An Open Label Phase Ib Dose Finding Study of BI 836880 in Combination With Ezabenlimab to Characterize Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy in Patients With Locally Advanced or Metastatic Non-squamous Non-Small Cell Lung Cancer and in Other Solid Tumors
Phase: PHASE1
Conditions: Non-squamous, Non-Small-Cell Lung Cancer, Neoplasms
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c16151514-12
EudraCT No.:
EU Trial No:
2017-001378-41
BI Trial No.:
1336-0011
BI Investigational 
Product(s):
BI 836880 (anti-VEGF/Ang2)
Ezabenlimab (BI 754091 [anti-PD-1])
Title:
An open label phase Ib dose finding study of BI 836880 in 
combination with ezabenlimab to characterize safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy in patients
with locally advanced or metastatic non-squamous Non-Small 
Cell Lung Cancer and in other solid tumors
Lay Title:
A study to test different doses of BI 836880 combined with 
ezabenlimab in patients with advanced non-small cell lung cancer 
followed by other types of advanced solid tumours
Clinical Phase:
Phase Ib
Trial Clinical 
Monitor:
Phone: 
Fax:  
Coordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 8)
Version and Date:
Version: 9.0
Date 18 May 2023
Page 1 of 340
Proprietary confidential information.
2023 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 836880 and BI 754091 (ezabenlimab)
Protocol date
19 Jan 2018
Revision date
18 May 2023
Trial number
1336-0011
Title of trial:
An open label phase Ib dose finding study of BI 836880 in 
combination with ezabenlimab to characterize safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy in patients with 
locally advanced or metastatic non-squamous Non-Small Cell Lung
Cancer and in other solid tumors
Coordinating 
Investigator
Phone: 
 
Fax: 
Trial site(s):
Multinational and multicentre study
Clinical phase:
Phase 1b
Study Design
This is a Phase Ib study, containing two parts; Part 1 (dose 
escalation of BI 836880 in combination with ezabenlimab) and Part 
2 (expansion phase in 8 cohorts).
Part 1:
Dose escalation of BI 836880 in combination with ezabenlimab in
check point inhibitor naïve or previously treated patients with 
locally advanced or metastatic non-squamous NSCLC who 
progressed during or after completion of at least 2 cycles first line
(in case of checkpoint inhibitor naïve patients) platinum-based
therapy and patients who progressed during or relapsed after 
completion of at least 2 cycles (in case of checkpoint inhibitor
relapsing patients) of  platinum-based chemotherapy and a 
checkpoint inhibitor treatment (monotherapy or in combination with 
chemotherapy).
Part 2:
Open label, non-randomized expansion phase to assess efficacy and  
safety of BI 836880 in combination with ezabenlimab:

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Cohort A (NSCLC):
Patient with pathologically confirmed locally advanced or metastatic 
non-squamous NSCLC who progressed during or after check-point 
inhibitor monotherapy treatment. Patient must also have received 
treatment with a platinum-based chemotherapy regimen and have 
progressed or be intolerant, or ineligible, as per applicable local 
practice.
Cohort B (NSCLC):
Patient with pathologically confirmed locally advanced or metastatic 
non-squamous NSCLC who progressed during or after 
platinum-based chemotherapy and a check-point inhibitor (CPI)
combination treatment as the most recent anticancer treatment.
Cohort C (SCLC):
Patient with pathologically confirmed locally advanced or metastatic 
Small Cell Lung Cancer (SCLC) with documented intolerance to 
platinum-based chemotherapy or refractory to platinum-based 
chemotherapy (progression during treatment or during < 90 days of the 
last dose of platinum-based chemotherapy). Patients who are platinum-
sensitive (progression ≥ 90 days of the last dose of platinum-based 
chemotherapy) must also have received one additional prior line of 
platinum-based chemotherapy, if eligible, with or without combination 
with CPI as per applicable local treatment country guidelines.
Cohort D (Glioblastoma):
Patient with histologically confirmed recurrent glioblastoma with no 
more than two previous lines of chemotherapy (concurrent and 
adjuvant temozolomide based chemotherapy including in 
combination with another investigational agent is considered one 
line of chemotherapy).
Cohort E (Melanoma):
Patient with histologically confirmed, unresectable, Stage IV 
metastatic melanoma who progressed during or after CPI based 
regimen. Patients with a BRAF mutation must have received
targeted treatment, or were not eligible, with a BRAF and MEK 
inhibitor as per applicable local country guidelines.
Cohort F (2nd line Hepatocellular Carcinoma):
Patient with locally advanced or metastatic and/or unresectable 
Hepatocellular Carcinoma (HCC) who were intolerant or progressed 
during 1st line sorafenib or lenvatinib treatment.
Cohort G (1st line Hepatocellular Carcinoma):

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Patient with locally advanced or metastatic and/or unresectable HCC
with no prior systemic treatment. This will be implemented only in
countries where this cohort is approved.
Cohort H (2nd line Hepatocellular Carcinoma – atezolizumab in 
combination with bevacizumab failures):
Patient with locally advanced or metastatic and/or unresectable 
Hepatocellular Carcinoma (HCC) who were intolerant or progressed 
during 1st line treatment with atezolizumab in combination with 
bevacizumab. This will be implemented only in countries where this 
cohort is approved.
Objective(s):
PART 1:
Primary objective:

To determine the Recommended Phase 2 Dose (RP2D) of 
BI 836880 in combination with ezabenlimab in check point 
inhibitor naïve or previously treated patients with locally 
advanced or metastatic non-squamous NSCLC who 
progressed during or after first line platinum-based
chemotherapy 
Secondary objective:

To provide safety data

To evaluate the basic pharmacokinetics of BI 836880 and 
ezabenlimab during combination therapy after the first and 
fourth infusion cycle.
PART 2:
Primary objective:

To assess anti-tumor activity of BI 836880 in combination 
with ezabenlimab in patients with locally advanced or 
metastatic non-squamous NSCLC and other solid tumors 
Secondary objective:

To provide safety data and further investigate clinical 
efficacy including disease control (DC), duration of objective 

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response (DoR), progression free survival (PFS), and tumor 
shrinkage.

To evaluate the basic pharmacokinetics of BI 836880 and 
ezabenlimab during combination therapy after the first 
infusion cycle.
Endpoints
Primary endpoints: 
PART 1:

The primary endpoint is the number of patients with dose 
limiting toxicity (DLT) within the first cycle of treatment (3 
weeks). 
PART 2:

The primary endpoint is Objective Response (OR) defined as 
best overall response (RECIST 1.1) of complete response 
(CR) or partial response (PR) from first treatment infusion 
until the earliest of disease progression, death or last 
evaluable tumor assessment before start of subsequent anti-
cancer therapy, lost to follow-up, or withdrawal of consent.
In case of recurrent glioblastoma (GBM), assessment will be 
based on RANO (Response Assessment in Neuro-Oncology) 
criteria.
Secondary endpoint(s):
PART 1:

Adverse events (AEs), drug related AEs, drug related AEs 
leading to dose reduction or discontinuation during treatment 
period.

Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the 
first and fourth infusion cycle.
PART 2:

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
Adverse events (AEs), drug related AEs, drug related AEs 
leading to dose reduction or discontinuation during treatment 
period

Disease control (DC), defined as best overall response of 
CR, PR, or stable disease (SD) (RANO for GBM & 
RECIST1.1 for all other cohorts) from first treatment 
infusion until the earliest of disease progression, death or last 
evaluable tumor assessment before start of subsequent anti-
cancer therapy, lost to follow-up or withdrawal of consent.

Duration of objective response (DoR), defined as the time
from first documented CR or PR (RANO for GBM & 
RECIST1.1 for all other cohorts) until the earliest of disease 
progression or death among patients with OR.

Progression-free survival (PFS) (RANO for GBM & 
RECIST1.1 for all other cohorts), defined as the time from 
first treatment infusion until disease progression or death 
from any cause, whichever occurs earlier. Tumour shrinkage 
(in millimeters), defined as the difference between the 
minimum post-baseline sum of diameters of target lesions 
(longest for non-nodal lesions, short axis for nodal lesions) 
and the baseline sum of diameters of the same set of target 
lesions in case of RECIST. In GBM, using RANO criteria, 
tumor shrinkage will be calculated based on the difference 
between the post-baseline and baseline measurements of the 
sum of product of the largest bi-dimensional measurements for 
all target lesions.

Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the 
first infusion cycle.
Number of patients 
entered: 
A total of approximately 420 patients (22 in Part 1 plus 398 in Part 
2) will be entered.
Number of patients on 
each treatment:
Part 1: 12 to 18 evaluable patients 
Part 2: 80 evaluable locally advanced or metastatic non-squamous 
NSCLC patients (Cohort A and B; 40 patients per cohort); 60 
evaluable patients in cohort F and 30 evaluable patients in each of 
the other 5 cohorts for a total of 290 patients.
Diagnosis:
Part 1:
Naïve or previously checkpoint inhibitor treated patients with locally 
advanced or metastatic non-squamous NSCLC who progressed 
during or after first line (in case of checkpoint inhibitor naïve 
patients) platinum-based therapy and patients who progressed during 
or relapsed after completion of at least 2 cycles (in case of 
checkpoint inhibitor relapsing patients) of platinum-based 

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chemotherapy and a checkpoint inhibitor treatment (monotherapy or 
in combination with chemotherapy). 
Part 2:
Cohort A and B: Patients with locally advanced or metastatic non-
squamous NSCLC who progressed or relapsed during or after a CPI
based treatment as monotherapy or in combination with platinum-
based chemotherapy. 
Cohort C: Patients with metastatic SCLC
Cohort D: Patients with recurrent glioblastoma
Cohort E: Patients with metastatic melanoma
Cohort F: Patients with 2nd line hepatocellular carcinoma
Cohort G: Patients with 1st line hepatocellular carcinoma (This will 
be implemented only in countries where this cohort is approved.)
Cohort H: Patients with 2nd line hepatocellular carcinoma –
atezolizumab + bevacizumab failures (This will be implemented 
only in countries where this cohort is approved.)
Main in- and exclusion 
criteria
Inclusion Criteria:
For Part 1:
1. Age ≥ 18 years
2. Pathologically confirmed diagnosis of non-squamous 
NSCLC
3. Locally advanced (stage IIIb) or metastatic (stage IV) 
NSCLC 
4. Documented disease progression or relapse (based on 
investigator’s assessment) during or after completion of at 
least 2 cycles of platinum-based chemotherapy as first line 
treatment of Stage IIIB/IV non- squamous NSCLC or for 
checkpoint inhibitor experienced patients during or after 
completion of at least 2 cycles of platinum-based 
chemotherapy and a checkpoint inhibitor treatment 
(monotherapy or in combination with chemotherapy). This 
includes patients relapsing within 6 months of completing 
(neo)adjuvant/curative-intent chemotherapy/CPI or 
chemoradiotherapy.
5. At least one target lesion (outside the brain), that can be 
accurately measured per RECIST v 1.1
6. Availability and willingness to provide a fresh tumour tissue 
sample obtained after relapse or progression on or after prior 
therapy. 
7. ECOG performance status of 0 or 1
8. Adequate hepatic, renal and bone marrow functions

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For Part 2:
1. Of full age (according to local legislation, usually ≥ 18 
years) at screening
2. At least one measurable target lesion outside the brain 
(excluding the glioblastoma patients), that can be accurately 
measured per RECIST v 1.1
3. ECOG performance status ≤ 1 (Karnofsky status for GBM)
Inclusion for:
Cohort A (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
non-squamous NSCLC 
-
Prior Check-point inhibitor monotherapy either as 1st or 
2nd line. Patient must also have received treatment with a 
platinum-based chemotherapy regimen and have 
progressed or be intolerant, or ineligible, as per 
applicable local practice.
-
Approximately 10 patients will be recruited who have 
primary resistance to CPI based therapy which is defined as 
those advanced or metastatic IIIB/IV non-squamous NSCLC 
patients who previously received at least 2 cycles of CPI 
treatment and progressed without achieving benefit (SD <4
months or progressive disease in <4 months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who had a documented minimum duration 
of benefit of (minimum of stable disease) 4 months and 
minimum treatment duration of 2 cycles on the previous CPI 
treatment without experiencing disease progression during 
that period.
Patients with NSCLC known to harbor an ALK 
rearrangement, or EGFR mutation, or other genomic 
aberrations (e.g., ROS rearrangement, BRAF V600E 
mutation), are only eligible after experiencing disease 
progression (during or after treatment) or intolerance to 
approved targeted therapy for respective genomic 
aberrations, as applicable per local country guidelines.
-
No more than one prior line of targeted therapy or 
chemotherapy regimen is allowed.
Cohort B (NSCLC):

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-
Pathologically confirmed locally advanced or metastatic 
non-squamous NSCLC 
-
1st line Platinum-based chemotherapy and a check-point 
inhibitor combination treatment as the most recent 
therapy before entering trial 
-
Approximately 10 patients will be recruited who have 
primary resistance to the combination therapy which is 
defined as those advanced or metastatic IIIB/IV non-
squamous NSCLC patients who previously received at least 
2 cycles of platinum-based chemotherapy and CPI treatment 
and progressed without achieving benefit (SD < 4 months or 
progressive disease in < 4 months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who had a documented minimum duration 
of benefit (minimum of stable disease) of 4 months when 
previously treated with at least 2 cycles of the CPI and 
platinum-based chemotherapy in a first line setting without 
experiencing disease progression during that period.
-
Patients with NSCLC known to harbor an ALK 
rearrangement, or EGFR mutation, or other genomic 
aberrations (e.g., ROS rearrangement, BRAF V600E 
mutation), are only eligible after experiencing disease 
progression (during or after treatment) or intolerance to 
approved targeted therapy for respective genomic 
aberrations, as applicable per local country guidelines. No 
more than one line of targeted therapy is allowed.
Cohort C (SCLC):
-
Pathologically confirmed locally advanced or metastatic 
SCLC 
-
Documented intolerance to platinum-based chemotherapy or 
refractory to platinum-based chemotherapy (progression during 
treatment or during < 90 days of the last dose of platinum-
based chemotherapy). Patients who are platinum-sensitive 
(progression ≥ 90 days of the last dose of platinum-based 
chemotherapy) must also have received one additional prior 
line of platinum-based chemotherapy, if eligible, with or 
without combination with CPI as per applicable local treatment 
country guidelines.
Cohort D (recurrent glioblastoma):
-
Histologically confirmed de novo glioblastoma (primary) at 
first or second recurrence after initial standard, control or 
experimental therapy that includes at a minimum RT.

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-
Unequivocal evidence of progressive disease on contrast-
enhanced brain CT or MRI as defined by RANO Criteria, or 
have documented recurrent glioblastoma on diagnostic 
biopsy.
-
No more than two lines of prior chemotherapy
(concurrent and adjuvant temozolomide based 
chemotherapy including in combination with another 
investigational agent is considered one line of 
chemotherapy). 
-
Only first and second recurrences of GBM are eligible
-
An interval of at least 12 weeks from the completion of 
radiation therapy to start of study drug unless there is a new 
area of enhancement consistent with recurrent tumor outside 
the radiation field or there is unequivocal histologic 
confirmation of tumor progression
-
Patient may have been operated for recurrence. If operated: 
residual and measurable disease after surgery is required;
surgical site must be adequately healed free of drainage or 
cellulitis, and the underlying cranioplasty must appear intact 
at the time of randomization
-
Karnofsky performance status (KPS) ≥ 70
-
MRI within 14 days prior to start of study drug
-
Patients should be immunocompetent (i.e. no concomitant 
treatment with dexamethasone (or equivalent), or receive 
stable/decreasing steroid levels not exceeding 2 mg/day 
dexamethasone (or equivalent) during the last 3 days prior to 
clinical screening; no severe lymphopenia).
Cohort E (Melanoma):
-
Histologically confirmed, unresectable, Stage IV metastatic 
melanoma.
-
Patients with a BRAF mutation must have received targeted 
treatment, or were not eligible, with a BRAF and MEK 
inhibitor as per applicable local country guidelines. In such 
a case no more than one line of targeted therapy is allowed.
-
At least one line of any kind of CPI based regimen as last 
treatment before entering the study
-
Documented progression during or after CPI therapy based 
regimen.
Cohort F (2nd line Hepatocellular Carcinoma):
-
Patients must have diagnosis of locally advanced or 
metastatic and/or unresectable histologically confirmed 
advanced hepatocellular carcinoma, not eligible for surgical 
and/or locoregional therapies.

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-
Patients should have progressed on or after first line 
treatment with sorafenib or lenvatinib or discontinued 
sorafenib or lenvatinib due to lack of tolerability after 
receiving at least two weeks of treatment. Reason for 
discontinuation must be documented.
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody to 
hepatitis B core antigen (anti-HBc), HBV DNA, anti-
hepatitis C virus (anti-HCV) and HCV RNA as applicable.
-
Child-Pugh score class A.
-
Anti-viral therapy per local standard-of-care if active 
hepatitis B virus (HBV). HBV DNA to be <500IU/ml and 
patients on anti HBV therapy for >4 weeks before entering 
the study.
Cohort G (1st line Hepatocellular Carcinoma):
(To be implemented only in countries where this cohort is 
approved.)
-
The subject should have diagnosis of locally advanced or 
metastatic and/or unresectable histologically confirmed 
advanced hepatocellular carcinoma that is not amenable to 
a curative treatment approach (e.g., transplant, surgery, 
ablation therapy) or locoregional therapy (e.g., TACE).
-
No prior systemic therapy for HCC. Previous use of herbal 
therapies/traditional Chinese medicines with anti-cancer 
activity included in the label is allowed, provided that these 
medications are discontinued prior to randomization.
-
Child-Pugh Score of A.
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody to 
hepatitis B core antigen (anti-HBc), HBV DNA, anti-
hepatitis C virus (anti-HCV) and HCV RNA as applicable.
-
Anti-viral therapy per local standard-of-care if active 
hepatitis B virus (HBV). HBV DNA to be <500IU/ml and 
patients on anti HBV therapy for >4 weeks before entering 
the study.
Cohort H (2nd line Hepatocellular Carcinoma –
atezolizumab + bevacizumab failures):
(To be implemented only in countries where this cohort is 
approved.)
-
Patients must have diagnosis of locally advanced or 
metastatic and/or unresectable histologically confirmed 
advanced hepatocellular carcinoma, not eligible for surgical 
and/or locoregional therapies.

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-
Patients should have progressed on or after first line 
treatment with atezolizumab in combination with 
bevacizumab or discontinued treatment due to lack of 
tolerability after receiving at least two cycles of treatment.
Reason for discontinuation must be documented. 
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody to 
hepatitis B core antigen (anti-HBc), HBV DNA, anti-
hepatitis C virus (anti-HCV) and HCV RNA as applicable.
-
Child-Pugh score class A.
Anti-viral therapy per local standard-of-care if active 
hepatitis B virus (HBV). HBV DNA to be <500IU/ml and 
patients on anti HBV therapy for >4 weeks before entering 
the study.
4. Adequate hepatic, renal and bone marrow functions
5. Availability and willingness to provide a fresh tumor tissue 
sample obtained after relapse or progression on or after prior 
therapy. In case a fresh biopsy cannot be obtained (e.g. 
inaccessible lesions or patient safety concern), an archived 
specimen obtained up to 6 months prior to cycle 1, visit 1 
(C1V1) may be submitted in case no systemic antineoplastic 
therapy has been administered between the biopsy and 
C1V1 (except for cohort D). For cohorts E, F and G, a fresh 
on-treatment biopsy is mandatory at C3D1, if possible from 
the same lesion as the pre-treatment biopsy.
6. Life expectancy ≥ 3 months after start of the treatment in the 
opinion of the investigator.     
Exclusion Criteria:
Part 2:
1
Not more than one CPI based treatment regimen prior to 
entering study (e.g., anti-Programmed Death receptor-1 (PD-
1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, 
or anti-cytotoxic T lymphocyte associated antigen-4 (anti-
CTLA-4) antibody). In case of CPIs combination, they need 
to be approved by the local regulatory agencies (e.g., 
Melanoma cohort (Cohort E)).
2
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection (exception for patients in HCC cohorts; Cohort F, 
G & cohort H).
3
Prior treatment with any antiangiogenic treatment (e.g. 
bevacizumab, cediranib, aflibercept, vandetanib, XL-184, 
sunitinib, etc) except for prior sorafenib or lenvatinib 
treatment in 2nd line HCC cohort (Cohort F) and for prior 

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treatment with atezolizumab in combination with 
bevacizumab in Cohort H.
4
Patients with known active second malignancy other than 
non-melanoma skin cancers, non-metastatic prostate cancer, 
in situ cervical cancer, and ductal or lobular carcinoma in 
situ of the breast. Patients are not considered to have a 
currently active malignancy if they have completed 
anticancer therapy and have been disease free for greater 
than 2 years prior to screening
Further exclusion criteria:
Exclusion criteria for Glioblastoma cohort (Cohort D):
5
Tumor primarily localized to the brainstem or spinal cord.
6
Presence of diffuse leptomeningeal disease or extracranial 
disease.
7
Is known to have IDH mutant variety of recurrent 
glioblastoma.
8
Any prior treatment with prolifeprospan 20 with carmustine 
wafer.
9
Any prior treatment with an intracerebral agent.
Exclusion criteria for Melanoma cohort (Cohort E):
10 Uveal or ocular melanoma.
Exclusion criteria for HCC cohorts (Cohorts F, G & H):
11 Co-infection with HBV and HCV or HBV and hepatitis D 
virus (HDV)
12 Known fibrolamellar HCC, sarcomatoid HCC, or mixed 
cholangiocarcinoma and HCC
13 History of hepatic encephalopathy
14 Untreated or incompletely treated varices with bleeding or 
high-risk for bleeding
15 Untreated active Hepatitis B virus (HBV)
16 Treatment with any HCV anti-viral therapy within 4 weeks 
prior to Cycle 1 Day 1
Test product(s):
BI 836880;
Ezabenlimab (BI 754091)
dose:
Part 1: 
BI 836880: starting dose 360mg
Ezabenlimab: 240mg

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Part 2:
RP2D of BI 836880 and Ezabenlimab
BI 836880: 720 mg
Ezabenlimab: 240 mg
Comparator products:
Not applicable
dose:
Not applicable
mode of 
administration:
Intravenous infusion
Duration of treatment:
Treatment may continue until disease progression, undue toxicity,
withdrawal of patient consent, or 53 cycles [approximately 3 years]
from the start of first treatment administration, whichever occurs 
first. Patients will be allowed to stay on treatment also in the case of 
initial radiological PD, until progression is confirmed or up to 53
cycles from the start of first treatment administration if the 
investigator considers that the treatment is beneficial for the patient.
Safety criteria:
Incidence and severity of adverse events graded according to the 
common terminology criteria for adverse events (CTCAE, version
5.0), incidence of dose limiting toxicities; laboratory parameters, 
vital signs, ECG
Statistical methods:
Part 1:
Dose escalation will be 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 BLRM. At the end of dose escalation, 
the toxicity probability at each dose (combination) level will be 
calculated to guide an estimate of the MTD and/or RP2D of the 
combination of BI 836880 plus ezabenlimab. 
Part 2: 
Objective response rate as primary endpoints will be estimated by 
Bayesian hierarchical model (BHM) approach, which assumes full 
exchangeability of model parameters and allows borrowing 
information across patients’ cohorts. Other efficacy endpoints and 
safety related data will be summarized descriptively. For PFS and 
duration of response, the median and 95% two-sided confidence 
interval will be presented using the Kaplan-Meier method. No 
hypothesis testing is planned in this trial.

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FLOW CHART (PART 1)
Trial Periods
Screen
Treatment cycles
EOT
EoR
FU / 
EoFU
Cycle
1, 2, 3, 4
          5, 6
7-53
Week
w1
w2
w3
w1
w2
w1
Visit
Screen
V1
V2
V3
V1
V2
V1
Day; visit window [days]
-21 
to
-1
d
1
d2
d3;
+1d
(1,2)*
d8;
-1/+2d
d15;
-1/+2d
d1
d8;
-1d/
+2d
d1
EoT (when 
defined)
Last
admin
+42d;
(+3d)
every 6
weeks (+/-
3d) until PD
Informed consent / IRT call
X
Demographics
X
Medical history
X
Review of in-/ exclusion criteria
X
Height
X
Weight
X
X
X
X
X
ECOG performance status
X
X
X
X
X
body temperature 
X
X
X (1,2)*
X
X
X
Blood pressure, heart rate 1
X
X
X
X
X
X
      X
X
       X
X
X
12-lead ECG 2
X
X
X (1,2)*
      X
       X
X
Echocardiography 3
X
if clinically indicated
X
General safety laboratory parameters4
X
X
X
X
X
X
X
X
X
Serum pregnancy test
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Physical examination 5
X
X
X
X
X
X
X
X
X
X
X
Adverse events 6
X
X
X
X
X
X
X
X
X
X
X
X
Eligibility for treatment / IRT call 7
X
X
X
Admin of ezabenlimab/ BI 836880 
X
X
X
Disease / response assessment
(clinical/imaging) 8
X
X
X
Pharmacokinetics 9
X
X (1,4) *
X (1,4)*
X
(1,4)*
X 

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Trial Periods
Screen
Treatment cycles
EOT
EoR
FU /
EoFU
Cycle *
1, 2, 3, 4
             5,6
7-53
Week
w1
w2
w3
w1
w2
w1
Visit
Screen
V1
V2
V3
V1
V2
V1
Day; visit window [days]
-21 
to
-1
d
1
d2
d3;
+1d
(1,2)*
d8;
-1/+2d
d15;
-1/+2d
d1
d8;
-
1/+2d
d1
EoT (when 
defined)
Last
admin
+42d;
(+3d)
every 6
weeks (+/-
3d) until PD
X (1)
X (1)
Reason for treatment discontinuation
X
Patients status
X
X
Next line of anti-cancer therapy
X
X
* number in brackets indicate the cycle this visit/assessment is applicable
EoC = End of Cycle; FU1 = 1st Follow-up visit
1  See Appendix 10.2
2  ECG for all patients according to flowchart schedule.
3 Echocardiography to be done within 7 days before treatment start and at EOT.
4 Safety lab to be done at local lab according to the Flowchart but should be more frequent in case of relevant findings based on medical opinion of the investigator.(Section 5.2.3)
5 Complete physical examination must be performed at screening and before start of treatment and EoT and EoR. For further time points, at minimum the actual health status of the
   patient should be assessed (see Section 5.2.1).
6  More details about AEs are provided in Section 5.2.7.

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7  For medication number allocation, it’s possible to conduct IRT call ahead of the planned visit (= day of administration).
    Start with administration of ezabenlimab and 15 min after the end of this infusion, BI 836880 should be administered (see Instructions for Pharmacist provided in the ISF)
8  The same method of assessment / same technique should be used also in follow up of identified and reported lesions. Baseline evaluation must be performed as close as possible 
    to the treatment start and no more than 28 days before start of treatment. Tumour assessment can be performed according to institutional practices and SOC from the data cut-off date for interim 
database lock forward, starting from first trial medication infusion.
9, 10 and 11: see Appendix 10.5 Table 10.5.1: 1

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FLOW CHART (PART 2)
Trial Periods
Screen
Treatment cycles
EOT
Safety Follow-
up
FU / 
EoFU
Cycle
1
2 - 53
Week
w1
w2
w3
w1
Visit
Screen
V1
V2
V3
V1
Day; visit window [days]
-21 
to
-1
d1
d2
d8;
(-1/+2d)
d15;
(-1/+2d)
d1;
(+2d )for cycle 2; 
ongoing cycles 
(-1/+2d)
EoT (when 
defined)
Last admin 
+42d;(+3d)
every 6
weeks (+/-
3d) until 
PD
Informed consent / IRT call
X
Demographics
X
Medical history
X
Review of in-/ exclusion criteria
X
Height
X
Weight
X
X
X
X
X
ECOG / Karnofsky performance status@
X
X
X
X
X
Body temperature 
X
X
X 
X
X
Blood pressure, heart rate 1
X
X
X
X
X
X
X
X
12-lead ECG 2
X
X
X ( 2,3,4,6, 8, 
10,12..)*
X
Echocardiography 3
X
if clinically indicated
X
Infectious Screen$
X
General safety laboratory parameters 4
X
X
X
X
X
X
Pregnancy test§
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
Physical examination 5
X
X
X
X
X
X
X
X
Adverse events 6
X
X
X
X
X
X
X
X
X
Eligibility for treatment / IRT call 7
X
X
Admin of ezabenlimab/ BI 836880 
X
X
Disease / response assessment
(clinical/imaging) 8
X
X

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Trial Periods
Screen
Treatment cycles
EOT
Safety Follow-
up
FU /
EoFU
Cycle
1
2 - 53
Week
w
1
w2
w3
w1
Visit
Screen
V
V2
V3
V1
Day; visit window [days]
-21 
to
-1
d1
d2
d8;
(-1/+2d)
d15;
(-1/+2d)
d1;
(+2d ) for cycle 2; 
ongoing cycles 
(1/+2d)
EoT (when 
defined)
Last admin
+42d; (+3d)
every 6
weeks (+/-
3d) until 
PD
Pharmacokinetics 9
X
X
X
X
* number in brackets indicate the cycle this visit/assessment is applicable
EoC = End of Cycle; FU1 = 1st Follow-up visit
1  See Appendix 10.2 for BP and HR should be measured before and after study drugs have been administered. Please follow the BP monitoring and study drug administration guidelines in
Appendix 10.2.1.
2  ECG for all patients according to flowchart schedule.- Cycle 1 to 4 pre and post treatment (within 60 min after completion of administration of BI 836880) and thereafter ECG at pre- and post 
treatment of BI 836880 performed every second cycle (cycle 6,8, 10…etc

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3  Echocardiography to be done within 21 days before treatment start and at EOT.
4  Safety lab to be done at local lab according to the Flowchart (up to 72 hours before treatment start ) but should be more frequent in case of relevant findings based on medical opinion of the 
investigator.(Section 5.2.3). 
5  Complete physical examination must be performed at screening and before start of treatment and EoT andSafety Follow-up visit. For further time points, at minimum the actual health status of 
the patient should be assessed (see Section 5.2.1).
6  more details about AE are provided in Section 5.2.7
7  For medication number allocation it’s possible to conduct IRT call ahead of the planned visit (= day of administration).
    Start with administration of ezabenlimab and 15 min (+/- 10 min) after the end of this infusion, BI836880 should be administered (see Instructions for Pharmacist provided in the ISF)
8 Tumour assessments should be done according to RECIST v1.1 and iRECIST for all cohorts except GBM. RANO/iRANO criteria to be followed for GBM cohort. Assessments should include 
computed tomography (CT) scans of the chest and abdomen only, 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. Baseline evaluation must be performed as close as possible to the treatment
start and no more than 28 days before start of treatment (For GBM – 14 days prior to treatment). Tumour assessment can be performed according to institutional practices and SOC from data 
cut-off date interim database lock forward. Assessments are always done prior to the start of the new treatment cycle.
9, 10 and 11: see Appendix 10.5 Table 10.5.1: 2
12  Cohorts F, G & H (HCC cohorts): only C1D1 sample to be collected. NO on-treatment samples.
13  ONLY Cohort F, G & H (HCC) cohorts
14  Cohorts F, G & H (HCC) cohorts: NO samples collected
From December 2021, no further blood samples should be obtained for central lab shipments.
§     Women of child-bearing potential must have a serum beta human chorionic gonadotropin (β-HCG) pregnancy test at screening. Thereafter, this test can be done in either serum or urine for 
all patients. as per Day 1 of each cycle, and at the EOT visit. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
$    Hepatitis B surface antigen (HBsAg; qualitative), hepatitis B core antibody (anti-HBc; qualitative), Hep B DNA, hepatitis C antibodies (Anti-HCV; qualitative), Hep C RNA, hepatitis D 
antibodies (Anti-HDV; qualitative) human immunodeficiency virus (HIV)-1 and HIV-2 antibody (at the discretion of the Investigator where clinically indicated) will be performed. For 
HCC cohorts (cohorts F & G) additional tests may include HBV DNA (if needed), HCV RNA (if needed) and Hepatitis D (anti-HDV qualitative).
@   Karnofsky performance status (KPS) to be implemented for GBM cohort

a Part 2/ Tumour biopsy

Mandatory pretreatment biopsy for cohort A, B, C, E, F, G and H: - The equivalent of 2 14 -16 G (or-I: 4 18 G) needle biopsies should be freshly taken during screening 
after IC signed and before first trial medication administration, In case a fresh baseline biopsy cannot be obtained (e.g. inaccessible lesions or patient safety concern), 20 archival 
4 µm sections from an archival block, taken within 6 months of trial start with no intermediate therapy have to be provided. 

Mandatory for cohorts E, F, G and H a fresh on-treatment biopsy: - The equivalent of 2 14-16 G (or 4 18G) needle biopsies at C3D1 (-/+ 7 days) if possible from the same 
lesion as the pre-treatment biopsy. Treatment to be initiated only after ensuring patient is stable and bleeding has stopped completely after biopsy.

Optional for cohorts A-C: - The equivalent of 4 18 G needle biopsies on treatment before start of Cycle 3 (-/+ 7 days, 6 weeks after treatment start) 
Note for on treatment biopsies: Biopsy to be performed on a lesion different than target lesion and if there is only one lesion than biopsy may be skipped in that patient. 
From December 2021, no further biopsies should be performed.

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART (PART 1) ....................................................................................................15
FLOW CHART (PART 2) ....................................................................................................18
TABLE OF CONTENTS ......................................................................................................21
ABBREVIATIONS................................................................................................................25
1.
INTRODUCTION...............................................................................................28
1.1
MEDICAL BACKGROUND.............................................................................28
1.2
DRUG PROFILE................................................................................................33
1.2.1
BI 836880 .............................................................................................................33
1.2.2
BI 754091 (Ezabenlimab) ...................................................................................35
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................36
1.4
BENEFIT - RISK ASSESSMENT.....................................................................38
1.4.1
Benefit-Risk Assessment in context of COVID-19 pandemic for patients 
participating in clinical trials investigating BI 836880 in combination with 
ezabenlimab .........................................................................................................39
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................42
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........42
2.1.1
Main objectives....................................................................................................42
2.1.2
Primary endpoint(s)............................................................................................42
2.1.3
Secondary endpoint(s) ........................................................................................43
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................46
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................46
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................49
3.3
SELECTION OF TRIAL POPULATION .......................................................50
3.3.1
Main diagnosis for trial entry ............................................................................50
3.3.2
Inclusion criteria .................................................................................................51
3.3.3
Exclusion criteria ................................................................................................58
3.3.4
Withdrawal of patients from therapy or assessments .....................................62
3.3.4.2 
Withdrawal of consent for trial participation........................................................63
3.3.4.3 
Discontinuation of the trial by the sponsor...........................................................63
4.
TREATMENTS...................................................................................................64
4.1
INVESTIGATIONAL TREATMENTS ...........................................................64
4.1.1
Identity of the Investigational Medicinal Products..........................................64

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4.1.2
Selection of doses in the trial..............................................................................65
4.1.2.1
Part 1 .....................................................................................................................65
4.1.2.2 
Part 2 .....................................................................................................................65
4.1.3
Method of assigning patients to treatment groups...........................................66
4.1.4
Drug assignment and administration of doses for each patient......................66
4.1.5
Blinding and procedures for unblinding...........................................................70
4.1.5.1 
Blinding.................................................................................................................70
4.1.5.2 
Unblinding and breaking the code ........................................................................70
4.1.6
Packaging, labelling, and re-supply...................................................................70
4.1.7
Storage conditions...............................................................................................70
4.1.8
Drug accountability.............................................................................................71
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................72
4.2.1
Other treatments and emergency procedures..................................................72
4.2.2
Restrictions ..........................................................................................................72
4.2.2.1 
Restrictions regarding concomitant treatment ......................................................72
4.2.2.2 
Restrictions on diet and life style..........................................................................73
4.2.2.3 
Restrictions regarding women of childbearing potential......................................73
4.3
TREATMENT COMPLIANCE........................................................................74
5.
ASSESSMENTS..................................................................................................75
5.1
ASSESSMENT OF EFFICACY........................................................................75
5.1.1
Tumor response assessments using RECIST 1.1..............................................75
5.1.2
Tumor response assessments using RANO.......................................................75
5.2
ASSESSMENT OF SAFETY.............................................................................78
5.2.1
Physical examination ..........................................................................................78
5.2.2
Vital signs.............................................................................................................79
5.2.3
Safety laboratory parameters ............................................................................80
5.2.4
Electrocardiogram ..............................................................................................81
5.2.5
Echocardiography...............................................................................................82
5.2.6
Other safety parameters.....................................................................................82
5.2.6.1 
Dose limiting toxicities (DLTs)............................................................................82
5.2.6.2
Definition of evaluable patient..............................................................................84
5.2.6.3
Maximum Tolerated Dose (MTD) and Recommended Phase II dose (RP2D) ....84
5.2.7
Assessment of adverse events.............................................................................84
5.2.7.1
Definitions of AEs ................................................................................................84
5.2.7.2 
Adverse event collection and reporting ................................................................88
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................91
5.3.1
Assessment of pharmacokinetics .......................................................................91
5.3.2
Methods of sample collection .............................................................................92
5.4.1
Methods of sample collection .............................................................................93

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5.4.3
Biobanking...........................................................................................................95
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................97
6.
INVESTIGATIONAL PLAN.............................................................................98
6.1
VISIT SCHEDULE.............................................................................................98
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................99
6.2.1
Screening and run-in period(s)..........................................................................99
6.2.2
Treatment period(s)..........................................................................................100
6.2.3 
End of treatment visit (EOT)...........................................................................100
6.2.4 
Residual effect period (REP)............................................................................100
6.2.5 
Extended follow-up period...............................................................................100
6.2.5.1
Follow-up for progression...................................................................................100
6.2.5.2
Follow-up for Overall Survival...........................................................................101
6.2.5.3
Trial completion for an individual patient ..........................................................101
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
.............................................................................................................................102
7.1
STATISTICAL DESIGN - MODEL...............................................................102
7.1.1
Statistical design - Part 1 (dose escalation).....................................................102
7.1.1.1 
Combination BLRM ...........................................................................................102
7.1.1.2
Statistical model assessment..............................................................................106
7.1.2
Statistical design - Part 2 (dose expansion cohorts).......................................106
7.2
NULL AND ALTERNATIVE HYPOTHESES .............................................108
7.3
PLANNED ANALYSES...................................................................................108
7.3.1
Primary endpoint analyses...............................................................................108
7.3.1.1 
Primary endpoint analyses for Part 1..................................................................108
7.3.1.2 
Primary endpoint analyses for Part 2..................................................................109
7.3.2
Secondary endpoint...........................................................................................109
7.3.2.1 
Secondary endpoint analyses for Part 1..............................................................109
7.3.2.2 
Secondary endpoint analyses for Part 2..............................................................109
7.3.4
Safety analyses...................................................................................................110
7.4
INTERIM ANALYSES ....................................................................................112
7.5
HANDLING OF MISSING DATA .................................................................112
7.6
RANDOMIZATION.........................................................................................113
7.7
DETERMINATION OF SAMPLE SIZE .......................................................113
7.7.1
Determination of sample size for Part 1..........................................................113
7.7.2
Determination of sample size for Part 2..........................................................113
7.7.3
Determination of additional sample size for stage II in cohort F.................116

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ......118
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT .........................................................................................................118
8.2
DATA QUALITY ASSURANCE ....................................................................119
8.3
RECORDS.........................................................................................................119
8.3.1
Source documents .............................................................................................119
8.3.2
Direct access to source data and documents...................................................120
8.3.3
Storage period of records .................................................................................121
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................121
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......121
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.....................................................................................................................121
8.6
TRIAL MILESTONES.....................................................................................122
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................122
9.
REFERENCES..................................................................................................124
9.1
PUBLISHED REFERENCES..........................................................................124
9.2
UNPUBLISHED REFERENCES....................................................................129
10.
APPENDICES...................................................................................................130
10.1
INSTRUCTIONS FOR USE............................................................................130
10.2
BLOOD PRESSURE MEASUREMENT PROCEDURE.............................130
10.2.1
Blood Pressure Management and Study Drug Administration Guidelines.131
10.3
IMMUNE-RELATED ADVERSE EVENTS AS ADVERSE EVENTS OF 
SPECIAL INTEREST......................................................................................132
10.4
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS .............134
10.5
HANDLING PROCEDURES FOR BLOOD SAMPLES FOR PLASMA
CONCENTRATION-TIME MEASUREMENTS .............................................142
 
 
10.6
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS ...............................................................................147
10.6.1
Hypothetical data scenarios .............................................................................148
10.6.2
Operating characteristics of combination BLRM..........................................150
10.7
APPENDIX - PERFORMANCE STATUS CRITERIA................................152
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................154
11.1
GLOBAL AMENDMENT 1 ............................................................................154
11.2
GLOBAL AMENDMENT 2 ............................................................................157
11.3
GLOBAL AMENDMENT 3 ............................................................................175
11.4
GLOBAL AMENDMENT 4 ............................................................................237
11.5
GLOBAL AMENDMENT 5 ............................................................................305
11.6
GLOBAL AMENDMENT 6 ............................................................................324
11.7
GLOBAL AMENDMENT 7 ............................................................................330
11.8
GLOBAL AMENDMENT 8 ............................................................................338

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ABBREVIATIONS
ABPM
Ambulatory Blood Pressure Measurement
AE
Adverse Event
AESI
AFP
Adverse Event of Special Interest
Alpha-Fetoprotein
AP
ANG2
Alkaline Phosphate
Angiopoietin-2
aPTT
Activated Partial Thromboplastin Time
AUC
Area under the Curve
b.i.d.
BHM
bis in die (twice daily dosing)
Bayesian Hierarchical Model
BLRM
Bayesian Logistic Regression Model
CBPM
Conventional Blood Pressure Measurement
CCDS
Company Core Data Sheet
CI
Confidence Interval
CML
Clinical Monitor Local
CPI
Check Point Inhibitor
CR
Complete Response
CrCl
Creatinine Clearance
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CTCAE
Common Terminology Criteria for Adverse Events
CT/MRI
Computed Tomography scan/ Magnetic Resonance Imaging
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DC
Disease Control
DCR
Disease Control Rate
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
DoR
Duration of Objective Response
ECOG
Eastern Cooperative Oncology Group
EDC
eCRF
EMA
Electronic Data Capture
Electronic Case Report Form
European Medicines Agency
EOT
EOR
End of Treatment
End of Residual Effect Period
EudraCT
EWOC
European Clinical Trials Database
Escalation With Overdose Control
FAS
Full Analysis Set
FC
FDA
GBM
Flow Chart
Food and Drug Administration
Glioblastoma
GCP
Good Clinical Practice

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GFR
Glomerular Filtration Rate
HPC
Human Pharmacology Centre
IB
Investigator’s Brochure
iCPD
Immune Confirmed Progression Disease
IEC
Independent Ethics Committee
INR
iRANO
International Normalised Ratio
immunotherapy Response Assessment for Neuro-Oncology
IRB
iRECIST
Institutional Review Board
Immunotherapy Response Evaluation Criteria In Solid Tumours
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intravenous
iUPD
KPS
Immune Unconfirmed Progression Disease
Karnofsky Performance Status
LDH
Lactate Dehydrogenase
LPDD
Last Patient Drug Discontinuation
LoEE
List of Essential Element 
LMWH
Low-Molecular-Weight Heparin
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Drug Regulatory Activities
MDSC
Myeloid-derived suppressor cells
MST
Medical Sub Team
MTD
NS NSCLC
NSCLC
Maximum Tolerated Dose
Non Squamous Non-Small Cell Lung Cancer
Non-Small Cell Lung Cancer
NSAID
Nonsteroidal anti-inflammatory drugs
OPU
Operative Unit
OR
Objective Response
ORR
Overall Response Rate
OS
Overall Survival
PD
Pharmacodynamics
PD-1
Programmed death 1
PDL-1
Programmed death-ligand 1
PK
Pharmacokinetics
PLT
Platelets
p.o.
per os (oral)
PR
Partial Response
PT
RANO
Prothrombin Time
Response Assessment for Neuro-Oncology
RECIST
Response Evaluation Criteria In Solid Tumours
q.d.
quaque die (once a day)
eDC
electronic Data Capturing
REP
Residual Effect Period
SAE
Serious Adverse Event
s.c.
SCLC
Subcutaneous
Small Cell Lung Cancer
SD
Stable disease

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SMC
Safety Monitoring Committee
SmPC
SOC
Summary of Product Characteristics
Standard of Care
SUSAR
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
UPCR
Urine Protein to Creatinine Ratio
VEGF
Vascular endothelial growth factor
WBC
White Blood Cells Count
WHO
World Health Organization
WOCBP
Woman of childbearing potential

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Angiogenesis is the formation of new blood vessels from pre-existing vasculature and is a
key process in tumor growth. The Ang2/Tie2 and the VEGF/VEGFR2 pathways have been
identified as key pathways mediating tumor angiogenesis (R13-0448). Multiple studies have
described increased VEGF levels in a variety of human cancers and the VEGF expression
levels have been correlated with poor survival (R15-1720). The VEGF neutralizing
monoclonal antibody bevacizumab has demonstrated anti-tumor activity in clinical trials and
is currently approved for several indications and setting, mainly in combination with standard
chemotherapy regimens (R15-1222).
Studies in mice have shown that Ang2, a ligand of the Tie2 receptor, controls vascular
remodeling by enabling the functions of other angiogenic factors, such as VEGF (R12-3593).
Ang2 is primarily expressed by endothelial cells, strongly induced by hypoxia and other
angiogenic factors and has been demonstrated to regulate tumor vessel plasticity, allowing
vessels to respond to VEGF and FGF2 (R12-3834).
The normal role of the immune system is to protect the body against the invasion of foreign 
agents such us bacteria, viruses and parasites as well as the body’s own malfunctioning cells. 
Once a mounted immune response (adaptive or innate) completes its task of eliminating the 
treat, the immune system deploys the immune system checkpoint program to dampen the 
immune response and minimize collateral immune-mediated damage to healthy tissue. The 
programmed-cell-death (PD-1, CD279) receptor and its ligands, programmed-cell-death 
ligand 1 (PD-L1, B7-H1; CD274) and programmed-cell-death ligand 2 (PDL-2; B7-DC; 
CD273) are the major immune checkpoint master switches. The expression of PD-1 on 
immune cells, including T and B lymphocytes, natural killer (NK) cells and antigen 
presenting cells is upregulated in response to inflammation in peripheral tissue. As with PD-1 
level, the expression of PD-L1 is also induced as a result of peripheral tissue inflammation. 
The interaction of PD-1 and PD-L1 in an inhibitory signal that interferes with antigen 
receptor signaling, marked changes in the cytokine profile decreased T-cell activation, 
increased activation of regulatory T-cells and increase in cytotoxic T-cell apoptosis. 
Collectively, these events lead to an immune suppressive environment and dampening of the 
immune response. Tumor immune evasion is achieved when PD-L1 within the tumour 
microenvironment engages PD-1 expressed on activated tumour infiltration T-cells and 
initiates the immune suppressive tumor microenvironment in which activated cytotoxic T-
cells are inactivated and some are sent down an apoptotic pathway.
VEGF-A induces accumulation of Myeloid-derived suppressor cells (MDSCs), immature 
DC, Treg and tumour-associated macrophage. MDSC are able to control activation of T-cell 
and NK cells. Anti-VEGF treatment significantly enhances dendritic cell maturation. (R17-
4036 R17-4037), decrease Treg either by inhibiting the accumulation of MDSCs and 
immature DC in tumor environment or directly through VEGF/VEGFR pathway inhibition of 
Treg. (R17-4038, R17-4039).

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Preclinical evidence of interaction between these 2 pathways was shown as well as 
encouraging antitumor activity of the combination of VEGF blockade and PD-1/PD-L1 
blockade.
During the last decade, notable changes occurred in the treatment of NSCLC resulting in a 
paradigm shift. The current treatment approach of NSCLC incorporates important predictive 
markers of benefit from specific agents such us pathology subtype (histology) and molecular 
genotype (EGFR mutation and EML4-ALK fusion gene). More recently immunotherapy 
treatments (checkpoint inhibitors) have changed the treatment strategy in NSCLC. 
First line treatment of advanced stage NSCLC has more recently been markedly transformed 
by the introduction anti PD-1/anti-PD-L1 immune checkpoint inhibitor (CPI) mAbs. 
Pembrolizumab is currently indicated for first line treatment of both squamous and non-
squamous NSCLC.  The use of pembrolizumab is currently restricted to patients whose 
tumors express high levels of PD-L1 (>50% of tumor cells being PD-L1 positive using IHC).  
For patient with low PD-L1 expressing tumors (1-49% of tumor cells being PD-L1 positive), 
first line treatment consists of a platinum-based chemotherapy (platinum plus gemcitabine or 
pemetrexed or taxane). Several platinum-based chemotherapy doublets have shown 
comparable efficacy with a higher response rate for cisplatin combinations compared to 
carboplatin combinations. Based on randomized phase III trials results, pemetrexed is 
preferred to gemcitabine in non-squamous tumors. Platinum-based chemotherapy doublets, 
excluding pemetrexed are also indicated in squamous tumors. 
The first-line treatment for patients with tumors harboring specific gene alterations that are 
key oncogenic events (EGFR mutation or EML4-ALK fusion gene), consists of a specific 
targeted therapy: EGFR TKI (e.g. erlotinib) for EGF-mutated patients and ALK inhibitor 
(e.g. crizotinib for ALK amplified patients). (R15-3759, R14-5319) Such treatment offers the 
possibility of a highly specific treatment of these molecularly defined NSCLC subtypes. The 
clinical benefit of adding bevacizumab in first line treatment to platinum-based chemotherapy 
is controversial with a benefit in terms of PFS and ORR. This improvement did not translate 
into a benefit in OS.
Maintenance therapy is indicated in patients who did not progress after completion of first 
line chemotherapy (4-6 cycles). Pemetrexed is indicated in non-progressive patients with 
non-squamous tumors (P13-07693), whilst EGFR TKIs can be used in patients with EGFR 
mutations (squamous and non-squamous tumors) with stable disease after induction therapy 
(R11-1185). 
Platinum-based chemotherapy is indicated for the second line treatment of patients who 
received prior systemic targeted therapy (EGFR TKI or ALK inhibitor). For patients 
previously treated with platinum doublet chemotherapy, single agent docetaxel, (R14-5321) 
pemetrexed or EGFR inhibitor should be used. 
More recently, three PD-1/anti-PD-L1 immune CPI have been approved for second line 
NSCLC treatment.  All three compounds (nivolumab, pembrolizumab and atezolizumab) are 
currently approved for second line treatment of both squamous and non-squamous NSCLC. 

