values.


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Table 7.8.2: 1 Primary laboratory tests
Label
Lab test name
Direction of 
interest
Potential Clinical significance rule
A1AGLP
Alpha-1 Glycoprotein
High4
>ULN and >baseline 
No CTCAE defined
ALP
Alkaline Phosphatase
High
CTCAE Grade 2 or higher3
ALT
Alanine 
Aminotransferase
High
CTCAE Grade 2 or higher3
AST
Aspartate 
Aminotransferase
High
CTCAE Grade 2 or higher3
BILI
Total Bilirubin
High
CTCAE Grade 2 or higher3
BILIND
Indirect Bilirubin
High
CTCAE Grade 2 or higher3 using 
grades defined for Total Bilirubin
BILDIR
Direct Bilirubin
High
CTCAE Grade 2 or higher3 using 
grades defined for Total Bilirubin
CK
Creatine Kinase
High
A1,2
CREAT
Creatinine
High
>1.5xULN and >baseline
Ambiguous CTCAE not used3
GLUC
Glucose
Low, High4
Low: A1,2
High: >10 mmol/L and > baseline
No CTCAE defined
HAPTOG
Haptoglobin
Low4
<LLN and <baseline
No CTCAE defined
HGB
Hemoglobin
Low
A1,2 (listed in CTCAEv5 as 
“Anemia”)
K
Potassium
Low4, High
Low: <3 mmol/L and <baseline
High: A1,2
LDH
Lactate 
Dehydrogenase
High4
≥3xULN and >baseline
No CTCAE defined
LYM
Lymphocytes
Low
A1,2
NEUT
Neutrophils
Low
A1,2
PLAT
Platelets
Low
A1,2
RETI
Reticulocytes
Low4
<LLN and <baseline
No CTCAE defined
SODIUM
Sodium
Low4, High
Low: <130 mmol/L and <baseline 
High: A1,2
T3FR
Triiodothyronine, Free
Low4, High4
Low: <LLN and <baseline
High: >ULN and >baseline
No CTCAE defined
T4FR
Thyroxine, Free
Low4, High4
Low: <LLN and <baseline
High: >ULN and >baseline
No CTCAE defined
TSH
Thyrotropin
Low4, High4
Low: <LLN and <baseline
High: >ULN and >baseline
No CTCAE defined


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Table 7.8.2: 1 Primary laboratory tests (cont’)
Label
Lab test name
Direction of 
interest
Potential Clinical significance rule
UREAN
Blood Urea Nitrogen
High4
>10 mmol/L and >baseline
No CTCAE defined
WBC
Leukocytes
Low
A1,2
1A= CTCAE grade 2 or greater with an increase of at least one CTCAE grade from baseline
2Separate shift tables for the low and high directions, when both directions are specified. Shift tables compare 
baseline vs. on-treatment CTCAE grades. CTCAE grading will not consider symptoms.
3CTCAE grades will not be defined for baseline values for ALP, ALT, AST, BILI (total, direct, and indirect) 
and CREAT. Special categories are defined for shift tables.
4Separate shift tables for the low and high directions, when both directions are specified. Shift tables compare 
baseline vs on-treatment using the three categories (1) below reference range, (2) within reference range, and (3) 
above reference range.
Table 7.8.2: 2 Secondary laboratory tests
Label
Lab test name
Direction 
of interest
Potential Clinical significance rule
ALB
Albumin
Low
A1
APTT
Activated Prothrombin Time
High
A1,2
CA
Calcium
Low, High
A1
CHOL
Cholesterol
High
A1
CL
Chloride
Low, High
Low: <80 mmol/L and <baseline
High: >120 mmol/L and >baseline 
No CTCAE defined
EOS
Eosinophils
High
>1.0 10**9/L and > baseline
No CTCAE defined
INR
Prothrombin Normalized 
ratio
High
>1.5 and >baseline
PHOS
Phosphate
Low, High
High: >1.7 mmol/L and >baseline
Low: <0.7 mmol/L and <baseline
PROT
Serum Protein
High
>ULN and >baseline 
No CTCAE defined
PT
Prothrombin Time
High
>ULN and > baseline
No CTCAE defined
TRIGL
Triglycerides
High
A1
UREA
Urea
High
>1.5 x ULN and >baseline
No CTCAE defined
URATE
Uric Acid
High
Females: >600 umol/L and >baseline
Males: >650 umol/L and >baseline
CTCAE based upon AE
1A= CTCAE grade 2 or greater with an increase of at least one CTCAE grade from baseline
2CTCAE grading will not consider symptoms presence of bleeding or use of anticoagulation.
Handling of CTCAE grade -1 and -9 laboratory parameters:
Generally, in case only one direction of worsening (high or low laboratory value) is specified 
in the CTCAE document, there is no need to examine the other direction. Therefore, for 