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The use of pembrolizumab is currently restricted to patients whose tumors express PD-L1 
(>1% of tumor cells being PD-L1 positive using IHC) where as nivolumab and 
atezolizumab’s use is open to patients regardless of PD-L1 expression levels. 
Previously, based on positive Phase III trial in advanced/metastatic NSCLC on 
(KEYNOTE 024 trial) showing PFS and OS improvement in pembrolizumab monotherapy 
arm (versus standard chemotherapy) (R16-4783), Pembrolizumab has been approved for 1st
line treatment in patients with tumors expressing PD-L1 in ≥50% of tumor cells. FDA based 
on KEYNOTE-042 (NCT02220894) trial approved pembrolizumab monotherapy for the 
first-line treatment of patients with stage III NSCLC who are not candidates for surgical 
resection or definitive chemoradiation or metastatic NSCLC. Patients’ tumors must have no 
EGFR or ALK genomic aberrations and express PD-L1 (Tumor Proportion Score [TPS] 
≥1%) determined by an FDA-approved test.
Atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin, is also indicated 
for the first-line treatment of patients with metastatic NSCLC with no EGFR or ALK 
genomic tumor aberrations.
Small cell lung cancer (SCLC) is a neuroendocrine tumor that represents about 15 percent of 
all lung cancers. SCLC occurs predominantly in smokers and is distinguished clinically from 
most types of non-small cell lung cancer (NSCLC) by its rapid doubling time, high growth 
fraction, and the early development of metastases. SCLC usually presents with disseminated 
disease, and treatment strategies have focused on systemic therapy. Although SCLC is highly 
responsive to both chemotherapy and radiotherapy (RT), it commonly relapses within months 
despite treatment. SCLC is usually staged as either limited or extensive. The standard 
treatment in limited SCLC is chemoradiation. The chemo drugs used are usually etoposide or 
irinotecan plus either cisplatin or carboplatin. Atezolizumab is approved as a first line 
treatment for extensive SCLC. The addition of atezolizumab to chemotherapy in the first-line 
treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall 
survival and progression-free survival than chemotherapy alone (IMpower 133). (R19-1714)
Nivolumab is approved for metastatic small cell lung cancer with progression after platinum 
based chemotherapy and at least one other line of therapy. Nivolumab monotherapy provided 
durable responses and was well tolerated as a third- or later-line treatment for recurrent SCLC
(CHECKMATE 032). (R19-1713)
High-grade gliomas are malignant and often rapidly progressive brain tumors that are divided 
into anaplastic gliomas (anaplastic astrocytoma, anaplastic oligodendroglioma) and 
glioblastoma based upon their histopathologic and molecular features. Despite the survival 
benefit associated with adjuvant radiation and chemotherapy, the majority of patients relapse 
following initial therapy. The most commonly used systemic agents in recurrent or 
progressive high-grade gliomas are bevacizumab, nitrosoureas, and temozolomide 
rechallenge (since the majority of patients will have received temozolomide at part of initial 
therapy). In the largest randomized trial to test whether combination therapy is superior to 
single-agent therapy, the addition of bevacizumab to lomustine improved progression-free 
but not overall survival compared with lomustine alone. Early experience with CPIs such as 
pembrolizumab and nivolumab in unselected patients with recurrent high-grade glioma has 
shown only modest activity. Preliminary results of a phase III trial of nivolumab versus 

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bevacizumab in recurrent glioblastoma found no difference in overall survival 
(CHECKMATE 143).
Most cases of malignant melanoma diagnosed at an early stage and surgical excision can be 
curative. However, a few patients have metastatic disease at presentation, and some develop 
metastases after their initial definitive treatment. High-dose interleukin-2 (IL-2) was the first 
treatment to modify the natural history of patients with metastatic melanoma resulting in cure 
in a small fraction of patients. However, its severe toxicity has limited its application to 
carefully selected patients treated at centers with experience in managing the side effects of 
treatment. Immunotherapy is an important systemic treatment modality for metastatic 
melanoma. Checkpoint inhibition with an anti-programmed cell death 1 (PD-1) antibody 
(pembrolizumab, nivolumab) in combination with the anti-cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) antibody ipilimumab has better efficacy (response rates, 
progression-free survival) than single-agent anti-PD-1 therapy in patients with advanced 
melanoma who are candidates for systemic therapy. Survival data from phase III trials 
suggest that 50 percent of patients receiving nivolumab (CHECKMATE-066) and 50 to 60 
percent of patients receiving the combination of nivolumab and ipilimumab (CHECKMATE-
067) will remain alive at three years. In the phase III KEYNOTE-006 trial, pembrolizumab 
demonstrated significantly longer PFS and improved overall survival compared with 
ipilimumab in patients with advanced melanoma. Overall survival was significantly 
prolonged with pembrolizumab compared with ipilimumab (four-year overall survival rate 
41.7 versus 34.1 percent; HR 0.73, 95% CI 0.61-0.89).
Hepatocellular carcinoma (HCC) typically diagnosed late in its course is an aggressive tumor 
that often occurs in the setting of chronic liver disease and cirrhosis. Although the mainstay 
of therapy is surgical resection, the majority of patients are not eligible because of tumor 
extent or underlying liver dysfunction. There has been a resurgence of interest and
enthusiasm for systemic therapy of HCC with the emergence of data showing that the 
molecularly targeted agents sorafenib, levatinib and regorafenib improve survival versus best 
supportive care alone. (R12-0948) Both sorafenib and levatinib have been for the first-line 
treatment of patients with unresectable HCC. Sorafenib HCC Assessment Randomized 
Protocol (SHARP) trial demonstrated that angiogenesis biomarkers Ang2 and VEGF were 
independent predictors of survival in patients with advanced HCC but not were predictive of 
response to sorafenib. Subsequently, a survival benefit has also been shown in the second-
line setting patients for HCC who had disease progression on or after sorafenib or were 
intolerant to sorafenib in nivolumab (CHECKMATE-040) and pembrolizumab (KEYNOTE-
224; NCT02702414) trials. Currently multiple phase III studies of CPI in combination with 
anti-angiogenics is being conducted in 1st line HCC. Atezolizumab in combination with 
bevacizumab received regulatory approval from the US Food and Drug Administration 
(FDA) in May 2020 and European Medical Agency (EMA) in Sep 2020 for the frontline 
treatment of patients with unresectable or metastatic HCC based on findings from the phase 3 
IMbrave150 trial. In the trial, the combination led to a 42% reduction in the risk of death 
compared with sorafenib. Based on the superior efficacy it is expected that atezolizumab in 
combination with bevacizumab or similar such combinations is expected to be the standard of 
care. It is important that further options for progressors on this first line treatment options be 
explored.

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The planned inclusion of a cohort of patients with locally advanced or metastatic and/or
unresectable hepatocellular carcinoma (HCC) with no prior systemic treatment is based on an
understanding of the mechanisms involved in the proposed combination therapy, and the
available evidence supporting the expectation of enhanced activity with the added inhibition 
of Ang2 signaling. Hepatocellular carcinoma (HCC) is a vascular tumor and angiogenesis is 
believed to play an important role in its progression. The role of anti-VEGF is well 
established in HCC.
Multikinase inhibitors targeting VEGFR like sorafenib and lenvatinib have been approved as
a first-line treatment in HCC. Given its high immunogenicity, immune checkpoint inhibitors 
(ICI), targeting the programmed cell death-1 (PD-1) axis have been approved either as 
monotherapies or in combination with other ICI, such as cytotoxic T lymphocyte antigen-4 
(CTLA-4).
Combination therapies involving antiangiogenics and ICI show improved response over 
antiangiogenic monotherapy (IMbrave150 trial). It is hypothesized that this is due to the 
complementary mechanisms involved.
The phase III IMbrave150 study conducted in the previously untreated HCC patients 
supported the combination of atezolizumab (anti-PDL1) with bevacizumab (anti-VEGF). 
Overall response rate was 27% with atezolizumab plus bevacizumab vs 12% compared to 
sorafenib based on independent assessment using RECIST 1.1 criteria. Median progression-
free survival (PFS) was also significantly increased (median 6.8 vs 4.3 months, HR = 0.59; 
95% CI = 0.47– 0.76, P < .0001).
The combination therapy being investigated in this trial addresses both mechanisms described 
above. It combines an anti-PD-1 agent (ezabenlimab) with a bispecific nanobody (BI 836880) 
that blocks VEGF and in addition Ang2. Data suggests that this added activity against Ang2 
may add to the overall response seen with the combination of ICI and anti-VEGF alone. The
rationale for this is described below. Ang2 leads to immune suppression by distinct 
mechanisms compared to VEGF. VEGF plays a key role in suppressing tumor immune 
response by negatively affecting the antigen presenting cells (APCs) (R20-2104) and effector 
T-cells (R20-2103, R20-2106) while augmenting the effects of immune suppressive cells 
such as T-regulatory cells (T-regs) (R20-2107) and myeloid derived suppressor cells 
(MDSCs) (R20-2102).
Ang-2 increases the neutrophil recruitment and adhesion of both neutrophils and TEMs to 
endothelium (R16-5098) and increases the conversion to M2-like macrophage phenotype
(R20-2101). Ang-2 further can stimulate TEMs to secrete IL-10, which can promote the 
expansion of T-regs and the inhibition of effector T-cells. The Sorafenib HCC Assessment 
Randomized Protocol (SHARP) trial demonstrated that angiogenesis biomarkers Ang2 and 
VEGF were independent predictors of survival in patients with advanced HCC (R12-0948). 
Furthermore, patients with high pre-treatment serum Ang-2 levels were found to respond 
poorly to CTLA-4 and PD-1 ICIs. Also, treatment with ICIs can lead to elevated Ang-2 
levels, resulting, again, in poor prognosis (R19-1712). In the Keynote-524 study evaluating 
the combination of pembrolizumab and lenvatinib in 1st line HCC patients it was observed 
that reduced decrease of Ang-2 was associated with a decrease in PFS suggesting a role for 
Ang-2in treatment resistance (R21-2811). Preclinical evidence also suggests a role of Ang-2 
in mediating resistance to VEGF signaling blockade (R15-5149)

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Based on the distinct role of Ang-2 in immune suppression of the tumor microenvironment 
and its role in conferring resistance to therapy targeting only VEGF, we believe selective 
triple inhibition of anti-VEGF, anti-Ang2 and PD-1 may confer a distinct advantage in the 
treatment of HCC patients. This is supported by preclinical data from a LL/2 (lewis lung) 
syngeneic tumour pre-clinical study (please refer to section 5.1.1.4 “Combining BI 836880 
with immune checkpoint inhibition” of the IB), as well as a study that investigated a 
combination of a PD1 antibody with a bispecific Ang-2/VEGFa antibody in multiple mouse 
in vivo models (R20-2105).
As of January 2022, a total of 252 patients have been treated in this ongoing Phase Ib study 
evaluating BI 836880 and ezabenlimab in patients with advanced or metastatic solid tumours. 
Clinical activity was observed across all cohorts. A total of 44 patients remain on treatment 
and continue to be followed up.
1.2
DRUG PROFILE
1.2.1
BI 836880
BI 836880 is a genetic fusion protein of one VEGF-A-binding and one Ang2-binding single 
domain antibodies (VHH, Nanobody®). The two single domain antibody moieties are linked 
via a human serum albumin-binding Alb11 domain, serving as half-life extension, and
glycine-serine linkers between the domains. The protein has a molecular mass of 40.7 kDa
(c02353883-09). The Nanobody® technology was originally developed following the 
discovery that camelidae (camels and llamas) possess fully functional antibodies that lack 
light chains. These heavy chain antibodies contain a single variable domain (VHH) and two 
constant domains CH3). The cloned and isolated VHH domain is a stable polypeptide 
harbouring the full antigen-binding capacity of the original heavy-chain antibody. These 
newly discovered VHH domains form the basis of a new generation of therapeutic antibodies 
named Nanobodies (R15-1719).
BI 836880 is highly selective for VEGF-A and Ang2, as he molecule did not bind to the 
related growth factors VEGF-B, -C, -D, placental growth factor (P1GF), and angiopoietin 1 
(Ang1). BI 836880 is highly potent and showed in vivo monotherapy efficacy (tumor growth
inhibition) in several tumor xenograft representing colon cancer (CXF 243), non-small cell
lung cancer (LXFE 211, LXFE 1422), mammary cancer (MAXF 401), ovarian cancer
(OVXF 1353), pancreatic cancer (PAXF 546) and renal cell cancer (RXF 1220).
A 13-week repeat dose administration of BI 836880 was performed in cynomolgus monkeys. 
BI 836880 was well tolerated up to the highest dose of 60 mg/kg. No mortality was attributed 
directly to BI 836880 administration. BI 836880 did not demonstrate any effects on 
neurological, renal, or cardiovascular functions including electrocardiograms (ECGs). In a 
monkey presenting the immunogenic reaction, membrano-proliferative glomerulopathy in the 
kidney was observed. This finding was considered a secondary response to immune complex 
deposition in the glomeruli and not directly related to BI 836880 administration.

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At the time of data cut off for IB version (17 Aug 2021), 421 patients had been treated
with BI 836880 in 5 clinical trials, either as a monotherapy (n = 62) or in a combination
therapy (n = 359). The combination therapy trials evaluate BI 836880 in combination with
ezabenlimab, an anti-PD-1 monoclonal antibody, administered every 3 weeks (1336-0011,
1336-0012 Part 2, 1381-0009 Module C). Of the 359 patients exposed to combination therapy
so far, 347 patients have been treated with the recommended Phase II dose (RP2D).
The most frequent adverse events (AEs) in patients treated with BI 836880 monotherapy
were hypertension (54.8%), asthenia (48.4%), vomiting (29.0%), nausea (27.4%), diarrhoea
(25.8%), and constipation (25.8%). One patient (1.6%) was reported with an AE requiring
dose reduction and 13 patients (21.0%) with AEs leading to treatment discontinuation. There
were 43.5% of patients with on-treatment SAEs; hypertension and pleural effusion (3 patients
[4.8%] each) were the only SAEs reported for more than 2 patients.
After evaluating all available PK, PD, efficacy, and safety data, the dose of 720 mg
BI 836880 every 3 weeks (q3w) was determined as a RP2D. The most common AEs reported
for this dosing regimen were hypertension (73.9%), asthenia (43.5%), vomiting (34.8%), and
nausea (39.1%). Hypertension (34.8%) was also the most frequently reported Grade 3 event.
Two patients (8.7%) were reported with a Grade 4 AE; these AEs were neutropenia and
dyspnoea. One patient in this dose group was reported with fatal AEs resulting from disease
progression: metastases to liver and hepatic failure.
Data pooled from the combination trials showed that 326 patients (90.8%) treated so far have
been reported with at least 1 AE. The most common individual AE (by preferred term) has
been hypertension (20.3%), followed by asthenia (17.5%), diarrhoea (17.3%), nausea
(16.7%), fatigue (15.3%), decreased appetite (12.8%), peripheral oedema (12.3%), and
vomiting (10.3%). Six patients (1.7%) have been reported with AEs requiring dose changes;
25 patients (7.0%) had an AE leading to treatment discontinuation. Hypertension (8.4%) has
been the most frequently reported Grade 3 event. Adverse events of Grade 4 have been
reported for 13 patients (3.6%); each Grade 4 AE has been reported for a single patient. There
have been 22 patients (6.1%) with AEs resulting in death; sepsis and general physical health
deterioration (3 patients each, 0.8%) as well as respiratory failure (2 patients, 0.6%) have
been the only fatal AEs reported for more than 1 patient. Adverse events under the SMQ
haemorrhages occurred in 28 patients (7.8%), with 4 patients (1.1%) presenting AEs of
Grade 3 and 3 patients (0.8%) presenting a Grade 5 AE. There have been 59 patients (16.4%)
reported with immune-related AEs according to investigator’s judgement; 7 patients (1.9%)
had Grade 3 AEs and 6 patients (1.7%) had Grade 4 AEs.
Laboratory values from all conducted trials did not show any event that met Hy’s law criteria.
The pharmacokinetics, pharmacodynamics and immunogenicity of BI 836880 were 
investigated based on data from the monotherapy Phase I studies. 
Maximum plasma concentrations were reached shortly after the end of infusion. BI 836880 
plasma concentration remained around the maximum for up to 8 h and started to decline 
afterwards slowly. Cmax and AUC increased in a dose-proportional manner over the entire 
dose range. As expected for a nanobody, the clearance was low, resulting in a terminal half-

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life of ~11 days. The volume of distribution was also low and in the range of the average 
blood volume. An accumulation ratio of 1.20 to 1.92 was observed, showing slight 
accumulation of BI 836880 after multiple dosing. No pharmacokinetic interaction between BI 
836880 and ezabenlimab was detected as the PK parameter were comparable between 
administration alone and in combination.
For a more detailed description of the drug profile refer to the current Investigator’s 
Brochures (IB).
1.2.2
BI 754091 (Ezabenlimab)
Ezabenlimab is a humanized IgG4 pro-monoclonal antibody showing potent and selective 
binding to human PD-1(c07895879-06). Ezabenlimab has highly human frameworks and a 
low predicted immunogenicity score. The ezabenlimab molecule has a molecular weight 
approximately 148 kilo Daltons. The antibody is composed of 2 heavy chains (446 amino 
acids each) and 2 light chains (218 amino acids each). The 4 polypeptide chains of the 
antibody are linked together by disulfide bonds. Each heavy chain contains one consensus 
sequence for N-linked glycosylation.
Ezabenlimab shows anti-tumor effects in vivo several mice model including in the syngenic 
MC-38 mouse model.
A 13-week repeat dose administration of ezabenlimab was performed in cynomolgus 
monkeys. Ezabenlimab was well tolerated and no related mortality or clinical signs, or 
changes to body weight, food consumption, respiratory rate or electrocardiogram were 
observed. 
Ezabenlimab exposure increased dose-proportionally and accumulated with repeat dosing for 
all tested dose levels. Ezabenlimab was still detectable after 4 week recovery period in the 
highest dose level (100 mg/kg). Engagement of ezabenlimab with target was assessed by 
measuring available ezabenlimab-free PD-1 on CD3+/CD95+ T cells. After 13 weeks of 

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dosing ezabenlimab resulted in in vivo target engagement at all dose levels. After 4 week 
recovery period; available PD-1 remained decreased in the 100 mg dose group demonstrating 
sustained target engagement throughout the recovery period.
As of November 1st 2021, 117 patients with advanced/metastatic solid tumours have been 
treated with single agent ezabenlimab, 111 of these patients were treated with the 240 mg 
q3w recommended phase II dose (RP2D). Additionally, 881 patients have been treated with 
the RP2D of ezabenlimab in combination with other agents. Three hundred and ninety four
patients treated in combination with BI754111 (anti-LAG-3 mAb), 381 patients were treated
in combination with BI 836880 (VEGF/Ang-2 inhibitor), 37 patients were treated in 
combination with BI 891065 (SMAC mimetic) and 11 patients were treated in combination 
with BI 754111 and BI 907828 (MDM2-p53 antagonist). 6 patients were treated with the 
combination of ezabenlimab and BI 907828 (MDM2 inhibitor), 5 patients were treated with 
the combination of ezabenlimab and BI 1387446 (STING agonist), 20 patients were treated 
with the combination of ezabenlimab plus BI 765063 (SIRPα antagonist), and 27 patients 
were treated with the combination of ezabenlimab plus BI 3018078 (anti-tumor vaccine).
The currently available ezabenlimab clinical data demonstrate that it is well tolerated. The 
most common AEs reported in patients treated with ezabenlimab monotherapy were fatigue 
(39.3%), nausea (29.9%) and decreased appetite (21.4%). There were no Grade 5 or treatment 
related Grade 4 events reported in patients treated with ezabenlimab monotherapy. 
Immunerelated AEs (irAEs) were reported in 32 patients (27.4%) on ezabenlimab 
monotherapy, the vast majority were Grade 1 and 2. There were no Grade 4 or Grade 5 irAEs 
and no infusion related reaction of any grade reported in patients treated with ezabenlimab
monotherapy.
Preliminary efficacy analysis shows overall objective response rate ezabenlimab
monotherapy of 16.2% across all cohorts (15 patients with confirmed partial response [PR] 
and 3 patients with complete responses [CR]) (95% CI 9.4, 23.2). All 3 patients with CRs and 
8 of the 15 patients with PR were still on treatment at the time of last data cut-off. Tumor 
responses were seen in diverse cancer types.
The available PK data show that ezabenlimab has a (at least) bi-phasic distribution. The 
volume of distribution ranged between 4.63 L and 5.88 L. The systemic clearance of 
ezeabenlimab ranged between 0.00971 L/h (80mg dose) and 0.0119 L/h (400mg dose) (i.e. 
approx. 0.0237 - 0.0286 L/day) resulting in gMean half-life estimates of 13.8 to 17.8 days.
Volume of distribution ranged from 4.63L to 5.88 L. The small total volume of distribution is 
consistent with a limited extravascular disposition as expected for a therapeutic antibody
For a more detailed description of the ezabenlimab profile, please refer to the current 
Investigator’s Brochures (IB).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Check point (PD-1 and PD-L1) inhibition and angiogenesis inhibition (VEGF, Ang-2) 
demonstrated antitumor activity with a clinical benefit in several tumor types. Despite this 
effect, an important number of patients will not respond to such therapy and most of patients 

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who benefit from treatment will relapse and die from their disease. Defining novel 
therapeutic strategy is needed to improve survival in patients with NSCLC patient and other 
solid tumors. 
It is well established that pro-angiogenic factors (e.g. VEGF-A) have an immunosuppressive 
effect in the tumour microenvironment. Preclinical data showed modulation of 
immunosuppressive cells by an anti-VEGF treatment and enhancement of antitumor effect of 
the combination of VEGF and PD-1 inhibition. Furthermore, internal BI preclinical data 
showed an additive effect of the angiopoietin inhibition on the top of the dual VEGF and PD-
1 inhibition (BI 836880 IB).
This scientific rationale and preclinical data support a combination trial of the triple 
inhibition of VEGF, Ang-2 and PD-1 inhibition. This trial will evaluate the tolerability of the 
combination of BI836880 and ezabenlimab and the effect of the triple inhibition in 2 
populations of patients with NSCLC, according to previous PD-1 / PD-L1 inhibitor treatment.
This combination will also be tested in other unmet need indications as exploratory expansion
cohorts in which either a high baseline Ang-2 or increase of Ang-2 at recurrence has been 
reported. Ang2 and VEGF have been reported as independent predictors of survival in 
patients with advanced HCC. Similarly, Ang2 and VEGF have also been reported as 
predictors of outcome for some CPI therapy in metastatic melanoma and supporting a rational 
combinatorial approach to improve the efficacy of immune therapy (R19-1712).
As of January 2022, a total of 252 patients have been treated in this ongoing Phase Ib study.
Clinical activity was observed across all cohorts.
DECISION TO TERMINATE THE TRIAL
Although a preliminary assessment of the available data from the ongoing clinical 
program for the ezabenlimab + BI 836880 combination exhibit signs of antitumor activity 
and a manageable safety profile for an overall positive benefit risk ratio, careful review of 
the full data set performed in the context of the current standards of care for the indications 
under study has led to the decision taken by the sponsor in December 2021 to discontinue 
recruitment in study 1336.11, and terminate further expansion of the study. 
An important consideration in the review process was whether the investigational 
combination treatment under study, namely BI 836880 plus ezabenlimab, had 
demonstrated benefit that delivered clear improvement over the current standards of care, 
some of which had evolved over the course of the study. The measure used to evaluate 
efficacy was the Objective Response Rate (ORR) which was the primary efficacy endpoint 
of the trial. It is important to note that at the time of this evaluation all cohorts had 
completed planned enrolment, and sufficient data had been collected to support a well-
informed decision. Based on this evaluation, the efficacy observed in the different 
indications did not show clear improvement over the standards of care relative to 
published efficacy results in the different indications, with the one possible promising 
result in the 2L HCC cohort. This finding, however, was confounded by the population 
studied. The 2L HCC cohort enrolled patients that had received prior 1L treatment with 
monotherapy anti-angiogenic TKi (i.e., either sorafenib or lenvatinib). Given the evolution 

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of the standard of care for 1L HCC, from monotherapy anti-angiogenic TKi treatment to 
combination treatment with immune checkpoint inhibitor plus an anti-angiogenic agent, it 
was determined that this cohort was not representative of what is expected to be the 2L 
HCC patient population moving forward. Based on this evaluation, the decision was taken 
to terminate the trial.
As a part of this decision, for patients still under active treatment, treatment with BI 836880 
plus ezabenlimab may continue until disease progression, undue toxicity, withdrawal of 
patient consent, or 53 cycles [approximately 3 years] from the start of first treatment 
administration, whichever occurs first (see Section 4.1.4, “Treatment duration” for full 
details).
1.4
BENEFIT - RISK ASSESSMENT
Both BI 836880 and ezabenlimab are currently tested in early phase clinical trials. At the time 
of data cut-off for this IB version (17 Aug 2020) 62 patients with solid tumours had been 
treated with BI 836880 monotherapy in 3 Phase I clinical trials testing either an every-3-week 
schedule (1336.1, 1336-0012 Part 1) or a weekly schedule (1336.6). Additional 81 patients
with solid tumours received BI 836880 in combination with a checkpoint inhibitor
Ezabenlimab in a Phase Ib trial (1336-0011) and in Part 2 of a Phase I trial (1336-0012). 
RP2D for both monotherapy and combination trials was determined to be 720 mg Q3W.
After completing a dose escalation phase and determination of RP2D of ezabenlimab is 
currently used in an expansion phase evaluating the preliminary efficacy of the compound in 
several tumor types including NSCLC. Three doses of ezabenlimab (80, 240 and 400 mg) 
were tested in the dose escalation part of the phase I trial in 9 patients with solid tumors. No 
DLTs drug related serious AEs were observed during the MTD evaluation period at any dose 
level. The most common reported AEs are nausea, fatigue, decrease appetite, constipation 
and arthralgia. Based on this dose escalation data, the dose of 240 mg is recommended for 
further development in monotherapy or as a starting dose in combination trials.
The combination of an immune CPI with a VEGF blocker has previously been tested in 
multiple phase I, phase II and phase III trial combining atezolizumab with bevacizumab in 
patients with advanced solid tumors. The safety of TECENTRIQ with bevacizumab, 
paclitaxel and carboplatin was evaluated in IMpower150 in metastatic NSCLC. This 
combination was well tolerated with most AEs being mild or moderate in severity. The only 
grade 3-4 events were hypertension. AEs included check-point inhibitor related events such 
as fatigue, chills, diarrhea, rash and pruritus and other AEs related to VEGF blockade 
(fatigue, hypertension, and epistaxis).
Based on the mode of action of ezabenlimab and BI 836880, published and internal 
preclinical data and available clinical data, it is expected that the combination will increase 
the anti-tumor efficacy resulting in an increase in response rate with prolonged duration of 
response as compared to each monotherapy.

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Despite the good safety profile reported for both drugs, patients should be advised of the 
potential risk of side effects from these investigational drugs. In Part 1, due to observed 
hypertension and potential infusion reactions, a 48-hour hospitalization was required after
first administration of trial medications for closer observation with access to intensive care 
for ensuring patient safety. 
In Part 2, hospitalization is optional. The period of surveillance after study drug
administration depends on the medical assessment of the investigator and is at the
investigator’s discretion. Please refer to Sections 5.2.1, 5.2.2, and 5.2.3.
Patients enrolled in Part 2 will continue to be excluded if they have uncontrolled hypertension
(defined as BP > 140/90 mmHg) at baseline, and/or a history of severe haemorrhage or
thromboembolism. The most frequent AEs in patients treated in the combination therapy 
trials were hypertension (19.8%, including 8.6% of Grade 3), followed by nausea (12.3%, no 
AEs of Grade ≥3), and cough and diarrhoea (11.1%, no AEs of Grade ≥3). No patients were 
reported with AEs requiring dose changes; 3 patients (3.7%) had an AE leading to treatment 
discontinuation. Infusion-related reactions and corresponding symptoms were reported in 8 
patients (9.9%), with no AEs being higher than Grade 3. Adverse events under the SMQ 
haemorrhages occurred in 4 patients (4.9%), with 2 patients (2.5%) presenting AEs of Grade 
3 and 1 patient presenting a Grade 5 AE. Eleven patients (13.6%) were reported with 
immune-related AEs according to investigator’s judgement; 1 AE was of Grade 3 and 1 was 
of Grade 4.
Other side effects may be rare and unknown with irreversible and/or life threatening effects. 
Patients should also be advised that there are other unknown risks associated with 
participation in a clinical trial. In summary, considering the unmet medical need for new 
treatment armamentarium in patients with advanced or metastatic NSCLC who are 
progressing during or after prior PD-1 /PD-L1 based therapy and other solid tumours, the 
anti-tumour activity of VEGF blockade or PD-1 inhibition and the good safety profiles of 
BI836880 and ezabenlimab monotherapy and the existing data suggesting that a combination 
of PD-1 blockade with VEGF blockade is a promising therapeutic strategy, the benefit risk 
assessment for patients included into this trial is considered to be favorable.
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 also Section 5.2.6, adverse events of special interest.
1.4.1
Benefit-Risk Assessment in context of COVID-19 pandemic for 
patients participating in clinical trials investigating BI 836880 in 
combination with ezabenlimab
Considering the mechanism of action of VEGF/Ang2 inhibition and PD-1receptor blockade, 
there is no evidence to suggest an increased risk of infection. Based on available data, 
treatment with BI 836880 alone and in combination with a PD-1 inhibitor is not anticipated to 
pose a higher risk of acquiring a COVID-19 infection in cancer patients.  Overlapping 

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toxicity with VEGF/Ang2 combined with PD1 with an increased risk of infection has not 
been observed.
Considerations around drug-drug interactions are not included in this benefit-risk assessment 
– this information is provided in the protocol, Investigator’s Brochure and the most recent 
label of the respective medication(s) used for treatment of COVID-19 infection.
BENEFITS AND RISKS CONCLUSIONS AND RECOMMENDATIONS
Patients in clinical trials with BI 836880 and ezabenlimab have advanced late stage cancer 
with limited treatment options. Given the life threatening nature of the underlying disease, the 
approach recommended by professional oncology organizations (e.g. ASCO, ESMO) remains 
to treat patients with cancer as under normal circumstances. No consensus on 
recommendations exist regarding holding chemotherapy or immunotherapy or delaying 
adjuvant therapy or radiotherapy treatment in cancer patients with no signs of a COVID-19 
infection. Withdrawing treatment in a cancer patient who may have few or any alternative 
treatment options requires a careful, individual evaluation. 
To date, there is no evidence suggesting a link between susceptibility to COVID-19 
infections and the inhibition of VEGF-A and Ang2 targeted by BI 836880. Also, there is no 
evidence suggesting a link between susceptibility to COVID-19 infections and the inhibition 
of PD-1/PDL-1. Available non-clinical and clinical data from completed clinical trials have 
not shown an increased risk of infections with BI 836880 and ezabenlimab. 
Considering the limited and sparse data on immune activation and the role of inflammation as 
well as other underlying factors that may increase the severity and mortality from COVID-19 
infection, there may be some factors representing the risk for using VEGF/Ang2 or PD1 that 
are currently still unknown. The information about the risk factors, the severity and the 
activity of immune response in patient with COVID-19 infections will be constantly 
monitored as it evolves. 
All up-to-date information about the investigational compounds (preclinical, clinical, clinical 
pharmacology) is included in the trial documentation, including IB, clinical trial protocol for 
the guidance of the investigator. The latter also outlines the pre-cautionary eligibility criteria, 
measures for management of associated AEs, required dose reductions etc. The protocol-
defined trial procedures themselves do not impose any increased risk to study participants in 
developing COVID-19 infection. The risk mitigation measures currently in place within the 
clinical trial protocols are a sufficient safeguard, as patients are frequently monitored with 
comprehensive safety evaluations. Based on laboratory data and any adverse event that may 
occur, clinical trial protocols include guidance for the continuation, interruption, dose 
reduction, and discontinuation of study drugs. 
Therefore, assuming the protocol-defined requirements for continued study drug 
administration are met, the decision about concomitant use of experimental anti-cancer 
therapy with VEGF/Ang2 and PD1 with COVID-19 treatment in case of contracted COVID-
19 infection will be left to the investigator’s benefit-risk assessment on a case-by-case basis.

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The investigators will take the totality of information related to each single patient and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each patient’s (continued) participation in the planned trials. BI as the sponsor, recommend to
adhere to the trial protocol and where required, will support the investigator in their decision 
finding, where this protects the safety, wellbeing and/or is in the best interest of the patient. 

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
PART 1:
Primary objective:
To determine the Recommended Phase 2 Dose (RP2D) of BI 836880 in combination with 
ezabenlimab in patients with locally advanced or metastatic non-squamous NSCLC who
progressed during or after first line (in case of checkpoint inhibitor naïve patients) platinum-
based therapy and patients who relapsed after completion of at least 2 cycles (in case of 
checkpoint inhibitor relapsing patients) of  platinum-based chemotherapy and a checkpoint 
inhibitor treatment (monotherapy or in combination with chemotherapy).
Secondary objective:

To provide safety data 

To evaluate the basic pharmacokinetics of BI 836880 and ezabenlimab during 
combination therapy after the first and fourth infusion cycle.
PART 2:
Primary objective:

To assess anti-tumour activity of BI 836880 in combination with ezabenlimab in 
patients with locally advanced or metastatic non-squamous NSCLC and other solid 
tumors 
Secondary objective:

To provide safety data and further investigate clinical efficacy including disease 
control (DC), duration of objective response (DoR), progression free survival (PFS), 
and tumour shrinkage

To evaluate the basic pharmacokinetics of BI 836880 and ezabenlimab during 
combination therapy after the first infusion cycle.
2.1.2
Primary endpoint(s)
PART 1:
The primary endpoint is the number of patients with DLTs within the first cycle of treatment, 
which will be assessed for dose escalation in order to meet the objective of determination of
the MTD of the combination BI 836880 and ezabenlimab in patients with locally advanced or 
metastatic non-squamous NSCLC.

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PART 2:
The primary endpoint is Objective Response (OR) defined as best overall response (RECIST 
1.1) of complete response (CR) or partial response (PR) from first treatment infusion until the 
earliest of disease progression, death or last evaluable tumour assessment before start of 
subsequent anti-cancer therapy, lost to follow-up, or withdrawal of consent. In case of 
recurrent glioblastoma (GBM), assessment will be based on RANO (Response Assessment in 
Neuro-Oncology) criteria.
2.1.3
Secondary endpoint(s)
PART 1:

Adverse events (AEs), drug related AEs, drug related AEs leading to discontinuation 
during treatment period.

Pharmacokinetic parameters Cmax, tmax, and AUC0-504h after the first and fourth 
infusion cycle. 
PART 2:

Adverse events (AEs), drug related AEs, drug related AEs leading to discontinuation 
during treatment period.

Disease control (DC), defined as best overall response of CR, PR, or stable disease 
(SD) by RECIST 1.1 (RANO for the GBM cohort) from first treatment infusion until 
the earliest of disease progression, death or last evaluable tumour assessment before 
start of subsequent anti-cancer therapy, lost to follow-up or withdrawal of consent.

Duration of objective response (DoR), defined as the time from first documented CR 
or PR by RECIST 1.1 (RANO for the GBM cohort) until the earliest of disease 
progression or death among patients with OR.

Progression-free survival (PFS) (RANO for the GBM cohort & RECIST 1.1 for all 
other cohorts) , defined as the time from first treatment infusion until disease 
progression or death from any cause, whichever occurs earlier.

Tumour shrinkage (in millimeters), defined as the difference between the minimum 
post-baseline sum of diameters of target lesions (longest for non-nodal lesions, short 
axis for nodal lesions) and the baseline sum of diameters of the same set of target 
lesions. In GBM, using RANO criteria, tumor shrinkage will be calculated based on 
the difference between the post-baseline and baseline measurements of the sum of 
product of the largest bi-dimensional measurements for all target lesions.

Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the first infusion cycle.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a Phase I, non-randomized, uncontrolled, open-label, dose escalating study of
BI 836880 administered in combination with ezabenlimab intravenously every 3 weeks. The 
eligible patient population will be CPI naïve and experienced patients with locally advanced 
or metastatic non - squamous NSCLC who progressed during or after first line platinum-
based chemotherapy or CPI monotherapy treatment or the combination of CPI and 
chemotherapy in Part 1. Part 2 will have additional expansion cohorts.
Part 1:
Dose escalation of BI 836880 in combination with ezabenlimab in patients with locally 
advanced or metastatic non-squamous NSCLC who progressed during or after first line (in
case of checkpoint inhibitor naïve patients) platinum-based therapy or relapsed after 
completion of at least 2 cycles (in case of checkpoint inhibitor relapsing patients) of 
platinum-based chemotherapy and a checkpoint inhibitor treatment (monotherapy or in 
combination with chemotherapy).
Dose escalation will start at combination of BI 836880 360mg and ezabenlimab 240mg and 
will be guided by Bayesian Logistic Regression Model (BLRM) Section 7.
At the first dose level, the first patient will be treated and observed for at least 15 days before 
allowing the second patient to receive BI 836880 and ezabenlimab infusions. 
A safety monitoring committee (SMC) meeting will be held to decide if the 2nd patient can 
be enrolled to the study. Subsequent enrollment at all dose levels within dose escalation, each 
patient in a given cohort (dose level) will be observed for a minimum of 48 hours after first 
BI 836880 and ezabenlimab application for acute reaction monitoring before allowing 
treatment for subsequent patient in the same cohort. As described in Section 6.1 of the 
protocol, during the treatment phase, after administration of BI 836880 and ezabenlimab, 
patients are required to be hospitalized under close surveillance with access to intensive care 
for at least 48 hours after administration of trial medication to allow close monitoring for 
infusion-related reactions or other adverse events and availability of patients for PK visits. 
The sponsor will contact the investigator to verify if any acute reaction was investigated 
before allowing treatment for subsequent patient in the same cohort. For any dose-escalation 
cohort, at least 2 patients will be required. After all patients in a cohort have either 
experienced a DLT or have been observed for at least one cycle (1 cycle is defined as 3 
weeks) without 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 which fulfil the EWOC criterion and dose escalation rules according to Section 4.1.3. 
Decision on further recruitment (dose escalation, de-escalation or cohort expansion) will be 
made by a Safety Monitoring Committee (SMC) based on the collected safety data as well as 
other data (e.g. PK/PD data) when available.
If DLTs are observed in the first 2 consecutive patients of a previously untested dose level,
subsequent enrolment to that cohort will be stopped. The BLRM will be re-run to confirm 

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that the dose-level still fulfils the EWOC criterion. Decision will be made whether the next 
patients will be enrolled on the same dose level, or if they will be enrolled to a lower dose 
level.
Part 2:
It is foreseen to treat up to 290 patients of full age (according to local legislation, usually ≥ 18 
years) at screening in different indications: patients with locally advanced or metastatic 2nd or 
3rd line CPI resistant non-squamous Non-Small Cell Lung Cancer (NSCLC), ≥2nd line Small 
Cell Lung Cancer (SCLC), recurrent glioblastoma, IO failure metastatic melanoma, 1st line 
HCC patients (cohort G), HCC patients who were intolerant or progressed during or after 
standard first line treatment with sorafenib or lenvatinib (cohort F) and HCC patients who 
were intolerant or progressed during or after standard first line treatment with atezolizumab 
in combination with bevacizumab (cohort H). Please note that the cohorts will run in 
parallel, not sequentially (see Figure 3.1: 1). The HCC cohorts (cohorts F, G, and H) will be 
implemented only in countries where these cohorts are approved.
Notes and justification of enrolling additional patients in cohort F (2nd line HCC 
patients pre-treated with sorafenib or lenvatinib):
At the time of protocol version 7, 30 patients in cohort F were treated and 40% confirmed 
responses (naïve estimate for observed complete or partial responses) with durable duration 
were observed among the second line HCC patients who were pre-treated with sorafenib and 
lenvatinib. Response rates of currently approved non-immuno-oncology treatments (e.g. 
Cabozatinib, Regorafenib, Ramucirumab) were reported from 4%-7% (R20-3048, R20-3049, 
R20-3057) in sorafenib pre-treated patients only. Among immuno-oncology treatments, 18% 
and 32.2% response rates were reported for pembrolizumab (R21-2759) and for combination 
treatment of nivolumab and ipilimumab (R21-2758) in sorafenib pre-treated patients. The 
efficacy results so far observed in cohort F are very promising and warrant further 
investigation. 30 additional patients are thus planned to be enrolled in cohort F. 
In particular, the patients in cohort F with treatment start date before 15-Jul-2021 are 
considered as stage I patients whereas patients starting treatment after 15-Jul-2021 (in 
accordance with protocol version 7) will be considered as stage II. An analysis is planned at 
the end of stage II, incorporating data from both stages, using a Bayesian method. An 
amendment may be made to further expand this cohort depending on the end of stage II 
result. The decision criterion as well as details of the statistical model are specified in Section 
7.1.2.
Based on the current clinical evidence observed in cohort F of the ongoing trial and the 
documented role of Ang-2 across other HCC studies, we would like to further explore this 
combination in 30 patients who have progressed with atezolizumab in combination with
bevacizumab in the 1st line setting (cohort H).
As of the decision of Boehringer Ingelheim in Dec 2021 no additional patients will be further 
included to the trial.

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Figure 3.1:1 Cohorts in the expansion phase (Part 2) of the study

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Figure 3.1:2 Study design
Doses and number of patients per cohort are given as examples and can be different based on 
the occurrence of DLTs and BLRM.
Routine safety laboratory exams will be performed by local laboratories. All trial relevant 
documentation will be stored in the Trial Master File (TMF) at Boehringer Ingelheim. In
addition, each site will have an ISF containing all trial documents relevant for the site.
As described in Section 6.1 of the protocol, the period of surveillance during the treatment
phase after administration of BI 836880 and ezabenlimab is at the investigator’s discretion.
Management guidelines have been provided for infusion related reactions (Section 5.2.7.1)
and hypertension episodes (Appendix 10.2.1).
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Part 1 is a Phase I, non-randomized, uncontrolled, open-label, dose escalating study of BI 
836880 administered in combination with ezabenlimab intravenously. The eligible patients 
are patients with locally advanced or metastatic non - squamous NSCLC who progressed 
during or after first line (in case of naïve patients) of platinum-based therapy. Additional we 
include patients who relapsed after completion of at least 2 cycles (in case of relapsed 
patients) of platinum-based chemotherapy and a checkpoint inhibitor treatment (monotherapy 
or in combination with chemotherapy). Dose escalation will be guided by a Bayesian logistic 
regression model (details refer to Section 7.1). 
Part 2 is an open-label expansion phase to assess efficacy and safety of BI 836880 in 
combination with ezabenlimab in pretreated or naïve check point inhibitor patients with 

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locally advanced or metastatic non-squamous NSCLC, small cell lung cancer, recurrent 
glioblastoma, malignant melanoma and 1st and 2nd line hepatocellular carcinoma.
Once RP2D is determined in Part 1, it is planned to enroll 320 patients as described in 
Section 3.1 for Part 2.
As of the decision of Boehringer Ingelheim in Dec 2021 no additional patients will be further 
included to the trial and the number of total enrolled patients will not be reached.
3.3
SELECTION OF TRIAL POPULATION
Eligible patients for Part 1 are patients with locally advanced or metastatic non-squamous 
NSCLC which progressed during or after first line (in case of naïve patients) of platinum-
based therapy and patients who relapsed after completion of at least 2 cycles (in case of 
relapsed patients) of  platinum-based chemotherapy and a checkpoint inhibitor treatment 
(monotherapy or in combination with chemotherapy). In Part 2, CPI pretreated or naïve 
patients with locally advanced or metastatic non-squamous NSCLC, small cell lung cancer, 
recurrent glioblastoma, malignant melanoma and hepatocellular carcinoma will be enrolled. 
This study is planned to be conducted in approximately 50 sites. These sites will be located in
in Australia, Asia (incl. China, South Korea, Japan), North America (incl. US) EU (incl. 
Germany, France, Spain, UK, Russia, Poland, Ukraine). Approximately 80 patients will be 
enrolled in the NSCLC cohort and 30 patients each in the SCLC, metastatic melanoma, 
recurrent glioblastoma, 1st and 2nd line HCC cohorts (Cohorts F and G). In addition, as of 
protocol version 7, 30 patients will be added to cohort F, and a new cohort H will start with 
30 patients to be enrolled. HCC cohorts will be implemented only in countries where this 
cohort is approved. In France and Germany, the 1st line HCC cohorts will not be submitted 
for approval. As of  the decision of Boehringer Ingelheim in December 2021, no additional 
patients will be further included to the trial.
Recruitment of patients in this trial is competitive, i.e. screening for the trial will stop once
the planned number of patients has been screened and entered. Investigators will be notified 
about screening completion and will then not be allowed to screen additional patients for this 
trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
In Part 1, the following patients are allowed for trial entry: patients with advanced/metastatic 
non squamous NSCLC who have progressed during or after first line (in case of naïve 
patients) of platinum-based therapy and patients who relapsed after completion of at least 2 
cycles (in case of relapsed patients) of a CPI treatment alone or in combination with 
platinum-based chemotherapy (monotherapy or in combination with chemotherapy). Patients 
included in Part 1 are not eligible to participate in Part 2.
In Part 2, the following patients are allowed for trial entry: patients with locally advanced or 
metastatic as 2nd and 3rd line CPI resistant NSCLC and 2nd line SCLC, recurrent glioblastoma, 

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IO failure metastatic melanoma, 1st line HCC patients and HCC patients who are intolerant or 
failed the first line treatment with sorafenib or lenvatinib or with combination of 
atezolizumab and bevacizumab.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
For PART 1:
1. Of full age (according to local legislation, usually ≥ 18 years) at screening.
2. Pathologically confirmed locally advanced or metastatic non-squamous NSCLC with 
PDL-1 expression available and >1% by IHC (as defined by the Pembrolizumab 
companion diagnostic test, determined by appropriate local pathology lab.
3.
No previous treatment with check-point inhibitor. Or patients with checkpoint inhibitor
based treatment as last therapy before entering the trial.
4.
Documented disease progression or relapse (based on investigator’s assessment) during 
or after completion of at least 2 cycles of platinum-based chemotherapy as first line 
treatment of Stage IIIB/IV non- squamous NSCLC or for checkpoint inhibitor 
experienced patients during or after completion of at least 2 cycles of platinum-based 
chemotherapy and a checkpoint inhibitor treatment (monotherapy or in combination with 
chemotherapy). This includes patients relapsing within 6 months of completing 
(neo)adjuvant/curative-intent chemotherapy/CPI or chemoradiotherapy.
5. At least one target lesion (outside the brain) that can be accurately measured per 
Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
6. Lesion with a diameter ≥ 2cm assessed by radiologist as suitable for DCE-MRI 
evaluation (Mandatory in Part 1, optional in Part 2).
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
8. Life expectancy ≥ 3 months after start of the treatment in the opinion of the investigator.
9. Recovery from all reversible adverse events of previous anti-cancer therapies to baseline 
or CTCAE grade 1, except for alopecia (any grade), sensory peripheral neuropathy, must 
be ≤ CTCAE grade 2 or considered not clinically significant.
10. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
11. Availability and willingness to provide a fresh tumour tissue sample obtained at baseline, 
and after 2 cycles of treatment.

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12. Adequate organ function defined as all of the following (all screening labs (see Table 
3.3.2: 1) should be performed at local lab within 10 days prior to treatment initiation):
Table 3.3.2: 1 Laboratory parameters
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1.5 x 109/L.
Platelets
≥75 x 109/L.
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L.
Renal
Creatinine OR
Measured or calculateda
creatinine clearance (Glomerular 
Filtration Rate (GFR) can also be 
used in place of creatinine or 
CrCl)
≤ 1.5 x ULN OR
≥50 mL/min for patients with creatinine levels >1.5x ULN.
Hepatic
Total bilirubin
≤1.5 times the upper limit of normal (ULN).
AST (SGOT) and ALT (SGPT)
≤2.5 x ULN OR ≤5 x ULN for patients with liver metastases.
Coagulation
International Normalised Ratio 
(INR) or Prothrombin Time (PT)
≤1.5xULN unless patient is receiving anticoagulant therapy as 
long as PT is within therapeutic range of intended use of 
anticoagulants.
Activated Partial Thromboplastin 
Time (aPTT)
≤1.5xULN unless patient is receiving anticoagulant therapy as 
long as PTT is within therapeutic range of intended use of 
anticoagulants.
a Creatinine clearance should be calculated per institutional standard.
13. 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 per 
ICH M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly, starting with the screening visit and through 6 months after the 
last dose of BI 836880 and ezabenlimab treatment, respectively. A list of contraception 
methods meeting these criteria is provided in the patient information. For further detail 
refer to Section 4.2.2.3.
Note: Female patients of childbearing potential must have a negative serum pregnancy
test within 72 hours prior to taking study medication during the screening period. At the 
following visits according to the flowchart a urine and/or serum pregnancy test is 
required. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. The serum pregnancy test must be negative for the patient 
to be eligible.

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1A 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.
For PART 2:
Main Inclusion Criteria for all cohorts
1. Of full age (according to local legislation, usually ≥ 18 years) at screening.
2. At least one measurable target lesion outside the brain (excluding the glioblastoma 
patients where brain lesions are allowed), that can be accurately measured per RECIST v 
1.1 or RANO.
3. ECOG performance status ≤ 1 (For glioblastoma cohort, Karnofsky status is applicable; 
see below).
4. Adequate organ function as all of the following (all screening labs should be performed at 
local lab within approximately 72 hours prior to treatment initiation):
    
System
Laboratory Value
Hematological
Absolute neutrophil count 
(ANC)
≥1.5 x 109/L.
Platelets
≥75 x 109/L.
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L.
Renal
Creatinine OR
Measured or calculateda
creatinine clearance (Glomerular 
Filtration Rate (GFR) can also be 
used in place of creatinine or 
CrCl)
≤ 1.5 x ULN OR
≥50 mL/min for patients with creatinine levels >1.5x ULN.
Hepatic
Total bilirubin
≤1.5 times the upper limit of normal (ULN).
AST (SGOT) and ALT (SGPT)
≤2.5 x ULN OR ≤5 x ULN for patients with liver metastases.
Coagulation
International Normalised Ratio 
(INR) or Prothrombin Time (PT)
≤1.5xULN, unless patient is receiving anticoagulant therapy as 
long as PT/INR is within therapeutic range of intended use of 
anticoagulants.

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Activated Partial Thromboplastin 
Time (aPTT)
≤1.5xULN, unless patient is receiving anticoagulant therapy as 
long as PTT is within therapeutic range of intended use of 
anticoagulants.
a Creatinine clearance should be calculated per institutional standard.
               
5. Availability and willingness to provide a fresh tumor tissue sample obtained after relapse 
or progression on or after prior therapy. For Part 2, In case a fresh biopsy cannot be 
obtained (e.g. inaccessible lesions or patient safety concern), an archived specimen 
obtained up to 6 months prior to cycle 1, visit 1 (C1V1) may be submitted in case no 
systemic antineoplastic therapy has been administered between the biopsy and C1V1 
(except for cohort D). For cohorts E, F and G, a fresh on-treatment biopsy is mandatory at 
C3D1, if possible from the same lesion as the pre-treatment biopsy.
6. Life expectancy ≥ 3 months after start of the treatment in the opinion of the investigator.
7. Recovery from all reversible adverse events of previous anti-cancer therapies to baseline
or CTCAE grade 1, except for alopecia (any grade), sensory peripheral neuropathy, must 
be ≤ CTCAE grade 2 or considered not clinically significant.
8. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
9. 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 per 
ICH M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly, for the entire duration of the trial treatment intake and for 6 
months after the end of the trial treatment. A list of contraception methods meeting these 
criteria is provided in the patient information. For further detail refer to Section 4.2.2.3.
Note: Female patients of childbearing potential must have a negative serum pregnancy 
test within 72 hours during the screening period. At the following visits according to the 
flowchart, a urine and/or serum pregnancy test is required. If the urine test is positive or
cannot be confirmed as negative, a serum pregnancy test will be required. The serum
pregnancy test must be negative for the patient to be eligible.
Inclusion for:
Cohort A (NSCLC):
-
Pathologically confirmed locally advanced or metastatic IIIB/IV non-squamous 
NSCLC 
-
Prior Check-point inhibitor monotherapy either as 1st or 2nd line. Patient must 
also have received treatment with a platinum-based chemotherapy regimen and 
have progressed or be intolerant, or ineligible, as per applicable local practice.
-
Approximately 10 patients will be recruited who have primary resistance to CPI 
based therapy which is defined as those advanced or metastatic IIIB/IV non-

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squamous NSCLC patients who previously received at least 2 cycles of CPI 
treatment and progressed without achieving benefit (RECIST v1.1 SD <4 months 
1A 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.
or progressive disease in <4 months).
Approximately 30 patients will be recruited who have secondary resistance to CPI 
based therapy which is defined as those advanced or metastatic IIIB/IV non-
squamous NSCLC patients who had a documented minimum duration of benefit 
of (minimum of stable disease) 4 months and minimum treatment duration of 2 
cycles on the previous CPI treatment without experiencing disease progression 
during that period. 
-
Patients with NSCLC known to harbor an ALK rearrangement, or EGFR 
mutation, or other genomic aberrations (e.g., ROS rearrangement, BRAF V600E 
mutation), are only eligible after experiencing disease progression (during or after 
treatment) or intolerance to approved targeted therapy for respective genomic 
aberrations, as applicable per local country guidelines.
-
No more than one prior line of targeted therapy or chemotherapy regimen is 
allowed.
-
Cohort B (NSCLC):
-
Pathologically confirmed locally advanced or metastatic IIIB/IV non-squamous 
NSCLC 
-
1st line Platinum-based chemotherapy and a check-point inhibitor 
combination treatment as the most recent therapy before entering trial 
-
Approximately 10 patients will be recruited who have primary resistance to the 
combination therapy which is defined as those advanced or metastatic IIIB/IV 
non-squamous NSCLC patients who previously received at least 2 cycles of 
platinum-based chemotherapy and CPI treatment and progressed without 
achieving benefit (RECIST v1.1 SD < 4 months or progressive disease in < 4
months).
-
Approximately 30 patients will be recruited who have secondary resistance to CPI 
based therapy which is defined as those advanced or metastatic IIIB/IV non-
squamous NSCLC patients who had a documented minimum duration of benefit 
(minimum of stable disease) of 4 months when previously treated with at least 2 
cycles of the CPI and platinum-based chemotherapy in a first line setting without 
experiencing disease progression during that period. 
-
Patients with NSCLC known to harbor an ALK rearrangement, or EGFR 
mutation, or other genomic aberrations (e.g., ROS rearrangement, BRAF V600E 
mutation), are only eligible after experiencing disease progression (during or after 
treatment) or intolerance to approved targeted therapy for respective genomic 
aberrations, as applicable per local country guidelines. No more than one line of 
targeted therapy is allowed.

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Cohort C (SCLC):
-
Pathologically confirmed locally advanced or metastatic SCLC. 
-
Documented intolerance to platinum-based chemotherapy or refractory to 
platinum-based chemotherapy (progression during treatment or during < 90 days 
of the last dose of platinum-based chemotherapy). Patients who are platinum-
sensitive (progression ≥ 90 days of the last dose of platinum-based chemotherapy) 
must also have received one additional prior line of platinum-based 
chemotherapy, if eligible, with or without combination with CPI as per applicable 
local treatment country guidelines.
Cohort D (recurrent glioblastoma):
-
Histologically confirmed denovo glioblastoma (primary) at first or second 
recurrence after initial standard, control or experimental therapy that includes at a 
minimum RT.
-
Unequivocal evidence of progressive disease on contrast-enhanced brain CT or 
MRI as defined by RANO Criteria, or have documented recurrent glioblastoma on 
diagnostic biopsy.
-
No more than two lines of prior chemotherapy (concurrent and adjuvant 
temozolomide based chemotherapy including in combination with another 
investigational agent is considered one line of chemotherapy). 
-
Only first and second recurrences of GBM are eligible.
-
An interval of at least 12 weeks from the completion of radiation therapy to start 
of study drug unless there is a new area of enhancement consistent with recurrent 
tumor outside the radiation field or there is unequivocal histologic confirmation of 
tumor progression.
-
Patient may have been operated for recurrence. If operated: residual and 
measurable disease after surgery is required; surgical site must be adequately 
healed free of drainage or cellulitis, and the underlying cranioplasty must appear 
intact at the time of randomization.
-
Karnofsky performance status ≥ 70.
-
MRI within 14 days prior to start of study drug.
-
Patients should be immunocompetent (i.e. no concomitant treatment with 
dexamethasone (or equivalent), or receive stable/decreasing steroid levels not 
exceeding 2 mg/day dexamethasone (or equivalent) during the last 3 days prior to 
clinical screening; no severe lymphopenia).
Cohort E (Melanoma):
-
Histologically confirmed, unresectable, Stage IV metastatic melanoma
-
Patients with a BRAF mutation must have received targeted treatment, or were 
not eligible, with a BRAF and MEK inhibitor as per applicable local country 
guidelines. In such a case no more than one line of targeted therapy is allowed.
-
At least one line of any kind of CPI based regimen as last treatment before 
entering the study
-
Documented progression during or after CPI therapy based regimen

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Cohort F (2nd line HepatocellularCarcinoma):
-
Patients must have diagnosis of locally advanced or metastatic and/or unresectable 
histologically confirmed advanced hepatocellular carcinoma, not eligible for 
surgical and/or locoregional therapies
-
Patients should have progressed on or after first line treatment with sorafenib or 
lenvatinib or discontinued sorafenib or lenvatinib due to lack of tolerability after 
receiving at least two weeks of treatment. Reason for discontinuation must be 
documented.
-
Documented virology status of hepatitis, as confirmed by screening hepatitis B 
surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), HBV 
DNA, anti-hepatitis C virus (anti-HCV) and HCV RNA as applicable.
-
Child-Pugh score class A
-
Anti-viral therapy per local standard-of-care if active hepatitis B virus (HBV). 
HBV DNA to be <500IU/ml and patients on anti HBV therapy for >4 weeks
before entering the study.
Cohort G (1st line Hepatocellular Carcinoma): To be implemented only in 
countries where this cohort is approved.
-
The subject should have have diagnosis of  locally advanced or metastatic and/or 
unresectable histologically confirmed advanced hepatocellular carcinoma that is 
not amenable to a curative treatment approach (eg, transplant, surgery, ablation 
therapy) or locoregional therapy (eg, TACE).
-
No prior systemic therapy for HCC. Previous use of herbal therapies/traditional 
Chinese medicines with anti-cancer activity included in the label is allowed, 
provided that these medications are discontinued prior to randomization.
-
Child-Pugh Score of A.
-
Documented virology status of hepatitis, as confirmed by screening hepatitis B 
surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), HBV 
DNA, anti-hepatitis C virus (anti-HCV) and HCV RNA as applicable.
-
Anti-viral therapy per local standard-of-care if active hepatitis B virus (HBV). 
HBV DNA to be <500IU/ml and patients on anti HBV therapy for >4 weeks 
before entering the study.
Cohort H (2nd line Hepatocellular Carcinoma - atezolizumab + bevacizumab
failures): To be implemented only in countries where this cohort is approved.
-
Patients must have diagnosis of locally advanced or metastatic and/or 
unresectable histologically confirmed advanced hepatocellular carcinoma, not 
eligible for surgical and/or locoregional therapies
-
Patients should have progressed on or after first line treatment with atezolizumab 
in combination with bevacizumab or discontinued due to lack of tolerability after 
receiving at least two cycles of treatment. Reason for discontinuation must be 
documented.
-
Documented virology status of hepatitis, as confirmed by screening hepatitis B 
surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), HBV 
DNA, anti-hepatitis C virus (anti-HCV) and HCV RNA as applicable.

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-
Child-Pugh score class A
-
Anti-viral therapy per local standard-of-care if active hepatitis B virus (HBV). 
HBV DNA to be <500IU/ml and patients on anti HBV therapy for >4 weeks
before entering the study.
3.3.3
Exclusion criteria
For PART 1:
1. Known hypersensitivity to the trial drugs or their excipients or risk of allergic of 
anaphylactic reaction to drug product according to Investigator judgement (e.g. 
patient with history of anaphylactic reaction or autoimmune disease that is not 
controlled by nonsteroidal anti-inflammatory drugs (NSAIDs), inhaled 
corticosteroids, or the equivalent of </= 10 mg/day prednisone).
2. Known immunodeficiency virus infection or an active hepatitis B or C virus infection.
3. History of severe hypersensitivity reactions to other mAbs.
4. Immunosuppressive corticosteroid doses (> 10 mg prednisone daily or equivalent) 
within 4 weeks prior to the first dose of trial medication.
5. Current or prior treatment with any systemic anti-cancer therapy either within 28 days 
or a minimum of 5 half-lives, whichever is shorter before start of treatment.
6. Serious concomitant disease, especially those affecting compliance with trial
requirements or which are considered relevant for the evaluation of the endpoints of 
the trial drug, such as neurologic, psychiatric, infectious disease or active ulcers 
(gastrointestinal 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.
7. Major injuries and/or surgery or bone fracture within 4 weeks of start of treatment, or 
planned surgical procedures during the trial period.
8. Patients with personal or family history of QT prolongation and/or long QT 
syndrome, or prolonged QTcF at baseline (> 480 ms). 
9. Significant cardiovascular/cerebrovascular diseases (i.e. uncontrolled hypertension, 
unstable angina, history of infarction within past 6 months, congestive heart failure > 
NYHA II).
Uncontrolled hypertension defined as: Blood pressure in rested and relaxed condition 
>= 140 mmHg, systolic or >= 90 mmHg diastolic (with or without medication), 
measured according to Appendix 10.2.
10. LVEF < 50%

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11. History of severe hemorrhagic or thromboembolic event in the past 12 months 
(excluding central venous catheter thrombosis and peripheral deep vein thrombosis).
12. Known inherited predisposition to bleeding or to thrombosis in the opinion of the
investigator.
13. Patient with brain metastases that are symptomatic and/or require therapy.
14. Patients who require full-dose anticoagulation (according to local guidelines).
No Vitamin K antagonist and other anticoagulation allowed; LMWH allowed only for 
prevention not for curative treatment.
15. History of pneumonitis within the last 5 years.
16. Patients who are under judicial protection and patients who are legally 
institutionalized.
17. Patients unable or unwilling to comply with protocol
18. Previous enrolment in this trial (Part 1 or Part 2).
19. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, 
makes them an unreliable trial patient or unlikely to complete the trial.
20. Women who are pregnant, nursing, or who plan to become pregnant in the trial
For PART 2:
1. Known hypersensitivity to the trial drugs or their excipients or risk of allergic of 
anaphylactic reaction to drug product according to Investigator judgement (e.g. patient 
with history of anaphylactic reaction or autoimmune disease that is not controlled by 
nonsteroidal anti-inflammatory drugs (NSAIDs), inhaled corticosteroids, or the 
equivalent of </= 10 mg/day prednisone).
2. Not more than one CPI based treatment regimen prior to entering study (eg. anti-
Programmed Death receptor-1 (PD-1), anti-Programmed Death-1 ligand-1 (PD-L1), 
anti-PD-L2, or anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) 
antibody).In case of CPIs combination, they need to be approved by the local 
regulatory agencies; for e.g., Melanoma cohort (Cohort E).
3. Known HIV infection 
4. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (exception for 
patients in HCC cohorts; Cohorts F, G & H).
5. History of severe hypersensitivity reactions to other mAbs.

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6. Immunosuppressive corticosteroid doses (> 10 mg prednisone daily or equivalent) 
within 4 weeks prior to the first dose of trial medication except for control of cerebral 
edema in case of recurrent glioblastoma (Cohort D).
7. Current or prior treatment with any systemic anti-cancer therapy (including 
radiotherapy) either within 28 days or a minimum of 5 half-lives, whichever is shorter 
before start of treatment.
8. Serious concomitant disease, especially those affecting compliance with trial 
requirements or which are considered relevant for the evaluation of the endpoints of 
the trial drug, such as neurologic, psychiatric, infectious disease or active ulcers 
(gastrointestinal 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.
9. Major injuries and/or surgery or bone fracture within 4 weeks of start of treatment, or 
planned surgical procedures during the trial period.
10. Patients with personal or family history of QT prolongation and/or long QT 
syndrome, or prolonged QTcF at baseline (> 480 ms). 
11. Significant cardiovascular/cerebrovascular diseases (i.e. uncontrolled hypertension, 
unstable angina, history of infarction within past 6 months, congestive heart failure > 
NYHA II).
Uncontrolled hypertension defined as: Blood pressure in rested and relaxed condition 
>= 140 mmHg, systolic or >= 90 mmHg diastolic (with or without medication), 
measured according to Appendix 10.2.
12. LVEF < 50%
13. History of severe hemorrhagic or thromboembolic event in the past 12 months
(excluding central venous catheter thrombosis and peripheral deep vein thrombosis).
14. Known inherited predisposition to bleeding or to thrombosis in the opinion of the 
investigator.
15. Patient with brain metastases that are symptomatic and/or require therapy.
16. Patients who require full-dose anticoagulation (according to local guidelines). No 
Vitamin K antagonist and other anticoagulation allowed; LMWH allowed only for 
prevention not for curative treatment.
17. History of pneumonitis (non-infectious) within the last 5 years
18. Patients who are under judicial protection and patients who are legally 
institutionalized.

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19. Patients unable or unwilling to comply with protocol
20. Previous enrolment in this trial.
21. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, 
makes them an unreliable trial patient or unlikely to complete the trial.
22. Women who are pregnant, nursing, or who plan to become pregnant in the trial
23. Symptomatic pleural effusion, pericardial effusion, or ascites
24. Prior treatment with any antiangiogenic treatment (e.g. bevacizumab, cediranib, 
aflibercept, vandetanib, XL-184, sunitinib, etc) except for prior sorafenib or lenvatinib
treatment in 2nd line HCC cohort (Cohort F) and for prior treatment with atezolizumab 
in combination with bevacizumab in Cohort H.
25. Has received a live vaccine within 30 days prior to the first dose of study drug
26. Patients with known active second malignancy other than non-melanoma skin 
cancers, non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular 
carcinoma in situ of the breast. Patients are not considered to have a currently active 
malignancy if they have completed anticancer therapy and have been disease free for 
greater than 2 years prior to screening
Further exclusion criteria:
Exclusion criteria for Glioblastoma cohort:
1. Has tumor primarily localized to the brainstem or spinal cord.
2. Has presence of diffuse leptomeningeal disease or extracranial disease.
3. Is known to have IDH mutant variety of recurrent glioblastoma.
4. Any prior treatment with prolifeprosan 20 with carmustine wafer.
5.
Any prior treatment with an intracerebral agent.
Exclusion criteria for Melanoma cohort:
1. Uveal or ocular melanoma
Exclusion criteria for HCC cohorts (cohorts F, G & H):
1. Co-infection with HBV and HCV or HBV and hepatitis D virus (HDV)
2. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and 
HCC

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3. Untreated active Hepatitis B virus (HBV)
4. History of hepatic encephalopathy
5. Participants with untreated or incompletely treated varices with bleeding or high-risk 
for bleeding
6. Treatment with any HCV anti-viral therapy within 4 weeks prior to Cycle 1 Day 1
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 implications, please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep 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 patient’s participation, 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 eCRF.
3.3.4.1 
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment 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.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).

The patient can no longer be treated with trial drug after a drug related Adverse Event 
CTCAE Grade 4.

The patient can no longer be treated with trial drug after a DLT, which did not recover to 
CTCAE Grade 1 or pre-treatment values within 2 weeks (not applicable for part 2)

The patient has repeatedly shown to be 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.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and Section 6.2.3.
For all patients, the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the eCRF. These data will be included in the trial database and reported.

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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, please see Section 3.3.4.1
above.
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:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial
4. Termination of the development of the compound in this indication.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
In this trial, the IMP BI 836880 will be switched to a new pharmaceutical formulation which 
is diluted in a standard 5% Glucose/Dextrose solution. The new formulation will be made 
available in this trial at the latest before expiry of the old formulation prepared with a drug 
specific Diluent. Details of the trial medications, BI 836880, ezabenlimab, and respective 
diluents, are presented in Tables 4.1.1: 1 and 4.1.1: 2, in the IBs for BI 836880 and 
ezabenlimab as well as in the Instruction for the Pharmacist (IfP).
Table 4.1.1: 1
BI 836880
Substance:
BI 836880
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/ml (vials with 10 ml)
Posology
rate controlled infusion on Day 1 of each 3-week 
cycle
Route of administration:
i.v.
Duration of use: 
until progression, unacceptable toxicity, or up to a 
maximum of 53 cycles
Table 4.1.1: 2
Ezabenlimab (BI 754091)
Substance:
Ezabenlimab (BI 754091)
Pharmaceutical formulation:
Solution for Infusion or Concentrate for solution for 
infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
20 mg /mL (15 mL vial) or 20 mg /mL (12 mL vial)
Posology
rate controlled infusion on Day 1 of each 3-week cycle
Route of administration:
i.v.
Duration of use: 
until progression, unacceptable toxicity, or up to a 
maximum of 53 cycles

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4.1.2
Selection of doses in the trial
4.1.2.1
Part 1
BI 836880 is currently tested as monotherapy in 2 phase I trials. 29 and 24 patients received 
BI 836880 in trial 1336.1 (every 3 week schedule) and in trial 1336.6 (weekly schedule), 
respectively. Dose levels between 40 mg and 1000 mg of BI 836880 were tested in the every 
3 week trial. Most commonly reported adverse events were hypertension, asthenia, nausea, 
vomiting, diarrhea and constipation. 5 DLTs occurred in the two studies (pulmonary 
embolism, proteinuria, hypertension, respiratory distress). Other relevant adverse events 
(mode of action related) include peripheral edema and bleeding (epistaxis). 
Based on safety data as well as PK and PD analysis, the dose of 720 mg is selected as 
recommended phase 2 dose (RP2D). This dose will be the highest dose that can be tested in 
combination with ezabenlimab. The dose below this dose tested in monotherapy trial (360 
mg) is safe and showed complete inhibition of systemic targets, and will used as starting dose 
for the combination with ezabenlimab. However because of the important safety difference 
between 360 and 720 mg (mainly occurrence and severity of hypertension), a BI 836880 
intermediate dose of 500 mg will be tested. The highest tested dose levels will be expanded 
before selection of BI 836880 dose to be used for Part 2 of the trial. 
In the monotherapy phase I trial (1381.1), a total of 9 patients received ezabenlimab at 3 dose 
levels (80 mg, 240 mg and 400 mg) in the dose escalation cohorts. There were no DLTs or 
drug-related SAE reported in any cohort. The most common reported AEs were nausea, 
fatigue, decreased appetite, constipation and arthralgia. Eight additional patients have been 
treated at dose of 240 mg in the expansion part of this trial. No grade 4, Grade 5 AE or DLT 
was reported.
The exploratory analysis of biomarker performed in these 9 patients shows 100% PD-1 
receptor occupancy in peripheral blood in all on-treatment patient samples compared to 
baseline throughout one treatment cycle. 
Plasma concentration of ezabenlimab appears to increase linearly (based on AUC0-504h 
Cmax and Cpre).  Furthermore, the observed ezabenlimab PK was compared with model 
simulated pembrolizumab PK (R17-2460). Observed ezabenlimab PK profiles overlap with
those simulated for pembrolizumab at a dose of 200 mg.
The dose of 240 mg of ezabenlimab once every 3 weeks was chosen to be further explored in 
monotherapy trials and is recommended as a starting dose in combination trials. The dose 
level of ezabenlimab will likely be fixed in this study unless safety signals suggest a dose 
adjustment.
4.1.2.2 
Part 2
Once at least 6 patients have received at least 1 cycle at the maximum dose level in Part 1, a 
safety evaluation of all patients treated in Part 1 will be performed. Based on all available
data, the SMC may approve the selected BI 836880 dose (RP2D) to be used in combination 

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with ezabenlimab for Part 2 of the trial. The RP2D assessment will be supported with the PK 
and PD analysis of at least 3 patients in each dose cohort.
Update after SMC decision:
The SMC selected the dose BI 836880 720 mg and for ezabenlimab 240 mg as dose for the 
Part 2 of this trial.
4.1.3
Method of assigning patients to treatment groups
After assessment of all in- and exclusion criteria, each eligible patient will be entered to 
treatment groups and the appropriate medication number will be assigned. Note that the 
medication number is different from the patient number (the latter is assigned directly after 
informed consent was obtained). Site personnel will enter the medication number in the CRF.
4.1.4
Drug assignment and administration of doses for each patient
Medication will be assigned via Interactive Response Technology (IRT) for each treatment
cycle. Each medication box does have a unique medication number. To facilitate the use of
the IRT, the Investigator will receive all necessary instructions.
The study drug will be prepared and handled according to “Instruction for Pharmacists”
which will be filed in ISF. Upon notification a patient entered the study; the pharmacy will
prepare the study drug in the assigned dosage for administration to the patient.
Ezabenlimab and BI 836880 will be given every 3 weeks as 2 separate consecutive intra-
venous infusions by authorized site staff in a specialized unit where emergency care can be 
provided (e.g. intensive care unit available, medical personal trained in advanced live 
support) according to “Instruction for Pharmacists”. 
The expected infusion time is 60 minutes for ezabenlimab and same for BI 836880;
ezabenlimab will be administered first, then 15 minutes (+/- 10 min) after the end of this 
infusion BI 836880 will be administered. 
In case of technical issues or complications during infusion, the total infusion time (including 
stop time and flushing) for BI836880 should not exceed 360 minutes.
For ezabenlimab, in case of technical issues or complications during infusion, the total 
infusion time (including stop time) should not exceed 180 minutes.
Appropriate drugs and medical equipment to treat anaphylactic reactions must be
immediately available, and study personnel must be trained to recognize and treat
anaphylaxis.
In the event of an infusion-related reaction ≤Grade 2, the infusion rate of ezabenlimab 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. Depending 

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on the time of occurrence and the severity of the reaction, the investigator may consider 
administering additional supportive medication, e.g. corticosteroids for re-introduction. 
Infusion rate and premedication for further treatment cycles should be adapted according to 
Investigator decision, but adaption of administration scheme need to be agreed with sponsor. 
If an infusion related reaction is Grade 3 or higher in severity at any point during the study, 
treatment with ezabenlimab has to be permanently discontinued.
Premedication: 
No premedication will be required for BI 836880 IV or ezabenlimab infusion. If a patient
expressed sign of infusion reaction at any BI 836880 treatment, a premedication will be
considered for all subsequent treatment infusions (dosage and schedule according
investigator’s decision) comparable to following scheme:

Acetaminophen/Paracetamol 650 mg - 1000 mg p.o., or equivalent

Antihistamine p.o. or i.v., equivalent to Diphenhydramine 50 mg i.v.
Drug re-administration criteria after the first cycle has been completed for Part 1:
Before initiating a new treatment cycle the actual health status will be assessed according to
Flow Chart and described in Section 5.2.5. To continue treatment with further cycles, all of 
the following criteria must be met:

No uncontrolled hypertension (according to Exclusion-Criterion #9)

QTcF <=480 ms (according to Exclusion-Criterion #8)

Acceptable tolerability (in case of an adverse event at the planned start of a treatment
cycle patients may continue therapy only after recovery to a level which would allow 
further therapy; i.e. CTCAE grade 1 or pre-treatment value or considered not 
clinically significant)
In case one of the above mentioned criteria is not fulfilled the patient should be re-evaluated 
for up to 2 weeks. Any case of a delay in treatment cycle should be communicated to the 
Clinical Monitor at Boehringer Ingelheim. The investigator in agreement with the Clinical 
Monitor will decide about further treatment of individual patient, based on known risk/benefit
of BI 836880 and ezabenlimab.
Rescreening is generally not allowed. In individual cases, rescreening can be considered in 
alliance with the sponsor.
In case of a DLT (drug related AEs CTCAE Grade 3, 4 according to Table 5.2.6.1: 1), the 
patient will discontinue treatment.
Once a DLT has recovered to CTCAE grade 1 or pre-treatment values, the study drugs may 
be re-started at a lower dose level in case the patients benefit from the study drug after 
discussion between investigator and Clinical Monitor at Boehringer Ingelheim.

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Drug re-administration criteria after the first cycle has been completed in Part 2: 
Before initiating a new treatment cycle the current health status of the patient will be assessed 
according to the Flow Chart. 
To continue treatment with further cycles, all of the following criteria must be met:
1. Pre-infusion SBP should be < 160 mmHg and pre-infusion DBP should be < 100 mmHg; 
study drug administration of both study drugs should be temporarily delayed until BP <
160/100. Please see Table 10.2.1: 1 in Appendix 10.2.1, which describes the guidelines 
for BP management and study drug administration. 
2. QTcF <=480 ms (according to Exclusion-Criterion #8) 
3. Echocardiography if clinically indicated (based on investigators judgment) with Left 
Ventricular Ejection Fraction (LVEF) ≥ 50%
4. Acceptable tolerability (in case of an adverse event at the planned start of a treatment 
cycle patients may continue therapy only after recovery to a level which would allow 
further therapy in the opinion of investigator). 
In case the above mentioned criteria 2, 3, and 4 are not fulfilled, the patient should be re-
evaluated as needed. Any case of a delay in treatment cycle should be communicated to the 
Clinical Monitor at Boehringer Ingelheim. The investigator in agreement with the Clinical 
Monitor will decide about further treatment of individual patient, based on known risk/benefit 
of BI 836880 and ezabenlimab. 
Dose reduction guidelines
Part 1:
Administration of trial drugs has to be stopped temporarily in case of a DLT (see Section
5.2.6.1). Patients may continue therapy only after recovery from DLT to at least fulfil 
retreatment criteria. The future dose of BI 836880 must be a tested dose which is one dose 
level below the dose received by the patient (Table 4.1.4: 1 and 4.1.4: 2 below) Treatment has 
to be discontinued in case the DLT is not reversible.
Table 4.1.4: 1 Dose reduction recommendations for BI 836880 in Part I
BI 836880 received dose 
BI 836880 reduced dose 
720 mg
500 mg
500 mg
360 mg
360 mg 
Stop BI 836880
In case of AEs (DLTs) that can be definitely characterized as ezabenlimab related, dose can 
be reduced.

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Table 4.1.4: 2 Dose reduction recommendations for ezabenlimab in Part I
Ezabenlimab received dose 
Ezabenlimab reduced dose 
240 mg
80 mg
For each drug, only one dose reduction will be allowed per patient. 
Part 2:
Dose reductions or escalations are not allowed for ezabenlimab in any patient. 
In the dose expansion study, only dose reductions/re-escalations are allowed for BI 836880.
Table 4.1.4: 3 Dose reduction recommendations for BI 836880 in Part 2
BI 836880 received dose 
BI 836880 reduced dose 
720 mg
480 mg
A dose reduction of BI 836880 from 720 mg to 480 mg is allowed, if investigator can 
attribute the AE unequivocally to the BI 836880 (for e.g., hypertension). If the reduced dose
is still intolerable, the dose maybe delayed (please see below the sub-section “Delay of 
treatment”). If the reduced dose is tolerable, and where deemed in the best interest of the 
patient, the investigator should re-escalate to the originally assigned dose of 720 mg of BI 
836880 as soon as deemed clinically appropriate.
Delay of treatment:
During combination therapy, if treatment is held or discontinued due to an AE(s), both BI
836880 and ezabenlimab will be held or discontinued together. If treatment is to be restarted 
after resolution (≤ Grade 1 or baseline) of the AE, preferably both BI 836880 and 
ezabenlimab must be started together.
In some cases, in discussions with the Sponsor, treatment with one of the two investigational 
drugs can be allowed if there is an AE reported which can be clearly attributed to one of the 
two drugs and further warrants a temporary discontinuation of this drug in the interest of the 
patient.
Treatment duration:
Treatment with BI 836880 plus ezabenlimab may continue until disease progression, undue 
toxicity, withdrawal of patient consent, or 53 cycles [approximately 3 years] from the start of 
first treatment administration, whichever occurs first. Patients will be allowed to stay on 
treatment also in the case of initial radiological PD, until progression is confirmed or up to 53
cycles from the start of first treatment administration if the investigator considers that the 
treatment is beneficial for the patient.

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Investigators may consider discontinuing BI 836880 and continue therapy with ezabenlimab 
for up to 53 cycles from the start of the first treatment administration if the patient has been 
on therapy ≥ 6 months, has achieved at least SD by RECIST 1.1 and can tolerate the therapy, 
and if the investigator considers this to be in the best interest of the patient.
For any patient still on treatment with the investigational combination of BI 836880 plus 
ezabenlimab 53 cycles from the start of the first treatment administration, treatment extension 
will be considered on a case-by-case basis upon request by the investigator for a maximum 
additional 6 cycles, to complete no later than 30 April 2025, if the investigator considers this 
to be in the best interest of the patient. After this date treatment with the investigational 
combination BI 836880 plus ezabenlimab will no longer be available.
Investigators are requested to prepare for discontinuation of patients from the current 
investigational treatment of BI 836880 plus ezabenlimab and to switch them to alternative 
available treatment options outside of the current protocol no later than by the final 
availability date of 30 April 2025.
4.1.5
Blinding and procedures for unblinding
4.1.5.1 
Blinding
Not applicable, as this is an open-label study.
4.1.5.2 
Unblinding and breaking the code
Not applicable.
4.1.6
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). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
BI 836880 vials (old and new formulation) and ezabenlimab vials (solution and concentrate 
for solution) must be stored in their original packaging. The study product must be stored 
according to the instructions on the label (in a refrigerator at 2-8°C). The Investigator, the
Pharmacist, or other personnel is allowed to store and dispense investigational product. They
will be responsible for ensuring that the investigational product used in the study is securely
maintained as specified by the sponsor and in accordance with the applicable regulatory
requirements.

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A temperature log must be maintained to make certain that the drug supplies are stored at the
correct temperature.
In-use-stability of ready to use solution refers to “Instructions for Pharmacists” as described
in Section 4.1.4.
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 CML (as provided in the list of contacts) must be 
contacted immediately.
4.1.8
Drug accountability
The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee,

Availability of a signed and dated clinical trial contract between the sponsor and 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 (if applicable).
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 < and/or > pharmacist < and/or > investigational drug storage manager must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the use by 
each patient, and the return to the sponsor or warehouse / drug distribution center or 
alternative disposal of unused products. If applicable, the sponsor or warehouse / drug 
distribution center will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor< and/or >appointed CRO, the investigator / pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the investigator’s possession.

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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
Concomitant (non-oncological) therapies starting or changing during the cycle of the trial
should be recorded in the electronic case report form (eCRF). Concomitant therapy, with 
reasons for taking each treatment, must be recorded in the eCRF during the screening and 
treatment periods, starting at the date of signature of the ICF and ending at the 30-day follow-
up visit. After the 42-day follow up, 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 eCRF.
4.2.1
Other treatments and emergency procedures
Potential side effects of BI 836880 or ezabenlimab have to be treated symptomatically. 
Symptomatic treatments of side effects or tumor-associated symptoms are allowed.
Concomitant medications, or therapy to provide adequate care, may be given as clinically
necessary. There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1 
Restrictions regarding concomitant treatment

Previous anti-cancer therapy must have been discontinued before first administration 
of trial drug and the patient must have recovered from all clinically relevant reversible 
toxicities (see Exclusion Criteria Section 3.3.3 for further details).

Concomitant anti-cancer therapy is not allowed. Radiotherapy for local symptom 
control of non-target lesions can be allowed after consulting the investigator and 
sponsor. Palliative radiotherapy will not be allowed during the first cycle for any 
lesion. Palliative radiotherapy is allowed only for non-target lesions, following 
discussion with the Medical Monitor, provided that the reason for radiotherapy does 
not reflect PD and does not interfere with response assessment. Lesions that have been 
exposed to radiotherapy are no longer evaluable, and may not be included in the 
assessment of the non-target lesions and the overall assessment. Unless in emergency 
situations, the Medical Monitor should be contacted prior to the administration of 
palliative radiotherapy in the expansion phase.

Immunosuppressive medications including, but not limited to systemic corticosteroids 
at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, 
and tumour necrosis factor-alpha 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 
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 patients in the cohort D (Glioblastoma) 

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higher doses of corticosteroids may be allowed as defined in the cohort-specific 
eligibility criteria. 

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 unless agreed to 
by the Principal Investigator. 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. If instructed by the Principal 
Investigator, patients should stop using these herbal medications 7 days prior to first 
dose of study treatment.

Full-dose anticoagulation (according to local guidelines) with Vitamin K antagonist 
and other anticoagulation is not allowed during the trial conduct; LMWH is allowed 
only for prevention not for curative treatment.

Any planned surgeries are not allowed (see Exclusion Criteria Section 3.3.3 for 
further details). Unplanned surgeries should be postponed whenever possible four 
weeks after stop of treatment. For urgent interventions patients should not be further 
treated and should be intensely monitored regarding wound healing and post-operative 
complications.
4.2.2.2 
Restrictions on diet and life style
No restriction.
4.2.2.3 
Restrictions regarding women of childbearing potential 
Women of childbearing potential must use the contraception methods described in the patient 
information. Due to the advanced stage of disease of Phase I trial patient populations and the 
high medical need, females of childbearing potential can be included in this trial provided 
that they agree to use a highly-effective contraception method. These are methods of birth 
control per the International Committee on Harmonisation (ICH) M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and correctly. 
Highly-effective methods of contraception include: 

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation, Oral, intravaginal, transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulation: 
oral, injectable, implantable

Intrauterine device 

Intrauterine hormone-releasing system 

Bilateral tubal occlusion 

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
Vasectomised partner o provided that partner is the sole sexual partner of the WOCBP 
trial participant and that the vasectomised partner has received medical assessment of 
the surgical success.

Sexual abstinence - defined as refraining from heterosexual intercourse during the 
entire period (stated above) of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 
Details of these contraception methods are described in the patient information in the ICF.
Women of childbearing potential must follow these methods during the trial and for at least 6 
months after the end of the trial treatment. Although use of a contraceptive pill is considered 
a highly-effective method of birth control, women of childbearing potential taking a 
contraceptive pill must use an additional barrier method for the entire duration of the trial 
treatment intake and for 6 months after the end of the trial treatment intake. 
Male patients with partners of childbearing potential must agree to use condoms and ensure 
their partner is using an additional highly-effective method of birth control, during the trial 
and until at least 6 months after the end of the trial treatment.
4.3
TREATMENT COMPLIANCE
BI 836880 and ezabenlimab 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 prescribed drug regimen. Missed 
or interrupted doses will be recorded in the eCRF with the associated reasons. The methods 
of collecting dosing information assure that total exposure can be calculated 
programmatically taken into account any missing doses.

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
The same method of assessment and the same technique should be used also in follow up of 
identified and reported lesions. Lesions in previously irradiated areas may not be used as 
target lesions (except recurrent glioblastoma after a period of 12 weeks). Baseline evaluation 
must be performed as close as possible to the treatment start and no more than 28 days before 
start of treatment. 
Efficacy endpoints will be assessed according to institutional practices and SOC from data 
cut-off date for interim database lock (iDBL) forward as specified in the flowchart.
All tumor imaging performed in this trial will be collected by authorized CRO and stored until 
shipment to Boehringer Ingelheim. The CRO will not be implicated in tumor response 
evaluation. This collected data might be considered for central review at a later time point. 
5.1.1
Tumor response assessments using RECIST 1.1
The tumor response will be evaluated according to Response evaluation criteria in solid 
tumors (RECIST) Version 1.1 (R09-0262) and iRECIST (R17-0923) for all cohorts except 
cohort D (GBM). Complete response/immune complete response (CR/iCR), Partial 
response/immune partial response (PR/iPR), stable disease/immune stable disease (SD/iSD) 
or progressive disease/immune unconfirmed progressive disease/immune confirmed 
progressive disease (PD/iUPD/iCPD) will be assessed by the Investigator. The images should 
include all known or suspected sites of disease using an appropriate method.
Best overall response will be assessed by tumor measurements according to RECIST version
1.1, and is defined as the best response recorded at any time from the date of first 
administration of study drug until progression.
5.1.2
Tumor response assessments using RANO
If there are multiple contrast-enhancing lesions, a minimum of the two largest lesions should 
be measured, and the sum of the products of the perpendicular diameters of these lesions 
should be determined, similar to the criteria proposed for systemic tumors in RECIST version 
1.1. However, given the heterogeneity of high-grade gliomas and the difficulty in measuring 
some lesions, a maximum of five of the largest lesions may be measured (R11-0753). 
Evaluable for objective response: only those patients who have measurable disease present 
at baseline and have received at least one dose of therapy will be considered evaluable for 
response. These patients will have their response classified according to the definitions stated 
below. 
Measurable disease: Bidimensionally, contrast-enhancing, measurable lesions with clearly 
defined margins by MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices 
which are at least 5 mm apart with 0 mm skip. Measurement of tumor around a cyst or 
surgical cavity, if necessary, requires a minimum thickness of 3 mm. 

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Non-measurable evaluable disease: Unidimensionally measurable lesions, masses with 
margins not clearly defined, lesions with maximal diameter < 1 cm.
Response assessments in GBM will be performed according to institutional practices and SOC 
from data cut-off date for iDBL forwards using the objective status categories per RANO and 
iRANO criteria (R20-0571), which, in addition to radiographic scans, comprise elements of the 
neurological exam, KPS, and steroid use. Response assessments are to be derived from baseline 
or Best Response (see below). 
Best Response:
This will be calculated from the sequence of objective status. For patients who are having all 
disease sites assessed at every evaluation period, the best response will be defined as the best 
objective status, measured according to RANO criteria described below. If the response does 
not persist at the next routinely scheduled scan, the response will still be recorded based on the 
prior scan, but will be designated as a non-sustained response. If the response is sustained, e.g. 
still present on the subsequent scan, it will be recorded as a sustained response, lasting until the 
time of tumor progression. Best response is unknown if the subject does not qualify for a best 
response or increasing disease and if all objective status determinations before progression are 
unknown. 
Objective Status (per RANO Criteria):
Complete Response (CR). All of the following criteria must be met:
a.
Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this 
scan will be considered only stable disease. 
b. No new lesions
c.
All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline.
d. Patients must be on no steroids or on physiologic replacement doses only.
e.
Stable or improved non-enhancing (T2/FLAIR) lesions
f.
Stable or improved clinically, for clinical signs and symptoms present at baseline 
and recorded to be disease related. 
Partial Response (PR). All of the following criteria must be met:
a.
≥ 50% decrease compared to baseline in the sum of products of perpendicular 
diameters of all measurable enhancing lesions sustained for at least 4 weeks. In the 
absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease.
b. No progression of non-measurable disease.
c.
No new lesions.
d. All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
e.
The steroid dose at the time of the scan evaluation should be no greater than the dose 
at time of baseline scan.

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f.
Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
steroid compared to baseline scan.
g. Stable or improved clinically, for clinical signs and symptoms present at baseline 
and recorded to be disease related.
Progressive Disease (PD). The following criteria must be met:
a.
25% increase in sum of the products of perpendicular diameters of enhancing lesions 
(over best response or baseline if no decrease) on stable or increasing doses of 
steroids and/or one or more of the following:
b. Significant increase in T2/FLAIR non-enhancing lesion on stable or incrasing doses 
of steroids compared to baseline scan or best response following initiation of 
therapy, not due to co-morbid events (radiation therapy, demylination, ischemic 
injury, infection, seizures, post-operative changes, or other treatment effects).
c.
Any new lesions
d. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection etc.). The definition of clinical deterioration is left to the discretion of the 
investigator but it is recommended that a decline in the KPS from 100 or 90 to 70 or 
less, a decline in KPS of at least 20 from 80 or less, or a decline in KPS from any 
baseline to 50 or less, for at least 7 days, be considered neurologic deterioration, 
unless attributable to co-morbid events or changes in steroid dose. 
e.
Failure to return for evaluation due to death or deteriorating condition. 
Stable Disease (SD). All of the following criteria must be met:
a.
Does not qualify for CR, PR, or PD.
b. All measurable and non-measurable sites must be assessed using the same 
techniques as baseline.
c.
Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of steroids 
compared to baseline scan. In the event that the steroid dose has been increased, the 
last scan considered to show stable disease will be the scan obtained when the 
steroid dose was equivalent to the baseline dose.
d. Stable clinically.
Unknown Response Status. Progressive disease has not been documented and one or more 
measurable or non-measurable lesions have not been assessed. 
These RANO Response Criteria are also summarized in the following table. 
Summary of the RANO Response Criteria
CR
PR
SD
PD#
T1-Gd+
None
≥ 50% decrease
< 50% decrease 
-
< 
25% 
increase
≥25% increase*

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Summary of the RANO Response Criteria
CR
PR
SD
PD#
T2/FLAIR
Stable 
or 
decrease
Stable 
or 
decrease
Stable 
or 
decrease
Increase*
New lesion
None
None
None
Present*
Corticosteroids
None
Stable 
or 
decrease
Stable 
or 
decrease
NA
Clinical Status
Stable 
or 
increase
Stable 
or 
increase
Stable 
or 
increase
Decrease*
Requirement 
for Response
All
All
All
Any*
# Progression occurs when any of the criteria with * is present. 
NA:   Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioration
iRANO:
Confirmation of progression on follow-up imaging 3 months after initial radiographic 
progression if:
1. No new or significantly worsened neurologic deficits not due to co-morbid event or 
concurrent medication AND
2. ≤ 6 months from initiation of immunotherapy
If follow-up imaging confirms progression, the date of actual progression should be back-
dated to the date of initial radiographic progression
• Appearance of new lesions solely does not define progressive disease ≤ 6 months from 
initiation of immunotherapy. The lesions are added to the total lesion areas for follow-up 
assessments.
5.2
ASSESSMENT OF SAFETY
The safety of BI 836880 in combination with ezabenlimab will be assessed by a descriptive 
analysis of incidence and severity of adverse events graded according to CTCAE version 5.0, 
the incidence of DLT, laboratory data, and results of physical examinations.
5.2.1
Physical examination
A complete physical examination (including cardiac, neurological, dermatological, 
pulmonological etc.), record of height (only at screening visit), weight and ECOG /Karnofsky 
performance score will be performed at screening and before start of treatment and EoT and 
Safety Follow-up. At further time points specified in the FC not a complete PE must be done, 
but at minimum the actual health status of the patient should be assessed (incl. evaluation of 
BP, ECG, lab values, AE, Concomitant Treatments, ECOG/Karnofsky as applicable). During 
the physical examination, the patient should be assessed for possible AEs.

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5.2.2
Vital signs
Vital signs (blood pressure, heart rate and body temperature) will be recorded at every visit 
indicated in the FC.
In Part 1, on days of study drug administration, blood pressure and heart rate will be
evaluated at three time points:
1. Pre-dose (-60 min. to -5 min.) before infusion of ezabenlimab,
2. 5 to 10 minutes before infusion of BI 836880,
3. 5 to 10 minutes after infusion of BI 836880.
In case of an infusion-related reaction, the Investigator should decide whether to intensify or
prolong monitoring of vital signs of the patient.
In Part 2, on days of study drug administration, blood pressure and heart rate will be 
evaluated at two time points:
1. Pre-dose (-60 min. to -5 min.), before infusion of ezabenlimab; the results should be
assessed using the BP management and study drug administration guidelines in
Appendix 10.3
2. 5 to 10 minutes after infusion of BI 836880.
In case of an infusion-related reaction, the Investigator should decide whether to intensify or
prolong monitoring of vital signs of the patient.
Frequency of blood pressure measurements at each time point
Systolic and diastolic blood pressure as well as pulse rate (electronically or by palpation,
count for 1 minute) will be measured after 5 minutes of rest in the seated position. 
In Part 1, the blood pressure measurement should be performed three times at each time point 
and the values of these measurements will be entered in the eCRF. In Part 2, only a single 
blood pressure measurement is required at each time point.
Further details on the procedure for blood pressure measurements are given in Appendix 
10.2.
Body temperature
Whenever possible the same method should be used for body temperature measurement in 
one patient. All methods used should deliver valid and reproducible results according to 
common clinical practice. Acceptable methods could be, but are not limited to: oral, rectal 
measurement with thermometer (digital, mercury or other fluid). Not preferred methods but 
accepted include: IR-measurement in ear, forehead or temple.
Body temperature measurements >= 38°C must be re-assessed after 1 hour, especially in 
cases were for febrile neutropenia is suspected (see CTCAE v. 5.0).

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5.2.3
Safety laboratory parameters
Blood and urine samples for assessment of general safety laboratory examinations have to be
collected at the time points specified in the Flow Chart, but should be more frequent in case
of relevant findings, e.g. in case of grade 4 neutropenia, as any non-proven recovery within 7
days will be counted as DLT or proteinurea, for which determination of CTCAE grade 2 vs.
grade 3 need to be done by quantitative measurement. Laboratory values planned for V1D1
(=day of administration) must be available before start of infusion in order to evaluate
eligibility of patient to receive treatment. Therefore it’s possible to take blood sample a
valuable time ahead (usually the day before treatment but possible up to approximately 72 
hours before). Safety laboratory examinations will include hematology, biochemistry, 
coagulation and urine analysis:
Hematology
Hemoglobin, white blood cell count (WBC) with
differential, platelets (PLT)
Biochemistry
Glucose, sodium, potassium, calcium, magnesium,
inorganic
phosphate, creatinine, AST, ALT, alkaline phosphatase
(AP), lactate dehydrogenase (LDH), bilirubin, serum urea 
nitrogen (or urea), thyroid panel [TSH, free T4, and free 
T3]), total protein, albumin, uric acid, CK, In case of 
pathological CK elevated, then CK-MB, additional 
troponin, and myoglobin as available should be reactively 
tested and the findings documented.
Serum immunoglobulin levels (IgG, IgM, IgA; IgE) and
direct antiglobulin test have to be measured at Screening
and at occurrence of infusion related reactions.
Coagulation
Activated partial thromboplastin time (aPTT), 
prothrombin time (PT) or international normalised 
ratio (INR) where indicated (e.g. treatment with 
vitamin K antagonists)
Urine
pH, glucose, erythrocytes, leukocytes, protein, nitrite 
will be analyzed primarily qualitatively by dipstick.
In case of clinically relevant findings, further evaluation
should be performed and the findings documented. A 
positive urine dipstick for protein of ≥ 2+ (CTCAE gr 2) 
has to be followed by a determination of the ratio of urine 
protein to creatinine (UPCR) in a morning spot urine 
sample. In case of a ratio ≥ 0.5, a 24 hour urine collection 
for protein loss has to be performed. The 24 hour urine 
collection will be repeated every time the UPCR ratio is 
≥0.5 as often as clinically indicated.
Pregnancy test                              A pregnancy test needs to be obtained at the time points 
indicated in the Flow Chart in patients of child bearing 
potential. A beta human chorionic gonadotropin (β-

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HCG) pregnancy test in serum will be performed for 
women of childbearing potential (WOCBP) at 
screening. Thereafter, this test may be done in serum or 
urine on Day 1 of each cycle, at the EOT visit. If the 
urine test is positive or cannot be confirmed as negative, 
a serum pregnancy test will be required.
Screening for Infections             HIV-1 and HIV-2 antibody (qualitative, as per 
applicable local regulations, at the discretion of the 
Investigator where clinically indicated). Hepatitis B 
serology (HBsAg, anti-HBc qualitative) and Hepatitis C 
serology (anti-HCV qualitative) for screening active 
Hepatitis B and Hepatitis C. For HCC cohorts (cohorts 
F, G & H) additional tests may include HBV DNA (if 
needed), HCV RNA (if needed) and Hepatitis D (anti-
HDV qualitative).
In case an administration is delayed due to an AE, the patient should visit the site at least
once a week for assessment of safety laboratory and AEs. More frequent visits may be
appropriate as assessed by the Investigator.
In case the criteria for potential hepatic injury are fulfilled, a number of additional measures 
will be performed (please see Section 5.2.6.1 and the DILI Checklist provided in the ISF eDC
system. The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.
5.2.4
Electrocardiogram
12-lead ECGs will be performed in all patients at various time points according to Study 
Flow chart:

At Screening, visits between administration and at EoT: only one time point will be 
evaluated.

At days of administration two time points will be evaluated:
For Part 1:
1. pre-dose (-60 min. to -5 min.)
2. shortly before the end of the infusion of trial medication
For Part 2:
1. Cycle 1 to 4 pre and post treatment (within 60 min after completion of 
administration of BI 836880) and thereafter ECG at pre- and post treatment of BI
836880 performed every second cycle (cycle 6, 8, 10, … etc.)
In case of drug-related ECG changes and whenever the investigator deems necessary, 
additional ECG monitoring will be performed in the respective and later cycles of treatment. 
Cardiac monitoring for patients presenting a QTc interval prolongation CTCAE grade ≥ 3
(i.e., average QTc >= 501 ms, or >60 ms change from baseline; or Torsade de pointes,
polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia) shall be 
followed as follows: 

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-
Continuous ECG monitoring until the QTc interval ≤480 ms 
-
Cardiologist opinion for potential treatment of this event as soon as the QTc 
interval prolongation is observed. 
-
Cardiologist recommendation after QTc interval decreases to Grade 1 (≤480 
ms) and potential follow-up. 
In order not to confuse ECG recording, PK samples should be taken after performing the 
ECG. Decision on patient’s eligibility will be taken based on Investigator medical opinion. 
Pathological ECG results will be recorded as AEs by the investigator.
5.2.5
Echocardiography 
Echocardiography have to be conducted at screening (not older than 21 days before treatment 
start) and at EoT-visit. During treatment phase it has only to be done when clinically 
indicated.
5.2.6
Other safety parameters
5.2.6.1 
Dose limiting toxicities (DLTs)
The occurrence of any of the toxicities presented in Table 5.2.6.1: 1 will be considered a 
DLT, if assessed by the investigator to be related to the administration of either of the study 
drugs. All DLTs occurring during Part 1 of the study will be considered an AESI and 
reported on the SAE form. Once the dose escalation part of the study has been completed 
(Part 1), DLTs no longer need to be reported (i.e. Part 2). 
Incidence and severity of adverse events will be graded according to the common 
terminology criteria for adverse events (CTCAE, version 5.0).
Table 5.2.6.1: 1 Dose Limiting Toxicities (according to CTCAE V5.0)
Drug related toxicity 
category
Criteria defining a DLT*
Hematologic
Grade 4 neutropenia (<500/mm3) lasting ≥5 days or complicated by infection
Grade ≥3 documented infection with neutropenia.
Grade ≥3 febrile neutropenia (ANC<1000/mm3 complicated by fever ≥38.3 °C or 
101°F°C or a sustained temperature of ≥38.0C (100.4 ° F) for more than 1 hour.
Grade 3 thrombocytopenia (>= 25,000/mm3 and <50,000/mm3) associated with 
bleeding or requiring platelet transfusion.
Grade 4 thrombocytopenia (<25,000/mm3).
Grade 4 anaemia (i.e., life-threatening consequences or urgent intervention 
indicated).