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calculating the change in CTCAE grade, patients with a CTCAE grade of -9 (no CTCAE 
grade defined) will be automatically treated as CTCAE grade 0 for all analyses. In laboratory 
listings, the CTCAE grade will be displayed as -9.
There are certain parameters for which CTCAE grades can only be differentiated by taking 
physiological consequences into account. These laboratory values will be coded as -1. As 
these definitions aggregate laboratory data and adverse events or concomitant therapies no 
analyses based on CTCAE grades will be done. Instead standard laboratory analyses as for 
laboratory parameters without CTCAE grade definitions will be done. Nevertheless, a 
laboratory listing including -1 values will be added to the CTR.
Corrected calcium:
The grading of hypocalcemia is based on corrected calcium as calcium can be falsely low if 
hypoalbuminemia is present. The following corrective calculation will be performed:
Corrected calcium (mg/dL) = Total Calcium (mg/dL) – 0.8[Albumin (g/dL)-4]
No correction of the reference range has to be done. The reported reference range of total 
calcium will be used for analyses. Corrected calcium can be only derived at a certain time 
point in case both laboratory values total calcium and albumin have been reported for the 
patient in the same laboratory sample. 
Hepatic enzyme elevations (potential Hy’s law cases): 
These are defined as those cases where a combination of all of the following events occurred: 
any on-treatment value of ALT and/or AST > 3ULN (upper limit of normal) with total 
bilirubin ≥ 2ULN and ALP < 2ULN. The events can occur in any order, but must occur 
within 14 days of the previous event, i.e. the second event must occur within 14 days of the 
first event, and the third event must occur within 14 days of the second event, etc. Patients 
with missing laboratory values for liver enzymes will be excluded from these analyses, but 
presented separately.
Tabulations of hepatic enzyme elevations and liver laboratory values will be done according 
to the FDA Drug Induced Liver Injury (DILI) guidance (10).
Hepatic enzyme elevations will be displayed for the treated set for the whole on-treatment 
period. 
7.8.3
Vital signs
Descriptive statistics are planned for the analysis of vital signs.
7.8.4
ECG
For all 3 trial parts, analyses of ECG will be descriptive in nature. Newly emergent 
abnormalities will be recorded and analysed as adverse events.
In addition, statistical ECG analyses will be performed for the centrally evaluated digital 
ECG recordings as follows.


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Derivation of ECG variables
Three replicate digital ECG recordings will be collected as specified in the flowchart of the 
CTP. Each of the three recorded single ECGs will then be evaluated semi-automatically for 
cardiac intervals, which comprise the RR, PR and QT interval and the QRS complex.
Measurements of these intervals will be made on four (possibly consecutive) cardiac cycles 
from the lead chosen (usually lead II). The measurements of the cardiac cycles will be stored 
in the database, i.e. usually 12 values per time point. The four cardiac cycles will be averaged 
prior to the calculation of the heart rate and heart rate corrected QT intervals (QTc).
The heart rate will be derived from the RR interval as 
HR [beats/min] = 60000/RR [ms]
Heart rate corrected QT intervals (generally denoted by QTc) will be calculated using 
Fridericia’s (QTcF) formula and Bazett’s formula (QTcB):