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Table 5.2.6.1: 1 Dose Limiting Toxicities (according to CTCAE V5.0) (cont’d)
Drug related toxicity 
category
Criteria defining a DLT*
Non-hematologic
Non-laboratory toxicity
Any Grade 4 or 5 AE other than disease progression.
Any Grade 2 drug-related uveitis or 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 occurred during Cycle 1 that persists 
and results in an inability to administer ezabenlimab or BI 836880 on Cycle 2 Day 
1.
Grade ≥ 2 pneumonitis of any duration
Any toxicity Grade ≥ 3 toxicity except:
o Grade 3 immune-related AE that resolves to ≤ Grade 1 or to baseline with 
immunosuppressive therapy within 2 weeks
o Grade 3 asymptomatic endocrine disorders (thyroid, pituitary, and/or adrenal 
insufficiency) that are managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy.
o Grade 3 or 4 elevation in serum amylase and/or lipase that is not associated 
with clinical or radiographic evidence of pancreatitis
o Grade 3 nausea or Grade 3 vomiting will be defined as DLT when it persists 
at Grade 3 longer than 48 hours despite adequate medical intervention. 
o Alopecia
o Grade 3 fatigue that persists less than 7 days
o Grade 3 infusion related reaction which can be controlled by appropriate 
medication according to investigator’s decision, and the subsequent infusion 
will not be delayed for more than two weeks.
o Grade 3 rash that resolves to ≤ Grade 1 within 2 weeks
o 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.
o Grade 3 tumour flare.
Laboratory toxicity
Hypertension: systolic blood pressure >=160 mm Hg or diastolic blood pressure 
>=100 mm Hg, confirmed by second measurement of an additional set of 3 BP 
measurements, or 3 sequential ambulatory blood pressure measurements when 
indicated (e.g. white coat effect), and which cannot be controlled by hypertensive 
medication and which requires a dose reduction / discontinuation of trial 
medication(s)
Grade3 proteinuria (urinary protein >=3.5 g/24 hrs; 4+ proteinuria)
AST or ALT >3 times ULN and concurrent total bilirubin >2 times ULN without 
initial findings of cholestasis.
≥ Grade 4 AST or ALT of any duration
NOTE: Any laboratory abnormality which is considered not clinically relevant by 
the investigator or resolves spontaneously, or resolves with appropriate treatment is 
not a DLT. Clinically relevant abnormalities must be documented as AEs.
Re-Treatment Delay
All related AE leading to an interruption of BI 836880 or ezabenlimab for more 
than 14 days until recovery to baseline.
*It is the responsibility of the investigator to follow-up on the toxicities in a timely manner.
Late immune-related DLTs are irAEs that meet the same grading criteria as DLT criteria, but 
occur after Cycle 1 administration during Part 1. These, as well as all toxicities will be 
monitored throughout the trial. If any late immune-related DLT is reported during dose-
escalation, the BLRM will be rerun including the late immune-related DLT, and updated 

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results will be reviewed in the SMC meeting to recommend the next dose level and cohort 
size.
5.2.6.2
Definition of evaluable patient
For decisions on dose escalation, an evaluable patient is defined as a patient who has received 
first cycle of combination treatment of BI 836880 and ezabenlimab and has been observed 3 
weeks for first cycle except patients discontinue in the first cycle due to DLT. Patients who 
discontinue during the first treatment cycle for reasons other than a DLT will be non-
evaluable for the determination of the MTD.
5.2.6.3
Maximum Tolerated Dose (MTD) and Recommended Phase II dose (RP2D)
The MTD may be considered reached if the probability that the true DLT rate is in target
interval (16% - 33%) is sufficiently large. For detailed definition see statistical part (Section 
7.1). The SMC may recommend stopping the dose finding phase after the criterion for MTD 
is fulfilled. Further patients may be included to confirm the MTD. If next dose level is 
recommended by the statistical model; however, the efficacy is considered sufficient at 
current dose level, the SMC may decide to include additional number of patients at this dose 
level, declare this dose as RP2D and no further dose escalation will happen.
Decision on next steps (dose escalation, de-escalation or cohort expansion) will be made by a 
SMC based on all available safety data, including DLT information from last cohort as 
described above but also findings from subsequent cycles as well as other data (e.g. PK/PD 
data) when available.
All SMC decisions of dose escalation, and to open a new cohort for recruitment will be
communicated to the Investigators. Once MTD and RP2D are defined this information will 
be sent to authorities according to local regulations.
5.2.7
Assessment of adverse events
5.2.7.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavorable 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.

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Serious adverse event
A serious adverse event (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 hospitalization or 
-
requires prolongation of existing hospitalization,
-
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 jeopardize 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 
hospitalization or development of dependency or abuse. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
AEs 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 5.2.7.2, 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 eDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.

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The following are considered as AESIs:
Dose Limiting Toxicities
All DLTs are considered to be AESIs, and must be reported as such. The definition of DLT is 
presented in Section 5.2.6.1. DLTs are no longer applicable in Part 2 of the study, therefore 
are no longer AESIs in Part 2. 
Persistent hypertension despite treatment
A hypertensive episode will be considered an AESI if:

SBP >= 140 mmHg or DBP >= 90 mmHg which persists longer than 2 days despite 
either he initiation of antihypertensive agent(s) in a patient without prior history of 
hypertension, or the intensification / addition of new antihypertensive agents in a 
patient with prior history of hypertension. 
Immune-related adverse events (irAE)
Although all irAEs are to be reported as AEs, only clinically important irAEs need to be 
reported as AESIs as defined by the sponsor in Appendix 10.3. Non-clinically important
irAEs, such as mild to moderate rash and hypothyroidism, for example, do not need to be 
reported as AESIs. If an Investigator determines that a severe irAE or other clinically 
significant irAE that is not included in Appendix 10.3 is medically significant, the 
investigator may also report this irAE as an AESI.
Recommendations for the management of irAEs are presented in Appendix 10.4. 
Infusion-related reactions
All infusion-related reactions need to be reported as AESIs.
In the event of an infusion-related reaction ≤Grade 2, the infusion rate of BI 836880 or 
ezabenlimab 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 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 study, treatment with BI 
836880 or ezabenlimab will be permanently discontinued.
As with any mAb, allergic reactions to BI 836880 and ezabenlimab administration are 
possible. Appropriate drugs and medical equipment to treat acute anaphylactic reactions must 
be immediately available, and trial personnel must be trained to recognize and treat 
anaphylaxis. The trial site must have immediate access to emergency resuscitation teams and 
equipment in addition to the ability to admit patients to an intensive care unit if necessary.

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The following events describe those events that are to be considered potential infusion-related 
AEs. Regardless of grade, these events are considered as AESIs and must be reported within 
24 hours of the event:

Allergic reaction

Anaphylaxis

Cytokine-release syndrome

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 must report that event as an AESI.
Potential DILI 
A potential DILI is defined by the following alterations of hepatic laboratory

Parameters:
o For patients with normal aminotransferase levels at baseline: 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 without evidence of 
cholestasis, OR aminotransferase elevations ≥10 fold ULN
o For patients with abnormal aminotransaminase levels at baseline >1 and <2.5 x 
ULN at baseline: An elevation of AST and/or ALT ≥3 fold the baseline value 
combined with an elevation of bilirubin ≥2 fold ULN and the baseline value in the 
same blood sample; OR Aminotransferase elevations ≥5 fold the baseline value.
o For patients with abnormal aminotransaminase levels at baseline >=2.5 and 
<=5 x ULN at baseline (patients with liver metastases only): An elevation of AST 
and/or ALT ≥2 fold the baseline value combined with an elevation of bilirubin ≥2 
fold ULN and the baseline value in the same blood sample; OR Aminotransferase 
elevations ≥3 fold the baseline value.
These lab findings constitute a potential DILI alert and the patients experiencing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF, 
unless an underlying other than study drug(s) cause has been determined.
In case of clinical symptoms of potential DILI (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 
analyzed, if necessary in an unscheduled blood test. Should the results meet the criteria of a 
potential DILI alert, the procedures described in the DILI checklist should be followed.
Severity of AEs
The severity of adverse events should be classified and recorded in the CRF according to the 
Common Terminology Criteria for Adverse Events (CTCAE).

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Causal relationship of AEs
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. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.7.2 
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF(s) by the 
Investigator (Figure 5.2.7.2: 1):

From signing the informed consent onwards until the end of the REP: all AEs (non-
serious and serious), and AESIs.

After the end of the REP (Safety Follow up visit) until individual patient’s end of trial:
any new occurrence of cancer of new histology, all related SAEs and all related AESIs.

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
After the individual patient’s end of trial: the investigator does not need to actively 
monitor the patient for new AEs but should report any new occurrence of cancer of new 
histology and 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 eCRF.
           
The rules for Adverse Event Reporting exemptions still apply, please see chapter 
“Exemptions to SAE reporting”.
Figure: 5.2.7.2:1 Adverse Events collection and reporting (Cancers of new histology to be 
reported as described above the figure, also during the extended follow up period and after
individual patient’s end of trial. The term “relevant” in this figure means “related”.)
The Residual Effect Period (REP) is defined as 42 days after the last trial medication
administration. All AEs which occurred through the treatment phase and throughout the REP 
will be considered as on treatment (Section 7.3.4). Events which occurred after the REP will 
be considered as post treatment events.
Patients who discontinue trial medication prematurely and agree to be contacted further, 
should be followed up as described in Section 3.3.4.1, withdrawal from trial treatment.  
If for a patient only vital status is collected after premature discontinuation of trial 
medication, from that time on until individual patient’s end of trial the investigator must 
report, if becoming aware of, all deaths/fatal AEs regardless of causal relationship, related 
SAEs, related AESIs and any new occurrence of cancer of new histology. After individual 
patient’s end of trial the same procedure applies as for patients without premature 
discontinuation of trial medication.
At any time the rules for Adverse Event Reporting exemptions still apply, please see chapter 
“Exemptions to SAE reporting”. 
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours ) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 

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timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator 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 eCRF and SAE form (if 
applicable):

Worsening of pre-existing conditions (for underlying disease refer to chapter
“Exemptions to SAE reporting”)

Changes in vital signs, ECG, echocardiography, physical examination and laboratory 
test results, if they are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after trial completion must be followed up until they 
have resolved, have been sufficiently characterized, or no further information can be 
obtained.
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.
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. 
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).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part 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.
Exemptions to SAE reporting
Protocol specified exempted events should be collected on the appropriate CRF page only.

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Disease Progression is a study endpoint for analysis of efficacy, and as such is exempted 
from reporting as an SAE. Progression of the patient's underlying malignancy will be 
recorded in the appropriate pages of the eCRF as part of efficacy data collection 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. Disease progression and death due to 
disease progression will therefore not be entered in the safety database and hence not get 
expeditiously reported.
However, if there is evidence suggesting a causal relationship between the study drugs and
the progression of the underlying malignancy, the event must be reported as SAE on the
eCRF, as well as on the SAE form (in such a situation no exemption applies).
Examples of exempted events of disease progression are:

Progression of underlying malignancy that is clearly consistent with suspected 
progression of the underlying malignancy as defined by the respective response 
criteria.

Hospitalization/procedures due solely to the progression of underlying malignancy.

Clinical symptoms and/or signs of progression (with or without confirmation by 
objective criteria e.g. imaging, clinical measurement): If the symptom/ sign can be 
determined to be exclusively due to the progression of the underlying malignancy and 
is consistent with the expected pattern of progression for the disease under study.
Disease progression is monitored at appropriate intervals by SMC and during Medical and 
Quality Review Meetings (MQRMs).
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Pharmacokinetic profiles of BI 836880 and ezabenlimab in plasma will be investigated within 
this trial. Standard plasma PK parameters as specified in Section 2.1.3 will be calculated.
Pharmacokinetic data may additionally be analyzed using population pharmacokinetic
approaches. For this purpose data may also be combined with data from other trials. 
Modelling activities will be planned and documented separately according to internal and 
external guidelines and SOP.
Exploratory pharmacokinetic and ADA analyses can be performed as necessary for safety 
review, for dose selection in part 2 of the trial as well as further project planning, but require 
sufficient lead time to collect samples, measure plasma concentrations, analyze data and 
prepare meaningful outputs. Exploratory data may also be used for modelling activities.
For the purpose of these exploratory analyses, PK plasma samples obtained up to at least 336
hours after drug administration will be used. A scientifically sound subset of the PK
parameters specified in Section 2.1.3 will be calculated which may include Cmax, AUC and 
t1/2, if these parameters can be reliably determined from the available samples and plasma

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concentration time profiles. In contrast to the final PK analysis, the exploratory analyses will 
be based on planned sampling times rather than on actual times; the outputs will not be 
validated. Minor discrepancies between interim and final results may therefore occur.
As of the decision of Boehringer Ingelheim in December 2021 no additional blood samples 
for pharmacokinetics will be collected.
5.3.2
Methods of sample collection
For quantification of analyte plasma concentrations, samples will be drawn at the time points
listed in the Flow Chart under PK sampling and specified in PK time schedules in Appendix 
10.5. The provided sampling timepoints are depicted as planned timepoints, however 
according to Section 4.1.4, the infusion time may be adapted. In this case, the PK sampling 
referring to the “end” time of the infusion should be performed shortly after the end of 
infusion including flushing of the tubes, no matter the duration of the infusion.
The subsequently requested PK sampling should be drawn as planned. Do not adapt the time 
because of the variation of the duration of the infusion schema.
Plasma will be divided into duplicate aliquots for each analyte (in total 4 aliquots) and stored 
frozen at about -70°C at the participating sites or logistics CRO until shipment on dry ice to 
the bioanalytical laboratory of Boehringer Ingelheim or a Boehringer Ingelheim selected and 
authorized CRO.
Details about sample collection, plasma preparation, required tubes, labelling of tubes,
storage and shipment (frequency and addresses) will be provided in a separate laboratory
manual.
After completion of the study, the plasma samples may be used for further methodological
investigations, e.g., for stability testing. However, only data related to the analyte will be
generated by these additional investigations, and such data will be reported separately. The 
study samples will be discarded no later than 3 years after the final study report has been
generated.

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5.4.1
Methods of sample collection
The following tumour biopsies will be mandatory for all patients in Part 1 (if possible from 
the same lesion):
-
the equivalent of two 14-16G needle biopsies freshly taken during screening after IC 
signed and before first trial medication administration.
-
the equivalent of two 14-16G needle biopsies on treatment before start of Cycle 3 (6 
weeks after treatment start).

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The following tumour biopsies in Part 2, will be:
-
Mandatory: The equivalent of two 16G (or 4 18 G) needle biopsies should be 
freshly taken during screening after IC signed and before first trial medication 
administration. In case a fresh baseline biopsy cannot be obtained (e.g. inaccessible 
lesions or patient safety concern), the equivalent of 2 archival 14-16G needle 
biopsies, or 20 archival 4 µm sections from an archival block, if taken within 6 
months of trial start with no intermediate therapy, have to be provided (except for 
cohort D). For cohorts E, F, G and H, a fresh on-treatment biopsy is mandatory at 
C3D1 (window of +/- 7 days), if possible from the same lesion as the pre-treatment 
biopsy.
-
Optional: The equivalent of four 18 G needle biopsies on treatment before start of 
Cycle 3 for cohorts A-C.
-
Note for on treatment biopsies: Biopsy to be performed on a lesion different than 
target lesion and if  there is only one lesion than biopsy may be skipped in that 
patient.
All samples must be adequately labelled by the trial site personnel. Details about tumor 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 
and the ISF. Measures to be taken to ensure that patient is stable and bleeding has completely 
stopped prior to initiating the treatment.
As of  the decision of Boehringer Ingelheim in December 2021 no additional biopsies will be 
collected.

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5.4.3
Biobanking
Participation in biobanking is voluntary and not a prerequisite for participation in the trial.
Biobanking will be realized only after a separate biobanking informed consent has been given 
in accordance with local ethical and regulatory requirements. Banked samples may be 
analyzed in the future for scientific evaluations or to further, 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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Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular:

Sample and data usage has to be in accordance with the separate biobanking 
informed consent.

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological 
samples collected in clinical trials.

An appropriate sample and data management system, including an audit trail for 
clinical data and samples to identify and destroy such samples according to ICF is in 
place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as
specified in the biobanking ICF.
The leftovers of the following biomarker samples as specified in Section 5.4 (‘Assessment of 
Biomarkers’) will be banked:

FFPE blocks of pre- and on-treatment biopsies.

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5.6
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an intravenously 
administered drug, and are widely used in clinical trials. The pharmacokinetic parameters and 
measurements outlined in Section 5.3 are generally used assessments of drug exposure. The 
biomarkers and pharmacodynamic parameters and measurements outlined in Section 5.4 are 
of exploratory nature only. The determination of the immunogenic response before or during 
treatment with NBEs is generally applied to monitor immunogenicity risks.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients must comply with all inclusion and exclusion criteria prior to the patient 
participation in the study (see Section 3.3).
All patients should adhere to the visit schedule as specified in the Flow Chart. In case a
patient misses a visit within one treatment cycle and the patient belatedly reports to the
investigator between the missed and the next scheduled visit, the delayed visit should be
scheduled as soon as possible and documented with the actual date and the reason for the
delayed visit. The next visit, should still take place at the time it was originally scheduled in
this treatment cycle. Some flexibility is allowed in scheduling the visits according to the time 
window specified in the Flow Chart.
However, in case the day of treatment administration (visit 1 day 1 of a cycle) is delayed, all
subsequent visits of a cycle will be recalculated based on the actual date of treatment of the
delayed cycle.
During the treatment phase, after administration of BI 836880 and ezabenlimab, patients are 
required to be hospitalized (refers only to Part 1, see Section 1.4) under close surveillance 
with access to intensive care for at least 48 hours after administration of trial medication to 
allow close monitoring for infusion-related reactions or other adverse events and availability 
of patients for PK visits. After good tolerability of the first two cycles of trail medication the 
investigator may evaluate the risk for an infusion-related reaction and other adverse events in 
view of relevant comorbidities or disease related symptoms, and as a result, shorten the 
duration of surveillance to 8 hours for cycles 3 and 4 (PK samples included) and at 
investigator’s discretion for further cycles.
During the treatment phase of Part 2, hospitalization is not required, and the period of 
surveillance is left at the discretion of the investigator. Investigators should consider that 
although infusion reactions to any monoclonal antibody typically develops within 30 minutes 
to two hours after the initiation of drug infusion, symptoms may be delayed for up to 24 
hours. Some patients may also develop severe hypertensive episodes, and treatment should be 
considered accordingly. Please see Section 4.1.4 for the required criteria to administer study 
drugs after the first cycle. Please see Section 5.2.7.1 for guidelines on how to report and
manage infusions related reactions, and Appendix 10.2.1 for BP management and study 
administration guidelines.
If pathological laboratory values or other issues require an additional unscheduled visit, a
new eCRF page will be created for the unscheduled visit. At the unscheduled visit, it is
sufficient to record only the clinical relevant labs/examinations performed.
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient, sponsor and investigator may agree on alternative, back-up or rescue 
methodology. The implementation of these measures will depend on patient’s consent,

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operational feasibility, local law and regulations. If alternative methodology is implemented, 
the deviations from the original plan will be precisely documented.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations as outlined in the Flow Chart will be performed at the respective visits.
Specific details to conduct of physical examination, collection of vital signs (including blood 
pressure measurement), laboratory investigations, assessment of ECG and echocardiography 
can be found in Sections 5.2.2, 5.2.3 and 5.2.4.
Procedure for collection of blood samples for PK, ADA and circulating biomarkers are given 
in Section 5.3 and 5.4.
A more detailed overview of collection of blood samples for PK, ADA and circulating
biomarkers is given in Appendix 10.5.
DCE-MRI will only be performed as described in Section 5.4.2.4.
6.2.1
Screening and run-in period(s)
The examinations required for the screening visit may be conducted within a time interval of 
21 days prior to the first study drug administration. Prior to any other study related procedure, 
written informed consent must be obtained from the patient.
ECOG and Physical examination can be performed the day prior to the start of treatment 
cycle.
CT/MRI images obtained prior to study participation can be used within the study as long as
they are not older than 28 days at day of first treatment.
For Glioblastoma patients only, MRI 14 days before treatment start is required.
Echocardiography must be obtained within 21 days before start of treatment.
It is possible to take blood sample a valuable time ahead (usually the day before treatment but 
possible up to 72 hours before).
For cohort D (Glioblastoma) patients, the baseline status on IDH and MGMT methylation 
need to be captured in the eCRF if available.
If for administrative or medical reasons, the patient is not entered within the defined 
screening period, re-assess of eligibility parameter could be allowed after discussion with 
Clinical Monitor. This should be considered as an exceptional situation and not a general 
rule. 
If the patient has been determined eligible by the investigator to enter the trial (refer to 
Section 3.3), the investigator will assign one or more medication number(s) to the patient 

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through the IRT system at Visit 1 (Section 4.1.3). First dose of BI 836880 + ezabenlimab will
be administered at the beginning of Visit 1 at the trial site (Day 1, cycle 1).
6.2.2
Treatment period(s)
A treatment cycle is defined as 3 weeks of duration. If initiation of a subsequent cycle is
delayed due to medical reasons, additional visits beyond Day 21 may be necessary and may
be performed at investigator’s discretion, and should be recorded in the eCRF.
During cycle 1 (for Part 1 and 2) and 4 (only for Part 1), intensive PK-sampling will be 
conducted and patients have to be observed closely for any adverse events. Therefore,
patients have to come to the clinic during the first four cycles every week to the clinic. In Part 
1 additional visits are needed at day 2 for cycles 1, 2 and 4 and at day 3 for cycle 1. In cycles
5 and 6 the patient is requested to come to the clinic on day 8 after administration of study 
drug. From cycle 7 onwards no additional visits, beside day 1 including drug administration, 
are requested by protocol. In Part 2 from cycle 2 onwards, no additional visits, beside day 1 
including drug administration, are requested by protocol.
For Part 1 and Part 2 disease response assessment by CT/MRI will be performed according to 
institutional practices and SOC.
6.2.3
End of treatment visit (EOT)
The EOT visit will be performed after permanent discontinuation of trial medication for any
reason as soon as possible but no later than 3 weeks 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.
6.2.4
Residual effect period (REP)
The REP is defined in Section 5.2.7.2. The End of REP the Safety Follow-up visit should not 
be performed earlier than 42 days after permanent discontinuation of the trial medication (last 
day medication was administered). In case the patient discontinued due to PD by RECIST 
1.1/RANO, one additional tumor assessment should be done at the Safety Follow-up visit or 
time close according to the applicable interval for images. The information collected at this 
visit should include all new AEs that occurred after EOT and a follow-up of adverse events 
ongoing at EOT. Any subsequent anti-cancer therapy administered between EoT and EoR 
should be reported.
6.2.5 
Extended follow-up period
6.2.5.1
Follow-up for progression
For patients who did not progress, additional follow-up visits after the Safety Follow-up visit 
will be performed every 6 weeks plus/minus 3 days.
The follow-up for progression period will end at the earliest of the following events:

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
Lost to follow-up

Disease progression

Start of a new anti–cancer therapy

Death

End of whole trial as specified in Section 8.6
At the end of the follow-up period, the EoFU (End of Follow-Up) visit has to be performed.
The following will be obtained and / or performed during the follow-up visits and the EoFU
visit.

Record all related SAEs and all related AESI and a follow-up of adverse events ongoing
since End of REP to EoFU as entered in source data

Concomitant medications for treatment of an adverse event reported in the (e)CRF
including trade name, indication and dates of administration

Perform tumour assessment and imaging if applicable

Treatment and date with any other anti-cancer drug including the name and type of the
anti-cancer drug and/or best supportive care

Outcome (date of and reason for death, in case the patient had PD the actual date of PD
shall be recorded)

6.2.5.2
Follow-up for Overall Survival
Sponsor has decided that as of this protocol amendment acknowledgement no further survival 
status follow-up will be collected.
6.2.5.3
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

Withdrawal to be followed-up

Death
At the earliest of the above criteria, the Patient Completion (PC) information should be
entered in the CRF.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a Phase I, open-label, dose-escalating trial to determine the Recommended Phase 2 
Dose (RP2D) of BI 836880 in combination with ezabenlimab in patients with locally 
advanced or metastatic non-squamous NSCLC during or after first line platinum-based 
chemotherapy or CPI monotherapy treatment or the combination of CPI and chemotherapy.
In addition, the safety and efficacy of BI 836880 in combination with ezabenlimab will be 
assessed. 
7.1.1
Statistical design - Part 1 (dose escalation)
7.1.1.1 
Combination BLRM
The objective of Part 1 of the trial is to determine RP2D of BI 836880 in combination with 
ezabenlimab based on MTD, patients are entered sequentially into escalating dose cohorts. 
The Part 1 dose finding will be guided by a Bayesian 5-parameter logistic regression model 
with overdose control (R13-4803, R15-4233).
The logistic regression model is defined as follows. Let π1,d1 be the probability of having a
DLT when giving dose d1 of BI 836880 as monotherapy, and π2,d2 be the probability of having 
a DLT when giving dose d2 of the combination partner ezabenlimab as monotherapy, 
respectively.
A logistic regression model is used to model the dose-toxicity relationship for each 
component individually:
BI 836880 part:
logit(π1,d1) =log(α1) + β1log(d1/d1*)
Ezabenlimab part:
logit(π2,d2) =log(α2) + β2log(d2/d2*)
where logit(π) = log(π /(1- π)), the reference doses d1* = 720 mg and d2* = 240 mg are set for 
BI 836880 and ezabenlimab, respectively.
Assuming no toxicity interaction between the two compounds, the probability of a DLT when 
giving the combination of dose d1, d2 is obtained as
π012,d1,d2 = π1,d1 + π2,d2 - π1,d1π2,d2
with corresponding odds
odds(π012,d1,d2)= π012,d1,d2 /(1- π012,d1,d2)
In order to account for a potential positive (higher toxicity than expected under
independence) or negative (lower toxicity than expected under independence) interaction

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between BI 836880  and ezabenlimab, a dose-dependent interaction term -∞<η<∞ is 
introduced to the model by the following definition:
odds(π12,d1,d2) = odds(π012,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 a variable describing the observed number of DLTs from 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 θ1 and θ2 will be specified as mixtures of two multivariate normal
distributions, i.e.
а(θk) = a1,k f1(θk) + a2,k f2(θk)
with
a1,k, a2,k the prior mixture weights, k=1,2 and
fi(θk) = MVN(μik, Σik) (k=1,2),
the multivariate normal distribution of the i-th component with mean vector μik and
covariance matrix Σik, where
Σ = 	


,

 ,
 ,

 ,
 ,


,

Mixture prior distributions have the advantage that they allow for specification of different
logistic dose-toxicity curves, therefore making the prior more robust.
A weakly informative normal prior distribution will be used for η.
The estimated probability π12,d1,d2 of a DLT at each dose combination d1, d2 from the model
will be summarized 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 level with the highest 
posterior probability of the DLT rate falling in the target interval [0.16, 0.33) among the dose 
combinations fulfilling the EWOC principle. Per EWOC it should be unlikely (i.e., <25% 
posterior probability) that the DLT rate at the dose combination will exceed 0.33. However, 
the maximum allowable dose increment for the subsequent cohort will be no more than 100% 
for each compound.
The MTD may be considered reached if one of the following criteria is fulfilled:
1. The posterior probability of the true DLT rate in the target interval [0.16, 0.33) of the
MTD is above 50%, OR
2. At least 8 patients have been treated in the study, of which at least 6 at the MTD.

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Prior derivation:
By the time BLRM is analyzed, safety data for ezabenlimab are expected to be available from 
BI Study 1381.1and preliminary safety data for BI 836880 will be available from the study 
1336.1. The information can be incorporated into the prior derivation meta-analytic 
predictive (MAP) approach. Exact details on the evaluations of the model using hypothetical 
data scenarios and operating characteristics are provided in the statistical appendix.
For illustrative purposes only, we assume the following hypothetical data on BI 836880 
(Table 7.1.1.1: 1) and ezabenlimab (Table 7.1.1.1: 2) are available and describe how prior 
distribution is derived using the MAP approach. However, at the time when BLRM is 
performed for 1336.11, actual data available will be used instead.
Table 7.1.1.1: 1
Hypothetical data for BI 836880
Dose BI 
836880 (mg)
N of patients 
treated
N of patients 
with DLTs 
during MTD 
evaluation period
N of patients with CTCAE Grade ≥ 3 
hypertension and require medical 
intervention within all cycles or DLTs 
during MTD evaluation period
40 
2
0
0
120
2
0
1
360
2
0
1
720
7
0
2
1000
5
1
3
Table 7.1.1.1: 2
Hypothetical data for ezabenlimab
Dose ezabenlimab (mg)
N of patients treated
N of patients with DLTs 
during MTD evaluation 
period
80 
3
0
240
6
0
400
3
0
The following steps were used to derive the prior distributions for all parameters:
For θ1:
1. The meta-analytic-predictive prior was derived using the DLTs information of 
BI 836880 from BI Study 1336.1. Small between study heterogeneity is assumed. 
This mixture component was assigned 80% weight.
2. A second meta-analytic-predictive prior was derived using the number of patients 
with CTCAE Grade ≥ 3 hypertension and require medical intervention within all 
cycles or DLTs during MTD evaluation period from Study 1336.1. Small between 
study heterogeneity is assumed. This component was added with 20% weight.

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For θ2:
1. The meta-analytic-predictive prior was derived using the DLTs information of 
ezabenlimab from BI study 1381.1. Small between study heterogeneity is assumed. 
This mixture component was assigned 90% weight. 
2. A high-toxicity weakly-informative component was added with 10% weight based on 
the a priori assumption that the median DLT rate at the starting dose of 80 mg would 
equal 3% and the median DLT rate at 240 mg would equal 50%. This yields μ22 = 0, 
1.151). The standard deviations were set such that large uncertainty about the 
parameter means is reflected, and the correlation was set to 0, thus yielding σ22,11 = 2, 
σ22,22 = 1 and ρ22 = 0, respectively.
The prior distribution for η will be based on the a priori assumption of positive interaction 
between the two compounds, a normal distribution with mean 0 and standard deviation 0.707 
was chosen. At the starting dose combination, the corresponding 95% prior interval covers an 
approximately 4-fold increase (or decrease) in the odds of a DLT over no interaction.
A summary of the prior distribution is provided in Table 7.1.1.1: 3. Additionally, the prior 
probabilities of DLT at different doses, as well as the corresponding probability of under-, 
targeted and overdosing, are shown in Table 7.1.1.1: 4.
Table 7.1.1.1: 3
Parameters for prior distributions
Parameter
Means, standard deviations, correlation
Mixture weight
log(α1), log(β1): component 1
-1.936, 0.078, 0.644, 0.863, -0.072
0.80
log(α1), log(β1): component 2
-0.338, -0.592, 0.496, 0.680, 0.135
0.20
log(α2), log(β2): component 1
-3.007, -2.291, 0.802, 1.002, 0.003
0.90
log(α2), log(β2): component 2
-0, 1.15, 2, 1, 0
0.10
Η
0, 0.707, n/a
n/a

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Table 7.1.1.1: 4
Prior probabilities of DLTs
Dose 
(mg)
Dose (mg)
Probability of true DLT rate in 
Descriptive 
Statistics
Quantiles
BI 836880
Ezabenlimab
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
360
80
0.612
0.250
0.138
0.174
0.141
0.024
0.128
0.533
360
240
0.535
0.272
0.193
0.214
0.192
0.028
0.149
0.813
500
80
0.527
0.299
0.174
0.200
0.147
0.037
0.153
0.573
500
240
0.452
0.308
0.239
0.242
0.199
0.035
0.177
0.829
720
80
0.354
0.409
0.237
0.247
0.154
0.063
0.201
0.634
720
240
0.338
0.328
0.334
0.292
0.214
0.041
0.231
0.857
1000
80
0.204
0.408
0.388
0.316
0.180
0.078
0.274
0.741
1000
240
0.261
0.269
0.470
0.363
0.249
0.038
0.309
0.917
7.1.1.2
Statistical model assessment
The model was assessed using 2 different metrics:
1. Hypothetical data scenarios: for various potential data constellations as they could 
occur in the actual trial, the maximal doses allowed in the next cohort by the model 
are investigated. Data scenarios thus provide a way to assess the ‘on-study’ behavior 
of the model.
2. Simulated operating characteristics: these illustrate for different assumed true dose 
toxicity relationships, how often a correct dose would be declared as MTD by the 
model. They are a way to assess the ‘long-run’ behavior of the model.
In summary, the model showed very good behavior as assessed by these metrics. More details 
can be found in Appendix 10.5. The simulations were conducted using R Version
3.3.2 in conjunction with WinBUGS Version 1.4.
7.1.2
Statistical design - Part 2 (dose expansion cohorts)
To effectively use the information from these patients’ cohorts in the assessment of the 
efficacy, a Bayesian hierarchical model (BHM) approach (R13-4803), which assumes full 
exchangeability of model parameters and allows borrowing information across patients’ 
cohorts, will be used to analyze the response rate endpoints.
The BHM has 2 main components: a data model and a parameter model, as well as priors for 
the parameter model. The data model is a binomial sampling model
r|n~Binomial n, p, j = 1, 2, 3, …
where n and r are the number of patients and the corresponding number of patients with 
response in each patient cohort. The parameter model for the log-odds parameters, including 
an adjustment for the target rates 

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 =  !" 	
#
1 −#
 − !" 	
#&
1 −#&

is specified as
θ| μ, τ ~ N(μ, τ), j = 1, 2, 3, …
where p& is the target response rate, μ denotes the “overall” mean of θ and τ determines the 
inter-cohort heterogeneity.
Prior distribution
A non-informative normal distribution with mean 0 and standard deviation of 2 is specified 
for the mean μ. For the inter-cohort heterogeneity parameter τ, a half normal distribution with 
parameter 1 is used which is a very conservative assumption regarding between-cohort
variability and hence leads to only little borrowing of data across patient cohorts because 
there is little prior information on the strength of the correlation between the treatment effects 
across cohorts.
Additional analysis of cohort F
Patients in cohort F starting treatment after 15-Jul-2021 (in accordance with protocol 
version7) will be considered as stage II patients whereas patients with treatment start date 
before 15-Jul-2021 are considered as stage I patients.
For cohort F, the first 30 patients treated in stage I were included in the aforementioned BHM 
model and the decision was made to expand this cohort. Patients to be treated in stage II will 
not be included in the BHM analysis A separate Bayesian model will be used to analyze the 
stage II patients’ data, while incorporating the stage I patients’ data in a robust meta-analytic 
predictive (MAP) prior as specified below.
The R package “RBesT” and functions gMAP(), automixfit() and robustify() are used to 
derive the robust MAP prior. At the first step, a MAP prior is derived with information from 
stage I (12/30 responders) together with a specification of weakly informative prior N (0,2)
for the intercept parameter and HN (0.125) for variance for moderate heterogeneity between 
stage I and stage II. At the second step, a weakly-informative component of Beta (0.6, 1.4) is 
added with 10% weight to make the MAP prior more robust by implementing the two-
component mixture structure (see Table 7.1.2: 1). The effective sample size of this robust 
MAP prior is estimated to be 14.
Table 7.1.2: 1
Robustified MAP prior
Parameter*
Beta parameters (a,b)
Mixture weight
Component 1
10.66, 15.82
0.90
Component 2
0.60, 1.40
0.10
*seed = 1209
After all of the approximately 30 patients are treated in stage II and sufficiently evaluable for 
efficacy, the posterior distribution will be derived including the stage I data in a beta-
binomial conjugate model with the above robust MAP prior. The Bayesian decision criterion, 

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to analyze the objective response rate (ORR) of the 30 additional patients in stage II is 
specified as: 
#!12345!4 #4!6765 528 (#9:: > 0.25|?727 @4!A 127"3 BB) > 0.85
The threshold of 0.25 for the objective response is selected based on the historical data of 
18% and 32.2% response rates reported for pembrolizumab (R21-2759)and for combination 
treatment of nivolumab and ipilumab (R21-2758) in sorafenib pre-treated patients.
A minimum observed response rate of 27% (naïve estimate) among 30 patients at stage I is 
required to pass this criterion. A further expansion of this cohort may be considered through a 
protocol amendment if this Bayesian decision criterion is passed.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing is planned in this trial. All analyses in this trial are descriptive 
and exploratory.
In cohort F, statistical criteria are defined and will be evaluated at the end of stage II. Please 
refer to Section 7.1.2 for more details on the final criterion and analysis. 
7.3
PLANNED ANALYSES
No per protocol set will be used in the analysis. However, important protocol deviations will 
be summarized. The TSAP will specify the important protocol deviations in detail.
For the determination of the MTD, only MTD-evaluable patients will be considered. For the 
analysis of secondary and 
 in Part 1, all patients in the treated set (i.e., 
patients treated with at least one dose of trial medication) will be included in the analysis. All 
analyses planned in Part 2 will be based on the treated set.
7.3.1
Primary endpoint analyses
7.3.1.1 
Primary endpoint analyses for Part 1
In order to identify the MTD(s) and the recommended dose(s) for Part 2 of the trial, the 
number of patients with DLTs at each dose combination during the Part 1 MTD evaluation 
period (the first cycle of the BI 836880 plus ezabenlimab combination) must be presented by 
descriptive statistics. Patients who discontinue during the first treatment cycle for reasons 
other than a DLT will be excluded from the determination of the MTD. In addition, the 
number of patients with DLTs that occurred during the entire treatment period will be 
summarized at each dose level. The BLRM will be rerun to re-evaluate the MTD and RP2D 
together with all relevant data collected during Part 2. 

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7.3.1.2 
Primary endpoint analyses for Part 2
The primary endpoint for Part 2 of the trial is OR defined by confirmed CR or PR according 
to RECIST 1.1 for all cohorts except GBM as assessed by the Investigator. OR in GBM 
cohort will be evaluated using RANO criteria. Overall response will be analyzed in terms of 
the shrinkage estimator of the OR rate (ORR) based on BHM.
Note on primary endpoint analysis in cohort F:
In addition, OR from stage I and stage II will be analyzed separately using a Bayesian 
approach with meta-analytic predictive (MAP) prior after completion of stage II. Please refer 
to Section 7.1.2 for more details on the derivation of the MAP prior and the final decision 
criterion. A naïve estimate (observed objective response rate) along with 95% CI (Clopper-
Pearson) will also be provided.
7.3.2
Secondary endpoint
7.3.2.1 
Secondary endpoint analyses for Part 1
All Adverse Events (AEs), drug related AEs and drug related AEs leading to dose reduction 
or discontinuation during treatment period will be summarized descriptively. 
Details on statistical inference for PK parameters, e.g., Cmax ,  tmax, AUC0-504h, and 
accumulation ratios RA after the first (Part 1 and 2) and fourth (Part 1) infusion cycle are 
described in Section 7.3.5.
7.3.2.2 
Secondary endpoint analyses for Part 2
Disease control (DC) will be analyzed in terms of DC rate (DCR), defined as the proportion 
of patients with best overall response of CR, PR, or SD according to RANO for GBM & 
RECIST1.1 for all other cohorts. Proportions will be presented with 95% two-sided 
confidence interval using the exact Clopper-Pearson method.
Duration of objective response (DoR) - for all patients with an OR, the duration of OR is 
defined as time from first documented CR or PR to the earliest of disease progression or 
death among patients with OR.  If a patient did not die or progress until the last visit in the 
study, this patient will be censored at the last time point known to be alive and progression-
free. The outcome will be assessed according to RANO for GBM & RECIST 1.1 for all other 
cohorts.
Progression-free survival (PFS) is defined as time from first treatment infusion until disease 
progression or death from any cause, whichever occurs earlier. If a patient did not die or 
progress until the last visit in the study, this patient will be censored at the last time point 
known to be alive and progression-free.

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Kaplan-Meier estimates will be used to analyze duration of OR and PFS.
Tumor shrinkage, the difference between the minimum post-baseline sum of lesion of target 
lesions and baseline sum of the same target lesions, will be summarized descriptively. 
PK parameters analyses for Cmax, tmax, AUC0-tz, CL, t1/2, and Vss after the first and fourth 
infusion cycle will be detailed in the TSAP.
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 
with an onset between start of treatment and end of the residual effect period (REP), a period 
of 42 days after the last dose of trial medication and adverse event that start before first dose 
of trial medication but deteriorate during treatment, will be considered “treatment-emergent” 
and 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 Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Laboratory data will be analyzed 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.

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Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.

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7.4
INTERIM ANALYSES
Part 1:
Interim safety evaluations will be performed as considered necessary. The dose-escalation 
design dictates that the sponsor and the SMC perform regular safety evaluations. Safety 
evaluations will be performed after each dose cohort by the SMC. The SMC will recommend 
the next dose level as well as the corresponding cohort size. SMC will recommend the RP2D 
that will be used in Part 2. SMC meeting minutes and outputs provided for these SMC meetings 
will be documented and archived.
Exploratory analyses of PK/PD may be performed at the end of Part 1 and additionally if 
considered informative for the study.
Part 2:
In Part 2, 290 patients are planned to be treated. 40 patients each are planned for cohorts A 
and B, and 30 patients each are planned for cohorts C, D, E, G, and H. In addition, as of 
protocol version 7, 30 more patients will be enrolled in addition to previously enrolled 30 
patients in cohort F. The Sponsor may pause enrollment in any cohort at any time to carefully 
evaluate the safety and efficacy data of patients already enrolled in a given cohort.
An interim futility analysis will be performed for cohorts C, D, E, F, G, and H in Part 2. The 
interim analyses for each cohort are planned to be conducted after 15 patients in that cohort 
have completed their two on-treatment imaging assessments (i.e., end of cycle 4 or later 
depending on the cohort). For each cohort, timing of the interim analysis may be adjusted 
according to actual recruitment rate to facilitate or avoid delay of the trial conduct. The 
Sponsor may pause enrollment in a cohort before making any decisions from the interim 
futility analysis. The two-stage design is planned to stop further recruitment of patients if the 
defined efficacy boundary (see Table 7.7.2: 1) is not met at the first stage. 
Exploratory analyses of PK/PD may be additionally performed during Part 2 and if 
considered informative for the study.
7.5
HANDLING OF MISSING DATA

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information on all AEs, with particular emphasis on potential DLTs. For partial or missing 
AE onset and/or end dates, BI internal rules will be followed (see Reference Document 001-
MCG-156_RD01 “Handling of missing and incomplete AE dates”).
7.6
RANDOMIZATION
No randomization will be performed. In Part 1, patients will be assigned to escalating dose 
groups by order of admission into the trial.
7.7
DETERMINATION OF SAMPLE SIZE
7.7.1
Determination of sample size for Part 1
For Part 1, no formal statistical power calculations of sample size were performed. 
Approximately 12-18 patients will be expected for the dose finding part and confirmation of 
RP2D. Fewer patients might be needed based on the recommendation of the SMC and the 
actual number of cohorts tested.
7.7.2
Determination of sample size for Part 2
For Part 2, below cohorts assume:

Cohort A:
- patients with locally advanced or metastatic non-squamous Non-Small Cell Lung 
Cancer with CPI monotherapy.

Cohort B: 
- patients with locally advanced or metastatic non-squamous Non-Small Cell Lung 
Cancer pre-treated with a combination of platinum-based chemotherapy and checkpoint 
inhibitor.

Cohort C: 
- patients with locally advanced or metastatic Small Cell Lung Cancer, with no more 
than one line of chemotherapy, except platinum sensitive patients.

Cohort D: 
- patients with histologically confirmed recurrent glioblastoma (primary), No more than 
two lines of prior chemotherapy (concurrent and adjuvant temozolomide based 
chemotherapy including in combination with another investigational agent is 
considered one line of chemotherapy).

Cohort E: 
- patients with histologically confirmed, unresectable, Stage IV metastatic melanoma, 
with least one line of any kind of immune therapy.

Cohort F (2nd line HCC): 
- patients with locally advanced or metastatic and/or unresectable Hepatocellular 
Carcinoma who were intolerant or progressed during 1st line sorafenib or lenvatinib 
treatment.

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
Cohort G (1st line HCC):
- patients with locally advanced or metastatic and/or unresectable HCC with no prior 
systemic treatment.

Cohort H (2nd line HCC – atezolizumab+bevacizumab failure only):
patients with locally advanced or metastatic and/or unresectable HCC who were 
intolerant or progressed during 1st line atezolizumab+bevacizumab treatment.
A total of approximately 290 patients will be treated for these 8 cohorts. 40 patients each are 
planned for cohorts A and B, and 30 patients are planned for cohorts C, D, E, G, H and 60 
patients for cohorts F.
For cohorts A, B, E, and H, there is no literature available for the target patients. As there 
are no treatments of proven efficacy for this population, it is assumed around 5% ORR with 
background therapy. The futility boundary for cohort E and cohort H is set as 7% at planned 
interim futility analysis timing. The early stopping probabilities are shown in Table 7.7.2: 1.
For cohort C (SCLC), around 20% ORR with anti-PD-1 antibody monotherapy is assumed. 
In Checkmate-032 (R19-1713) which is an open label phase I/II trial of Nivolumab in 
patients with SCLC who experienced disease progression after platinum-based 
chemotherapy, the ORR was 12% [95% CI, 6.5-19.5] (N=109). In KEYNOTE-158 (R19-
1713), which is a phase II basket study of Pembrolizumab, patients with advanced SCLC had 
an ORR of 18.7% [95% CI, 11.8-27.4] (N=107). In KEYNOTE-028 (R19-1713), which is a 
phase Ib basket trial, patients with extensive-stage SCLC showed an ORR of 33% [95% CI, 
16-55] (N=24). Based on above result, the futility boundary for cohort C is set as 20% at 
planned interim futility analysis timing.
For cohort D (GBM), around 20% ORR with Bevacizumab is assumed. In a recent phase II 
study (R22-0513) comparing standard dose bevacizumab versus low dose bevacizumab plus 
lomustine, in patients with recurrent glioblastoma following standard radiation and 
temozologmide, the ORR was 19% [95% CI, 8-36] (N = 36) based on RANO criteria for the 
standard dose bevacizumab arm. Based on above results, the futility boundary for cohort D is 
set as 20% at planned interim futility analysis timing.
For cohort F (2nd line HCC with sorafenib or lenvatinib failure with treatment start date 
before 15-Jul-2021 (stage I)), around 15% ORR with anti-PD-1 antibody monotherapy is 
assumed. In Checkmate-040 (R17-3829) which is an open label phase I/II trial of Nivolumab 
in patients with advanced hepatocellular carcinoma, the ORR was 20% [95% CI, 15-26] 
(N=50) in dose expansion phase and 15% [95% CI, 6-28] (N=10) in the dose escalation 
phase. In KEYNOTE-224 (R19-0168) which is a phase 2 study of Pembrolizumab in 
patients with advanced hepatocellular carcinoma previously treated with sorafenib, the ORR 
was 17% [95% CI, 11-26] (N=104). Based on above result, the futility boundary for cohort F 
is set as 15% at planned interim futility analysis timing.
Note: Stage II patients (treatment start date after 15-Jul-2021 according to protocol version 7) 
were not considered in the above sample size justification. Please refer to Section 7.7.3 below 
for the sample size justification of the stage II patients.

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For cohort G (1st line HCC), around 20% ORR with target monotherapies is assumed. In 
REFLECT (R20-3051), which is a Phase 3 study comparing Lenvatinib vs. Sorafenib, the 
ORR was 19% [95%, CI 17-21] (N = 478) for Lenvatinib and 7% [95%, CI 6-8] (N = 476) 
for Sorafenib. In IMbrave150 (R22-0533), which is a Phase III trial comparing Atezolizumab 
plus Bevacizumab vs. Sorafenib, the ORR for Sorafenib arm observed was 12% [95% CI, 7-
17] (N = 165). In Checkmate-459 (R22-0532), which is a phase III study comparing 
Nivolumab vs. Sorafenib, the observed ORR was 7% [95% CI, 4-10] (N = 372). Based on 
above result, the futility boundary for cohort G is set as 20% at planned interim futility 
analysis timing.
Proposed sample size will provide accumulative safety and tolerability data for the 
investigational combination across different tumor types. Different homogeneous scenarios 
and heterogeneous scenarios as well as different sample sizes are considered in the 
simulations to assess the operating characteristics of the BHM approach. The simulation 
results as shown in Table 7.7.2: 2 below show that, with the proposed cohort size and interim 
futility analysis in SCLC, MLN, GBM and HCC cohorts, the BHM approach has reasonable 
probability of reaching the pre-specified response rate under a wide range of scenarios. The 
probability of observing a > 15% increase in the shrinkage estimator of the ORR under 
negative scenario is well controlled on cohort level (< 1%). Desirable true positive 
probabilities (~> 60%) and false negative probabilities (<2%) are also demonstrated under 
nugget scenarios for each cohort on proposed sample size. 
Table 7.7.2: 1
Early stopping probabilities at interim for cohorts C-H based on 
observed ORR under different scenarios
Scenario
ORR (%) in cohort
(C,D,E,F,G,H)
Early stopping criterion 
Observed ORR
Early stopping probability
In cohort C/D/E/F/G/H
Positive:
(40,40,25,35,40,25)
Cohort C: <20% (<3 out of 15)
Cohort D: <20% (<3 out of 
15)
Cohort E: <7% (<2 out of 15)
Cohort F: <15% (<3 out of 15)
Cohort G: <20% (<3 out of 
15)
Cohort H: <7% (<2 out of 15)
3%/3%/8%/6%/3%/8%
Negative:
(20,20,5,15,20,5)
40%/40%/83%/60%/40%/83%
Intermediate: 
(30,30,15,25,30,15)
13%/13%/32%/24%/13%/32%
Nugget 1:
(20,20,5,15,20,5)
40%/40%/83%/60%/40%/83%
Nugget 2:
(20,20,25,15,20,5)
40%/40%/8%/60%/40%/83%
Nugget 3:
(40,40,25,35,40,25)
3%/3%/8%/6%/3%/8%

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Table 7.7.2: 2
Operating characteristics of the Bayesian Hierarchical Modelling 
approach for final analysis under different scenarios with futility 
evaluation at the interim
Sample 
size
Scenario 
(ORR (%) in each 
patient cohort)
Probability 
of shrinkage 
estimator of 
the ORR ≥
(20%,20%, 
35%,35%, 
20%,30%, 
35%,20%) 
in at least 
one cohort at 
final
Probability of 
shrinkage estimator of 
the ORR ≥
(20%,20%,
35%,35%,
20%,30%,
35%,20%) 
in each cohort at final
Probability 
of shrinkage 
estimator of 
the ORR ≥
(25%,25%, 
40%,40%, 
25%,35%, 
40%,25%) 
in at least 
one cohort at 
final
Probability of 
shrinkage estimator of 
the ORR ≥
(25%,25%,
40%,40%,
25%,35%,
40%,25%)  
in each cohort at final
(40,40, 
30,30, 
30,30, 
30,30)
Positive:
(25,25,40,40,25,35,40,25)
99%
91%/91%/82%/82%/ 
86%/82%/81%/85%
84%
49%/47%/47%/46%/
46%/47%/46%/46%
Negative: 
(5,5,20,20,5,15,20,5)
1.2%
0.0%/0.0%/0.2%/0.4%/
0.0%/0.0%/0.6%/0.0%
0.3%
0.0%/0.0%/0.0%/0.1%/
0.0%/0.0%/0.2%/0.0%
Intermediate: 
(15,15,30,30,15,25,30,15)
30%
10%/8%/5%/6%/
9%/6%/8%/7%
8%
1%/0.9%/1%/1%/
0.8%/0.7%/2%/1%
Nugget 1:
(25,25,20,20,5,15,20,5)
77%
56%/58%/1%/0.7%/
0.0%/0.6%/0.8/0.0%
49%
32%/28%/0.4%/0.1%/
0.0%/0.1%/0.0%/0.0%
Nugget 2: 
(25,25,20,20,25,15,20,5)
89%
63%/61%/1%/1%/
58%/0.5%/1%/0.0%
65%
35%/34%/0.2%/0.3%/
31%/0.0%/0.1%/0.0%
Nugget 3:
(5,5,40,40,25,35,40,25)
96%
0.0%/0.2%/59%/59%/ 
61%/62%/60%/61%
80%
0.0%/0.0%/32%/32%/
31%/32%/33%/31%
(30,30, 
25,25, 
25,25,
25,25)
Positive:
(25,25,40,40,25,35,40,25)
99%
89%/89%/79%/79%/
88%/81%/77%/87%
81%
49%/47%/46%/45%/ 
47%/46%/46%/46%
Negative: 
(5,5,20,20,5,15,20,5)
2%
0.0%/0.0%/0.5%/0.7%/
0.0%/0.0%/1%/0.0%
0.3%
0.0%/0.0%/0.1%/0.1%/
0.0%/0.0%/0.1%/0.0%
Intermediate: 
(15,15,30,30,15,25,30,15)
34%
12%/9%/6%/7%/
10%/7%/9%/9%
10%
2%/1%/1%/2%/
1%/0.8%/2%/2%
Nugget 1:
(25,25,20,20,5,15,20,5)
69%
50%/50%/2%/1%/
0.0%/0.9%/0.9%/0.0%
45%
29%/27%/0.3%/0.3%/ 
0.0%/0.1%/0.1%/0.0%
Nugget 2: 
(25,25,20,20,25,15,20,5)
84%
57%/55%/1%/1%/
53%/1%/1%/0.0%
63%
32%/30%/0.3%/0.3%/ 
29%/0.0%/0.4%/0.0%
Nugget 3:
(5,5,40,40,25,35,40,25)
93%
1%/1%/54%/54%/
61%/59%/56%/62%
75%
0.0%/0.0%/31%/31%/
30%/30%/31%/30%
7.7.3
Determination of additional sample size for stage II in cohort F
With an additional sample size of approximately 30 in stage II, the probability to pass the 
defined Bayesian decision criterion (in Section 7.1.2) is 96% when the true underlying ORR 
is 40%. When true underlying ORR is 20%, the probability to pass the defined Bayesian 
decision criterion is 24% (Table 7.7.3: 1).

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Table 7.7.3: 1
Probability of satisfying statistical criterion after stage II
True ORR
Probability of 
satisfying
statistical criterion 
after stage II
0.20
0.24
0.25
0.49
0.30
0.72
0.35
0.88
0.40
0.96
0.45
0.98

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC)
and the harmonised standards for Medical Devices (ISO 14155, current version).
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), the EU 
regulation 536/2014 the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) 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 Boehringer Ingelheim 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 regards 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.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
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 Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. 

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The patient must be given sufficient time to consider participation in the trial. The 
investigator obtains written consent of the patient’s own free will with the informed consent 
form after confirming that the patient understands the contents. The investigator must sign (or 
place a seal on) and date the informed consent form. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent.
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.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.
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, would be acceptable.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see Section 8.3.2).

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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.
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 CRF, 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 
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.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of 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 / IEC review 
and regulatory inspections. Direct access must be provided to the CRF 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 CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs 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 GCP.

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8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including 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.
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 5.2.7.2, if applicable.
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.
8.5.1
Collection, storage and future use of biological samples and 
corresponding data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analyzing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.

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
Samples and data are used only if an appropriate informed consent is available.
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 of the last patient in the whole trial
(“Last Patient Out”), or when all patients have been discontinued from study treatment and 
followed until the end of REP.
The “Last Patient Drug Discontinuation” (LPDD) 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 LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the 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.
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 Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A Study Monitoring Committee (SMC) composed of participating investigators and members 
of the BI trial team will be established to review individual and aggregated safety and 
efficacy data at regular intervals to determine the safety profile and risk/benefit ratio and 

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recommend next dose level/does appropriateness of further enrolment. Details of the SMC 
responsibilities and procedures are described in the SMC charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the (Investigator Site File) ISF. The investigators will have access to the 
BI clinical trial portal (Clinergize) to facilitate document exchange and maintain electronic 
ISF. 
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,
-
ensure appropriate training and information of Local Clinical Monitors (CML), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT Manual and Central Laboratory Manual, available in the ISF.

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9.
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9.1
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ESMO 2016 press release: pembrolizumab new option for first line 
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Angiopoietin 2 stimulates TIE2-expressing monocytes to suppress T cell 
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al. Model-based characterization of the pharmacokinetics of 
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solid tumors. CPT Pharmacometrics Syst Pharmacol 2017. 6(1):49-57
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expansion trial. Lancet 389, 2492 - 2502 (2017)
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Antiangiogenic agents can increase lymphocyte infiltration into tumor and 
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Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al, 
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and augments their inherent proangiogenic functions. Cancer Res 
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S, et al. VEGF inhibits T-cell development and may contribute to tumor-
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Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, et al. Vascular 
endothelial growth factor affects dendritic cell maturation through the 
inhibition of nuclear factor-kappaB activation in hemopoietic progenitor 
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Schmittnaegel M, Rigamonti N, Kadioglu E, Cassara A, Rmili CW, 
Kiialainen A, et al. Dual angiopoietin-2 and VEGFA inhibition elicits 
antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci 
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Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, et al. 
VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells 
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BY, et al. Cabozantinib in patients with advanced and progressing 
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Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al, . 
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Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al,. 
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9.2
UNPUBLISHED REFERENCES
c02353883-09
. Investigator’s Brochure BI 836880 Version 9 03 Nov 2021.
c07895879-06
Investigator’s Brochure BI 754091 Version 6 19 January 2022.

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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
Instructions for Pharmacist: available in the ISF.
10.2
BLOOD PRESSURE MEASUREMENT PROCEDURE
Blood pressure measurements should be performed on the same arm and, if possible, by the
same person. The machines or devices to be used for blood pressure measurement should be 
certified. The same method and device must be used throughout the trial for a patient i.e. if a
patient receives the first blood pressure measurement for example with an electronic device,
the same method and device should be used throughout the study for this patient
(without switching to manual blood pressure measurement). On the other hand, inter-patient
variability is acceptable, i.e. a study site is allowed to consistently use an electronic device to
measure the blood pressure in a given patient throughout the study and a manual technique in
another patient. The blood pressure measurement should be taken after the patient has rested quietly
in a seated position for at least five minutes.
In Part 1, three blood pressure measurements will be taken two minutes apart and all three
results have to be entered in the eCRF.
In Part 2, only a single blood pressure measurement is required per scheduled time point, i.e. 
one measurement before the study drugs have been administered, and one measurement after 
the study drugs are administered. Please see Section 5.2.2 for further details, and Appendix 
10.2.1 for management guidelines. 

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10.2.1
Blood Pressure Management and Study Drug Administration 
Guidelines
Table 10.2.1: 1 BP management and study drug administration guidelines following 
completion of cycle 1, based on pre-infusion SBP and DBP measured on 
study drug administration visits. 
Pre-infusion clinic 
BP (mmHg) on 
pre-planned 
infusion visits
SBP <160 and 
DBP <100
SBP 160-179 or 
DBP 100-109
SBP≥180 or 
DBP≥110
Hypertensive 
crisis**
Action to be taken 
with BI 836880 
and ezabenlimab
Proceed with 
study drug 
administration 
as scheduled / 
re-start.
Temporarily delay 
administration of both study 
drugs until BP < 160/100.
Delay 
administration 
of both study 
drugs until next 
pre-scheduled 
study drug 
administration.
Discontinue 
both study 
drugs.
Antihypertensive
treatment
As deemed 
necessary by the 
investigator.*
Wait 10-15 minutes and ensure 
patient is relaxed, and re-measure 
BP:
- If BP <160/100 on re-
assessment, administer both 
study drugs;
- If SBP remains 160-179 or 
DBP 100-109, initiate / 
modify antihypertensive 
regimens, delay 
administration of both study 
drugs, and re-assess within 
12-48 hours of 
antihypertensive agent 
initiation/modification.
After 12-48 hours:
- If BP <160/100, administer 
both study drugs.
- If BP remains ≥160/100, 
repeat after 10-15 minutes; if 
BP remains ≥160/100 hold 
study drug administration 
until next pre-planned 
infusion visit, and initiate / 
modify antihypertensive 
regimens.
Initiate / modify 
antihypertensive 
regimens, and 
re-assess at the 
next scheduled 
infusion visit. 
Emergency 
admission
for in-patient 
care
* Investigators should consider initiating / modifying antihypertensive regimens if SBP < 160 mmHg or DBP > 100 mmHg 
if their medical assessment is that lowering BP further is clinically indicated (for example, patient has cardiovascular risk
factors), and discontinuing or modifying antihypertensive agents if there are symptoms /signs of hypotension. 
** Hypertensive crisis defined as patients with significantly elevated blood pressure with signs or symptoms of acute, 
ongoing target-organ damage.

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10.3
IMMUNE-RELATED ADVERSE EVENTS AS ADVERSE EVENTS OF
SPECIAL INTEREST
Please see below in the Table 10.3: 1 regarding irAEs which must be reported as AESIs. 
Table 10.3: 1 irAEs which must be reported as AESIs.
Immune-related adverse events of special interest
Pneumonitis (reported as an AESI if ≥Grade 2)

Acute interstitial pneumonitis

Interstitial lung disease

Pneumonitis
Colitis (reported as an AESI 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 AESI 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 AESI)

Type 1 diabetes mellitus (if new onset)

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Table 10.3: 1 irAEs which must be reported as AESIs.(cont’d)
Immune-related adverse events of special interest
Hematologic (reported as an AESI 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 AESI 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 AESI)

Allergic reaction

Anaphylaxis

Cytokine release syndrome

Serum sickness

Infusion reactions

Infusion-like reactions
Neurologic (reported as an AESI)

Autoimmune neuropathy

Guillain-Barre syndrome

Demyelinating polyneuropathy

Myasthenic syndrome
Ocular (report as an AESI 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 10.3: 1 irAEs which must be reported as AESIs.(cont’d)
Immune-related adverse events of special interest
Renal (reported as an AESI 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 AESI)

Dermatitis exfoliative

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis
Skin (reported as an AESI if ≥ Grade 3)

Pruritus

Rash

Rash generalized

Rash maculopapular

Any rash considered clinically significant in the physician’s judgment
Other (reported as an AESI)

Myocarditis

Pancreatitis

Pericarditis

Any other Grade 3 event that is considered immune-related by the physician
10.4
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, 
-
For irAEs listed below, it is not considered applicable stating that only if a causal 
relationship to one trial drug can be unequivocally established, the other trial drug 
may be continued. On combination treatment both drugs (BI 836880 and 

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ezabenlimab) will be stopped, paused, or re-exposed together. Any exceptions to this 
have to be agreed with the sponsor.
-
BI ezabenlimab and BI 836880 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). A dose reduction of BI 836880 may be considered, but is not required for the 
first occurrence of an irAE grade 1.
-
For most Grade 2 irAEs, ezabenlimab and BI 836880 should be withheld and 
treatment with corticosteroids is commonly warranted, usually with an initial dose of 
0.5 to 1 mg/kg daily. Restart of therapy is commonly possible once symptoms and/or 
laboratory values have resolved to grade 1 or less, and on corticosteroid ≤ 10 mg per 
day prednisone / prednisone equivalent per day. A dose reduction of BI 836880
should be considered, but is not required for the first occurrence of an irAE, but is 
mandatory if the same irAE recurs upon rechallenge with BI 836880.
-
For Grade 3 irAEs, ezabenlimab and BI 836880 has to be withheld, and treatment 
with high-dose corticosteroids (1-2mg/kg/d) is usually warranted. Upon improvement, 
steroids should be tapered 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 corticosteroid ≤ 10 mg per day, restarting of ezabenlimab and BI 836880 may 
be considered for selected irAEs, but caution is advised, in particular in patients with 
early-onset irAEs. Expert consultancy is recommended prior to restart of therapy.
-
Most Grade 4 irAEs warrant permanent discontinuation of ezabenlimab and BI
836880.
-
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. 
-
A dose reduction of BI 836880 may be considered, but is not required for the first
occurrence of an endocrine irAE.
In case of prolonged steroid therapy or treatment with immunosuppressive consider the 
possibility of opportunistic infections and tuberculosis reactivation, administer prophylactic 
antibiotics where appropriate. 
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.

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Ezabenlimab and BI 836880 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 >10x ULN if baseline was >2.5-
5x ULN] or total bilirubin >3x ULN [or >5x ULN if baseline was >1.5-3x 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.
For BI 836880, up to 1 dose reductions are allowed if the treatment pause due to an AE. Dose
adjustment of ezabenlimab besides interrupting of both compounds or permanently 
discontinuing ezabenlimab are not allowed (see Section 4.1.4).
Pneumonitis:

For Grade 1 pneumonitis with radiographic evidence of worsening, withhold 
ezabenlimab and BI 836880 until improvement or resolution; ezabenlimab and BI 
836880 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 ezabenlimab and BI 836880 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 ezabenlimab and BI 836880 and
immediately initiate treatment according to available guidelines.
Diarrhoea/Colitis:

For Grade 1 diarrhoea/colitis, consider interruption of ezabenlimab and BI 836880
therapy.

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
For Grade 2 diarrhea/colitis, withhold ezabenlimab and BI 836880 until patient´s
symptoms recovered to grade 1 or less. Consider initiating treatment with steroids.

For Grade 3 diarrhoea/colitis, withhold ezabenlimab and BI 836880 and immediately 
start treatment (steroids, non-steroidal immunosuppressants) as per available 
guidelines.

For Grade 4 diarrhoea/colitis, permanently discontinue ezabenlimab and BI 836880 
and immediately commence adequate therapy (e.g. i.v. corticosteroids).

For Grade 1-3 colitis, restart of ezabenlimab and BI 836880 may be considered once
symptoms improve to Grade 1 or less without need for continued steroids. After 
careful benefit risk assessment, ezabenlimab and BI 836880 may also be restarted 
after recovery to grade 1 or less, and on corticosteroid ≤10 mg per day

Ezabenlima and BI 836880 should be permanently discontinued for recurrent
diarrhoea/colitis of any grade.
Diabetes

Consider withholding ezabenlimab and BI 836880 in case of grade 2 hyperglycemia.

Check for ketonuria. In case of new onset of diabetes or unexpected worsening of 
preexisting 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
Ezabenlimab and BI 836880 should be withheld until glucose level is controlled 
with insulin with no sign of ketoacidosis.

Ezabenlimab and BI 836880 may be restarted once insulin therapy has established 
stable glycemic control.
Thyroid disorders:
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in
thyroid function (at screening and in regular intervals during treatment as indicated in Flow
Chart (safety lab) and Section 5.2.3, and as indicated based on clinical evaluation) and for 
clinical signs and symptoms of thyroid disorders. For diagnosed thyroid disorders, thyroid 
hormone supplementation and monitoring should occur as per available guidelines.

Primary hypothyroidism:
-
For Grade 1 hypothyroidism, ezabenlimab and BI 836880 may be continued, 
with regular monitoring of thyroid values.
-
For Grade 2 hypothyroidism, consider withholding ezabenlimab and BI 836880
-
For Grade 3-4 hypothyroidism, withhold ezabenlimab and BI 836880, consider
admission and IV therapy, especially in case of myxedema
-
Ezabenlimab and BI 836880 may be restarted once symptoms resolve to 
baseline with appropriate thyroid hormone supplementation

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
Primary hyperthyroidism:
-
For Grade 1 hyperthyroidism, ezabenlimab and BI 836880 may be continued, 
with regular monitoring of thyroid values.
-
For Grade 2 hyperthyroidism, consider withholding ezabenlimab and BI 
836880, initiate therapy as per available guidelines.
-
For Grade 3-4 hyperthyroidism, withhold ezabenlimab and BI 836880. Consider 
hospitalization, especially in case of Thyrotoxicosis.
-
Ezabenlimab and BI 836880 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 ezabenlimab and BI 836880 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 ezabenlimab and BI 836880 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 ezabenlimab and BI 836880 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
(Section 5.2.7).

For Grade 1 hepatitis (elevated AST/ALT < 3x ULN and/or total bilirubin <1.5x 
ULN), ezabenlimab and BI 836880 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), 
ezabenlimab and BI 836880 should be suspended. Monitoring of liver values every 3 
days is recommended. Initiate treatment according to available guidelines. Restarting 
of ezabenlimab and 836880 may be considered upon recovery to grade 1 or less, and 
on corticosteroid ≤ 10 mg per day.

For Grade 3 or higher hepatitis, ezabenlimab and BI 836880 has to be permanently 
discontinued. Immediately initiate treatment as per guidelines. 

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For eligible patients with elevated screening/baseline AST/ALT (>2.5-5x ULN or bilirubin
>1.5-3x ULN):

Carefully monitor patients for signs of autoimmune hepatitis.

In case of increased levels of AST/ALT >2x baseline to ≤10x ULN and/or bilirubin 
>2x baseline to ≤5x ULN, ezabenlimab and BI 836880 should be suspended.
Monitoring of liver values every 3 days or more frequently, if clinically indicated, is 
recommended. Restarting of ezabenlimab and BI 836880 may be considered upon 
recovery to baseline or less, and on corticosteroid ≤10 mg per day.
-
In case of increased AST/ALT >10x ULN and/or bilirubin >5x ULN, ezabenlimab
and BI 836880 have to be permanently discontinued. Initiate treatment as per 
guidelines.
Nephritis

For Grade 1 nephritis, consider temporarily withholding ezabenlimab and BI 836880.

For Grade 2 nephritis, withhold ezabenlimab and BI 836880. Consult nephrology. 
Initiate treatment according to guidelines. In case of no improvement or worsening, 
permanently discontinue ezabenlimab and BI 836880. Ezabenlimab and BI 836880 
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 ezabenlimab and BI 836880. 
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.

Ezabenlimab and BI 836880 should also be permanently discontinued for recurrent 
nephritis grade 2 or higher.
Rash

For Grade 1 rash, continue ezabenlimab and BI 836880. Initiate topical treatment.  

For Grade 2 rash, ezabenlimab and BI 836880 may be continued, in case of no 
improvement upon weekly monitoring, consider interruption of ezabenlimab and BI 
836880 therapy. Treat topically, add systemic therapies as clinically appropriate. 

For Grade 3 rash, withhold ezabenlimab and BI 836880. 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 
ezabenlimab and BI 836880 might be restarted, especially in case no alternative anti-
neoplastic therapy is available. 

For Grade 4 rash, ezabenlimab and BI 836880 should be permanently discontinued.

Ezabenlimab and BI 836880 should also be discontinued for recurrent rash grade 3 or 
higher.
Bullous dermatosis

For Grade 1 bullous dermatosis, use local wound care and observation. Ezabenlimab
and BI 836880 can be continued. 

For Grade 2 bullous dermatosis, withhold ezabenlimab and BI 836880. Administer 
topical therapy, add systemic therapy as clinically adequate. 

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
For Grade 3 bullous dermatosis, withhold ezabenlimab and BI 836880, initiate topical 
and systemic therapy as per available guidelines. Restarting of ezabenlimab and BI 
836880 may be considered after dermatology consultation. 

For Grade 4 bullous dermatosis, permanently discontinue ezabenlimab and BI 
836880.
Severe cutaneous adverse reaction (SCAR), Stevens Johnson Syndrome (SJS), Toxic 
Epidermal Necrolysis (TEN)

For Grade 2 events, withhold ezabenlimab and BI 836880, initiate treatment as per 
available guidelines. Closely monitor for improvement or worsening. 

For Grade 3 events, withhold ezabelimab and BI 836880. 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 ezabenlimab and BI 836880, 
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, ezabenlimab and BI 836880 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

Ezabenlimab and BI 836880 should be permanently discontinued for any grade.
  
Myasthenia gravis

For Grade 2 myasthenia gravis, withhold ezabenlimab and BI 836880.

For Grade 3 or 4 myasthenia gravis, permanently discontinue ezabenzimab and BI 
836880
Guillain Barré Syndrome (GBS)

Discontinue ezabenlimab and BI 836880 permanently for any grade GBS. 
Transverse Myelitis

Discontinue ezabenlimab and BI 836880 permanently for any grade transverse 
myelitis. 
Peripheral neuropathy, autonomic neuropathy

For Grade 1 events, may continue ezabenlimab and BI 836880, but with low threshold 
to discontinue while monitoring closely for worsening. 

For Grade 2 events, withhold ezabenlimab and BI 836880 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 ezabenlimab and BI 836880. 
Inflammatory Arthritis

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
For Grade 1 arthritis, ezabenlimab and BI 836880 can be continued. Administer
analgetic treatment (acetaminophen, NSAID). 

For Grade 2-4 arthritis, withhold ezabenlimab and BI 836880. Initiate treatment as per 
available guidelines, care regarding reactivation of tuberculosis/opportunistic 
infections in case of prolonged immunosuppressive/disease modifying anti-rheumatic 
drugs DMARD therapy. 
Ezabenlimab and BI 836880 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, ezabenlimab and BI 836880 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 ezabenlimab and BI 836880, discontinue permanently 
in patients with objective findings (elevated enzymes, abnormal EMG, abnormal 
muscle MRI or biopsy). Initiate therapy as per available guidelines. Resuming 
ezabenlimab and BI 836880 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 ezabenlimab and BI 836880. 

Ezabenlimab and BI 836880 should be permanently discontinued if there is any 
evidence of myocardial involvement.
Polymyalgia-like syndrome

For Grade 1 event, ezabenlimab and BI 836880 can be continued.   

For Grade 2 event, withhold ezabenlimab and BI 836880 and promptly initiate 
adequate therapy. If no improvement, treat as grade 3.

For Grade 3 or Grade 4 event, withhold ezabenlimab and BI 836880, promptly initiate 
adequate therapy. Rheumatology consultancy is highly recommended. 
Ezabenlimaband BI 836880 may be resumed after careful assessment of risks and benefits, 
rheumatology consultancy highly recommended prior to reinitiation. Ezabenlimab and BI 
836880 may only be re-started upon recovery to grade 1 or less and on corticosteroid ≤ 10 mg 
per day. 
Myocarditis

Discontinue ezabenlimab and BI 836880 permanently for any grade of myocarditis. 
Uveitis/Iritis, Episcleritis

For Grade 1 events, treatment with ezabenlimab and BI 836880 can continue. Treat 
topically as needed.

For Grade 2 events, withhold therapy with ezabenlimab and BI 836880, urgent 
ophthalmology referral is recommended. Initiate topical treatment, consider systemic 
therapy if needed. Restart of ezabenlimab and BI 836880 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 

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topical/ocular steroids is permitted and does not prohibit resuming ezabenlimab and 
BI 836880 therapy. 

For Grade 3 or 4 events, permanently discontinue ezabenlimab and BI 836880 
therapy. Seek emergent ophthalmology consultation. Initiate adequate local and 
systemic treatment.   
Autoimmune-hemolytic anemia (AIHA)

For Grade 1 AIHA, continue treatment with ezabenlimab and BI 836880. Close 
follow-up of anemia and other lab values. 

For Grade 2-4 AIHA, discontinue ezabenlimab and BI 836880 permanently. Initiate 
systemic therapy as per guideline. Consult Hematology.
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 ezabenlimab and BI 836880. 

For HUS (TTP excluded), withhold ezabenlimab and BI 836880 for grade 1 and grade 
2, provide supportive care. Upon full recovery, ezabenlimab and BI 836880 may be 
restarted after carefully weighing of risks and benefits. 

For Grade 3 or Grade 4 HUS, discontinue ezabenlimab and BI 836880 permanently. 
Immune thrombocytopenia (ITP)

In case of Grade 1 ITP, ezabenlimab and BI 836880 can be continued. 

For Grade 2 or Grade 3 ITP, withhold ezabenlimab and BI 836880 and initiate 
systemic therapy. ezabenlimab and BI 836880 may be restarted upon resolution to at 
least grade 1. 

For Grade 4 ITP, permanently discontinue ezabenlimab and BI 836880. 
Infusion related reactions (IRRs):

Signs and symptoms of IRRs usually develop during or shortly after ezabenlimab
infusion and generally resolve completely within 24 hours of completion of infusion. 
If symptoms develop during infusion, they may be managed with slowing or transient 
interruption of infusion.
Please refer to Section 5.2.7 for more details about infusion related reactions.
10.5
HANDLING PROCEDURES FOR BLOOD SAMPLES FOR PLASMA
CONCENTRATION-TIME MEASUREMENTS
Handling procedures for blood samples are presented in the Laboratory Manual.

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10.6
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS
The combination BLRMs with overdose control is introduced in Section 7.1 with the prior 
distributions for the model parameters fully specified. It will be used to guide dose escalation 
in this study for the BI 836880 plus ezabenlimab combination in the dose-escalation part of
this study. Once patients in each cohort have completed the combination MTD evaluation 
period, 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 summarized 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 evaluate the model behavior and model 
performance. To evaluate the model behavior, Section 10.5.1 illustrates a series of different 
scenarios that mimic the once which might arise during the actual study conduct. On-study 
recommendations for the next dose combinations by the BLRM with overdose control 
principle are also provided under various hypothetical outcome scenarios in early cohorts to 
show how EWOC facilitates on-trial dose-escalation decisions.

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10.6.1
Hypothetical data scenarios
These scenarios reflect potential on-study data constellations and related escalation as 
allowed by the model. It is assumed that each cohort has 3 patients who are all evaluable. At 
the 1st occurrence of a DLT, additional 3 patients will be added to the current cohort. For 
each scenario, the probability of overdose for the current dose, as well as the next potential 
dose and related probabilities of under-dosing, target dosing, and over-dosing are shown (see 
Table 10.6.1: 1).
For example, Scenario 1A represents the case that no DLT is observed in the first 2 patients 
at the starting dose combination of BI 836880 360 mg plus ezabenlimab 240 mg (denoted by 
360 mg/240 mg for easier reference). In this case, there are 2 next allowed dose combinations 
from the model, i.e., 500 mg/240 mg, and 720 mg/240 mg, among which, 720 mg/240 mg has 
the highest probability of being in the target region. Scenario 1B shows 1 DLT observed in 3 
patients at 360mg/240mg, the dose recommended will remain at this level. But if 3 more 
patients is added to this cohort and number of DLT remains at 1, the next dose allowed will 
be 500mg/240mg (Scenario 1C). 
Scenario 2D: after no DLT observed in 2 patients of 360mg/240mg dose combination, if 2 
DLT observed in 6 patients of 500mg/240mg cohort, the dose cannot be escalated further. 
Scenario 3A: no DLT in first 3 cohort, the next recommended dose combination will be
1000mg/240mg.  If there is 1 DLT out of 3 or 6 patients in 720mg/240mg cohort, the dose 
recommended will remain at 720mg/240mg as shown in Scenario 3B-3E.

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Table 10.6.1: 1
Hypothetical data scenarios 
Scenario
Dose 
comb.
BI 836880/
ezabenlimab
(mg/mg)
# 
DLT
# 
Pat
Current 
Dose: 
P(OD)
Next 
allowed 
dose 
comb. 
(mg/mg)*
Summary 
of 
toxicity 
of 
next 
Combination dose 
P(under 
dose)
P(target 
dose)
P(over 
dose)
1A
360/240
0
2
0.075
500/240
720/240
0.578     
0.427    
0.312 
0.363  
0.110
0.210
1B
360/240
1
3
0.226
360/240
0.391
0.384
0.226
1C
360/240
1
6
0.080
500/240
0.461     
0.406  
0.133
2A
360/240
500/240
0
0
2
3
0.034
720/240
0.551     
0.347 
0.102
2B
360/240
500/240
0
1
2
3
0.151
500/240
0.434
0.415
0.151
2C
360/240
500/240
0
1
2
6
0.055
720/240
0.392     
0.449  
0.160
2D
360/240
500/240
0
2
2
6
0.188
500/240
0.313    
0.499 
0.188
3A
360/240
500/240
720/240
0
0
1
2
3
3
0.139
720/240
0.395     
0.466  
0.139
3B
360/240
500/240
720/240
0
0
1
2
3
6
0.053
720/240
0.539  
0.408
0.053
3C
360/240
500/240
720/240
0
0
2
2
3
6
0.168
720/240
0.289
0.543 
0.168
3D
360/240
500/240
720/240
0
1
2
2
6
6
0.222
720/240
0.201
0.577
0.222
The simulations for scenarios and operating characteristics were conducted using R Studio 
Version 3.2.2 in conjunction with WinBUGS 1.4.3.

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10.6.2
Operating characteristics of combination BLRM
Operating characteristics are a way to assess the long-run behavior of a model by illustrating 
the precision of 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 10.6.2: 1 describes 3 assumed true dose-toxicity scenarios which were used to assess 
the operating characteristics of the combination model. These scenarios reflect a wide range 
of possible cases as follows:

Scenario C1: aligned with prior means

Scenario C2: low-toxicity scenario

Scenario C3: high-toxicity scenario
Table 10.6.2: 1 Assumed True Dose-Toxicity Scenarios
Scenario C1, P(DLT)
  Dose ezabenlimab (mg)
Dose BI 836880 (mg)
80    
240
360
0.138      
0.193        
500
0.174
0.239
720
0.237
0.334
1000
0.388
0.470
Scenario C2, P(DLT)
Dose ezabenlimab (mg)
Dose BI 836880 (mg)
80    
240
360
0.07
0.10
500
0.08
0.15
720
0.10
0.20
1000
0.20
0.30
Scenario C3, P(DLT)
Dose ezabenlimab (mg)
Dose BI 836880 (mg)
80    
240    
360
0.20       
0.30
500
0.25
0.35
720
0.30     
0.45
1000
0.45
0.65
Bold numbers indicate true DLT rates in the target interval (0.16, 0.33).

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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 maximal dose combination possible and satisfies the overdose criterion 
if it is ≤300% increase from the current dose.

If the recommended dose combination satisfying the overdose criterion is > 300% 
increase in dose for each compound, then escalate to the highest dose combination 
which is ≤300% increase from the current dose for each compound.

If any DLT occurs, extra 3 patients will be tested at the current dose combination.
The MTD was considered reached if the following conditions are satisfied:

The next recommended dose is the same as the current dose;

At least 1 DLT is observed;

At least 6 patients have been treated at the MTD dose combination declared by the 
model;

At least 9 patients have been evaluated OR the posterior probability of targeted 
toxicity reaches 50%.
It was then assessed how often a dose was declared as MTD with true DLT rate in the
underdose, 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 10.6.2: 2.
Table 10.6.2: 2 Simulated Operating Characteristics
Scenario
% of Trials Declaring an MTD with True 
DLT Rate in
# Patients
# DLT
Underdose
Target
dose
Overdose
Stopped
Mean
(Min-Max)
Mean
(Min-Max)
C1: 
Aligned 
with prior
33.6
51.9
14.3
0.2
12.75
(6-30)
3.28
(1-12)
C2: Low 
Tox
50.4
49.6
0
0
15.13 
(6-33)
2.209 
(1-10)
C3: High 
Tox
0
91.8
8.2
0
12.74 
(6-30)
3.28
(1-12)
In Scenario C1, which reflects the case that the true dose-toxicity is approximately aligned 
with prior means, almost all of the simulated trials identified the MTD. Approximately 52% 
of trials were in the target interval and none of them were in the underdose interval. There 
were 14.3% in the overdose interval and 0.2% of the trials were prematurely stopped either 
because the MTD was not identified or because the probability of overdose associated with 
the simulated starting dose had already exceeded the 25% threshold.

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Scenario C2 (Low-toxicity scenario) shows similar results with previous Scenario 1 overall. 
No simulated trials declared a MTD with a true DLT rate in the overdose interval. All of the 
simulated trials identified the MTD with approximately 50% in the target dose interval and 
50% are in the underdose interval, and no trials were prematurely stopped.
Scenario C3 (High-toxicity scenario) illustrates a case with higher-than-expected toxicity. In 
this case, approximately 92% of the simulated trials identified the MTD within the target 
interval. Approximately 8% of the simulated trials declared the MTD in the overdose 
interval, but no trials were prematurely stopped. 
By reviewing the metrics presented in Table 10.6.2: 2 it can be seen that the model is not 
sensitive to different scenarios of true DLT rates. Across three scenarios, the average number 
of patients participated in dose-escalation ranges from 12.74 to 15.13 and the average number 
of DLTs observed ranged from 2.209 to 3.28. 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.
In summary, the considered data scenarios demonstrate reasonable operating characteristics 
of the model. 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 SMC in deciding the dose combinations to be tested in order to 
determine the MTD estimates.
10.7
APPENDIX - PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction.
100
Normal, no complaints, no evidence 
of disease.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
1
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work).
80
Normal activity with effort; some 
signs or symptoms of disease.
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
2
In bed <50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours.
60
Requires occasional assistance, but 
is able to care for most of his/her 
needs.
50
Requires considerable assistance 
and frequent medical care.

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ECOG Performance Status Scale
Karnofsky Performance Scale
3
In bed >50% of the time. Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours.
40
Disabled, requires special care and 
assistance.
30
Severely disabled, hospitalization 
indicated. Death not imminent.
4
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair.
20
Very sick, hospitalization indicated. 
Death not imminent.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
23 Apr 2018
EudraCT number
EU number
2017-001378-41
BI Trial number
1336-0011
BI Investigational Product(s)
BI 836880
BI 754091
Title of protocol
An open label phase Ib dose finding study of BI 
836880 in combination with BI 754091 to 
characterize safety, tolerability, pharmacokinetics, 
pharmacodynamics and efficacy in check point 
inhibitor naïve patient with locally advanced or 
metastatic non-squamous Non-Small Cell Lung 
Cancer  who progressed during or after first line 
platinum-based treatment.
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Coverpage
Description of change
Format changes of the coverpages. New TCM 
included:
Phone: 
 
Fax: 
Rationale for change
New TCM included
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
Information added:
At first dose level, first patient will be treated and 
observed for at least 15 days before allowing the 
second patient to receive BI 836880 and BI 
745901 infusions. 
A safety monitoring committee (SMC) meeting 
will be held to decide if the 2nd patient can be 
enrolled to the study. Subsequent enrollment at all 

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dose levels within dose escalation, each patient in 
a given cohort (dose level) will be observed for a 
minimum of 48 hours after first BI 836880 and BI 
745901 application for acute reaction monitoring 
before allowing treatment for subsequent patient 
in the same cohort. As descript at the point 6.1 of 
the protocol, during the treatment phase, after 
administration of BI 836880 and BI 754091, 
patients are required to be hospitalized under 
close surveillance with access to intensive care for 
at least 48 hours after administration of trial 
medication to allow close monitoring for 
infusion-related reactions or other adverse events 
and availability of patients for PK visits. The 
sponsor will contact the investigator to verify if 
any acute reaction was investigated before 
allowing treatment for subsequent patient in the 
same cohort.
Rationale for change
To plan a sequential administration for patients in 
the 1st cohort (Part I) after the first patient.
Section to be changed
3.3.2 Inclusion Criteria
Description of change
Change of the contraception days from 120 to 150
Male or female patients. Women of childbearing 
potential (WOCBP) and men able to father a child 
must be ready and able to use highly effective 
methods of birth control per ICH M3 (R2) that 
result in a low failure rate of less than 1% per year 
when used consistently and correctly, starting 
with the screening visit and through 150 days 
after the last dose of BI 836880 and BI 754091 
treatment, respectively.
Rationale for change
In view of the preliminary pharmacokinetic data 
observed in humans for BI 754091 (t1/2 ~29 days), 
it would be appropriate to adapt the duration of 
contraceptive measures, according to the 
instructions of CTFG related to the contraception.
Section to be changed
5.2.4 Electrocardiogram
Description of change
Information added
Cardiac monitoring for patients presenting a QTc 
interval prolongation CTCAE grade ≥ 3 ‘>500 
ms) shall be followed as follows: 
Continuous ECG monitoring until the QTc 
interval < 480 ms 

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- Cardiologist opinion for potential 
treatment of this event as soon as the QTc 
interval prolongation is observed. 
- Cardiologist recommendation after QTc 
interval normalisation (< 480 ms) and 
potential follow-up
Rationale for change
To describe the procedure for handling of 
CTCAE>= Grade 3 QTC interval prolongation

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11.2
GLOBAL AMENDMENT 2
Date of amendment
21 Feb 2019
EudraCT number
EU number
2017-001378-41
BI Trial number
1336-0011
BI Investigational Product(s)
BI 836880
BI 754091
Title of protocol
An open label phase Ib dose finding study of BI 
836880 in combination with BI 754091 to 
characterize safety, tolerability, pharmacokinetics, 
pharmacodynamics and efficacy in check point 
inhibitor naïve patient with locally advanced or 
metastatic non-squamous Non-Small Cell Lung 
Cancer  who progressed during or after first line 
platinum-based treatment.
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Title
Description of change
Changed from:
An open label phase Ib dose finding study of BI 
836880 in combination with BI 754091 to 
characterize safety, tolerability, pharmacokinetics, 
pharmacodynamics and efficacy in check point 
inhibitor naïve patient with locally advanced or 
metastatic non-squamous Non-Small Cell Lung 
Cancer  who progressed during or after first line 
platinum-based treatment.
To:
An open label phase Ib dose finding study of BI 
836880 in combination with BI 754091 to 
characterize safety, tolerability, pharmacokinetics, 
pharmacodynamics and efficacy in check point 
inhibitor naïve and previously treated patients
with locally advanced or metastatic non-squamous 
Non-Small Cell Lung Cancer  
Rationale for change
The title was adapted to the new population
Section to be changed
Synopsis - Title
Description of change
Changed from:

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An open label phase Ib dose finding study of BI 
836880 in combination with BI 754091 to 
characterize safety, tolerability, pharmacokinetics, 
pharmacodynamics and efficacy in check point 
inhibitor naïve patient with locally advanced or 
metastatic non-squamous Non-Small Cell Lung 
Cancer  who progressed during or after first line 
platinum-based treatment
To:
An open label phase Ib dose finding study of BI 
836880 in combination with BI 754091 to 
characterize safety, tolerability, pharmacokinetics, 
pharmacodynamics and efficacy in check point 
inhibitor naïve and previously treated patient with 
locally advanced or metastatic non-squamous 
Non-Small Cell Lung Cancer  
Rationale for change
The title was adapted to the new population
Section to be changed
Synopsis – study design
Description of change
Changed from:
This is a Phase Ib study, containing two parts; Part 
1 (dose escalation of BI 836880 in combination 
with BI 754091) and Part 2 (expansion phase in 
two cohorts) in patients with locally advanced or 
metastatic non-squamous NSCLC who progressed
during or after first line platinum-based therapy. 
Part 1:
Dose escalation of BI 836880 in combination with 
BI 754091 in check point inhibitor naive patients 
with locally advanced or metastatic non-squamous 
NSCLC who progressed during or after first line 
platinum-based therapy. 
To:
This is a Phase Ib study, containing two parts; Part 
1 (dose escalation of BI 836880 in combination 
with BI 754091) and Part 2 (expansion phase in 
two cohorts).
Part 1:
Dose escalation of BI 836880 in combination with 
BI 754091 in check point inhibitor naïve or 
previously treated patients with locally advanced 
or metastatic non-squamous NSCLC who 

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progressed during or after first line (in case of CPI
naïve patients) platinum-based therapy and 
patients who progressed during or relapsed after 
completion of at least 2 cycles (in case of CPI
relapsing patients) of platinum-based 
chemotherapy and a CPI treatment (monotherapy 
or in combination with chemotherapy).
Rationale for change
Adapted to the new population
Section to be changed
Synopsis - objectives
Description of change
Changed from:
Primary objective:

To determine the Recommended Phase 2 
Dose (RP2D) of BI 836880 in 
combination with BI 754091 in check 
point inhibitor naïve patients with 
locally advanced or metastatic non-
squamous NSCLC who progressed 
during or after first line platinum-based.
To:
Primary objective:

To determine the Recommended Phase 2 
Dose (RP2D) of BI 836880 in 
combination with BI 754091 in check 
point inhibitor naïve or previously 
treated patients with locally advanced or 
metastatic non-squamous NSCLC who 
progressed during or after first line 
platinum-based chemotherapy. 
Rationale for change
Adapted regarding the new population and 
clarification
Section to be changed
Synopsis- diagnosis
Description of change
Changed from:
Patients with locally advanced or metastatic non-
squamous NSCLC progressing during or after first 
line platinum-based therapy with either low PD-
L1 expression (PD-L1 expression in 1-49% of 
tumor cells) or high PD-L1 expression (PD-L1 
expression in ≥50% of tumor cells)
To:
Naïve or previously CPI treated patients with 
locally advanced or metastatic non-squamous 
NSCLC who progressed during or after first line
(in case of CPI naïve patients) platinum-based
therapy and patients who progressed during or 

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relapsed after completion of at least 2 cycles (in 
case of CPI relapsing patients) of platinum-based 
chemotherapy and a CPI treatment (monotherapy 
or in combination with chemotherapy).
Patient´s with either low PD-L1 expression (PD-
L1 expression in 1-49% of tumor cells) or high 
PD-L1 expression (PD-L1 expression in ≥50% of 
tumor cells).
Rationale for change
Adaption regarding the added population
Section to be changed
Synopsis –main in- and exclusion criteria #4
Description of change
Changed from:
Documented disease progression or relapse (based 
on investigator’s assessment) during or after 
completion of at least 2 courses of platinum-based 
chemotherapy as first line treatment. This includes 
patients relapsing within 6 months of completing 
(neo)adjuvant/curative-intent chemotherapy or 
chemoradiotherapy
To:
1. Documented disease progression or relapse 
(based on investigator’s assessment) during or 
after completion of at least 2 cycles of 
platinum-based chemotherapy as first line 
treatment of Stage IIIB/IV non- squamous 
NSCLC or for CPI experienced patients 
during or after completion of at least 2 cycles 
of platinum-based chemotherapy and a CPI
treatment (monotherapy or in combination 
with chemotherapy). This includes patients 
relapsing within 6 months of completing 
(neo)adjuvant/curative-intent 
chemotherapy/CPI or chemoradiotherapy
Rationale for change
Adaption to the population
Section to be changed
Synopsis – test Product(s)
Description of change
Deletion of:
and diluent for BI 836880 drug product
Rationale for change
Adaption to new BI 836880 formulation
Synopsis – Safety criteria
Info of change from CTCAE verion 4.03 to 
version 5.0
CTCAE version change
Section to be changed
Flow Chart 
Description of change
Change of the EoR visit window from alst admin 
+42 (-2 /+3)to :
EoR last admin+42 (+3)

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Rationale for change
Should not be shorter than 42 days
Section to be changed
Flow chart food note #8
Description of change
Change from:
Tumour assessment should be done every 6 weeks 
starting from first trial medication infusion.
To:
Tumour assessment should be done every 6 weeks 
(in accordance to local requirements) starting 
from first trial medication infusion.
Rationale for change
Adding local requirements information
Section to be changed
Abbreviations
Description of change
Adding ANG2 Angiopoietin-2
Rationale for change
Adding missing information
Section to be changed
Section 2.1.1
Description of change
Change from:
PART 1:
Primary objective:

To determine the Recommended Phase 
2 Dose (RP2D) of BI 836880 in 
combination with BI 754091 in check 
point inhibitor naïve patients with 
locally advanced or metastatic non-
squamous NSCLC who progressed 
during or after first line platinum-based 
treatment, and.
To:
Primary objective:

To determine the Recommended Phase 2 
Dose (RP2D) of BI 836880 in combination 
with BI 754091 in patients with locally 
advanced or metastatic non-squamous 
NSCLC who progressed during or after 
first line (in case of CPI naïve patients) 
platinum-based therapy and patients who 
relapsed after completion of at least 2 
cycles (in case of CPI relapsing patients) 
of platinum-based chemotherapy and a 
CPI treatment (monotherapy or in 
combination with chemotherapy).
Rationale for change
Adaption to the new added population
Section to be changed
3.1 
Description of change
Change from:
The eligible patient population will be check point 
inhibitor naive patients with locally advanced or 
metastatic non - squamous NSCLC who 

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progressed during or after first line platinum-
based treatment. The trial will consist in 2 Parts; 
Part 1 and part 2:
Part 1:
Dose escalation of BI 836880 in combination with 
BI 754091 in patients with locally advanced or 
metastatic non-squamous NSCLC progressing 
during or after first line platinum-based therapy. 
To:
The eligible patient population will be check point 
inhibitor naïve and experienced patients with 
locally advanced or metastatic non - squamous 
NSCLC.  Patients who progressed during or after 
first line (in case of CPI naïve patients) platinum-
based therapy and patients who progressed during 
or relapsed after completion of at least 2 cycles (in 
case of CPI relapsing patients) of  platinum-based 
chemotherapy and a CPI treatment (monotherapy 
or in combination with chemotherapy).. The trial 
will consist in 2 Parts; Part 1 and part 2:
Part 1:
Dose escalation of BI 836880 in combination with 
BI 754091 in patients with locally advanced or 
metastatic non-squamous NSCLC who progressed
during or after first line (in case of CPI naïve 
patients) platinum-based therapy or relapsed after 
completion of at least 2 cycles (in case of CPI
relapsing patients) of platinum-based 
chemotherapy and a CPI treatment (monotherapy 
or in combination with chemotherapy).
Rationale for change
Adaption regarding the added population
Section to be changed
3.2
Description of change
Changed from:
The eligible patients are patients with locally 
advanced or metastatic non - squamous NSCLC 
who progressed during or after first line platinum-
based treatment.
To:
The eligible patients are patients with locally 
advanced or metastatic non - squamous NSCLC 
who progressed during or after first line (in case 
of naïve patients) of platinum-based therapy. 
Additional we include patients who relapsed after 
completion of at least 2 cycles (in case of relapsed 

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patients) of platinum-based chemotherapy and a 
CPI treatment (monotherapy or in combination 
with chemotherapy).
Rationale for change
Adaption regarding the added population
Section to be changed
3.3
Description of change
Changed from:
Eligible patients are patients with locally 
advanced or metastatic non-squamous NSCLC 
which progressed during or after first line 
platinum-based treatment and who are check point 
inhibitor naïve. 
To:
Eligible patients are patients with locally 
advanced or metastatic non-squamous NSCLC 
which progressed during or after first line (in case 
of naïve patients) of platinum-based therapy and 
patients who relapsed after completion of at least 
2 cycles (in case of relapsed patients) of  
platinum-based chemotherapy and a CPI treatment 
(monotherapy or in combination with 
chemotherapy).
Rationale for change
Adaption regarding the added population
Section to be changed
3.3.1
Description of change
Changed from:
Patients with advanced/metastatic non squamous 
NSCLC who have progressed during or after first 
line platinum- based therapy. Patients should be 
check point inhibitors naïve.
To:
Patients with advanced/metastatic non squamous 
NSCLC who have progressed during or after first 
line (in case of naïve patients) of platinum-based
therapy and patients who relapsed after 
completion of at least 2 cycles (in case of relapsed 
patients) of  platinum-based chemotherapy and a 
CPI treatment (monotherapy or in combination 
with chemotherapy).
Rationale for change
Section to be changed
3.3.2 Inclusion Criteria 
Description of change
Inclusion criteria #3 and #4 were changed from:
1. No previous treatment with check-point 
inhibitor. 

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2.
Documented disease progression or 
relapse (based on investigator’s 
assessment) during or after completion of 
at least 2 cycles of platinum-based 
chemotherapy as first line treatment of 
Stage IIIB/IV NSCLC. This includes 
patients relapsing within 6 months of 
completing (neo)adjuvant/curative-intent 
chemotherapy or chemoradiotherapy
To:
1. No previous treatment with check-point 
inhibitor. Or patients with CPI based 
treatment as last therapy before entering 
the trial.
2. Documented disease progression or 
relapse (based on investigator’s 
assessment) during or after completion of 
at least 2 cycles of platinum-based 
chemotherapy as first line treatment of 
Stage IIIB/IV non- squamous NSCLC or 
for CPI experienced patients during or 
after completion of at least 2 cycles of 
platinum-based chemotherapy and a CPI
treatment (monotherapy or in combination 
with chemotherapy). This includes patients 
relapsing within 6 months of completing 
(neo)adjuvant/curative-intent 
chemotherapy/CPI or chemoradiotherapy
Section to be changed
3.3.3 Exclusion Criteria
Description of change
8. Patients with personal or family history of QT 
prolongation and/or long QT syndrome, or 
prolonged QTcF at baseline (> 470 ms). 
Changed to:
1. Patients with personal or family history of QT 
prolongation and/or long QT syndrome, or 
prolonged QTcF at baseline (> 480 ms). 
Rationale for change
Clarification of the QTcF
Rationale for change
Adaption regarding the new population
Section to be changed
3.3.4.1 Withdrawal from trial treatment
Description of change
Added information:

The patient can no longer be treated with trial 
drug after a drug related Adverse Event 
CTCAE Grade 4.