QTcF [ms] =  (1000/RR)^(1/3) * QT [ms]

QTcB [ms] = (1000/RR)^(1/2) * QT [ms]
Further aggregation of the three replicate ECG intervals and HR at each scheduled time point 
will then be performed using arithmetic means. Additional averaging over 1-3 time points 
will be performed to derive the baseline values: they will be calculated as the mean values of 
the 1-3 triplicate ECG recordings collected pre-dose on Day 1.These mean values will be 
used for the derivation of the ECG variables as they are specified in Section 5.4.3.
ECG analyses
For all ECG variables, listings of individual data will be shown in the appendix of the CTR. 
Absolute values and changes from baseline in QTcB interval as well as the percentage 
changes for PR interval and QRS complex will only be displayed in listings. 
Absolute values and changes from baseline in QTcF interval, QT interval, HR, PR interval, 
and QRS complex will be summarised descriptively by treatment, cycle, day, and time point 
using the ECG set. The time profiles of mean and standard deviation for the absolute values 
and changes from baseline on treatment will be displayed graphically by treatment.
Frequency tables will be provided for all categorical variables including notable findings and 
qualitative ECG findings. The tables will be presented separately for the visit days where an 
ECG profile has been taken as well as for the overall on-treatment period using the maximum 
value per patient. Frequencies of the increases in QTcF and QT intervals above thresholds as 
defined in Section 5.4.3 between baseline and on-treatment will be displayed in two-way shift 
tables by treatment. Frequency tables with regard to the new onset of qualitative 
(morphological) ECG findings will display categories of grouped findings based on the 
CDISC (EGTEST) terminology as well as the frequencies per each observed type of finding. 
These descriptive analyses will be performed for patients in the ECG Set separately for Part 
A, B and C.
For all patients with any notable finding (see Section 5.4.3), a separate listing in Section 15 of 
the CTR will be created and the corresponding time profiles will be shown. Notable findings 
of patients in the TS who are excluded from the ECG Set will be listed in separate listings.


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7.8.5
Others
Pregnancy tests: 
A listing showing the results of pregnancy tests will be provided. 


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
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 Jan; 45(2): 228-47 [R09-0262]
3.
Seymour L, Bogaerts J, Perone A, Ford R, Schwartz LH, Mandrekar S, et al. RECIST 
Working Group. iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017; 18(3): e148-e152 [R17-0923]
4.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
5.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
6.
001-MCG-156: "Handling and summarization of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
7.
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.
8.
001-MCP-090: "BI Style Guide", current version; IDEA for CON.
9.
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON.
10. Guidance for industry: drug-induces liver injury: premarketing clinical evaluation 
(July 2009).
Silver Spring: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center for 
Biologics Evaluation and Research (CBER) (2009) [P09-12413]
11. Ring A. Statistical models for heart rate correction of the QT interval.
Stat Med 29, 786 - 796 (2010) [R10-2920]
12. Hoffman D, Kringle R, Lockwood G, Turpault S, Yow E, Mathieu G. Nonlinear 
mixed effects modelling for estimation of steady state attainment. Pharm Stat. 2005. 
[R05-0788]


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TSAP for BI Trial No: 1379.1
Page 46 of 48
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TSAP for BI Trial No: 1379.1
Page 47 of 48
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TSAP for BI Trial No: 1379.1
Page 48 of 48
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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
18-AUG-2017
None
This is the initial TSAP with 
necessary information for trial 
conduct
Final
01-OCT-2018
All
This is the final TSAP
Revised
22-AUG-2019
Sections 
4-
Updates to Section 4. 
 
 
 
 
 
 
. Description of the interim 
futility analysis for Part C added in 
Section 7.4.
 
 
Revised
21-DEC-2020
Sections 
4, 
 
 
6.3,
7.8.2, 
Section 4 updated to explain
cancellation of Part C planned 
analyses.
 
 
 
Section 6.3 updated to clarify the 
definition of MTD set.
 
Section 7.8.2 updated to clarify 
classification of lab parameters, 
clinical significance rules and 
outputs.