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
The patient can no longer be treated with trial 
drug after a DLT, which did not recover to 
CTCAE Grade 1 or pre-treatment values 
within 2 weeks.
Rationale for change
Request by the German EC
Section to be changed
4.1.1 Identity of the Investigational Medicinal 
Products
Description of change
In this trial the IMP BI 836880 will be switched to 
a new pharmaceutical formulation which is 
diluted in a standard 5% Glucose/Dextrose 
solution. The new formulation will be made 
available in this trial at the latest before expiry of 
the old formulation prepared with a drug specific 
Diluent. Details of the trial medications, BI 
836880, BI 754091, and respective diluents, are 
presented in Tables 4.1.1: 1 and 4.1.1:2, in the
IB’s for BI 836880 and BI 754091 as well as in
the Instruction for the Pharmacist (IfP).
Deletion of Table 4.1.1: 2
Rationale for change
Change of the IMP formulation BI 836880. 
Diluent will not be used anymore with the new 
formulation.
Section to be changed
4.1.4 Re-treatment criteria
Description of change
Adding of information:
In case of a DLT (drug related AEs CTCAE 
Grade 3, 4 according to Table 5.2.6.1: 1) the 
patient will discontinue treatment.
Once a DLT has recovered to CTCAE grade 1 or 
pre-treatment values, the study drugs may be re-
started at a lower dose level in case the patients 
benefits from the study drug after discussion 
between investigator and Clinical Monitor at 
Boehringer Ingelheim
And change of 

QTcF <=470 ms (according to Exclusion-
Criterion #8)
To:

QTcF <=480 ms (according to Exclusion-
Criterion #8)
Rationale for change
Request by German EC, clarification on the QTcF
Section to be changed
4.1.7 Storage condition
Description of change
Change from:

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BI 836880 vials and Diluent Buffer vials and 
BI754091 vials must be stored in their original 
packaging.
To:
BI 836880 vials (old and new formulation) and 
BI754091 vials must be stored in their original 
packaging.
Rationale for change
Adaption regarding new IMP formulation
Section to be changed
5.2.2 Body temperature
Description of change
Change from:
Not acceptable/preferred methods include: IR-
measurement in ear, forehead or temple.
To:
Not preferred methods but accepted include: IR-
measurement in ear, forehead or temple.
Rationale for change
Clarification
Section to be changed
5.2.3 Safety laboratory parameter
Description of change
Change from:
In case the criteria for hepatic injury are fulfilled, 
a number of additional measures will be 
performed (please see Section 5.2.6.1 and the 
DILI Checklist provided in the ISF eDC system. 
The amount of blood taken from the patient 
concerned will be increased due to this additional 
sampling.
To:
In case the criteria for potential hepatic injury are 
fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the 
DILI Checklist provided in the ISF eDC system. 
The amount of blood taken from the patient 
concerned will be increased due to this additional 
sampling.
Rationale for change
Clarification by adding the word “potential”
Section to be changed
5.2.4 Electrocardiogram
Description of change
Change from:
Cardiac monitoring for patients presenting a QTc 
interval prolongation CTCAE grade ≥ 3 ‘>500 
ms) shall be followed as follows: 
- Continuous ECG monitoring until the 
QTc interval < 480 ms 

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- Cardiologist opinion for potential 
treatment of this event as soon as the QTc 
interval prolongation is observed. 
- Cardiologist recommendation after QTc 
interval normalisation (< 480 ms) and 
potential follow-up.
To:
Cardiac monitoring for patients presenting a QTc 
interval prolongation CTCAE grade ≥ 3 (i.e., 
average QTc >= 501 ms, or >60 ms change from 
baseline; or Torsade de pointes, polymorphic 
ventricular tachycardia, or signs/symptoms of 
serious arrhythmia) shall be followed as follows: 
- Continuous ECG monitoring until the 
QTc interval ≤480 ms 
- Cardiologist opinion for potential 
treatment of this event as soon as the QTc 
interval prolongation is observed. 
- Cardiologist recommendation after QTc 
interval decreases to Grade 1 (≤480 ms) 
and potential follow-up. 
Rationale for change
Needed clarification regarding cardiac monitoring.
Section to be changed
5.2.6.1 Dose limiting toxicities (DLTs
Description of change
Changed from:
The occurrence of any of the toxicities presented 
in Table 5.2.6.1: 1 will be considered a DLT, if 
assessed by the investigator to be related to the 
administration of either study drug. A DLT 
occurring during Part 1 of the study will be 
considered an AESI and reported on the SAE 
form.
Incidence and severity of adverse events will be 
graded according to the common terminology 
criteria for adverse events (CTCAE, version 4.03), 
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.

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Table 5.2.6.1: 1 Dose Limiting Toxicities 
(according to CTCAE V4.03)
Drug related 
toxicity 
category
Criteria defining a DLT*
Hematologic

Grade 4 neutropenia lasting ≥5 
days or complicated by infection

Grade ≥3 documented infection 
with neutropenia.

Grade ≥3 febrile neutropenia 
(ANC<1000/mm3 complicated by 
fever
≥38.5°C or a sustained 
temperature of ≥38.0°C for more 
than 1 hour.

Grade 3 thrombocytopenia 
associated with bleeding or 
requiring platelet transfusion.

Grade 4 thrombocytopenia 
(<25,000/m3).

Grade 4 anaemia.
Table 5.2.6.1: 1 Dose Limiting Toxicities 
(according to CTCAE V4.03) (cont’d)
Drug related 
toxicity 
category
Criteria defining a DLT*
Non-
hematologic
Non-laboratory toxicity

Any Grade 4 or 5 AE other than 
disease progression.

Any Grade 2 drug-related uveitis or 
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 or 
BI 836880 on Cycle 2 Day 1.

any grade ≥ 2 pneumonitis of any 
duration

Any toxicity Grade ≥ 3 toxicity 
except:
o
Grade 3 immune-related AE 
that resolves to ≤ Grade 1 or to 
baseline with 
immunosuppressive therapy 
within 2 weeks
o
Grade 3 asymptomatic 
endocrine disorders (thyroid, 
pituitary, and/or adrenal 
insufficiency) that are managed 
with or without systemic 

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corticosteroid therapy and/or 
hormone replacement therapy.
o
Grade 3 or 4 elevation in serum 
amylase and/or lipase that is not 
associated with clinical or 
radiographic evidence of 
pancreatitis
o
Grade 3 nausea or vomiting that 
lasts <48 hours, and resolves to 
≤Grade 1 either spontaneously 
or with conventional medical 
intervention
o
Alopecia
o
Grade 3 fatigue that persists 
less than 7 days
o
Grade 3 infusion related 
reaction which can be 
controlled by appropriate 
medication according to 
investigator’s decision, and the 
subsequent infusion will not be 
delayed for more than two 
weeks.
o
Grade 3 rash that resolves to ≤ 
Grade 1 within 2 weeks
o
Grade 3 or 4 elevation in serum 
amylase and/or lipase that is not 
associated with clinical or 
radiographic evidence of 
pancreatitis
o
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.
o
Grade 3 tumour flare.
Laboratory toxicity

Hypertension: systolic blood 
pressure >=160 mm Hg or diastolic 
blood pressure >=100 mm Hg, 
confirmed by second measurement
of an additional set of 3 BP 
measurements, or 3 sequential 
ambulatory blood pressure 
measurements when indicated (e.g. 
white coat effect), and which cannot 
be controlled by hypertensive 
medication and which requires a 
dose reduction / discontinuation of 
trial medication(s)

Grade>=3 proteinuria (urinary 
protein >= 3.5 g/day)

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To:
The occurrence of any of the toxicities presented 
in Table 5.2.6.1: 1 will be considered a DLT, if 
assessed by the investigator to be related to the 
administration of either of the study drugs. All
DLTs occurring during Part 1 of the study will be 
considered an AESI and reported on the SAE 
form.
Incidence and severity of adverse events will be 
graded according to the common terminology 
criteria for adverse events (CTCAE, version 5.0), 
Table 5.2.6.1: 1 Dose Limiting Toxicities 
(according to CTCAE V5.0
Drug related 
toxicity 
category
Criteria defining a DLT*
Hematologic

Grade 4 neutropenia (<500/mm3)
lasting ≥5 days or complicated by 
infection

Grade ≥3 documented infection 
with neutropenia.

Grade ≥3 febrile neutropenia 
(ANC<1000/mm3 complicated by 
fever
≥38.3 °C or 101°F°C or a 
sustained temperature of ≥38.0C
(100.4 ° F) for more than 1 hour.

Grade 3 thrombocytopenia (>= 
25,000/mm3 and <50,000/mm3)   
associated with bleeding or 
requiring platelet transfusion.

Grade 4 thrombocytopenia 
(<25,000/mm3).
Grade 4 anaemia (i.e., life-threatening 
consequences or urgent intervention 
indicated)

.
Table 5.2.6.1: 1 Dose Limiting Toxicities 
(according to CTCAE V5.0) (cont’d)
Drug related 
toxicity 
category
Criteria defining a DLT*
Non-
hematologic
Non-laboratory toxicity

Any Grade 4 or 5 AE other than 
disease progression.

Any Grade 2 drug-related uveitis or 
eye pain or blurred vision that does 
not respond to topical therapy and 

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does not improve to Grade 1 severity 
within 2 weeks or requires systemic 
treatment.

Any treatment-related Grade ≥ 2 
toxicity that occurred during Cycle 1
that persists and results in an 
inability to administer BI 754091 or 
BI 836880 on Cycle 2 Day 1.

any grade ≥ 2 pneumonitis of any 
duration

Any toxicity Grade ≥ 3 toxicity 
except:
o
Grade 3 immune-related AE 
that resolves to ≤ Grade 1 or to 
baseline with 
immunosuppressive therapy 
within 2 weeks
o
Grade 3 asymptomatic 
endocrine disorders (thyroid, 
pituitary, and/or adrenal 
insufficiency) that are managed 
with or without systemic 
corticosteroid therapy and/or 
hormone replacement therapy.
o
Grade 3 or 4 elevation in serum 
amylase and/or lipase that is not 
associated with clinical or 
radiographic evidence of 
pancreatitis
o
Grade 3 nausea or vomiting that 
lasts <48 hours, and resolves to 
≤Grade 1 either spontaneously 
or with conventional medical 
intervention
o
Alopecia
o
Grade 3 fatigue that persists 
less than 7 days
o
Grade 3 infusion related 
reaction which can be 
controlled by appropriate 
medication according to 
investigator’s decision, and the 
subsequent infusion will not be 
delayed for more than two 
weeks.
o
Grade 3 rash that resolves to ≤ 
Grade 1 within 2 weeks
o
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.
o
Grade 3 tumour flare.
Laboratory toxicity

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
Hypertension: systolic blood 
pressure >=160 mm Hg or diastolic 
blood pressure >=100 mm Hg, 
confirmed by second measurement 
of an additional set of 3 BP 
measurements, or 3 sequential 
ambulatory blood pressure 
measurements when indicated (e.g. 
white coat effect), and which cannot 
be controlled by hypertensive 
medication and which requires a 
dose reduction / discontinuation of 
trial medication(s)

Grade3 proteinuria (urinary protein 
>=3.5 g/24 hrs; 4+ proteinuria)
Rationale for change
Clarification and adaptions to CTCAE V5.0
Section to be changed
10.2       BLOOD PRESSURE MEASUREMENT 
PROCEDURE
Description of change
Change from:
The preferred method of blood pressure
measurement is by a standard mercury
sphygmomanometer. If a standard mercury
sphygmomanometer is not available, alternative
devices according to website dableducational.org
may be used. At screening, blood pressure should
be taken in both arms. If the pressures differ by
more than 10 mmHg (as in the presence of a
subclavian steal syndrome), the arm with the
higher pressure (either systolic or - if needed to
decide - diastolic) should be used for subsequent
measurements. Blood pressure measurements
should be performed on the same arm and, if
possible, by the same person. The same method
and device must be used throughout the trial for a
patient i.e. if a patient receives the first blood
pressure measurement for example with an
electronic device, the same method and device
should be used throughout the study for this
patient (without switching to manual blood
pressure measurement). On the other hand, inter-
patient variability is acceptable, i.e. a study site is
allowed to consistently use an electronic device to
measure the blood pressure in a given patient
throughout the study and a manual technique in
another patient. After patients have rested quietly,
in the seated position for five minutes, three blood
pressure measurements will be taken two minutes
apart and all three results have to be entered in the

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eCRF. The seated pulse rate will be taken during
the two-minute interval between the second and
third blood pressure reading. Blood pressure
measurements should be recorded to the nearest 2
mmHg only when measured with a manual
sphygmomanometer; when digital devices are
used the value from the device should be rounded
to the nearest 1 mmHg. For calculation of mean
values, decimal places should be rounded to
integers (e.g. a DBP of 94.5 would be rounded to
95 mmHg and a DBP of 109.4 would be rounded
to 109 mmHg). The above mentioned procedure is
considered as standardized conventional blood
pressure measurement (CBPM).
In case of a suspected “white coat effect” it is
recommended to repeat the measurement in a
pleasant condition after sufficient rest. Ambulatory
blood pressure measurement (ABPM) can be an
option in specific cases to observe BP profiles
over a longer period (e.g. during infusion and
thereafter) and even outside the hospital in private
surrounding. However treatment decisions should
be based whenever possible on CBPM as
described above and ABPM should be used for
observation only. In case BP values from ABPM
should be used for treatment related decisions, this
has to be taken from appropriate timepoints and
validated ABPM devices according to website
dableducational.org should be used. Values from
self-blood pressure measurement (SBPM)
communicated from patient to investigator is not
considered valuable for study related decisions.
Blood pressure measurements should be 
performed on the same arm and, if possible, by the 
same person. The machines or devices to be used 
for blood pressure measurement should be 
certified. The same method and device must be 
used throughout the trial for a patient i.e. if a 
patient receives the first blood pressure 
measurement for example with an electronic 
device, the same method and device should be 
used throughout the study for this patient 
(without switching to manual blood pressure 
measurement). On the other hand, inter-patient 
variability is acceptable, i.e. a study site is allowed 

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to consistently use an electronic device to measure 
the blood pressure in a given patient throughout 
the study and a manual technique in another 
patient. After patients have rested quietly, in 
seated position for minutes, three blood pressure 
measurements will be taken two minutes apart and 
all three results have to be entered in the eCRF. 
In case of a suspected “white coat effect” it is 
recommended to repeat the measurement in a
pleasant condition after sufficient rest. Values 
from self-blood pressure measurements (SBPM) 
communicated from patient to investigator are not 
considered valuable for study related decisions.
Rationale for change
Adaption of regarding clinical standard methods
Section to be changed
Table 10.6.1: 1
Description of change
PK VEGF/ANG2 sample V4D3 was deleted 
wording adapted to:
According to Section 4.1.4 of the protocol, the 
infusion time may be adapted. In this case, the PK 
sampling referring to the” start” and “end” time of 
the infusion should be performed shortly after the 
end of infusion, no matter the duration of the 
infusion.
The subsequently requested PK sampling should 
be drawn as planned. Do not adapt the time 
because of the variation of the duration of the 
infusion schema.
Rationale for change
Typo in the tracker and clarification

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11.3
GLOBAL AMENDMENT 3
Date of 
amendment
12 Jul 2019
EudraCT 
number
EU number
2017-001378-41
BI Trial 
number
1336-0011
BI 
Investigational 
Product(s)
BI 836880
BI 754091
Title of 
protocol
An open label phase Ib dose finding study of BI 836880 in 
combination with BI 754091 to characterize safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy in check point 
inhibitor naïve and previously treated patients with locally advanced or 
metastatic non-squamous Non-Small Cell Lung Cancer  
Global Amendment due to urgent safety reasons
Global Amendment
Section to be 
changed
Title
Description of 
change
Changed from:
An open label phase Ib dose finding study of BI 836880 in 
combination with BI 754091 to characterize safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy in check point 
inhibitor naïve and previously treated patients with locally advanced or 
metastatic non-squamous Non-Small Cell Lung Cancer  
To:
An open label phase Ib dose finding study of BI 836880 in 
combination with BI 754091 to characterize safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy in patients with 
locally advanced or metastatic non-squamous Non-Small Cell Lung
and in other solid tumors
Rationale for 
change
The title was adapted to the new populations
Section to be 
changed
Lay Title
Description of 
change
Changed from:
This study aims to find the best doses of BI 836880 combined with BI 
754091 in patients with a certain type of advanced lung cancer 
(NSCLC).

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To:
A study to test different doses of BI 836880 combined with BI 754091 in 
patients with advanced non-small cell lung cancer followed by other types 
of advanced solid tumours
Rationale 
for change
The title was adapted to the new populations
Section to 
be changed
Synopsyis Title
Description 
of change
Changed from:
An open label phase Ib dose finding study of BI 836880 in combination 
with BI 754091 to characterize safety, tolerability, pharmacokinetics, 
pharmacodynamics and efficacy in check point inhibitor naïve and 
previously treated patients with locally advanced or metastatic non-
squamous Non-Small Cell Lung Cancer  
To:
An open label phase Ib dose finding study of BI 836880 in combination 
with BI 754091 to characterize safety, tolerability, pharmacokinetics, 
pharmacodynamics and efficacy in previously treated patients with locally 
advanced or metastatic non-squamous Non-Small Cell Lung and in other 
solid tumors
Rationale 
for change
The title was adapted to the new populations
Section to 
be changed
Synopsis study design
Description 
of change
Changed from:
This is a Phase Ib study, containing two parts; Part 1 (dose escalation of 
BI 836880 in combination with BI 754091) and Part 2 (expansion phase in 
two cohorts).
To:
This is a Phase Ib study, containing two parts; Part 1 (dose escalation of 
BI 836880 in combination with BI 754091) and Part 2 (expansion phase in 
6 cohorts). 
Rationale 
for change
The title was adapted to the new populations
Section to 
be changed
Synopsis study design

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Description 
of change
Changed from:
Part 2: Open label, non-randomized expansion phase to assess efficacy 
and safety of BI 836880 in combination with BI 754091 in check point 
inhibitor naïve patients with locally advanced or metastatic non-squamous 
NSCL, PD-L1 high and PD-L1 low, 
             Cohort A: Patients with locally advanced or metastatic non-
squamous NSCLC with low PD-L1 expression (PD-L1 expression in 1-
49% of tumor cells)
Cohort B: Patients with locally advanced or metastatic non-
squamous NSCLC with high PD-L1 expression (PD-L1 expression in ≥
50% of tumor cells)
To:
Part 2: Open label, non-randomized expansion phase to assess efficacy 
and safety of BI 836880 in combination with BI 754091:
      
Cohort A (NSCLC):
Patient with pathologically confirmed locally advanced or metastatic non-
squamous NSCLC who progressed during or after check-point inhibitor 
monotherapy treatment as the most recent anticancer treatment.
Cohort B (NSCLC):
Patient with pathologically confirmed locally advanced or metastatic non-
squamous NSCLC who progressed during or after 
platinum-based chemotherapy and a check-point inhibitor combination 
treatment as the most recent anticancer treatment.
Cohort C (SCLC):
Patient with pathologically confirmed locally advanced or metastatic Small 
Cell Lung Cancer (SCLC) who progressed during or after first line
standard chemotherapy regimen.
Cohort D (Glioblastoma):
Patient with histologically confirmed recurrent glioblastoma with no more 
than one previous line of chemotherapy (concurrent and adjuvant 
temozolomide based chemotherapy including in combination with another 
investigational agent is considered one line of chemotherapy).
Cohort E (Melanoma):
Patient with histologically confirmed, unresectable, Stage IV metastatic 
melanoma who progressed during or after CPI based regimen.

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Cohort F (Hepatocellular Carcinoma):
Patient with locally advanced or metastatic and/or unresectable 
Hepatocellular Carcinoma (HCC) who were intolerant or progressed during 
1st line sorafenib or lenvatinib treatment; subsequent CPI therapy is allowed 
as the most recent anticancer treatment
Rationale 
for change
Adapted regarding the new populations
Section to 
be changed
Synopsis -Objectives
Description 
of change
Changed from:
PART 2:
Primary objective:

To assess anti-tumour activity of BI 836880 in combination with 
BI 754091 in check point inhibitor naïve patients with locally 
advanced or metastatic non-squamous NSCLC who progressed 
during or after first line platinum-based treatment.
o
Cohort A: Patients with locally advanced or metastatic 
non-squamous NSCLC with low PD-L1 expression (PD-L1 
expression in 1-49% of tumor cells)
o
Cohort B: Patients with locally advanced or metastatic 
non-squamous NSCLC with high PD-L1 expression (PD-
L1 expression in ≥50% of tumor cells)
Secondary objective:

To provide safety data and further investigate clinical efficacy 
including disease control (DC), duration of objective response 
(DoR), progression free survival (PFS), and tumour shrinkage

To evaluate the basic pharmacokinetics of BI 836880 and BI 
754091 during combination therapy after the first and fourth 
infusion cycle.

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To:
PART 2:
Primary objective:

To assess anti-tumour activity of BI 836880 in combination with 
BI 754091 in patients with locally advanced or metastatic non-
squamous NSCLC and other solid tumors.
Secondary objective:

To provide safety data and further investigate clinical efficacy 
including disease control (DC), duration of objective response 
(DoR), progression free survival (PFS), and tumour shrinkage.

To evaluate the basic pharmacokinetics of BI 836880 and BI 
754091 during combination therapy after the first infusion cycle.
Rationale 
for change
Adaption regarding the new populations
Section to 
be changed
Synopsis - Endpoints
Description 
of change
Changed from:
PART 2:
The primary endpoint is Objective Response (OR), defined as best overall 
response (RECIST1.1) of complete response (CR) or partial response (PR) 
from first treatment infusion until the earliest of disease progression, death 
or last evaluable tumour assessment before start of subsequent anti-cancer 
therapy, lost to follow-up, withdrawal of consent.
To:
PART 2:
The primary endpoint is the shrinkage estimator of objective response 
(OR) based on BHM. OR is defined as best overall response (RECIST1.1) 
of complete response (CR) or partial response (PR) from first treatment 
infusion until the earliest of disease progression, death or last evaluable 

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tumour assessment before start of subsequent anti-cancer therapy, lost to 
follow-up or withdrawal of consent.
Rationale 
for change
Synopsis Endpoints – Secondary endpoints/part 2
Section to 
be changed
Changed from:

Pharmacokientic parameters Cmax, tmax, AUC0-504h after the first 
and fourth infusion cycle.
To:

Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the first 
infusion cycle.
Description 
of change
Adaption to new requirements
Rationale 
for change
Adaption regarding the new populations
Section to 
be changed
Synopsis_ Number of patients entered:
Description 
of change
Changed from:
A total of 80 patients approximately will be entered 
(Part 1 and Part 2)
To:
A total of 255 patients (28 part 1 plus 227 part 2) approximately will be 
entered
(Part 1 and Part 2)
Rationale 
for change
Adaption to the additional needed patients
Section to 
be changed
Synopsis- Number of patients on each treatment:
Description 
of change
Changed from:
Part 1: 20 to 25 evaluable patients 
Part 2 : 60 evaluable patients (30 patients per cohort)
To:
Part 1: 12 to18 evaluable patients 
Part 2: 80 evaluable locally advanced or metastatic non-squamous 
NSCLC patients (Cohort A and B; 40 patients per cohort) and 30 
evaluable patients in each of the other 4 cohorts. In total 200 patients.
Rationale 
for change
Adaption to the additional needed patients
Section to 
be changed
Synopsis- Diagnosis
Description 
of change
Changed from:
Naïve or previously checkpoint inhibitor treated patients with locally 
advanced or metastatic non-squamous NSCLC who progressed during or 
after first line (in case of checkpoint inhibitor naïve patients) platinum-
based therapy and patients who progressed during or relapsed after 
completion of at least 2 cycles (in case of checkpoint inhibitor relapsing 

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patients) of platinum-based chemotherapy and a checkpoint inhibitor 
treatment (monotherapy or in combination with chemotherapy).
Patients with either low PD-L1 expression (PD-L1 expression in 1-49% of 
tumor cells) or high PD-L1 expression (PD-L1 expression in ≥50% of 
tumor cells).
To:
Part 1:
Naïve or previously checkpoint inhibitor CPI treated patients with locally 
advanced or metastatic non-squamous NSCLC who progressed during or 
after first line (in case of checkpoint inhibitorCPI naïve patients) 
platinum-based therapy and patients who progressed during or relapsed 
after completion of at least 2 cycles (in case of checkpoint inhibitorCPI
relapsing patients) of  platinum-based chemotherapy and a checkpoint 
inhibitor CPI treatment (monotherapy or in combination with 
chemotherapy). 
Part 2:
Cohort A and B: Patients with locally advanced or metastatic non-
squamous NSCLC who progressed or relapsed during or after a CPI based 
treatment as monotherapy or in combination with platinum-based 
chemotherapy. 
Cohort C: Patient with metastatic SCLC
Cohort D: Patients with recurrent glioblastoma
Cohort E: Patients with metastatic melanoma
Cohort F: Patients with hepatocellular carcinoma
Rationale 
for change
Adaptions regarding the new cohorts in part 2
Section to 
be changed
Synopsis- Main in- and exclusion criteria
Description 
of change
Changed from:
1.   Age ≥ 18 years
2. Pathologically confirmed diagnosis of non-squamous NSCLC 
3. Locally advanced (stage IIIb) or metastatic (stage IV) NSCLC 
4. Documented disease progression or relapse (based on 
investigator’s assessment) during or after completion of at least 2 
cycles of platinum-based chemotherapy as first line treatment of 
Stage IIIB/IV non- squamous NSCLC or for checkpoint inhibitor 
experienced patients during or after completion of at least 2 cycles 
of platinum-based chemotherapy and a checkpoint inhibitor 
treatment (monotherapy or in combination with chemotherapy). 

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This includes patients relapsing within 6 months of completing 
(neo)adjuvant/curative-intent chemotherapy/CPI or 
chemoradiotherapy
5. At least one target lesion (outside the brain), that can be accurately 
measured per RECIST v 1.1
6. Availability and willingness to provide a fresh tumour tissue 
sample obtained after relapse or progression on or after prior 
therapy. For Part 2, In case a fresh biopsy cannot be obtained (e.g. 
inaccessible lesions or patient safety concern), an archived 
specimen obtained up to 6 months prior to cycle 1, visit 1 (C1V1) 
may be submitted in case no systemic antineoplastic therapy has 
been administered between the biopsy and C1V1
7. ECOG performance status of 0 or 1
8. Adequate hepatic, renal and bone marrow functions
9. No prior therapy with any immune checkpoint inhibitor
To:
Inclusion Criteria:
For part 1:

Age ≥ 18 years

Pathologically confirmed diagnosis of non-squamous NSCLC 

Locally advanced (stage IIIb) or metastatic (stage IV) NSCLC 

Documented disease progression or relapse (based on 
investigator’s assessment) during or after completion of at least 2 
cycles of platinum-based chemotherapy as first line treatment of 
Stage IIIB/IV non- squamous NSCLC or for checkpoint inhibitor 
experienced patients during or after completion of at least 2 cycles 
of platinum-based chemotherapy and a checkpoint inhibitor 
treatment (monotherapy or in combination with chemotherapy). 
This includes patients relapsing within 6 months of completing 
(neo)adjuvant/curative-intent chemotherapy/CPI or 
chemoradiotherapy.

At least one target lesion (outside the brain), that can be accurately 
measured per RECIST v 1.1

Availability and willingness to provide a fresh tumour tissue 
sample obtained after relapse or progression on or after prior 
therapy. 

ECOG performance status of 0 or 1

Adequate hepatic, renal and bone marrow functions
For part 2:
1
Of full age (according to local legislation, usually ≥ 18 years) at 
screening
2
At least one target lesion outside the brain (excluding the 
glioblastoma patients), that can be accurately measured per 
RECIST v 1.1
3
ECOG performance status ≤ 1 

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Inclusion for:
Cohort A (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
non-squamous NSCLC 
-
Prior Check-point inhibitor monotherapy either as 1st 
or 2nd line as the last therapy before entering trial.  No 
more than one regimen of prior chemotherapy.
-
Approximately 10 patients will be recruited who have 
primary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who previously received at least 2 cycles 
of CPI treatment without achieving benefit (SD <6 months 
or progressive disease in <6 months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who had a documented minimum duration 
of benefit of 6 months and minimum treatment duration of 
2 months on the previous CPI treatment without 
experiencing disease progression during that period.
-
Patients with NSCLC known to harbor an ALK 
rearrangement, or EGFR mutation are only eligible after 
experiencing disease progression (during or after
treatment) or intolerance to EGFR TKI or ALK TKI 
therapy.
Cohort B (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
non-squamous NSCLC 
-
1st line Platinum-based chemotherapy and a check-
point inhibitor combination treatment as the most recent 
therapy before entering trial 
-
Approximately 10 patients will be recruited who have 
primary resistance to the combination therapy which is 
defined as those advanced or metastatic IIIB/IV non-
squamous NSCLC patients who previously received at 
least 2 cycles of platinum-based chemotherapy and CPI 
treatment without achieving benefit (SD < 8 months or 
progressive disease in < 8 months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who had a documented minimum duration 

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of benefit (minimum of stable disease) of 8 months who 
received CPI and platinum-based chemotherapy in a first 
line setting.
-
Patients with NSCLC known to harbor an ALK 
rearrangement, or EGFR mutation are only eligible after 
experiencing disease progression (during or after
treatment) or intolerance to EGFR TKI or ALK TKI 
therapy.
Cohort C (SCLC):
-
Pathologically confirmed locally advanced or metastatic 
SCLC 
-
No more than one line of chemotherapy with or without 
in combination with CPI
Documented disease progression during or after first line 
standard chemotherapy regimen with or without in 
combination with CPIs
Cohort D (recurrent glioblastoma):
-
Histologically confirmed denovo glioblastoma (primary) 
-
No more than one line of chemotherapy (concurrent and 
adjuvant temozolomide based chemotherapy including in 
combination with another investigational agent is 
considered one line of chemotherapy). 
-
Documented first progression after radiotherapy (RT) and
concurrent/adjuvant chemotherapy 
-
An interval of at least 12 weeks from the completion of 
radiation therapy to start of study drug unless there is a 
new area of enhancement consistent with recurrent tumor 
outside the radiation field or there is unequivocal histologic 
confirmation of tumor progression
-
Patient may have been operated for recurrence. If operated: 
residual and measurable disease after surgery is required;
surgical site must be adequately healed free of drainage or 
cellulitis, and the underlying cranioplasty must appear 
intact at the time of randomization
Cohort E (Melanoma):
-
Histologically confirmed, unresectable, Stage IV 
metastatic melanoma
-
At least one line of any kind of CPI based regimen as 
last treatment before entering the study
-
Documented progression during or after CPI therapy based
regimen

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Cohort F (Hepatocellular Carcinoma):
-
Patients must have diagnosis of locally advanced or 
metastatic and/or unresectable histologically confirmed 
advanced hepatocellular carcinoma, not eligible for 
surgical and/or locoregional therapies
-
Patients should have progressed or discontinued first line 
treatment with sorafenib or lenvatinib, due to lack of 
tolerability. Patients who received 2nd line treatment with 
anti-PD1 therapy (but not other therapy) after failure of 
sorafenib are also eligible.
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody to 
hepatitis B core antigen (anti-HBc), and/or anti-hepatitis C 
virus (anti-HCV)
-
Child-Pugh score class A
-
Anti-viral therapy per local standard-of-care if active 
hepatitis B virus (HBV) (but not other therapy) after 
failure of sorafenib are also eligible.
4
Adequate hepatic, renal and bone marrow functions
5
Availability and willingness to provide a fresh tumor tissue sample 
obtained after relapse or progression on or after prior therapy. In 
case a fresh biopsy cannot be obtained (e.g. inaccessible lesions or 
patient safety concern), an archived specimen obtained up to 6 
months prior to cycle 1, visit 1 (C1V1) may be submitted in case 
no systemic antineoplastic therapy has been administered between 
the biopsy and C1V1 (except for cohort D). For cohorts E and, F, a 
fresh on-treatment biopsy is mandatory at C3D1, if possible from 
the same lesion as the pre-treatment biopsy.
6
Life expectancy ≥ 3 months after start of the treatment in the 
opinion of the investigator 
     
Exclusion Criteria:
Part 2:
1
Not more than one CPI based treatment regimen prior to entering 
study (eg. anti-Programmed Death receptor-1 (PD-1), anti-
Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-
cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-4) 
antibody); Exception is for Melanoma cohort (Cohort E) 

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2
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection (exception for patients in HCC cohort Cohort F).
3
Prior treatment with any antiangiogenic treatment (e.g. 
bevacizumab, cediranib, aflibercept, vandetanib, XL-184, 
sunitinib, etc) except for sorafenib and lenvatinib in HCC cohort 
(Cohort F)
4
Patients with known active second malignancy other than non-
melanoma skin cancers, non-metastatic prostate cancer, in situ 
cervical cancer, and ductal or lobular carcinoma in situ of the 
breast. Patients are not considered to have a currently active 
malignancy if they have completed anticancer therapy and have 
been disease free for greater than 2 years prior to screening
Further exclusion criteria:
Exclusion criteria for Glioblastoma:
5
Tumor primarily localized to the brainstem or spinal cord.
6
Presence of diffuse leptomeningeal disease or extracranial disease.
Exclusion criteria for Melanoma cohort:
7
Uveal or ocular melanoma
Exclusion criteria for HCC cohort:
8
Co-infection with HBV and HCV or HBV and hepatitis D virus 
(HDV)
9
Known fibrolamellar HCC, sarcomatoid HCC, or mixed 
cholangiocarcinoma and HCC
10 History of hepatic encephalopathy
11 Untreated or incompletely treated varices with bleeding or high-
risk for bleeding
12 Untreated active Hepatitis B virus (HBV)
13 Treatment with any HCV anti-viral therapy within 4 weeks prior to 
Cycle 1 Day 1
Rationale 
for change
Adaption to the new patient population
Section to 
be changed
Synopsis - Statistical methods
Description 
of change
Changed from:
Part 2: 
Efficacy response endpoints and safety related data will be summarized 
descriptively. For PFS and duration of response, the median and 95% two-
sided confidence interval will be presented using the Kaplan-Meier 
method. No hypothesis testing is planned in this trial

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To:
Part 2: 
Objective response rate as primary endpoints will be estimated by 
Bayesian hierarchical model (BHM) approach, which assumes full 
exchangeability of model parameters and allows borrowing information 
across patients’ cohorts. Other efficacy endpoints and endpoints and 
safety related data will be summarized descriptively. For PFS and 
duration of response, the median and 95% two-sided confidence interval 
will be presented using the Kaplan-Meier method. No hypothesis testing 
is planned in this trial
Rationale 
for change
Adaption to the additional cohorts
Section to 
be changed
Abbreviations
Description 
of change
Adding of different abbreviations
Rationale 
for change
To address changes for CTP v 4.0
Section to 
be changed
Change of the Flowchart
Description 
of change
Changed from:
Flowchart part1and part2 
To:
2 different Flow charts one for part 1 and one for part 2 
Rationale 
for change
Adaption to the different needs for the part 2
Section to 
be changed
1.1
Description 
of change
Changed from:
VEGF-A induces accumulation of MDSCs, immature DC, Treg and 
tumour-associated macrophage. To:
VEGF-A induces accumulation of Myeloid-derived suppressor cells 
(MDSCs), immature DC, Treg and tumour-associated macrophage. 
Rationale 
for change
Adaption to the different needs for the part 2
Section to 
be changed
1.1

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Description 
of change
Changed from:
More recently, three PD-1/anti-PD-L1 immune checkpoint inhibitor have 
been approved for second line NSCLC treatment.  All three compounds 
(nivolumab, pembrolizumab and atezolizumab) are currently indicated for 
second line treatment of both squamous and non-squamous NSCLC. The 
use of pembrolizumab is currently restricted to second line patients whose 
tumors express PD-L1 (>1% of tumor cells being PD-L1 positive using 
IHC) where as nivolumab and atezolizumab’s use is open to patients 
regardless of PD-L1 expression levels. 
Furthermore, and based on positive Phase III trial in advanced/metastatic 
NSCLC on (KEYNOTE 024 trial) showing PFS and OS improvement in 
pembrolizumab monotherapy arm (versus standard chemotherapy) 
(R16-4783), Pembrolizumab has been approved for 1st line treatment in 
patients with tumors expressing PD-L1 in ≥50% of tumor cells. 
To:
More recently, three PD-1/anti-PD-L1 immune CPI have been approved 
for second line NSCLC treatment.  All three compounds (nivolumab, 
pembrolizumab and atezolizumab) are currently approved for second line 
treatment of both squamous and non-squamous NSCLC. The use of 
pembrolizumab is currently restricted to patients whose tumors express 
PD-L1 (>1% of tumor cells being PD-L1 positive using IHC) where as 
nivolumab and atezolizumab’s use is open to patients regardless of PD-L1 
expression levels. 
Previously, based on positive Phase III trial in advanced/metastatic 
NSCLC on (KEYNOTE 024 trial) showing PFS and OS improvement in 
pembrolizumab monotherapy arm (versus standard chemotherapy) 
(R16-4783), Pembrolizumab has been approved for 1st line treatment in 
patients with tumors expressing PD-L1 in ≥50% of tumor cells. FDA 
based on KEYNOTE‑042 (NCT02220894) trial approved pembrolizumab 
monotherapy for the first-line treatment of patients with stage III NSCLC 
who are not candidates for surgical resection or definitive chemoradiation 
or metastatic NSCLC. Patients’ tumors must have no EGFR or ALK 
genomic aberrations and express PD-L1 (Tumor Proportion Score [TPS] 
≥1%) determined by an FDA-approved test.
Atezolizumab in combination with bevacizumab, paclitaxel, and 
carboplatin, is also indicated for the first-line treatment of patients with 
metastatic NSCLC with no EGFR or ALK genomic tumor aberrations.
Small cell lung cancer (SCLC) is a neuroendocrine tumor that represents 
about 15 percent of all lung cancers. SCLC occurs predominantly in 
smokers and is distinguished clinically from most types of non-small cell 
lung cancer (NSCLC) by its rapid doubling time, high growth fraction, 
and the early development of metastases. SCLC usually presents with 

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disseminated disease, and treatment strategies have focused on systemic 
therapy. Although SCLC is highly responsive to both chemotherapy and 
radiotherapy (RT), it commonly relapses within months despite treatment.
SCLC is usually staged as either limited or extensive. The standard 
treatment in limited SCLC is chemoradiation. The chemo drugs used are 
usually etoposide or irinotecan plus either cisplatin or carboplatin.
Atezolizumab is approved as a first line treatment for extensive SCLC. 
The addition of atezolizumab to chemotherapy in the first-line treatment 
of extensive-stage small-cell lung cancer resulted in significantly longer 
overall survival and progression-free survival than chemotherapy alone
(IMpower 133). (R19-1714) Nivolumab is approved for metastatic small 
cell lung cancer with progression after platinum based chemotherapy and 
at least one other line of therapy. Nivolumab monotherapy provided 
durable responses and was well tolerated as a third- or later-line treatment 
for recurrent SCLC (CHECKMATE 032). (R19-1713)
High-grade gliomas are malignant and often rapidly progressive brain 
tumors that are divided into anaplastic gliomas (anaplastic astrocytoma, 
anaplastic oligodendroglioma) and glioblastoma based upon their 
histopathologic and molecular features. Despite the survival benefit 
associated with adjuvant radiation and chemotherapy, the majority of 
patients relapse following initial therapy. The most commonly used 
systemic agents in recurrent or progressive high-grade gliomas are 
bevacizumab, nitrosoureas, and temozolomide rechallenge (since the 
majority of patients will have received temozolomide at part of initial 
therapy). In the largest randomized trial to test whether combination 
therapy is superior to single-agent therapy, the addition of bevacizumab to 
lomustine improved progression-free but not overall survival compared 
with lomustine alone. Early experience with CPIs such as pembrolizumab 
and nivolumab in unselected patients with recurrent high-grade glioma 
has shown only modest activity. Preliminary results of a phase III trial of 
nivolumab versus bevacizumab in recurrent glioblastoma found no 
difference in overall survival (CHECKMATE 143)
Most cases of malignant melanoma diagnosed at an early stage and
surgical excision can be curative. However, a few patients have metastatic 
disease at presentation, and some develop metastases after their initial 
definitive treatment. High-dose interleukin-2 (IL-2) was the first treatment 
to modify the natural history of patients with metastatic melanoma 
resulting in cure in a small fraction of patients. However, its severe 
toxicity has limited its application to carefully selected patients treated at 
centers with experience in managing the side effects of treatment.
Immunotherapy is an important systemic treatment modality for 
metastatic melanoma. Checkpoint inhibition with an anti-programmed cell 
death 1 (PD-1) antibody (pembrolizumab, nivolumab) in combination 
with the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) 

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antibody ipilimumab has better efficacy (response rates, progression-free 
survival) than single-agent anti-PD-1 therapy in patients with advanced 
melanoma who are candidates for systemic therapy. Survival data from 
phase III trials suggest that 50 percent of patients receiving nivolumab
(CHECKMATE-066) and 50 to 60 percent of patients receiving the 
combination of nivolumab and ipilimumab (CHECKMATE-067) will 
remain alive at three years. In the phase III KEYNOTE-006 trial, 
pembrolizumab demonstrated significantly longer PFS and improved 
overall survival compared with ipilimumab in patients with advanced 
melanoma. Overall survival was significantly prolonged with 
pembrolizumab compared with ipilimumab (four-year overall survival 
rate 41.7 versus 34.1 percent; HR 0.73, 95% CI 0.61-0.89).
Hepatocellular carcinoma (HCC) typically diagnosed late in its course is 
an aggressive tumor that often occurs in the setting of chronic liver 
disease and cirrhosis. Although the mainstay of therapy is surgical 
resection, the majority of patients are not eligible because of tumor extent 
or underlying liver dysfunction. There has been a resurgence of interest 
and enthusiasm for systemic therapy of HCC with the emergence of data 
showing that the molecularly targeted agents sorafenib, levatinib and 
regorafenib improve survival versus best supportive care alone. Both 
sorafenib and levatinib have been for the first-line treatment of patients 
with unresectable HCC. (R12-0948) Sorafenib HCC Assessment 
Randomized Protocol (SHARP) trial demonstrated that angiogenesis 
biomarkers Ang2 and VEGF were independent predictors of survival in 
patients with advanced HCC but not were predictive of response to 
sorafenib. Subsequently, a survival benefit has also been shown in the 
second-line setting patients for HCC who had disease progression on or 
after sorafenib or were intolerant to sorafenib in nivolumab
(CHECKMATE-040) and pembrolizumab (KEYNOTE-224; 
NCT02702414) trials. Both have received approval based on these 
studies.
Rationale 
for change
New information and adaption for the changes in part 2
Section to 
be changed
1.2
Description 
of change
Changed from:
There was a moderate (~ 2-fold) BI836880 is currently tested in 
monotherapy in 2 phase I trials. Nineteen and 10 patients received 
BI836880 in trial 1336.1 (every 3 weeks schedule) and in trial 1336.6 
(weekly schedule), respectively. Dose levels between 40 mg and 1000 mg 
of BI 836880 are tested. In the every 3 weeks trial, the dose of 720 mg is 
currently expanded to confirm it as recommended phase 2 dose.

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To:
BI836880 is currently tested in monotherapy in 2 phase I trials. As of 
August 2018, 47 patients had been treated with BI836880 monotherapy in 
2 Phase I dose escalation clinical trials: trial (1336.1), BI 836880 given 
every 3 weeks and trial (1336.6) BI 836880 given every one week. Dose 
levels between 40 mg and 1000 mg of BI 836880 are tested. In the every 3 
weeks trial, the dose of 720 mg is currently expanded to confirm it as 
recommended phase 2 dose.
Rationale 
for change
New available information
Section to 
be changed
1.2
Description 
of change
Changed from:
An exploratory, preliminary PK and biomarker analysis performed in 
these two trials has shown that systemic VEGF levels are completely 
blocked already at the lowest dose of 40 mg i.v., while systemic ANG2 
levels were blocked dose-dependently showing complete inhibition at 
dosages starting at 360 mg 3-weekly or 120 mg weekly. At these dosages 
both, systemic VEGF and ANG2, remain below limit of quantitation even 
before start of next treatment. 
Plasma concentrations of BI 836880 increased dose-dependently (based 
on Cmax and AUC), over the dose ranges 40-1000 mg (1336.1 q3w) and 
40-180 mg (1336.6 qw). A slight accumulation could be observed over 
treatment cycles 1, 2 and 4 based on Cmax and partial AUCs in both trials 
(accumulation ratios were up to 1.5) while the elimination seemed dose-
independent. In 1336.1 (q3w), the gmean half-life over all dose groups 
was 197 hours (cycle 1, n=12), 238 hours (cycle 2, n=7), and 343 hours 
(cycle 4, n=4). It seems as if the required trough values of 20 mg/L 
(according to preclinical experiments) could be achieved at dosages 
starting from 720 mg q3w. 
For a more detailed description of the drug profile refer to the current 
Investigator’s Brochures (IB).
BI 754091 is a humanized IgG4 pro-monocolonal antibody showing 
potent and selective binding to human PD-1. BI 754091 has highly human 
frameworks and a low predicted immunogenicity score. The BI 754091 
molecule has a molecular weight approximately 148 kilodaltons.
To:
PK and biomarker analysis performed in 1336.1 has shown that systemic 
VEGF levels are completely blocked already at the lowest dose of 40 mg 
i.v., while systemic ANG2 levels were blocked dose-dependently showing 

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complete inhibition at dosages starting at 360 mg 3-weekly or 120 mg 
weekly. At these dosages both, systemic VEGF and ANG2, remain below 
limit of quantitation even before start of next treatment. 
Plasma concentrations of BI 836880 increased dose-dependently (based 
on Cmax and AUC), over the dose ranges 40-1000 mg (1336.1 q3w) and 
40-180 mg (1336.6 qw). A slight accumulation could be observed over 
treatment cycles 1, 2 and 4 based on Cmax and partial AUCs 
(accumulation ratios were up to 1.5) while the elimination seemed dose-
independent. In 1336.1 (q3w), the the gMean half-life over all dose groups 
ranged from 210 to 289 hours It seems as if the required trough values of 
20 mg/L (according to preclinical experiments) could be achieved at 
dosages starting from 720 mg q3w (c23621412-01).
In an exploratory, preliminary PK and biomarker analysis performed the 
results of the 1336.6 could be confirmed.
For a more detailed description of the drug profile refer to the current 
Investigator’s Brochures (IB).
BI 754091 is a humanized IgG4 pro-monocolonal antibody showing potent 
and selective binding to human PD-1. BI 754091 has highly human 
frameworks and a low predicted immunogenicity score. The BI 754091 
molecule has a molecular weight approximately 148 kilo Daltons.
Rationale 
for change
New scientific information available
Section to 
be changed
1.2
Description 
of change
Changed from:
BI 754091 is currently being tested in the 1381.1 monotherapy first in man 
trial and 1381.2 combination trial. In 1381.1, a total of 17 patients received 
BI 754091 monotherapy, 9 patients has been treated in the dose escalation 
part at 3 dose levels (80 mg, 240 mg and 400 mg) and 8 patients in the 
expansion part. In the dose escalation part, there were no DLTs or drug-
related SAE reported in any cohort. The most common reported AEs are 
nausea, fatigue, decreased appetite, constipation and arthralgia. The dose of 
240 mg of BI 754091 once every 3 weeks was chosen to be further explored 
in monotherapy expansion and is recommended as a starting dose in 
combination trials.
In the expansion part, the 8 patients received BI 754091 at 240 mg. The 
most common reported AEs are fatigue and nausea. No patient had a 
Grade 4, Grade 5 AE or a DLT.

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To:
A total of 139 patients have been dosed with BI 754091 in clinical trials, 56 
patients with monotherapy BI 754091, and 83 patients with BI 754091 plus 
BI 754111 ((monoclonal IgG4pro antibody targeting the human LAG-3).
At the data cut-off, there were no DLTs or Grade 5 AEs experienced by any 
patient on monotherapy treatment. The overall most common AEs for 
patients treated with monotherapy BI 754091 were fatigue, nausea, and 
decreased appetite. Thirteen of the 56 patients on monotherapy BI 754091 
experienced irAEs of rash, maculo-papular rash, colitis, diarrhoea,
hypothyroidism, increased ALT, increased AST, arthralgia, pneumonitis, 
and pruritus. There were one ≥ Grade 3 irAE (Grade 3 increased AST) 
experienced by patients in the monotherapy population.
Rationale 
for change
New available information
Section to 
be changed
1.3
Description 
of change
Changed from:
Either check point (PD-1 and PD-L1) inhibition or angiogenesis inhibition 
(VEGF, Ang-2) inhibition demonstrate antitumor activity with a clinical 
benefit in NSCLC patients outcome. Despite this effect, an important 
number of patients will not respond to such therapy and most of patients 
who benefit from treatment will relapse and die from their disease. 
Defining novel therapeutic strategy is needed to improve NSCLC patient 
outcome. 
….
This trial will evaluate the tolerability of the combination of BI836880 
and BI 754091 and the effect of the triple inhibition in 2 populations of 
patients with NSCLC, according to the PD-L1 status. This will allow a 
decision on further development of this combination in NSCLC patients 
and the start of a dedicated Phase II program. 
To:
Check point (PD-1 and PD-L1) inhibition and angiogenesis inhibition 
(VEGF, Ang-2) demonstrated antitumor activity with a clinical benefit in 
several tumor types. Despite this effect, an important number of patients 
will not respond to such therapy and most of patients who benefit from 
treatment will relapse and die from their disease. Defining novel 
therapeutic strategy is needed to improve survival in patients with NSCLC 
patient and other solid tumors. 
….
This trial will evaluate the tolerability of the combination of BI836880 
and BI 754091 and the effect of the triple inhibition in 2 populations of 
patients with NSCLC, according to previous PD-1 / PD-L1 inhibitor 
treatment. This combination will also be tested in other unmet need 

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indications as exploratory expansion cohorts in which either a high 
baseline Ang-2 or increase of Ang-2 at recurrence has been reported. 
Ang2 and VEGF have been reported as independent predictors of survival 
in patients with advanced HCC. Similarly, Ang2 and VEGF have also 
been reported as predictors of outcome for some CPI therapy in metastaic 
melanoma and supporting a rational combinatorial approach to improve 
the efficacy of immune therapy. (R19-1712) This will allow a decision on 
further development of this combination in patients and the start of a 
dedicated Phase II/III program
Rationale 
for change
Adaption to the new part 2
Section to 
be changed
1.4
Description 
of change
Changed from:
Most of these reported AEs were grade 1-2 (CTCAE version 4.03) (See 
BI 836880 IB section 6.3). In total, 3 dose limiting toxicities were 
reported and consisted in pulmonary embolism in 1 patient (trial 1336.1) 
proteinuria in 1 patient (1336.6) and proteinuria and hypertension in 1 
patient (1336.6).
To:
Most of these reported AEs were grade 1-2 (CTCAE version 4.03). In 
total, 5 dose limiting toxicities were reported. In trial 1336.1 one patient 
treated on the highest dose level (1000mg) experienced a pulmonary 
embolism. In trial1336.6 4 patients were reported with DLTs (proteinuria,
proteinuria and hypertension, hypertention and respiratory distress one 
patient each). (See BI 836880 IB section 6.3).
Rationale 
for change
New available information
Section to 
be changed
1.4
Description 
of change
Changed from:
The combination of an immune checkpoint inhibitor with a VEGF blocker 
has previously been tested in a phase I trial combining atezolizumab with 
bevacizumab in patients with renal cell carcinoma….
Despite the good safety profile reported for both drugs, patients should be 
advised of the potential risk of side effects from these investigational
drugs. Due to observed hypertension and potential infusion reactions, a 48 
hours hospitalization is required after first administration of trial 
medications for closer observation with access to intensive care for 
ensuring patient safety.

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To:
The combination of an immune CPI with a VEGF blocker has previously 
been tested in multiple phase I, phase II and phase III trial combining 
atezolizumab with bevacizumab in patients with advanced solid tumors. 
The safety of TECENTRIQ with bevacizumab, paclitaxel and carboplatin 
was evaluated in IMpower150 in metastatic NSCLC.
… Despite the good safety profile reported for both drugs, patients should 
be advised of the potential risk of side effects from these investigational 
drugs. In Part 1, due to observed hypertension and potential infusion 
reactions, a 48 hours hospitalization is required after first administration 
of trial medications for closer observation with access to intensive care 
for ensuring patient safety. In Part 2, hospitalization is optional.
Furthermore, Patients with uncontrolled hypertension, with history of 
severe haemorrhage or thromboembolism are not allowed to participate to 
this study. Other side effects may be rare and unknown with irreversible 
and/or life-threatening effects. Patients should also be advised that there 
are other unknown risks associated with participation in a clinical trial.
Rationale 
for change
New available information
Section to 
be changed
1.4
Description 
of change
Changed from:
In summary, considering the unmet medical need for new treatment 
armamentarium in patients with advanced or metastatic NSCLC who are 
progressing during or after prior therapy with platinum-based 
chemotherapy, the anti-tumour activity of VEGF blockade or PD-1 
inhibition and the good safety profiles of BI836880 and BI 754091 
monotherapy and the existing data suggesting that a combination of PD-1 
blockade with VEGF blockade is a promising therapeutic strategy, the 
benefit risk assessment for patients included into this trial is considered to 
be favourable.
To:
In summary, considering the unmet medical need for new treatment 
armamentarium in patients with advanced or metastatic NSCLC who are 
progressing during or after prior PD-1 /PD-L1 based therapy and other 
solid tumours, the anti-tumour activity of VEGF blockade or PD-1 
inhibition and the good safety profiles of BI836880 and BI 754091 
monotherapy and the existing data suggesting that a combination of PD-1 
blockade with VEGF blockade is a promising therapeutic strategy, the 
benefit risk assessment for patients included into this trial is considered to 
be favourable.

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Rationale 
for change
New available information
Section to 
be changed
2.1.1 Main Objectives –Part 2
Description 
of change
Changed from:
PART 2:
Primary objective:

To assess anti-tumour activity of BI 836880 in combination with BI 
754091 in check point inhibitor naïve patients with locally 
advanced or metastatic non-squamous NSCLC who progressed 
during or after first line platinum-based treatment.
o
Cohort A: Patients with locally advanced or metastatic non-
squamous NSCLC with low PD-L1 expression (PD-L1 
expression in 1-49% of tumor cells)
o
Cohort B: Patients with locally advanced or metastatic non-
squamous NSCLC with high PD-L1 expression (PD-L1 
expression in ≥50% of tumor cells)
To:
PART 2:
Primary objective:

To assess anti-tumour activity of BI 836880 in combination with BI 
754091 in patients with locally advanced or metastatic non-
squamous NSCLC and other solid tumors 
Secondary objective:

To provide safety data and further investigate clinical efficacy 
including disease control (DC), duration of objective response 
(DoR), progression free survival (PFS), and tumour shrinkage

To evaluate the basic pharmacokinetics of BI 836880 and BI 
754091 during combination therapy after the first infusion cycle.
Section to 
be changed
2.1.2 Primary endpoints
Description 
of change
Change from:
PART 2:
The primary endpoint is Objective Response (OR), defined as best overall 
response of complete response (CR) or partial response (PR) from first 
treatment infusion until the earliest of disease progression, death or last 
evaluable tumour assessment before start of subsequent anti-cancer 
therapy, lost to follow-up, withdrawal of consent.

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To:
PART 2:
The primary endpoint is the shrinkage estimator of Objective Response 
(OR) based on BHM, defined as best overall response of complete 
response (CR) or partial response (PR) from first treatment infusion until 
the earliest of disease progression, death or last evaluable tumour 
assessment before start of subsequent anti-cancer therapy, lost to follow-
up, withdrawal of consent.
Rationale 
for change
Re-worded for better clarity
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
Description 
of change

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Rationale 
for change
Section to 
be changed
3.1
Description 
of change
Changed from:
This is a Phase I, non-randomized, uncontrolled, open-label, dose 
escalating study of BI 836880 administered in combination with BI 
754091 intravenously every 3 weeks. The eligible patient population will 
be check point inhibitor naïve and experienced patients with locally 
advanced or metastatic non - squamous NSCLC.  Patients who progressed 
during or after first line (in case of checkpoint inhibitor naïve patients) 
platinum-based therapy and patients who progressed during or relapsed 
after completion of at least 2 cycles (in case of checkpoint inhibitor 
relapsing patients) of  platinum-based chemotherapy and a checkpoint 
inhibitor treatment (monotherapy or in combination with chemotherapy).
The trial will consist in 2 Parts; Part 1 and part 2:

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To:
This is a Phase I, non-randomized, uncontrolled, open-label, dose 
escalating study of BI 836880 administered in combination with BI 
754091 intravenously every 3 weeks. The eligible patient population will 
be CPI naïve and experienced patients with locally advanced or metastatic 
non - squamous NSCLC who progressed during or after first line 
platinum-based chemotherapy or CPI monotherapy treatment or the 
combination of CPI and chemotherapy. The trial will consist in 2 Parts; 
Part 1 and part 2:
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
3.1 Part 2
Description 
of change
Changed from:
Open label, non-randomized expansion phase to assess efficacy and safety 
of BI 836880 in combination with BI 754091 in check point inhibitor 
naive patients with locally advanced or metastatic non-squamous PD-L1 
high and PD-L1 low, NSCLC
It is fore seen to enroll up to 60 patients in part 2. Eligible patients will be 
entered in 2 Cohorts, 30 patients per cohort according to their PD-L1 
expression level:

Cohort A: Patients with locally advanced or metastatic 
non-squamous NSCLC with low PD-L1 expression (PD-L1 
expression in 1-49% of tumor cells)

Cohort B: Patients with locally advanced or metastatic 
non-squamous NSCLC with high PD-L1 expression (PD-
L1 expression in ≥50% of tumor cells)
To:
It is foreseen to enroll up to 200 patients full of age (according to local 
legislation, usually ≥ 18 years) at screening in 5 different indications:
Patients with locally advanced or metastatic 2nd line CPI resistant non-
squamous Non-Small Cell Lung Cancer (NSCLC)  and ≥2nd line Small 
Cell Lung Cancer (SCLC) and recurrent glioblastoma and IO failure 
metastatic melanoma and HCC patients who were intolerant or progressed 
during or after standard first line treatment with sorafenib or lenvatinib. 
Patients who received 2nd line treatment with anti-PD1 therapy (but not 
other therapy) after failure of sorafenib or lenvatinib are also eligible (see 
image below – please note the cohorts will run in parallel, not 
consequential).
Figure added

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Rationale 
for change
Adaption to the new requirements
Section to 
be changed
3.1
Description 
of change
Figure 3.1:1 changed 
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
3.2
Description 
of change
Changed from:
This is a Phase I, non-randomized, uncontrolled, open-label, dose 
escalating study of BI 836880 administered in combination with BI 
754091 intravenously. The eligible patients are patients with locally 
advanced or metastatic non - squamous NSCLC who progressed during or 
after first line (in case of naïve patients) of platinum-based therapy.
Additional we include patients who relapsed after completion of at least 2 
cycles (in case of relapsed patients) of platinum-based chemotherapy and
a checkpoint inhibitor treatment (monotherapy or in combination with 
chemotherapy). Dose escalation will be guided by a Bayesian logistic 
regression model (details refer to Section 7.1). 
Once RP2D is determined in Part 1, it is planned to enroll 60 patients (30 
per arm) as described in Section 3.1.
To:
In the part 1, this is a Phase I, non-randomized, uncontrolled, open-label, 
dose escalating study of BI 836880 administered in combination with BI 
754091 intravenously. The eligible patients are patients with locally 
advanced or metastatic non - squamous NSCLC who progressed during or 
after first line (in case of naïve patients) of platinum-based therapy. 
Additional we include patients who relapsed after completion of at least 2 
cycles (in case of relapsed patients) of platinum-based chemotherapy and a 
checkpoint inhibitor treatment (monotherapy or in combination with 
chemotherapy). Dose escalation will be guided by a Bayesian logistic 
regression model (details refer to Section 7.1). 
Part 2 is an open-label expansion phase to assess efficacy and safety of BI 
836880 in combination with BI 754091 in pretreated or naïve check point 
inhibitor patients with locally advanced or metastatic non-squamous 
NSCLC, small cell lung cancer, recurrent glioblastoma, malignant 
melanoma and hepatocellular carcinoma.
Once RP2D is determined in Part 1, it is planned to enroll up to 200
patients as described in Section 3.1.

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Rationale 
for change
Adaption to the new requirements
Section to 
be changed
3.3
Description 
of change
Changed from:
Eligible patients are patients with locally advanced or metastatic non-
squamous NSCLC which progressed during or after first line (in case of 
naïve patients) of platinum-based therapy and patients who relapsed after 
completion of at least 2 cycles (in case of relapsed patients) of  platinum-
based chemotherapy and a checkpoint inhibitor treatment (monotherapy or 
in combination with chemotherapy). In trial Part 2, patients should have 
either low PD-L1 expression (PD-L1 expression in 1-49% of tumor cells) 
or high PD-L1 expression (PD-L1 expression in ≥50% of tumor cells). 
This study is planned to be conducted in approximately 4 sites per country 
in Germany, France, Spain, Taiwan, Korea, US and other EU countries. 
Approximately 80 patients will be enrolled.
To:
Eligible patients for Part 1 are patients with locally advanced or metastatic 
non-squamous NSCLC which progressed during or after first line (in case 
of naïve patients) of platinum-based therapy and patients who relapsed
after completion of at least 2 cycles (in case of relapsed patients) of  
platinum-based chemotherapy and a checkpoint inhibitor treatment 
(monotherapy or in combination with chemotherapy). In Part 2, CPI 
pretreated or naïve patients with locally advanced or metastatic non-
squamous NSCLC, small cell lung cancer, recurrent glioblastoma, 
malignant melanoma and hepatocellular carcinoma will be enrolled. This 
study is planned to be conducted in approximately 50 sites. These sites 
will be located in in Australia, Asia (incl. China, South Korea), North 
America (incl. US) EU (incl. Germany, France, Spain, UK, Russia, 
Poland, Ukraine). Approximately 80 patients will be enrolled in the 
NSCLC cohort and 30 patients each in the SCLC, metastatic melanoma, 
recurrent glioblastoma and HCC cohorts.
Rationale 
for change
Adaption to new settings
Section to 
be changed
3.3.1
Description 
of change
Changed from:
Patients with advanced/metastatic non squamous NSCLC who have 
progressed during or after first line (in case of naïve patients) of platinum-
based therapy and patients who relapsed after completion of at least 2 
cycles (in case of relapsed patients) of  platinum-based chemotherapy and
a checkpoint inhibitor treatment (monotherapy or in combination with 
chemotherapy). Patients included in Part1 are not eligible to participate in 
Part 2.

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Please refer to Section 8.3.1 (Source Documents) for the documentation 
requirements pertaining to the in- and exclusion criteria.
To:
For the part 1 we look for patients with advanced/metastatic non 
squamous NSCLC who have progressed during or after first line (in case 
of naïve patients) of platinum-based therapy and patients who relapsed
after completion of at least 2 cycles (in case of relapsed patients) of a CPI 
treatment alone or in combination with platinum-based chemotherapy
(monotherapy or in combination with chemotherapy). Patients included in 
Part1 are not eligible to participate in Part 2.
For the part 2 we look for patients with locally advanced or metastatic 2nd
line CPI resistant NSCLC and 2nd line SCLC, recurrent glioblastoma, IO 
failure metastatic melanoma and HCC pts who are intolerant or failed the 
first line treatment with sorafenib or lenvatinib.  Patients who received 2nd
line treatment with anti-PD1 therapy (but not other therapy) after failure 
of sorafenib or lenvatinib are also eligible.
Rationale 
for change
Adaption to new settings
Section to 
be changed
3.3.2
Description 
of change
Changed from:
Added: For the part 1
.
#11 Availability and willingness to provide a fresh tumour tissue sample 
obtained at baseline, (Part 1 and Part 2) and after 2 cycles of treatment 
(Part 1 only). For Part 2, in case a fresh baseline biopsy cannot be 
obtained (e.g. inaccessible lesions or patient safety concern), an archived 
specimen obtained up to 6 months prior to first study treatment may be 
submitted in case no systemic antineoplastic therapy has been 
administered between the biopsy and first study treatment.
To:
#11 Availability and willingness to provide a fresh tumour tissue sample 
obtained at baseline, and after 2 cycles of treatment 
Added:For the part 2:
Main Inclusion Criteria for all cohorts
1. Of full age (according to local legislation, usually ≥ 18 years) at 
screening

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2. At least one measurable untreated lesion according to RECIST v1.1
3. ECOG performance status ≤ 1   
4. Adequate organ function as all of the following (all screening labs 
should be performed at local lab within 10 days prior to treatment 
initiation):
    
System
Laboratory Value
Hematological
Absolute 
neutrophil count 
(ANC)
≥1.5 x 109/L.
Platelets
≥75 x 109/L.
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L.
Renal
Creatinine OR
Measured or 
calculateda
creatinine 
clearance 
(Glomerular 
Filtration Rate 
(GFR) can also be 
used in place of 
creatinine or 
CrCl)
≤ 1.5 x ULN OR
≥50 mL/min for patients with 
creatinine levels >1.5x ULN.
Hepatic
Total bilirubin
≤1.5 times the upper limit of normal 
(ULN).
AST (SGOT) and 
ALT (SGPT)
≤2.5 x ULN OR ≤5 x ULN for patients 
with liver metastases.
Coagulation

International 
Normalised Ratio 
(INR) or 
Prothrombin 
Time (PT)

≤1.5xULN unless patient is receiving 
anticoagulant therapy as long as PT is 
within therapeutic range of intended 
use of anticoagulants.

Activated Partial 
Thromboplastin 
Time (aPTT)

≤1.5xULN unless patient is receiving 
anticoagulant therapy as long as PTT is 
within therapeutic range of intended 
use of anticoagulants.
a Creatinine clearance should be calculated per institutional 
standard.
            

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5. Availability and willingness to provide a fresh tumor tissue sample 
obtained after relapse or progression on or after prior therapy. For Part 
2, In case a fresh biopsy cannot be obtained (e.g. inaccessible lesions 
or patient safety concern), an archived specimen obtained up to 6 
months prior to cycle 1, visit 1 (C1V1) may be submitted in case no 
systemic antineoplastic therapy has been administered between the 
biopsy and C1V1 (except for cohort D). For cohorts E and, F, a fresh 
on-treatment biopsy is mandatory at C3D1, if possible from the same 
lesion as the pre-treatment biopsy.
6. Life expectancy ≥ 3 months after start of the treatment in the opinion 
of the investigator
7. Recovery from all reversible adverse events of previous anti-cancer 
therapies to baseline
or CTCAE grade 1, except for alopecia (any grade), sensory peripheral 
neuropathy, must be ≤ CTCAE grade 2 or considered not clinically 
significant.
8. Signed and dated written informed consent in accordance with ICH-
GCP and local legislation prior to admission to the trial
9. 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 per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and 
correctly, starting with the screening visit and through 150 days after 
the last dose of BI 836880 and BI 754091 treatment, respectively. A 
list of contraception methods meeting these criteria is provided in the 
patient information. For further detail refer to Section 4.2.2.3.
Note: Female patients of childbearing potential must have a negative 
urine or serum pregnancy test within 72 hours prior to taking study 
medication. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. The serum 
pregnancy test must be negative for the patient to be eligible.
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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Inclusion for:
Cohort A (NSCLC):
-
Pathologically confirmed locally advanced or metastatic IIIB/IV 
non-squamous NSCLC 
-
Prior Check-point inhibitor monotherapy either as 1st or 2nd 
line as the last therapy before entering trial.  No more than one 
regimen of prior chemotherapy.
-
Approximately 10 patients will be recruited who have primary 
resistance to CPI based therapy which is defined as those 
advanced or metastatic IIIB/IV non-squamous NSCLC patients 
who previously received at least 2 cycles of CPI treatment 
without achieving benefit (RECIST v1.1 SD <6 months or 
progressive disease in <6 months).
-
Approximately 30 patients will be recruited who have secondary 
resistance to CPI based therapy which is defined as those 
advanced or metastatic IIIB/IV non-squamous NSCLC patients 
who had a documented minimum duration of benefit of 
(minimum of stable disease) 6 months and minimum treatment 
duration of 2 months on the previous CPI treatment without 
experiencing disease progression during that period.
Patients with NSCLC known to harbor an ALK rearrangement, or 
EGFR mutation are only eligible after experiencing disease 
progression (during or after treatment) or intolerance to EGFR TKI 
or ALK TKI therapy.
-
Cohort B (NSCLC):
-
Pathologically confirmed locally advanced or metastatic IIIB/IV 
non-squamous NSCLC 
-
1st line Platinum-based chemotherapy and a check-point 
inhibitor combination treatment as the most recent therapy 
before entering trial 
-
Approximately 10 patients will be recruited who have primary 
resistance to the combination therapy which is defined as those 
advanced or metastatic IIIB/IV non-squamous NSCLC patients 
who previously received at least 2 cycles of platinum-based 
chemotherapy and CPI treatment without achieving benefit 
(RECIST v1.1 SD < 8 months or progressive disease in < 8 
months).
-
Approximately 30 patients will be recruited who have secondary 
resistance to CPI based therapy which is defined as those 
advanced or metastatic IIIB/IV non-squamous NSCLC patients 
who had a documented minimum duration of benefit (minimum 

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of stable disease) of 8 months who received CPI and platinum-
based chemotherapy in a first line setting.
-
Patients with NSCLC known to harbor an ALK rearrangement, 
or EGFR mutation are only eligible after experiencing disease 
progression (during or after treatment) or intolerance to EGFR 
TKI or ALK TKI therapy.
Cohort C (SCLC):
-
Pathologically confirmed locally advanced or metastatic SCLC
-
No more than one line of chemotherapy with or without 
combination with CPI
-
Documented disease progression during or after first line 
standard chemotherapy regimen with or without combination 
with anti-PD (L)1
Cohort D (recurrent glioblastoma):
-
Histologically confirmed denovo glioblastoma (primary) 
-
No more than one line of chemotherapy (concurrent and 
adjuvant temozolomide based chemotherapy including in 
combination with another investigational agent is considered one 
line of chemotherapy). 
-
Documented first progression after radiotherapy (RT) and
concurrent/adjuvant chemotherapy 
-
An interval of at least 12 weeks from the completion of radiation 
therapy to start of study drug unless there is a new area of 
enhancement consistent with recurrent tumor outside the 
radiation field or there is unequivocal histologic confirmation of 
tumor progression
-
Patient may have been operated for recurrence. If operated: 
residual and measurable disease after surgery is required; surgical 
site must be adequately healed free of drainage or cellulitis, and 
the underlying cranioplasty must appear intact at the time of 
randomization
Cohort E (Melanoma):
-
Histologically confirmed, unresectable, Stage IV metastatic 
melanoma
-
At least one line of any kind of CPI based regimen as last 
treatment before entering the study
-
Documented progression during or after CPI therapy based 
regimen

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Cohort F (Hepatocellular Carcinoma):
-
Patients must have diagnosis of locally advanced or metastatic 
and/or unresectable histologically confirmed advanced 
hepatocellular carcinoma, not eligible for surgical and/or 
locoregional therapies
-
Patients should have progressed or discontinued first line 
treatment with sorafenib or lenvatinib, due to lack of tolerability.
Patients who received 2nd line treatment with anti-PD1 therapy 
(but not other therapy) after failure of sorafenib are also eligible.
-
Child-Pugh score class A
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody to 
hepatitis B core antigen (anti-HBc), and/or anti-hepatitis C virus 
(anti-HCV)
-
Anti-viral therapy per local standard-of-care if active hepatitis B 
virus (HBV)
Rationale 
for change
Adaption for the new cohorts
Section to 
be changed
3.3.3 Exclusion Criteria
Description 
of change
Added info for Part 1 exclusion criteria
And:
For the part 2:
1. Known hypersensitivity to the trial drugs or their excipients or risk of 
allergic of anaphylactic reaction to drug product according to 
Investigator judgement (e.g. patient with history of anaphylactic 
reaction or autoimmune disease that is not controlled by nonsteroidal 
anti-inflammatory drugs (NSAIDs), inhaled corticosteroids, or the 
equivalent of </= 10 mg/day prednisone).
2. Not more than one CPI based treatment regimen prior to entering 
study (eg. anti-Programmed Death receptor-1 (PD-1), anti-
Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic 
T lymphocyte associated antigen-4 (anti-CTLA-4) antibody); 
Exception is for Melanoma cohort (Cohort E)
3. Known HIV infection 
4. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection 
(exception for patients in HCC cohort).

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5. History of severe hypersensitivity reactions to other mAbs.
6. Immunosuppressive corticosteroid doses (> 10 mg prednisone daily or 
equivalent) within 4 weeks prior to the first dose of trial medication.
7. Current or prior treatment with any systemic anti-cancer therapy either 
within 28 days or a minimum of 5 half-lives, whichever is longer
before start of treatment.
8. Serious concomitant disease, especially those affecting compliance 
with trial requirements or which are considered relevant for the 
evaluation of the endpoints of the trial drug, such as neurologic, 
psychiatric, infectious disease or active ulcers (gastrointestinal 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.
9. Major injuries and/or surgery or bone fracture within 4 weeks of start 
of treatment, or planned surgical procedures during the trial period.
10. Patients with personal or family history of QT prolongation and/or 
long QT syndrome, or prolonged QTcF at baseline (> 480 ms). 
11. Significant cardiovascular/cerebrovascular diseases (i.e. uncontrolled 
hypertension, unstable angina, history of infarction within past 6 
months, congestive heart failure > NYHA II).
Uncontrolled hypertension defined as: Blood pressure in rested and 
relaxed condition >= 140 mmHg, systolic or >= 90 mmHg diastolic 
(with or without medication), measured according to Appendix 10.2.
12. LVEF < 50%
13. History of severe hemorrhagic or thromboembolic event in the past 12 
months
(excluding central venous catheter thrombosis and peripheral deep 
vein thrombosis).
14. Known inherited predisposition to bleeding or to thrombosis in the 
opinion of the investigator.
15. Patient with brain metastases that are symptomatic and/or require 
therapy.
16. Patients who require full-dose anticoagulation (according to local 
guidelines).

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17. No Vitamin K antagonist and other anticoagulation allowed; LMWH 
allowed only for prevention not for curative treatment.
18. History of pneumonitis within the last 5 years
19. Patients who are under judicial protection and patients who are legally 
institutionalized.
20. Patients unable or unwilling to comply with protocol
21. Previous enrolment in this trial.
22. Chronic alcohol or drug abuse or any condition that, in the 
investigator’s opinion, makes them an unreliable trial patient or 
unlikely to complete the trial.
23. Women who are pregnant, nursing, or who plan to become pregnant 
in the trial
24. Symptomatic pleural effusion, pericardial effusion, or ascites
25. Prior treatment with any antiangiogenic treatment (e.g. bevacizumab, 
cediranib, aflibercept, vandetanib, XL-184, sunitinib, etc) except for 
sorafenib and lenvatinib in HCC cohort (Cohort F)
26. Has received a live vaccine within 30 days prior to the first dose of 
study drug
27. Patients with known active second malignancy other than non-
melanoma skin cancers, non-metastatic prostate cancer, in situ 
cervical cancer, and ductal or lobular carcinoma in situ of the breast. 
Patients are not considered to have a currently active malignancy if 
they have completed anticancer therapy and have been disease free for 
greater than 2 years prior to screening
Further exclusion criteria:
Exclusion criteria for Glioblastoma cohort:
1. Has tumor primarily localized to the brainstem or spinal cord.
2. Has presence of diffuse leptomeningeal disease or extracranial 
disease.
Exclusion criteria for Melanoma cohort:
1. Uveal or ocular melanoma

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Exclusion criteria for HCC cohort:
1. 1.Co-infection with HBV and HCV or HBV and hepatitis D virus 
(HDV)
2. Known fibrolamellar HCC, sarcomatoid HCC, or mixed 
cholangiocarcinoma and HCC
3. History of hepatic encephalopathy
4. Participants with untreated or incompletely treated varices with 
bleeding or high-risk for bleeding
5. Treatment with any HCV anti-viral therapy within 4 weeks prior to 
Cycle 1 Day 1
Rationale 
for change
Adding information for the Part 2 
Section to 
be changed
4.1.2.1
Description 
of change
Changed from:
BI836880 is currently tested in monotherapy in 2 phase I trials. 19 and 
10 patients received BI836880 in trial 1336.1 (every 3 week schedule) 
and in trial 1336.6 (weekly schedule), respectively. Dose levels between 
40 mg and 1000 mg of BI 836880 were tested in the every 3 week trial. 
Most commonly reported adverse events are hypertension, asthenia, 
nausea, vomiting, diarrhea and constipation. Other relevant adverse 
events (mode of action related) include, peripheral edema, bleeding 
(epistaxis), and proteinuria. At BI 836880 dose of 1000 mg, 1 DLT 
(pulmonary embolism) amongst the 5 treated patients was reported. BI 
836880 720 mg dose level has been expanded and 9 additional patients 
have been treated. No Grade 4 AE or DLT was reported amongst the 16 
patient treated at this dose level. 
Exploratory PK and PD analysis was performed. BI 836880 plasma 
kinetics are dose-proportional over the dose ranges 40-1000 mg (Trial 
1336.1 q3w) based on Cmax and partial AUCs. The gmean half-life over 
all dose groups was 197 hours (cycle 1, n=12), 238 hours (cycle 2, n=7), 
and 343 hours (cycle 4, n=4). The required trough values of 20 mg/L 
(according to preclinical experiments) could be achieved at dosages 
starting from 720 mg every 3 weeks.
Biomarker analysis has shown complete systemic VEGF levels blocked 
at the lowest dose of 40 mg. Systemic ANG2 levels were blocked dose-
dependently showing complete inhibition at dosages starting at 360 mg 
every 3-weeks. At these dosages both, systemic VEGF and ANG2, 
remain below limit of quantitation even before start of next treatment. 

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Based on safety data as well as PK and PD analysis, the dose of 720 mg is 
selected as recommended phase 2 dose (RP2D). This dose will be the 
highest dose that can be tested in combination with BI 754091. The dose 
below this dose tested in monotherapy trial (360 mg) is safe and showed 
complete inhibition of systemic targets, and will used as starting dose for 
the combination with BI 754091. However because of the important 
safety difference between 360 and 720 mg (mainly occurrence and 
severity of hypertension), a BI 836880 intermediate dose will be tested. 
The 2 highest tested dose levels will be expanded before selection of BI 
836880 dose to be used for Part 2 of the trial.
To:
BI836880 is currently tested in monotherapy in 2 phase I trials. 29 and 24
patients received BI836880 in trial 1336.1 (every 3 week schedule) and in 
trial 1336.6 (weekly schedule), respectively. Dose levels between 40 mg 
and 1000 mg of BI 836880 were tested in the every 3 week trial. Most 
commonly reported adverse events are hypertension, asthenia, nausea, 
vomiting, diarrhea and constipation. 5 DLTs were reported among the two 
studies (pulmonary embolism, proteinuria, hypertension, respiratory 
distress). Other relevant adverse events (mode of action related) include, 
peripheral edema, bleeding (epistaxis), and proteinuria.
Based on safety data as well as PK and PD analysis, the dose of 720 mg is 
selected as recommended phase 2 dose (RP2D). This dose will be the 
highest dose that can be tested in combination with BI 754091. The dose 
below this dose tested in monotherapy trial (360 mg) is safe and showed 
complete inhibition of systemic targets, and will used as starting dose for 
the combination with BI 754091. However because of the important 
safety difference between 360 and 720 mg (mainly occurrence and 
severity of hypertension), a BI 836880 intermediate dose of 500 mg will 
be tested. The highest tested dose levels will be expanded before selection 
of BI 836880 dose to be used for Part 2 of the trial.
Section to 
be changed
4.1.2.2 Part 2
Description 
of change
Change from:
Once the 2 highest tested doses are completed and at least 9 patients 
received at least 1 cycle at each dose level, an interim safety, PK and PD 
analysis of all patients treated in Part 1 will be performed. Based on all 
this data, the SMC will select BI 836880 dose (RP2D) to be used in 
combination with BI 754091 for Part 2 of the trial. 
To:
Once at least 6 patients have received at least 1 cycle at the maximum 
dose level, a safety evaluation of all patients treated in Part 1 will be 
performed. Based on all this safety data, the SMC may approve the 

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selected BI 836880 dose (RP2D) to be used in combination with BI 
754091 for Part 2 of the trial. This data will be supported with the PK and 
PD analysis of at least 3 patients in each dose cohort.
Rationale
for change
Adaption because of new available data, SMC agreed
Rationale 
for change
New available Information
Section to 
be changed
4.1.4
Description 
of change
Changed from:
… In case no relevant infusion reactions are observed, this can be shorten 
to about 30 minutes but should not be prolonged to more than 6 hours for 
BI 836880 and should not be prolonged to more than 2 hours for BI 
754091, also in case of technical issues.
To:
In case no relevant infusion reactions are observed, this can be shorten to 
about 30 minutes for BI836880 only but should not be prolonged to more 
than 6 hours for BI 836880 and should not be prolonged to more than 2 
hours for BI 754091, also in case of technical issues.
Rationale 
for change
Clarification
Section to 
be changed
4.1.4 Re-treatment criteria
Description 
of change
Changed from:

QTcF <=480 ms (according to Exclusion-Criterion #8)
To:

In the Part 1: QTcF <=480 ms (according to Exclusion-Criterion #8)
Rationale 
for change
Clarification for Part 1
Section to 
be changed
4.1.4 Dose reduction guidelines
Description 
of change
Changed from:
Administration of trial drugs has to be stopped temporarily in case of a 
DLT (see Section 5.2.6.1). Patients may continue therapy only after 
recovery from DLT to at least fulfil retreatment criteria. The future dose 
of BI 836880 must be a tested dose which is one dose level below the 
dose received by the patient (Table 4.1.4: 1 below) Treatment has to be 
discontinued in case the DLT is not reversible.

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Table 4.1.4: 1 Dose reduction recommendations for BI 836880 
BI 836880 received dose 
BI 836880 reduced dose 
720 mg
500 mg
500 mg
360 mg
360 mg 
Stop BI 836880
In case of AEs (DLTs) that can be definitely characterized as BI 754091 
related, dose can be reduced.
Table 4.1.4: 2 Dose reduction recommendations for BI 754091
BI 754091 received dose 
BI 754091 reduced dose 
240 mg
80 mg
For each drug, only one dose reduction will be allowed per patient. 
To:
Part 1:
Administration of trial drugs has to be stopped temporarily in case of a 
DLT (see Section 5.2.6.1). Patients may continue therapy only after 
recovery from DLT to at least fulfil retreatment criteria. The future dose of 
BI 836880 must be a tested dose which is one dose level below the dose 
received by the patient (Table 4.1.4: 1 and 4.1.4: 2 below) Treatment has 
to be discontinued in case the DLT is not reversible.
Table 4.1.4: 1 Dose reduction recommendations for BI 836880 in Part 1
BI 836880 received dose 
BI 836880 reduced dose 
720 mg
500 mg
500 mg
360 mg
360 mg 
Stop BI 836880
In case of AEs (DLTs) that can be definitely characterized as BI 754091 
related, dose can be reduced.

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Table 4.1.4: 2 Dose reduction recommendations for BI 754091 in Part 1
BI 754091 received dose 
BI 754091 reduced dose 
240 mg
80 mg
For each drug, only one dose reduction will be allowed per patient. 
Part 2:
In the dose expansion study, dose reductions or escalations of BI 836880 
or BI 754091 in any patient is not allowed. The dose may be delayed for 
up to 6 weeks because of AEs, following discussion with the sponsor.
During combination therapy, if treatment is held or discontinued due to an 
AE(s), both BI 836880 and BI 754091 will be held or discontinued 
together. If treatment is to be restarted after resolution (≤ Grade 1 or 
baseline) of the AE, both BI 836880 and BI 754091 must be started 
together.
Rationale 
for change
Clarification regarding the Part 2 procedure
Section to 
be changed
4.2.2.1
Description 
of change
Changed from:
Previous anti-cancer therapy must have been discontinued before first 
administration of trial drug and the patient must have recovered from all 
clinically relevant reversible toxicities (see Exclusion Criteria Section 
3.3.3 for further details).
Concomitant anti-cancer therapy is not allowed.
Radiotherapy for local symptom control of non-target lesions can be 
allowed after consulting the investigator and sponsor.
To:

Previous anti-cancer therapy must have been discontinued before 
first administration of trial drug and the patient must have 
recovered from all clinically relevant reversible toxicities (see 
Exclusion Criteria Section 3.3.3 for further details).

Concomitant anti-cancer therapy is not allowed. Radiotherapy for 
local symptom control of non-target lesions can be allowed after 
consulting the investigator and sponsor.

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
Immunosuppressive medications including, but not limited to 
systemic corticosteroids at doses exceeding 10 mg/day of 
prednisone or equivalent, methotrexate, azathioprine, and tumour 
necrosis factor-alpha 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 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.

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 
unless agreed to by the Principal Investigator. 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. If instructed by the Principal Investigator, patients should 
stop using these herbal medications 7 days prior to first dose of study 
treatment.
Rationale 
for change
Clarification to the restrictions
Section to 
be changed
4.2.2.3
Description 
of change
Added info:
Due to the advanced stage of disease of Phase I trial patient populations 
and the high medical need, females of childbearing potential can be 
included in this trial provided that they agree to use a highly-effective 
contraception method. These are methods of birth control per the 
International Committee on Harmonisation (ICH) M3 (R2) that result in a 
low failure rate of less than 1% per year when used consistently and 
correctly.
Highly-effective methods of contraception include:

Oral, injected, or implanted hormonal methods of contraception, or

Intrauterine device or intrauterine system, or

‘Double-barrier’ methods of contraception: Male condom in 
combination with female diaphragm/cervical cap plus spermicidal 
foam/gel/film/cream.
Details of these contraception methods are described in the patient 
information in the ICF.

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Women of childbearing potential must follow these methods during the 
trial and for at least 6 months after the end of the trial treatment. Although 
use of a contraceptive pill is considered a highly-effective method of birth 
control, women of childbearing potential taking a contraceptive pill must 
use an additional barrier method for the entire duration of the trial
treatment intake and for 6 months after the end of the trial treatment 
intake.
Male patients with partners of childbearing potential must agree to use 
condoms and ensure their partner is using an additional highly-effective 
method of birth control, during the trial and until at least 6 months after 
the end of the trial treatment.
Rationale 
for change
More details regarding restrictions for women of childbearing potential
Section to 
be changed
5.1 
Description 
of change
Changed from:
… Efficacy endpoints will be assessed every 6 weeks at time points 
specified in the FC. An additional evaluation at EoT is only applicable; 
when patient has no PD documented, will not continue with regular 
imaging in Follow-up period and did not have imaging within the last 4 
weeks before EoT. At EoR visit, in case a patient has discontinued due to 
PD by RECIST 1.1, one additional tumour assessment should be done.
To:
Efficacy endpoints will be assessed every 2 cycles (6 weeks) as specified 
in the FC. An additional evaluation at EoT is only applicable; when 
patient has no PD documented, will not continue with regular imaging in 
Follow-up period and did not have imaging within the last 4 weeks before 
EoT. At EoR visit, in case a patient has discontinued due to PD by 
RECIST 1.1, one additional tumor assessment should be done in case no 
other cancer treatment has been initiated.
Rationale 
for change
Clarification of wording.
Section to 
be changed
5.2.2
Description 
of change
Changed from:
Blood pressure
Systolic and diastolic blood pressure as well as pulse rate (electronically 
or by palpation, count for 1 minute) will be measured after 5 minutes of 
rest in the seated position. The blood pressure measurement should be 
performed three times at each time point and the values of these 
measurements will be entered in the eCRF. Further details on the 
procedure for blood pressure measurements are given in Appendix 10.2.

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To:
Blood pressure
Systolic and diastolic blood pressure as well as pulse rate (electronically 
or by palpation, count for 1 minute) will be measured after 5 minutes of 
rest in the seated position. 
In Part 1, the blood pressure measurement should be performed three 
times at each time point and the values of these measurements will be 
entered in the eCRF. In Part 2, only a single blood pressure measurement 
is required at each time point.
Rationale 
for change
Adaptions regarding needed information for Part 2
Section to 
be changed
5.2.4
Description 
of change
Changed from:

At days of administration two time points will be evaluated:
1.
pre-dose (-60 min. to -5 min.),
2.
shortly before the end of the infusion of trial medication.
To:

For the part 1:
1.
pre-dose (-60 min. to -5 min.)
2.
shortly before the end of the infusion of trial medication
For the part 2:
1.        1st cycle pre and post treatment. Cycle 2,3 and 4 only one 
ECG pre treatment and then on ECG at pre treatment performed 
every second cycle (cycle 6,8, 10…etc)
2.
shortly before the end of the infusion of trial medication
(only at cycle 1).
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
5.2.6.1:11 Dose Limiting Toxicities (according to CTCAE V5.0) (cont’d)
Description 
of change
Changed from:

any grade ≥ 2 pneumonitis of any duration
To:

Grade ≥ 2 pneumonitis of any duration
Info added:
o
Grade 3 nausea or Grade 3 vomiting will be defined as DLT when it persists at 
Grade 3 longer than 48 hours despite adequate medical intervention. 

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Rationale 
for change
Clarifications to DLTs
Section to 
be changed
5.2.7.1
Description 
of change
Changed from:
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 (Appendix 
10.3). 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. 
To:
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. Although all irAEs are to be reported as AEs, only clinically 
important irAEs need to be reported as AESIs as defined by the sponsor in
Appendix 10.3. If an Investigator determines that a Grade 3 adverse event 
that is not included in Appendix 10.3 is an irAE, that event should also be 
reported as an AESI.
Rationale 
for change
Clarification to Immune related events 
Section to 
be changed
5.3.1.
Description 
of change
Changed from:
Pharmacokinetic profiles of BI 836880 and BI 754091 in plasma will be 
investigated after the first and after the fourth infusion cycle. Standard 
plasma PK parameters as specified in Section 2.1.3 will be calculated.
To:
Pharmacokinetic profiles of BI 836880 and BI 754091 in plasma will be 
investigated within this trial. Standard plasma PK parameters as specified 
in Section 2.1.3 will be calculated.
Rationale 
for change
Clarification Pharmacokinetic profiles

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Section to 
be changed
5.4
Description 
of change

Changed from:

Determination of myeloid-derived suppressor cells (MDSCs), 
PD1+ and LAG3+ T-cells, PD-L1+ monocytes, as well as 
activated T-effector memory cells and activated dendritic cells in 
blood (PBMCs; see Section 5.4.2.1)

Mechanism-related cytokines (e.g. ANG2, VEGF; IL-2, IFN-γ), 
as well as exploratory immune-related cytokines in blood 
(cytokines; see Section 5.4.2.2)

The ratio of kynurenine: tryptophan will be determined in blood 
(KYN:TRP; section see Section 5.4.2.2)

PD-L1, PD-1, CD-8 positive cells in tumour biopsies taken 
baseline and on treatment (dose escalation Part 1 only) (other 
markers may be added if scientific rationale arises; see Section 
5.4.2.3).
To:
Determination of myeloid derived suppressor cells (MDSCs), PD1+ and 
LAG3+ T-cells, PD-L1+monocytes, as well as regulatory T cells and 
activated T-effector memory and potentially PBMC subsets in blood 
(PBMCs; see Section 5.4.2.1)

Mechanism-related cytokines (e.g. ANG2, VEGF; IL-2, IFN-γ), 
as well as exploratory immune-related cytokines in blood 
(cytokines; see Section 5.4.2.2) . For the HCC cohort, AFP will 
also be measured as a marker for disease severity.

The ratio of kynurenine: tryptophan will be determined in blood 
(KYN:TRP; section see Section 5.4.2.2)

PD-L1, PD-1, CD-8 positive cells in tumour biopsies taken at 
baseline and on treatment (dose escalation Part 1 and cohorts E & 
F Part 2) (other markers may be added if scientific rationale 
arises; see Section 5.4.2.3).
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
5.4.1.

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Description 
of change
Change from:
The following tumour biopsies will be mandatory for all patients in Part 
1 (if possible from the same lesion):
-
the equivalent of 2 fine needle biopsies freshly taken during 
screening after IC signed and before first trial medication 
administration.
-
the equivalent of 2 fine needle biopsies on treatment before start of 
Cycle 3 (6 weeks after treatment start).
The following tumour biopsies in Part 2, will be:
-
Mandatory: A minimum of 2 fine needle biopsies should be 
freshly taken during screening after IC signed and before first trial 
medication administration.  In case a fresh baseline biopsy cannot 
be obtained (e.g. inaccessible lesions or patient safety concern), 
the equivalent of 2 archival fine needle biopsies, or 22 archival 4 
µm sections from an archival block, if taken within 6 months of 
trial start with no intermediate therapy, have to be provided.
-
Optional: The equivalent of 2 fine needle biopsies on treatment 
before start of Cycle 3.
To:
The following tumour biopsies will be mandatory for all patients in Part 
1 (if possible from the same lesion):
-
the equivalent of two 14-16G needle biopsies freshly taken during 
screening after IC signed and before first trial medication 
administration.
-
the equivalent of two 14-16G fine needle biopsies on treatment 
before start of Cycle 3 (6 weeks after treatment start).
The following tumour biopsies in Part 2, will be:
-
Mandatory: A minimum of two 14-16G fine needle biopsies 
should be freshly taken during screening after IC signed and 
before first trial medication administration. In case a fresh baseline 
biopsy cannot be obtained (e.g. inaccessible lesions or patient 
safety concern), the equivalent of 2 archival 14-16G needle 
biopsies, or 26 archival 4 µm sections from an archival block, if 
taken within 6 months of trial start with no intermediate therapy, 
have to be provided (except for cohort D). For cohorts E and, F, a 
fresh on-treatment biopsy is mandatory at C3D1, if possible from 
the same lesion as the pre-treatment biopsy.

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-
Optional: The equivalent of two 14 -16 G needle biopsies on 
treatment before start of Cycle 3 for cohorts A-C.
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
Description 
of change
Rationale 
for change
Section to 
be changed
Description 
of change
Rationale 
for change
Section to 
be changed
Description 
of change

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Rationale 
for change
Section to 
be changed
Description 
of change
Section to 
be changed
6.1
Rationale 
for change
Added:
During the treatment phase, after administration of BI 836880 and BI 
754091, patients are required to be hospitalized (refers only to Part 1, see 
Section 1.4) under close surveillance with access to intensive care for at 
least 48 hours after administration of trial medication to allow close 
monitoring for infusion-related reactions or other adverse events and 
availability of patients for PK visits
Description 
of change
Clarification to Part 2 procedure
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
6.2.2
Description 
of change
Changed from:
During cycle 1 and 4 intensive PK-sampling will be conducted and 
patients have to be observed closely for any adverse events. Therefore 
patients have to come to the clinic during the first four cycles every week 
to the clinic. Additional visits are needed at day 2 for cycles 1, 2 and 4 and 
at day 3 for cycle 1. In cycles 5 and 6 the patient is requested to come to 
the clinic on day 8 after administration of study drug. From cycle 7 
onwards no additional visits, beside day 1 including drug administration, 
are requested by protocol.
Disease response assessment by CT/MRI will be performed at the end of 
every other cycle (CT to be performed every 6 weeks starting from first 
trial medication administration).
Follow up period and trial completion

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To:
During cycle 1 (for Part 1 and 2) and 4 (only for Part 1) intensive PK-
sampling will be conducted and patients have to be observed closely for 
any adverse events. Therefore patients have to come to the clinic during 
the first four cycles every week to the clinic. In Part 1 additional visits are 
needed at day 2 for cycles 1, 2 and 4 and at day 3 for cycle 1. In cycles 5 
and 6 the patient is requested to come to the clinic on day 8 after 
administration of study drug. From cycle 7 onwards no additional visits, 
beside day 1 including drug administration, are requested by protocol. In 
For Part 2 tumour assessment should be done every 6 weeks (in 
accordance to local requirements). Assessments are always done prior to 
the start of the new treatment cycle. At EOT and EOR only when 
applicable (see section 5.1)
For Part 1 disease response assessment by CT/MRI will be performed at 
the end of every other cycle (CT to be performed every 6 weeks starting 
from first trial medication administration).
Follow up period and trial completion.
For Part 2 tumour assessment should be done every 6 weeks (in 
accordance to local requirements). Assessments are always done prior to 
the start of the new treatment cycle. At EOT and EOR only when 
applicable (see section 5.1)
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
7.1
Description 
of change
Changed from:
This is Phase I, open-label, dose-escalating trial to determine the 
Recommended Phase 2 Dose (RP2D) of BI 836880 in combination with 
BI 754091 in patients with locally advanced or metastatic non-squamous 
NSCLC who progressed during or after first line platinum-based 
treatment. In addition, the safety and efficacy of BI836880 combination 
with BI 754091 will be assessed. 
To:
This is Phase I, open-label, dose-escalating trial to determine the 
Recommended Phase 2.  Dose (RP2D) of BI 836880 in combination with 
BI 754091 in patients with locally advanced or metastatic non-squamous 
NSCLC during or after first line platinum-based chemotherapy or CPI 
monotherapy treatment or the combination of CPI and chemotherapy. 
Rationale 
for change
Clarification to the wording

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Section to 
be changed
7.1.2
Description 
of change
Changed from:
Part 2 of the trial will be designed as Open label, non-randomized 
expansion phase to assess  efficacy and  safety of BI 836880 in 
combination with BI 754091 in patients with locally advanced or 
metastatic non-squamous PD-L1 high and PD-L1 low, check point
inhibitor naive NSCLC. The analyses of the safety and efficacy for this 
portion of the trial will be descriptive and exploratory in nature. 
To:
To effectively use the information from these patients’ cohorts in the 
assessment of the efficacy, a Bayesian hierarchical model (BHM) 
approach (R13-4803), which assumes full exchangeability of model 
parameters and allows borrowing information across patients’ cohorts, 
will be used to analyse the response rate endpoints.
The BHM has 2 main components: a data model and a parameter model, 
as well as priors for the parameter model. The data model is a binomial 
sampling model
r|n~Binomial n, p, j = 1, 2, 3, …
where n and r are the number of patients and the corresponding number 
of patients with response in each patient cohort. The parameter model for 
the log-odds parameters, including an adjustment for the target rates 
 =  !" 	
#
1 −#
 − !" 	
#&
1 −#&

is specified as
θ| μ, τ ~ N(μ, τ), j = 1, 2, 3, …
where p& is the target response rate, μ denotes the “overall” mean of θ
and τ determines the inter-cohort heterogeneity.
Prior distribution
A non-informative normal distribution with mean 0 and standard 
deviation of 2 is specified for the mean μ. For the inter-cohort 
heterogeneity parameter τ, a half normal distribution with parameter 1 is 
used which is a very conservative assumption regarding between-cohort 
variability and hence leads to only little borrowing of data across patient 
cohorts because there is little prior information on the strength of the 
correlation between the treatment effects across cohorts
Rationale 
for change
Adaption to the new requirements

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Section to 
be changed
7.3.1.1 and 7.3.1.2
Description 
of change
Change from:
7.3.1.1 
Primary endpoint analyses for Part 1
In order to identify the MTD(s) and the recommended dose(s) for Part 2 
of the trial, the number of patients with DLTs at each dose combination 
during the Part 1 MTD evaluation period (the first cycle of the BI 836880 
plus BI 754091 combination) must be presented by descriptive statistics. 
Patients who discontinue during the first treatment cycle for reasons other 
than a DLT will be excluded from the determination of the MTD. In 
addition, the number of patients with DLTs that occurred during the entire 
treatment period, including Part 1 and Part 2, will be summarised at each 
dose level. The BLRM will be rerun to re-evaluate the MTD and RPIID 
together with all relevant data collected during Part 2. 
To:
7.3.1.1 
Primary endpoint analyses for Part 1
In order to identify the MTD(s) and the recommended dose(s) for Part 2 
of the trial, the number of patients with DLTs at each dose combination 
during the Part 1 MTD evaluation period (the first cycle of the BI 836880 
plus BI 754091 combination) must be presented by descriptive statistics. 
Patients who discontinue during the first treatment cycle for reasons other 
than a DLT will be excluded from the determination of the MTD. In 
addition, the number of patients with DLTs that occurred during the entire 
treatment period will be summarised at each dose level. The BLRM will 
be rerun to re-evaluate the MTD and RP2D together with all relevant data 
collected during Part 2. 
7.3.1.2 
Primary endpoint analyses for Part 2
The primary endpoint for Part 2 of the trial is OR defined by confirmed 
CR or PR according to RECIST 1.1 as assessed by the Investigator. 
Overall response will be analyzed in terms of OR rate (ORR), defined as 
the proportion of patients with best overall response of CR or PR 
determined and confirmed by RECIST 1.1. 
Section to 
be changed
7.3.1.2 Primary endpoint analyses for Part 2
Description 
of change
Change from:
The primary endpoint for Part 2 of the trial is OR defined by confirmed 
CR or PR according to RECIST 1.1 as assessed by the Investigator. 
Overall response will be analyzed in terms OR rate (ORR), defined as the 
proportion of patients with best overall response of CR or PR determined 
and confirmed by RECIST 1.1.

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To:
The primary endpoint for Part 2 of the trial is OR defined by confirmed 
CR or PR according to RECIST 1.1 as assessed by the Investigator. 
Overall response will be analyzed in terms of the shrinkage estimator of 
the OR rate (ORR) based on BHM. 
Rationale 
for change
New information regarding Part 2
Rationale 
for change
Clarification for Part 1 and new information regarding Part 2
Section to 
be changed
7.3.2.1
Description 
of change
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
7.4
Description 
of change
Changed from:
Interim safety evaluations will be performed as considered necessary. The 
dose-escalation design dictates that the sponsor and the SMC perform 
regular safety evaluations. Safety evaluations will be performed after each 
dose cohort by the SMC. The SMC will recommend the next dose level as 
well as the corresponding cohort size. SMC will recommend the RP2D that 
will be used in Part 2. SMC meeting minutes and outputs provided for these 
SMC meetings will be documented and archived.
Exploratory analyses of PK/PD may be performed at the end of Part 1 and 
additionally if considered informative for the study.
To:
Part 1
Interim safety evaluations will be performed as considered necessary. The 
dose-escalation design dictates that the sponsor and the SMC perform 
regular safety evaluations. Safety evaluations will be performed after each 
dose cohort by the SMC. The SMC will recommend the next dose level as 
well as the corresponding cohort size. SMC will recommend the RP2D that 

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will be used in Part 2. SMC meeting minutes and outputs provided for these 
SMC meetings will be documented and archived.
Exploratory analyses of PK/PD may be performed at the end of Part 1 and 
additionally if considered informative for the study.
Part 2:
In Part 2 we are randomizing 200 patients. 40 patients for the each of the 
cohorts A and B, and 30 patient for each of the cohorts C, D, E and F. An 
interim futility analysis will be performed for cohort C, D, E and F in Part 
2. Until any decision from the futility analysis is done, the enrolment of 
next patient will not be stopped. The two-stage design is planned to stop 
further recruitment of patient if the defined efficacy boundary (see Table 
7.7.2: 1) is not met at the first stage. 
The interim analyses for each cohort will be conducted after 15th patients 
in that cohort have completed their two on-treatment imaging assessment 
(i.e. end of cycle 4). 
In addition, if considered necessary interim analysis may be performed for 
evaluation of the efficacy and safety aspects as each cohort is finished
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
7.7.1
Description 
of change
Change from:
For Part 1, no formal statistical power calculations of sample size were 
performed. Approximately 20-25 patients will be expected for the dose 
finding part and confirmation of RP2D. Fewer patients might be needed 
based on the recommendation of the SMC and the actual number of 
cohorts tested.
To:
For Part 1, no formal statistical power calculations of sample size were 
performed. Approximately 12-18 patients will be expected for the dose 
finding part and confirmation of RP2D. Fewer patients might be needed 
based on the recommendation of the SMC and the actual number of 
cohorts tested.
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
7.7.2

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Description 
of change
Changed from:
For Part 2, it is assumed that BI 836880 in combination with BI 754091 
will have an ORR of at least 30% in patients with locally advanced or 
metastatic non-squamous NSCLS with low PD-L1 expression. For a 
cohort with 30 evaluable patients, an ORR of greater than 25% would be 
observed with a probability of approximately 72% assuming a true 
response rate of 30%. The probability of observing a false positive signal, 
i.e., to observe an ORR of more than 25% if the underlying true ORR is 
10%, is around 1%. In patients with high PD-L1 expression, it is assumed 
that BI 836880 in combination with BI 754091 will have an ORR of at 
least 50%. For a cohort with 30 evaluable patients, an ORR of greater than 
45% would be observed with a probability of approximately 71% 
assuming a true response rate of 50%. The probability of observing a false 
positive signal, i.e., to observe an ORR of greater than 45% if the 
underlying true ORR is 30%, is around 4%. Table 7.7.2: 1 summarizes the 
probability of observing certain ORRs based on different assumption of 
the underlying ORR.
Table 7.7.2: 1 Probabilities of observing certain objective response rates
Table not shown because of format reasons
To:
For Part 2, below cohorts are assume:

Cohort A: patients with locally advanced or metastatic non-squamous 
Non-Small Cell Lung Cancer with CPI monotherapy

Cohort B: patients with locally advanced or metastatic non-squamous 
Non-Small Cell Lung Cancer pre-treated with a combination of 
platinum-based chemotherapy and checkpoint inhibitor

Cohort C: patients with locally advanced or metastatic Small Cell 
Lung Cancer, with no more than one line of chemotherapy

Cohort D: patients with histologically confirmed recurrent 
glioblastoma (primary), with no more than one line of chemotherapy 
(concurrent and adjuvant temozolomide based chemotherapy)

Cohort E: patients with histologically confirmed, unresectable, Stage 
IV metastatic melanoma, with least one line of any kind of immune 
therapy

Cohort F: patients with locally advanced or metastatic and/or 
unresectable Hepatocellular Carcinoma (HCC) who were intolerant or 
progressed during 1st line sorafenib or lenvatinib treatment; subsequent 
CPI therapy is allowed as the most recent anticancer treatment.
A total of approximate 200 patients will be enrolled for these 6 cohorts. 40 
patients each are planned for cohort A and B and 30 patients each are 
planned for cohort C to F.

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For cohorts A, B, and E (MLN), there is no literature available for the 
target patients. As there are no treatments of proven efficacy for this 
population, it is assumed around 5% ORR with background therapy. The 
futility boundary for cohort E is set as 7% at planned interim futility 
analysis timing. The early stopping probabilities are shown in Table 7.7.2: 
1.
For cohort C (SCLC), around 20% ORR with anti-PD-1 antibody 
monotherapy is assumed. In Checkmate-032 (R19-1713) which is an open 
label phase I/II trial of Nivolumab in pateints with SCLC who experienced 
disease progression after platinum-based chemotherapy, the ORR was 
12% [95%CI, 6.5-19.5] (N=109). In KEYNOTE-158 (R19-1713), which is 
a phase II basket study of Pembrolizumab, patient with advanced SCLC 
had an ORR of 18.7% [95%CI, 11.8-27.4] (N=107). In KEYNOTE-028 
(R19-1713), which is a phase Ib basket trial, patients with extensive-stage 
SCLC showed an ORR of 33% [95%CI, 16-55] (N=24). Based on above 
result, the futility boundary for cohort C is set as 20% at planned interim 
futility analysis timing.
For cohort D (GBM), around 25% ORR with Bevacizumab is assumed. In 
AVF3708 (R11-2708), which is an open-label study in patients with 
glioblastoma who had progressed following initial treatment with 
temozolomide and radiation, the ORR was 28% [95%CI, 19-40] (N=85). 
Based on above results, the futility boundary for cohort D is set as 25% at 
planned interim futility analysis timing.
For cohort F (HCC), around 15% ORR with anti-PD-1 antibody 
monotherapy is assumed. In Checkmate-040 (R17-3829) which is an open 
label phase I/II trial of Nivolumab in patients with advanced hepatocellular 
carcinoma, the ORR was 20% [95%CI, 15-26] (N=50) in dose expansion 
phase and 15% [95% CI, 6-28] (N=10) in the dose escalation phase. In 
KEYNOTE-224 (R19-0168) which is a phase 2 study of Pembrolizumab 
in patients with advanced hepatocellular carcinoma previously treated with 
sorafenib , the ORR was 17% [95% CI, 11-26] (N=104). Based on above 
result, the futility boundary for cohort F is set as 15% at planned interim 
futility analysis timing.
Different homogeneous scenarios and heterogeneous scenarios as well as 
different sample sizes are considered in the simulations to assess the 
frequentist operating characteristics of the BHM approach. The simulation 
results as shown in Table 7.7.2: 2 below show that, with the proposed 
cohort size, the BHM approach has reasonable probability of reaching the 
pre-specified response rate under a wide range of scenarios.

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Table 7.7.2: 1 Early stopping probabilities at interim based on observed 
ORR under different scenarios
Table 7.7.2: 2 Operating characteristics of the Bayesian Hierarchical 
Modelling approach for final analysis under different 
scenarios with interim analysis based on observed ORR
Tables not shown because of format reasons
Rationale 
for change
Adaption to the new requirements
Section to 
be changed
9.2
Description 
of change
Added information
c23621412-01 
 
 A First in human Phase I, non-ramdomized, 
open label multi-center dose escalation trial of BI 836880 
administered by repeated intravenous infusions in patietns 
with solid tumors. 1336.1 30 April 2019
Rationale 
for change
New available information
Section to 
be changed
9.1.
Description 
of change
Added information:
R11-2708
Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff 
D, Abrey LE, Yung WKA, Paleologos N, Nicholas MK, 
Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy 
T. Bevacizumab alone and in combination with irinotecan 
in recurrent glioblastoma. J Clin Oncol 27 (28), 4733 -
4740 (2009)
R12-0948
Llovet JM, Pena CEA, Lathia CD, Shan M, Meinhardt G, 
Bruix J, SHARP Investigators Study Group. Plasma 
biomarkers as predictors of outcome in patients with 
advanced hepatocellular carcinoma. Clin Cancer Res, 
(2012)
R17-3829
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, 
Hsu C, et al
Nivolumab in patients with advanced hepatocellular 
carcinoma (CheckMate 040): an open-label, non-
comparative, phase 1/2 dose escalation and expansion trial.
Lancet 389, 2492 - 2502 (2017)

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R19-0168
Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer 
D, et al, KEYNOTE-224 Investigators
Pembrolizumab in patients with advanced hepatocellular 
carcinoma previously treated with sorafenib (KEYNOTE-
224): a non-randomised, open-label phase 2 trial.
Lancet Oncol 19, 940 - 952 (2018)
R19-1712
Wu X, Giobbie-Hurder A, Liao X, Connelly C, Connolly 
EM, Li J, et al. Angiopoietin-2 as a biomarker and target for 
immune checkpoint therapy. Cancer Immunol Res 5 (1), 17 
- 28 (2016)
R19-1713
Ready N, Farago AF, Braud F de, Atmaca A, Hellmann 
MD, Schneider JG, et al. Third-line nivolumab monotherapy 
in recurrent SCLC: CheckMate 032. J Thorac Oncol 14 (2), 
237 - 244 (2019)
R19-1714
Horn L, Mansfield AS, Szczesna A, Havel L, Krakowski M, 
Hochmair MJ, et al, IMpower133 Study Group. First-line 
atezolizumab plus chemotherapy in extensive-stage small-
cell lung cancer. N Engl J Med 379 (23), 2220 - 2229 (2018)
Rationale 
for change
New available information
Section to 
be 
changed
10.3 IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL 
INTEREST
Descriptio
n of 
change
New added table:
Table 10.3: 1 irAEs which must be reported as AESIs.
Immune-related adverse events of special interest
Pneumonitis (reported as an AESI if ≥Grade 2)

Acute interstitial pneumonitis

Interstitial lung disease

Pneumonitis
Colitis (reported as an AESI 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

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Endocrine (reported as an AESI 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 AESI)

Type 1 diabetes mellitus (if new onset)
Hematologic (reported as an AESI 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 AESI 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 AESI)

Allergic reaction

Anaphylaxis

Cytokine release syndrome

Serum sickness

Infusion reactions

Infusion-like reactions

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Neurologic (reported as an AESI)

Autoimmune neuropathy

Guillain-Barre syndrome

Demyelinating polyneuropathy

Myasthenic syndrome
Ocular (report as an AESI if ≥ Grade 2 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE)

Uveitis

Iritis
Renal (reported as an AESI 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 AESI)

Dermatitis exfoliative

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis
Skin (reported as an AESI if ≥ Grade 3)

Pruritus

Rash

Rash generalized

Rash maculopapular

Any rash considered clinically significant in the physician’s judgment
Other (reported as an AESI)

Myocarditis

Pancreatitis

Pericarditis
Any other Grade 3 event that is considered immune-related by the physician
Rational
e for 
change
Clarification to irAEs
Section 
to be 
changed
10.5.1

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Description 
of change
Table 10.5.1: 1 info: “for Part 1” added
Added:
Table 10.5.1: 2 Time schedule for PK blood sampling during treatment 
cycles for Part 2
Rationale 
for change
Adaption to the new study requirements

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11.4
GLOBAL AMENDMENT 4
Date of 
amendment
03 Mar 2020
EudraCT 
number
EU number
2017-001378-41
BI Trial 
number
1336-0011
BI 
Investigational 
Product(s)
BI 836880
BI 754091
Title of 
protocol
An open label phase Ib dose finding study of BI 836880 in 
combination with BI 754091 to characterize safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy in patients with 
locally advanced or metastatic non-squamous Non-Small Cell Lung
Cancer and in other solid tumors
Global Amendment due to urgent safety reasons
Global Amendment
Section to be 
changed
Synopsis – Study Design
Description of 
change
Change from:
This is a Phase Ib study, containing two parts; Part 1 (dose escalation 
of BI 836880 in combination with BI 754091) and Part 2 (expansion 
phase in 6 cohorts).
Part 1:
Dose escalation of BI 836880 in combination with BI 754091 in check
point inhibitor naïve or previously treated patients with locally 
advanced or metastatic non-squamous NSCLC who progressed during 
or after completion of at least 2 cycles first line (in case of checkpoint 
inhibitor naïve patients) platinum-based therapy and patients who 
progressed during or relapsed after completion of at least 2 cycles (in 
case of checkpoint inhibitor relapsing patients) of  platinum-based 
chemotherapy and a checkpoint inhibitor treatment (monotherapy or in 
combination with chemotherapy).
Part 2: Open label, non-randomized expansion phase to assess 
efficacy and safety of BI 836880 in combination with BI 754091:
      
Cohort A (NSCLC):
Patient with pathologically confirmed locally advanced or metastatic non-
squamous NSCLC who progressed during or after check-point inhibitor 
monotherapy treatment as the most recent anticancer treatment.

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Cohort B (NSCLC):
Patient with pathologically confirmed locally advanced or metastatic non-
squamous NSCLC who progressed during or after 
platinum-based chemotherapy and a check-point inhibitor (CPI)
combination treatment as the most recent anticancer treatment.
Cohort C (SCLC):
Patient with pathologically confirmed locally advanced or metastatic 
Small Cell Lung Cancer (SCLC) who progressed during or after first 
line standard chemotherapy regimen.
Cohort D (Glioblastoma):
Patient with histologically confirmed recurrent glioblastoma with no 
more than one previous line of chemotherapy (concurrent and 
adjuvant temozolomide based chemotherapy including in combination 
with another investigational agent is considered one line of 
chemotherapy).
Cohort E (Melanoma):
Patient with histologically confirmed, unresectable, Stage IV 
metastatic melanoma who progressed during or after CPI based 
regimen.
Cohort F (Hepatocellular Carcinoma):
Patient with locally advanced or metastatic and/or unresectable 
Hepatocellular Carcinoma (HCC) who were intolerant or progressed 
during 1st line sorafenib or lenvatinib treatment; subsequent CPI therapy 
is allowed as the most recent anticancer treatment.
To:
This is a Phase Ib study, containing two parts; Part 1 (dose escalation 
of BI 836880 in combination with BI 754091) and Part 2 (expansion 
phase in 7 cohorts).
Part 1:
Dose escalation of BI 836880 in combination with BI 754091 in check
point inhibitor naïve or previously treated patients with locally 
advanced or metastatic non-squamous NSCLC who progressed during 
or after completion of at least 2 cycles first line (in case of checkpoint 
inhibitor naïve patients) platinum-based therapy and patients who 
progressed during or relapsed after completion of at least 2 cycles (in 
case of checkpoint inhibitor relapsing patients) of  platinum-based 
chemotherapy and a checkpoint inhibitor treatment (monotherapy or in 
combination with chemotherapy).

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Part 2: Open label, non-randomized expansion phase to assess 
efficacy and safety of BI 836880 in combination with BI 754091:
Cohort A (NSCLC):
Patient with pathologically confirmed locally advanced or metastatic non-
squamous NSCLC who progressed during or after check-point inhibitor 
monotherapy treatment. Patient must also have received treatment with 
a platinum-based chemotherapy regimen and have progressed or be 
intolerant, or ineligible, as per applicable local practice.
Cohort B (NSCLC):
Patient with pathologically confirmed locally advanced or metastatic non-
squamous NSCLC who progressed during or after 
platinum-based chemotherapy and a check-point inhibitor (CPI)
combination treatment as the most recent anticancer treatment.
Cohort C (SCLC):
Patient with pathologically confirmed locally advanced or metastatic 
Small Cell Lung Cancer (SCLC) with documented intolerance to 
platinum-based chemotherapy or refractory to platinum-based 
chemotherapy (progression during treatment or during < 90 days of the 
last dose of platinum-based chemotherapy). Patients who are platinum-
sensitive (progression ≥ 90 days of the last dose of platinum-based 
chemotherapy) must also have received at least one other prior line of 
platinum-based chemotherapy, if eligible, with or without combination 
with CPI as per applicable local treatment country guidelines.
Cohort D (Glioblastoma):
Patient with histologically confirmed recurrent glioblastoma with no 
more than two previous lines of chemotherapy (concurrent and 
adjuvant temozolomide based chemotherapy including in combination 
with another investigational agent is considered one line of 
chemotherapy).
Cohort E (Melanoma):
Patient with histologically confirmed, unresectable, Stage IV 
metastatic melanoma who progressed during or after CPI based 
regimen. Patients with a BRAF mutation must have received targeted 
treatment, or were not eligible, with a BRAF and MEK inhibitor as per 
applicable local country guidelines.
Cohort F (2nd line Hepatocellular Carcinoma):
Patient with locally advanced or metastatic and/or unresectable 
Hepatocellular Carcinoma (HCC) who were intolerant or progressed 
during 1st line sorafenib or lenvatinib treatment; subsequent CPI therapy 
is allowed as the most recent anticancer treatment.

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Cohort G (1st line Hepatocellular Carcinoma):
Patient with locally advanced or metastatic and/or unresectable HCC
with no prior systemic treatment. This will be implemented only in 
countries UK, Korea, Taiwan, Hong Kong, Poland, Ukraine, Russia, 
Spain, USA, Australia
Rationale for 
change
Wording of local AMs were included, # of cohorts was adapted, 
information regarding Cohort D – Glioblastoma and additional Cohort 
G – naïve HCC was added
Section to be 
changed
Synopsis - Endpoints
Description of 
change
Change from:
Primary endpoints: 
PART 1:
The primary endpoint is the number of patients with dose limiting 
toxicity (DLT) within the first cycle of treatment (3 weeks). 
PART 2:
The primary endpoint is the shrinkage estimator of objective response 
(OR) based on BHM. OR is defined as best overall response 
(RECIST1.1) of complete response (CR) or partial response (PR) from 
first treatment infusion until the earliest of disease progression, death 
or last evaluable tumour assessment before start of subsequent anti-
cancer therapy, lost to follow-up or withdrawal of consent.
Secondary endpoint(s):
PART 1:

Adverse events (AEs), drug related AEs, drug related AEs 
leading to dose reduction or discontinuation during treatment 
period.
PART 2:

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
Adverse events (AEs), drug related AEs, drug related AEs 
leading to dose reduction or discontinuation during treatment 
period

Disease control (DC), defined as best overall response of CR, 
PR, or stable disease (SD) (RECIST1.1) from first treatment 
infusion until the earliest of disease progression, death or last 
evaluable tumour assessment before start of subsequent anti-
cancer therapy, lost to follow-up or withdrawal of consent.

Duration of objective response (DoR), defined as the time from 
first documented CR or PR (RECIST1.1) until the earliest of 
disease progression or death among patients with OR.

Progression-free survival (PFS) (RECIST1.1), defined as the 
time from first treatment infusion until disease progression or 
death from any cause, whichever occurs earlier.

Tumour shrinkage (in millimeters), defined as the difference 
between the minimum post-baseline sum of diameters of target 
lesions (longest for non-nodal lesions, short axis for nodal 
lesions) and the baseline sum of diameters of the same set of 
target lesions.

Pharmacokinetic parameters Cmax, tmax0-504h after the first 
and fourth infusion cycle.
To:
Primary endpoints: 
PART 1:
The primary endpoint is the number of patients with dose limiting 
toxicity (DLT) within the first cycle of treatment (3 weeks). 
PART 2:
The primary endpoint is the shrinkage estimator of objective response 
(OR) based on BHM. OR is defined as best overall response 
(RECIST1.1) of complete response (CR) or partial response (PR) from 
first treatment infusion until the earliest of disease progression, death 
or last evaluable tumor assessment before start of subsequent anti-
cancer therapy, lost to follow-up or withdrawal of consent. In case of 
recurrent glioblastoma (GBM) assessment will be based on RANO 
(Response Assessment in Neuro-Oncology) criteria.
Secondary endpoint(s):

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PART 1:

Adverse events (AEs), drug related AEs, drug related AEs 
leading to dose reduction or discontinuation during treatment 
period.

Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the first 
infusion cycle.
PART 2:

Adverse events (AEs), drug related AEs, drug related AEs 
leading to dose reduction or discontinuation during treatment 
period

Disease control (DC), defined as best overall response of CR, 
PR, or stable disease (SD) (RANO for GBM & RECIST1.1 for 
all other cohorts) from first treatment infusion until the earliest 
of disease progression, death or last evaluable tumor 
assessment before start of subsequent anti-cancer therapy, lost 
to follow-up or withdrawal of consent.

Duration of objective response (DoR), defined as the time from 
first documented CR or PR (RANO for GBM & RECIST1.1 
for all other cohorts) until the earliest of disease progression or 
death among patients with OR.

Progression-free survival (PFS) (RANO for GBM & 
RECIST1.1 for all other cohorts), defined as the time from first 
treatment infusion until disease progression or death from any 
cause, whichever occurs earlier.

Tumour shrinkage (in millimeters), defined as the difference 
between the minimum post-baseline sum of diameters of target 
lesions (longest for non-nodal lesions, short axis for nodal 
lesions) and the baseline sum of diameters of the same set of 
target lesions in case of RECIST. In GBM, using RANO 
criteria, tumor shrinkage will be calculated based on the 
difference between the post-baseline and baseline 
measurements of the sum of product of the largest bi-
dimensional measurements for all target lesions.

Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the first 
and fourth infusion cycle.
Rationale for 
change
Information regarding RANO for GBM cohort D was added
Section to be 
changed
Synopsis – Number of patient entered
Description of 
change
Changed from:

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A total of 255 patients (28 part 1 plus 227 part 2) approximately will 
be entered
(Part 1 and Part 2)
To:
A total of 315 patients (22 part 1 plus 293 part 2) approximately will 
be entered
(Part 1 and Part 2)
Rationale for 
change
Screening failure rate was increased, Part 1 patient # was adapted and 
additional patient for cohort G were added.
Section to be 
changed
Synopsis – Number of patients on each treatment
Description of 
change
Changed from:
Part 1: 12 to 18 evaluable patients
Part 2: 80 evaluable locally advanced or metastatic non-squamous 
NSCLC patients (Cohort A and B, 40 patients per cohort) and 30 
evaluable paients in each of the other 4 cohorts. In total 200 patients.
To:
Part 1: 12 to 18 evaluable patients 
Part 2: 80 evaluable locally advanced or metastatic non-squamous 
NSCLC patients (Cohort A and B; 40 patients per cohort) and 30 
evaluable patients in each of the other 5 cohorts. In total 230
Rationale for 
change
Patient for new cohort G were added
Section to be 
changed
Synopsis – Diagnosis cohort F and G
Description of 
change
Changed from:
Cohort F: Patients with hepatocellular carcinoma
To:
Cohort F: Patients with 2nd line hepatocellular carcinoma
Cohort G: Patients with 1st line hepatocellular carcinoma (This will be 
implemented only in UK, Korea, Taiwan, Hong Kong, Poland, 
Ukraine, Russia, Spain, USA, Australia.
Rationale for 
change
Information regarding change study design adapted.
Section to be 
changed
Synopsis: Main in- and exclusion criteria Part 2
Description of 
change
Change from:
Inclusion Criteria:
For Part 1:
1. Age ≥ 18 years

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2. Pathologically confirmed diagnosis of non-squamous 
NSCLC 
3. Locally advanced (stage IIIb) or metastatic (stage IV) 
NSCLC 
4. Documented disease progression or relapse (based on 
investigator’s assessment) during or after completion of at 
least 2 cycles of platinum-based chemotherapy as first line 
treatment of Stage IIIB/IV non- squamous NSCLC or for 
checkpoint inhibitor experienced patients during or after 
completion of at least 2 cycles of platinum-based 
chemotherapy and a checkpoint inhibitor treatment 
(monotherapy or in combination with chemotherapy). This 
includes patients relapsing within 6 months of completing 
(neo)adjuvant/curative-intent chemotherapy/CPI or 
chemoradiotherapy.
5. At least one target lesion (outside the brain), that can be 
accurately measured per RECIST v 1.1
6. Availability and willingness to provide a fresh tumour tissue 
sample obtained after relapse or progression on or after prior 
therapy. 
7. ECOG performance status of 0 or 1
8. Adequate hepatic, renal and bone marrow functions
For Part 2:
1. Of full age (according to local legislation, usually ≥ 18 
years) at screening
2. At least one target lesion outside the brain (excluding the 
glioblastoma patients), that can be accurately measured per 
RECIST v 1.1
3. ECOG performance status ≤ 1 
Inclusion for:
Cohort A (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
non-squamous NSCLC 
-
Prior Check-point inhibitor monotherapy either as 1st 
or 2nd line as the last therapy before entering trial.  No 
more than one regimen of prior chemotherapy.
-
Approximately 10 patients will be recruited who have 
primary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who previously received at least 2 cycles 
of CPI treatment without achieving benefit (SD <6 months 
or progressive disease in <6 months).

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-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who had a documented minimum duration 
of benefit of (minimum of stable disease) 6 months and 
minimum treatment duration of 2 months on the previous 
CPI treatment without experiencing disease progression 
during that period.
-
Patients with NSCLC known to harbor an ALK 
rearrangement, or EGFR mutation are only eligible after 
experiencing disease progression (during or after 
treatment) or intolerance to EGFR TKI or ALK TKI 
therapy.
Cohort B (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
non-squamous NSCLC 
-
1st line Platinum-based chemotherapy and a check-
point inhibitor combination treatment as the most recent 
therapy before entering trial 
-
Approximately 10 patients will be recruited who have 
primary resistance to the combination therapy which is 
defined as those advanced or metastatic IIIB/IV non-
squamous NSCLC patients who previously received at 
least 2 cycles of platinum-based chemotherapy and CPI 
treatment without achieving benefit (SD < 8 months or 
progressive disease in < 8 months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who had a documented minimum duration 
of benefit (minimum of stable disease) of 8 months who
received CPI and platinum-based chemotherapy in a first 
line setting.
-
Patients with NSCLC known to harbor an ALK 
rearrangement, or EGFR mutation are only eligible after 
experiencing disease progression (during or after 
treatment) or intolerance to EGFR TKI or ALK TKI 
therapy.
Cohort C (SCLC):
-
Pathologically confirmed locally advanced or metastatic 
SCLC 

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-
No more than one line of chemotherapy with or without 
in combination with CPI
-
Documented disease progression during or after first line 
standard chemotherapy regimen with or without in 
combination with CPIs
Cohort D (recurrent glioblastoma):
-
Histologically confirmed denovo glioblastoma (primary) 
-
No more than one line of chemotherapy (concurrent and 
adjuvant temozolomide based chemotherapy including in 
combination with another investigational agent is 
considered one line of chemotherapy). 
-
Documented first progression after radiotherapy (RT) and 
concurrent/adjuvant chemotherapy 
-
An interval of at least 12 weeks from the completion of 
radiation therapy to start of study drug unless there is a 
new area of enhancement consistent with recurrent tumor 
outside the radiation field or there is unequivocal histologic 
confirmation of tumor progression
-
Patient may have been operated for recurrence. If operated: 
residual and measurable disease after surgery is required; 
surgical site must be adequately healed free of drainage or 
cellulitis, and the underlying cranioplasty must appear 
intact at the time of randomization
Cohort E (Melanoma):
-
Histologically confirmed, unresectable, Stage IV 
metastatic melanoma
-
At least one line of any kind of CPI based regimen as 
last treatment before entering the study
Documented progression during or after CPI therapy based 
regimen
Cohort F (Hepatocellular Carcinoma):
-
Patients must have diagnosis of locally advanced or 
metastatic and/or unresectable histologically confirmed 
advanced hepatocellular carcinoma, not eligible for 
surgical and/or locoregional therapies
-
Patients should have progressed or discontinued first line 
treatment with sorafenib or lenvatinib, due to lack of 
tolerability. Patients who received 2nd line treatment with 

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anti-PD1 therapy (but not other therapy) after failure of 
sorafenib are also eligible. 
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody to 
hepatitis B core antigen (anti-HBc), and/or anti-hepatitis C 
virus (anti-HCV)
-
Child-Pugh score class A
-
Anti-viral therapy per local standard-of-care if active 
hepatitis B virus (HBV)
4. Adequate hepatic, renal and bone marrow functions
5.
Availability and willingness to provide a fresh tumor tissue 
sample obtained after relapse or progression on or after prior 
therapy. In case a fresh biopsy cannot be obtained (e.g. 
inaccessible lesions or patient safety concern), an archived 
specimen obtained up to 6 months prior to cycle 1, visit 1 
(C1V1) may be submitted in case no systemic antineoplastic 
therapy has been administered between the biopsy and C1V1 
(except for cohort D). For cohorts E and, F, a fresh on-
treatment biopsy is mandatory at C3D1, if possible from the 
same lesion as the pre-treatment biopsy.
6. Life expectancy ≥ 3 months after start of the treatment in the 
opinion of the investigator      
Exclusion Criteria:
Part 2:
1
Not more than one CPI based treatment regimen prior to 
entering study (eg. anti-Programmed Death receptor-1 (PD-
1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, 
or anti-cytotoxic T lymphocyte associated antigen-4 (anti-
CTLA-4) antibody); Exception is for Melanoma cohort 
(Cohort E)  
2
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection (exception for patients in HCC cohort Cohort F).
3
Prior treatment with any antiangiogenic treatment (e.g. 
bevacizumab, cediranib, aflibercept, vandetanib, XL-184, 
sunitinib, etc) except for sorafenib and lenvatinib in HCC 
cohort (Cohort F)
4
Patients with known active second malignancy other than 
non-melanoma skin cancers, non-metastatic prostate cancer, 
in situ cervical cancer, and ductal or lobular carcinoma in situ 
of the breast. Patients are not considered to have a currently 
active malignancy if they have completed anticancer therapy 

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and have been disease free for greater than 2 years prior to 
screening
Further exclusion criteria:
Exclusion criteria for Glioblastoma:
5
Tumor primarily localized to the brainstem or spinal cord.
6
Presence of diffuse leptomeningeal disease or extracranial 
disease.
Exclusion criteria for Melanoma cohort:
7
Uveal or ocular melanoma
Exclusion criteria for HCC cohort:
8
Co-infection with HBV and HCV or or HBV and hepatitis D 
virus (HDV)
9
Known fibrolamellar HCC, sarcomatoid HCC, or mixed 
cholangiocarcinoma and HCC
10 History of hepatic encephalopathy
11 Untreated or incompletely treated varices with bleeding or 
high-risk for bleeding
12 Uuntreated active Hepatitis B virus (HBV) 
13 Treatment with any HCV anti-viral therapy within 4 weeks 
prior to Cycle 1 Day 1
To 
For Part 2:
1. Of full age (according to local legislation, usually ≥ 18 years) 
at screening
2. At least one measurable target lesion outside the brain 
(excluding the glioblastoma patients), that can be accurately 
measured per RECIST v 1.1
3. ECOG performance status ≤ 1 (Karnofsky status for GBM)
Inclusion for:
Cohort A (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
non-squamous NSCLC 
-
Prior Check-point inhibitor monotherapy either as 1st 
or 2nd line. Patient must also have received treatment 
with a platinum-based chemotherapy regimen and have 
progressed or be intolerant, or ineligible, as per 
applicable local practice.

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-
Approximately 10 patients will be recruited who have 
primary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who previously received at least 2 cycles
of CPI treatment and progressed without achieving benefit 
(SD <4 months or progressive disease in <4 months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who had a documented minimum duration 
of benefit of (minimum of stable disease) 4 months and 
minimum treatment duration of 2 cycles on the previous 
CPI treatment without experiencing disease progression 
during that period.
-
Patients with NSCLC known to harbor an ALK 
rearrangement, or EGFR mutation, or other genomic 
aberrations (e.g., ROS rearrangement, BRAF V600E 
mutation), are only eligible after experiencing disease 
progression (during or after treatment) or intolerance to 
approved targeted therapy for respective genomic 
aberrations, as applicable per local country guidelines.
-
No more than one prior line of targeted therapy or 
chemotherapy regimen is allowed.
Cohort B (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
non-squamous NSCLC 
-
1st line Platinum-based chemotherapy and a check-
point inhibitor combination treatment as the most recent 
therapy before entering trial 
-
Approximately 10 patients will be recruited who have 
primary resistance to the combination therapy which is 
defined as those advanced or metastatic IIIB/IV non-
squamous NSCLC patients who previously received at 
least 2 cycles of platinum-based chemotherapy and CPI 
treatment and progressed without achieving benefit (SD < 
4 months or progressive disease in < 4 months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined 
as those advanced or metastatic IIIB/IV non-squamous 
NSCLC patients who had a documented minimum duration 
of benefit (minimum of stable disease) of 4 months when 
previously treated with at least 2 cycles of the CPI and 
platinum-based chemotherapy in a first line setting without 
experiencing disease progression during that period.

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-
Patients with NSCLC known to harbor an ALK 
rearrangement, or EGFR mutation, or other genomic 
aberrations (e.g., ROS rearrangement, BRAF V600E 
mutation), are only eligible after experiencing disease 
progression (during or after treatment) or intolerance to 
approved targeted therapy for respective genomic 
aberrations, as applicable per local country guidelines. No 
more than one line of targeted therapy is allowed.
Cohort C (SCLC):
-
Pathologically confirmed  locally advanced or metastatic 
SCLC 
-
Documented intolerance to platinum-based chemotherapy or 
refractory to platinum-based chemotherapy (progression 
during treatment or during < 90 days of the last dose of 
platinum-based chemotherapy). Patients who are platinum-
sensitive (progression ≥ 90 days of the last dose of platinum-
based chemotherapy) must also have received at least one 
other prior line of platinum-based chemotherapy, if eligible, 
with or without combination with CPI as per applicable local 
treatment country guidelines.
Cohort D (recurrent glioblastoma):
-
Histologically confirmed denovo glioblastoma (primary) at 
first or second recurrence after initial standard, control or 
experimental therapy that includes at a minimum RT.
-
Unequivocal evidence of progressive disease on contrast-
enhanced brain CT or MRI as defined by RANO Criteria, 
or have documented recurrent glioblastoma on diagnostic 
biopsy.
-
No more than two lines of prior chemotherapy
(concurrent and adjuvant temozolomide based 
chemotherapy including in combination with another 
investigational agent is considered one line of 
chemotherapy). 
-
Only first and second recurrences of GBM are eligible
-
An interval of at least 12 weeks from the completion of 
radiation therapy to start of study drug unless there is a 
new area of enhancement consistent with recurrent tumor 
outside the radiation field or there is unequivocal histologic 
confirmation of tumor progression
-
Patient may have been operated for recurrence. If operated: 
residual and measurable disease after surgery is required;
surgical site must be adequately healed free of drainage or 

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cellulitis, and the underlying cranioplasty must appear 
intact at the time of randomization
-
Karnofsky performance status (KPS) ≥ 70
-
MRI within 14 days prior to start of study drug
-
Patients should be immunocompetent (i.e. no concomitant 
treatment with dexamethasone (or equivalent), or receive 
stable/decreasing steroid levels not exceeding 2 mg/day 
dexamethasone (or equivalent) during the last 3 days prior 
to clinical screening; no severe lymphopenia).
Cohort E (Melanoma):
-
Histologically confirmed, unresectable, Stage IV 
metastatic melanoma.
-
Patients with a BRAF mutation must have received 
targeted treatment, or were not eligible, with a BRAF and 
MEK inhibitor as per applicable local country guidelines.
In such a case no more than one line of targeted therapy is 
allowed.
-
At least one line of any kind of CPI based regimen as 
last treatment before entering the study
-
Documented progression during or after CPI therapy based 
regimen.
Cohort F (2nd line Hepatocellular Carcinoma):
-
Patients must have diagnosis of locally advanced or 
metastatic and/or unresectable histologically confirmed 
advanced hepatocellular carcinoma, not eligible for 
surgical and/or locoregional therapies
-
Patients should have progressed on or after first line 
treatment with sorafenib or lenvatinib or discontinued 
sorafenib or lenvatinib due to lack of tolerability after 
receiving at least two weeks of treatment. Reason for 
discontinuation must be documented.Patients who 
received 2nd line treatment with anti-PD1 therapy (but not 
other therapy) after failure of sorafenib or lenvatinib are 
also eligible.
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody 
to hepatitis B core antigen (anti-HBc), HBV DNA, anti-
hepatitis C virus (anti-HCV) and HCV RNA as applicable.
-
Child-Pugh score class A
-
Anti-viral therapy per local standard-of-care if active 
hepatitis B virus (HBV). HBV DNA to be <500IU/ml and 

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patients on anti HBV therapy for >4 weeks before entering 
the study.
-
-
Cohort G (1st line Hepatocellular Carcinoma): (To be 
implemented only in UK, Korea, Taiwan, Hong Kong, 
Poland, Ukraine, Russia, Spain, USA, Australia) )The 
subject should have have diagnosis of  locally advanced or 
metastatic and/or unresectable histologically confirmed 
advanced hepatocellular carcinoma that is not amenable to 
a curative treatment approach (eg, transplant, surgery, 
ablation therapy) or locoregional therapy (eg, TACE).
-
No prior systemic therapy for HCC. Previous use of herbal 
therapies/traditional Chinese medicines with anti-cancer 
activity included in the label is allowed, provided that 
these medications are discontinued prior to randomization.
-
Child-Pugh Score of A.
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody 
to hepatitis B core antigen (anti-HBc), HBV DNA, anti-
hepatitis C virus (anti-HCV) and HCV RNA as applicable.
-
Anti-viral therapy per local standard-of-care if active 
hepatitis B virus (HBV). HBV DNA to be <500IU/ml and 
patients on anti HBV therapy for >4 weeks before entering 
the study.
4. Adequate hepatic, renal and bone marrow functions
5.
Availability and willingness to provide a fresh tumor tissue 
sample obtained after relapse or progression on or after prior 
therapy. In case a fresh biopsy cannot be obtained (e.g. 
inaccessible lesions or patient safety concern), an archived 
specimen obtained up to 6 months prior to cycle 1, visit 1 
(C1V1) may be submitted in case no systemic antineoplastic 
therapy has been administered between the biopsy and C1V1 
(except for cohort D). For cohorts E, F and G, a fresh on-
treatment biopsy is mandatory at C3D1, if possible from the 
same lesion as the pre-treatment biopsy.
6. Life expectancy ≥ 3 months after start of the treatment in the 
opinion of the investigator      
Exclusion Criteria:
Part 2:
1
Not more than one CPI based treatment regimen prior to 
entering study (eg. anti-Programmed Death receptor-1 (PD-1), 

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anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or 
anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-
4) antibody) unless combination CPIs approved by the local 
regulatory agencies; For eg.,  Melanoma cohort (Cohort E) 
2
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection (exception for patients in HCC cohorts; Cohort F & 
cohort G).
3
Prior treatment with any antiangiogenic treatment (e.g. 
bevacizumab, cediranib, aflibercept, vandetanib, XL-184, 
sunitinib, etc) except for sorafenib and lenvatinib in 2nd line 
HCC cohort (Cohort F).
4
Patients with known active second malignancy other than non-
melanoma skin cancers, non-metastatic prostate cancer, in situ 
cervical cancer, and ductal or lobular carcinoma in situ of the 
breast. Patients are not considered to have a currently active 
malignancy if they have completed anticancer therapy and 
have been disease free for greater than 2 years prior to 
screening
Further exclusion criteria:
Exclusion criteria for Glioblastoma:
5
Tumor primarily localized to the brainstem or spinal cord.
6
Presence of diffuse leptomeningeal disease or extracranial 
disease.
7
Is known to have IDH mutant variety of recurrent 
glioblastoma.
8
Any prior treatment with prolifeprospan 20 with carmustine 
wafer.
9
Any prior treatment with an intracerebral agent.
Exclusion criteria for Melanoma cohort:
10 Uveal or ocular melanoma
Exclusion criteria for HCC cohorts (Cohorts F & G):
11 Co-infection with HBV and HCV or HBV and hepatitis D 
virus (HDV)
12 Known fibrolamellar HCC, sarcomatoid HCC, or mixed 
cholangiocarcinoma and HCC
13 History of hepatic encephalopathy
14 Untreated or incompletely treated varices with bleeding or 
high-risk for bleeding
15 Untreated active Hepatitis B virus (HBV) 
16 Treatment with any HCV anti-viral therapy within 4 weeks 
prior to Cycle 1 Day 1

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Rationale for 
change
Adapting the information regarding implemented local AMs and 
changes to cohort D, F and G
Section to be 
changed
Synopsis - Dose
Description of 
change
Added Information:
Part 2:
RP2D of BI 836880 and BI 754091
BI 836880: 720 mg
BI 754091: 240 mg
Rationale for 
change
Dose which was found to be used for Part 2
Section to be 
changed
Flowchart Part 2
Description of 
change

EoR 42 days, was changed to “Safety Follow-op” visit (SFV) 30 
days after last IMP administration

Karnofsky performance was added

Infection screening was added

Height and weight on SFV was added

Disease response assessment deleted for cycle 1

Tumor biopsy info adjusted from cycle 1 to screening period
Footnote information changed to:
1  See Appendix 10.2 for BP and HR should be measured before and after study drugs have 
been administered. Please follow the BP monitoring and study drug administration guidelines 
in
Appendix 10.2.1.
2  ECG for all patients according to flowchart schedule.- Cycle 1 to 4 pre and post treatment 
(within 60 min after completion of administration of BI 836880) and thereafter ECG at pre- and 
post treatment of BI 836880 performed every second cycle (cycle 6,8, 10…etc
3  Echocardiography to be done within 21 days before treatment start and at EOT.
4  Safety lab to be done at local lab according to the Flowchart (up to 72 hours before treatment 
start ) but should be more frequent in case of relevant findings based on medical opinion of the 
investigator.(Section 5.2.3). 
5  Complete physical examination must be performed at screening and before start of treatment 
and EoT andSafety Follow-up visit. For further time points, at minimum the actual health status 
of the patient should be assessed (see Section 5.2.1).
6  more details about AE are provided in Section 5.2.7
7  For medication number allocation it’s possible to conduct IRT call ahead of the planned visit 
(= day of administration).
    Start with administration of BI 754091 and 15 min (+/- 10 min) after the end of this infusion, 
BI836880 should be administered (see Instructions for Pharmacist provided in the ISF)
8  Tumour assessments should be done according to RECIST v1.1 and iRECIST for all cohorts 
except GBM. RANO criteria to be followed for GBM cohort. Assessments 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. Baseline evaluation must be performed as close as possible to the  
treatment start and no more than 28 days before start of treatment (For GBM – 14 days prior to 
treatment).. Tumour assessment should be done every 6 weeks (in accordance to local 

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requirements). Assessments are always done prior to the start of the new treatment cycle 
(window is up to minus 7 days).
At EOT and Safety Follow-up visit only when applicable (see Section 5.1).
9, 10 and 11: see Appendix 10.5 Table 10.5.1: 2
12: Cohort F & G (HCC cohort): only C1D1 sample to be collected. NO on-treatment 
samples.
13: ONLY Cohort F & G (HCC) cohort
14: Cohort F & G (HCC) cohort: NO samples collected
§  Women of child-bearing potential must have a  serum beta human chorionic gonadotropin 
(β-HCG) pregnancy test at screening. Thereafter, this test can be done in either serum or urine 
on Day 1 of each cycle, and at the EOT visit. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.
$ Hepatitis B surface antigen (HBsAg; qualitative), hepatitis B core antibody (anti-HBc; 
qualitative), Hep B DNA, hepatitis C antibodies (Anti-HCV; qualitative), Hep C RNA, 
hepatitis D antibodies (Anti-HDV; qualitative) human immunodeficiency virus (HIV)-1 and 
HIV-2 antibody (at the discretion of the Investigator where clinically indicated) will be 
performed. 
@ Karnofsky performance status (KPS) to be implemted for GBM cohort

a Part 2/ Tumour biopsy

Mandatory pretreatment biopsy for cohort A, B, C, E, F , G: - The 
equivalent of 2 14 -16 G (cohorts A-C:  3 18 G) needle biopsies should be 
freshly taken during screening after IC signed and before first trial medication 
administration, In case a fresh baseline biopsy cannot be obtained (e.g. 
inaccessible lesions or patient safety concern), 26 archival 4 µm sections from 
an archival block, taken within 6 months of trial start with no intermediate 
therapy have to be provided. 

Mandatory for cohorts E, F and G, a fresh on-treatment biopsy: - The 
equivalent of 2 14-16 G needle biopsies at C3D1 (-/+ 7 days) if possible from 
the same lesion as the pre-treatment biopsy. Treatment to be initiated only 
after ensuring patient is stable and bleeding has stopped completely after 
biopsy.

Optional for cohorts A-C: - The equivalent of 3 18 G needle biopsies on 
treatment before start of Cycle 3 (-/+ 7 days, 6 weeks after treatment start) 
Note for on treatment biopsies: Biopsy to be performed on a lesion different than target lesion 
and if there is only one lesion than biopsy may be skipped in that patient.
Rationale for 
change
Adding and adapting information regarding new procedures and 
changes
Section to be 
changed
1.1 Medical background
Description of 
change
Added:
. Currently multiple phase III studies of CPI in combination with anti-
angiogenics is being conducted in 1st line HCC.
Rationale for 
change
Updating the information.
Section to be 
changed
1.2 Drug Profile
Description of 
change
This several parts for both compounds were updated
Rationale for 
change
The information was updated regarding the latest information for both 
compound regarding drug development and IB information.
Section to be 
changed
1.4 Risk Benefit Assessment

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Description of 
change
Change from:
Two Phase I trial testing BI 836880 monotherapy given i.v. in an 
every 1 or 3 week schedule are ongoing. Interim safety analysis of 
BI836880 phase I trials confirm the expected safety profile of the 
compound with hypertension, asthenia, nausea, vomiting, diarrhea and 
constipation being the most commonly reported AEs. Most of these 
reported AEs were grade 1-2 (CTCAE version 4.03). In total, 5 dose 
limiting toxicities were reported. In trial 1336.1 one patient treated on 
the highest dose level (1000mg) experienced a pulmonary embolism. 
In trial1336.6 4 patients experienced DLTs (proteinuria, proteinuria 
and hypertension, hypertension and respiratory distress one patient 
each) . (See BI 836880 IB section 6.3).
To:
Three Phase I trial testing BI 836880 monotherapy given i.v. in an 
every 1 or 3 week schedule are ongoing. Interim safety analysis of 
BI836880 phase I trials confirm the expected safety profile of the 
compound with hypertension, asthenia, nausea, vomiting, diarrhea and 
constipation being the most commonly reported AEs. Most of these 
reported AEs were grade 1-2 (CTCAE version 4.03). In total, 5 dose 
limiting toxicities were reported. In trial 1336.1(q3w dosing) one 
patient treated on the highest dose level (1000mg) experienced a 
pulmonary embolism. In trial1336.6 (q1w) 4 patients experienced 
DLTs (proteinuria, proteinuria and hypertension, hypertension and 
respiratory distress one patient each).  Additionally, monotherapy trial 
in Japanese patients (1336.12) is also ongoing. In the Part-1 of 1336-
0011 trial 1 DLT was reported at 360 mg dose cohort. (See BI 836880 
IB section 6.3).
Change from:
In Part 2, hospitalization is optional. Furthermore, Patients with 
uncontrolled hypertension, with history of severe haemorrhage or 
thromboembolism are not allowed to participate to this study. Other 
side effects may be rare and unknown with irreversible and/or life-
threatening effects. Patients should also be advised that there are other 
unknown risks associated with participation in a clinical trial.
To:
In Part 2, hospitalization is optional. The period of surveillance after 
study drug administration depends on the medical assessment of the 
investigator, and is at the investigator´s discretion. Please refer to 
Sections 5.2.1, 5.2.2, and 5.2.3.

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Patients enrolled in Part 2 will continue to be excluded if they have 
uncontrolled hypertension (defined as BP > 140/90 mmHg) at 
baseline, and/or a history of severe haemorrhage or thromboembolism. 
Other side effects may be rare and unknown with irreversible and/or 
life threatening effects. Patients should also be advised that there are 
other unknown risks associated with participation in a clinical trial.
Rationale for 
change
Update because of the latest available information.
Section to be 
changed
2.1.2 Primary Endpoints
Description of 
change
Change from:
PART 2:
The primary endpoint is the shrinkage estimator of Objective 
Response (OR) based on Bayesian Hierarchical Model (BHM) defined 
as best overall response of complete response (CR) or partial response 
(PR) from first treatment infusion until the earliest of disease 
progression, death or last evaluable tumour assessment before start of 
subsequent anti-cancer therapy, lost to follow-up, withdrawal of 
consent.
To:
PART 2:
The primary endpoint is the shrinkage estimator of Objective 
Response (OR) based on Bayesian Hierarchical Model (BHM) defined 
as best overall response (RECIST 1.1) of complete response (CR) or 
partial response (PR) from first treatment infusion until the earliest of 
disease progression, death or last evaluable tumour assessment before 
start of subsequent anti-cancer therapy, lost to follow-up, withdrawal 
of consent. In case of recurrent glioblastoma (GBM) assessment will 
be based on RANO (Response Assessment in Neuro-Oncology) 
criteria.
Rationale for 
change
Adapting the endpoints regarding the Glioblastoma Cohort D
Section to be 
changed
2.1.3 Secondary Endpoints – Part 2
Description of 
change
Change from:
PART 2:

Adverse events (AEs), drug related AEs, drug related AEs 
leading to dose reduction or discontinuation during treatment 
period

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
Disease control (DC), defined as best overall response of CR, 
PR, or stable disease (SD) by RECIST1.1 criteria from first 
treatment infusion until the earliest of disease progression, 
death or last evaluable tumour assessment before start of 
subsequent anti-cancer therapy, lost to follow-up or withdrawal 
of consent.

Duration of objective response (DoR), defined as the time from 
first documented CR or PR by RECIST1.1) until the earliest of 
disease progression or death among patients with OR.

Progression-free survival (PFS) (RECIST1.1), defined as the 
time from first treatment infusion until disease progression or 
death from any cause, whichever occurs earlier.

Tumour shrinkage (in millimeters), defined as the difference 
between the minimum post-baseline sum of diameters of target 
lesions (longest for non-nodal lesions, short axis for nodal 
lesions) and the baseline sum of diameters of the same set of 
target lesions.

Pharmakinetic parameters Cmax, tmax, AUC0-504h after the first 
and fourth infusion cycle.
To:
PART 2:

Adverse events (AEs), drug related AEs, drug related AEs 
leading to discontinuation during treatment period

Disease control (DC), defined as best overall response of CR, 
PR, or stable disease (SD) by RECIST1.1 (RANO for the 
GBM cohort) from first treatment infusion until the earliest of 
disease progression, death or last evaluable tumour assessment 
before start of subsequent anti-cancer therapy, lost to follow-up 
or withdrawal of consent.

Duration of objective response (DoR), defined as the time from 
first documented CR or PR by RECIST1.1 (RANO for the 
GBM cohort) until the earliest of disease progression or death 
among patients with OR.

Progression-free survival (PFS) (RANO for the GBM cohort & 
RECIST1.1 for all other cohorts), defined as the time from first 
treatment infusion until disease progression or death from any 
cause, whichever occurs earlier.

Tumour shrinkage (in millimeters), defined as the difference 
between the minimum post-baseline sum of diameters of target 

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lesions (longest for non-nodal lesions, short axis for nodal 
lesions) and the baseline sum of diameters of the same set of 
target lesions. In GBM, using RANO criteria, tumor shrinkage 
will be calculated based on the difference between the post-
baseline and baseline measurements of the sum of product of 
the largest bi-dimensional measurements for all target lesions.

Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the first 
infusion cycle.
Rationale for 
change
Adapting the Cohort D regarding RANO measurements
Section to be 
changed
Description of 
change
Rationale for 
change
Section to be 
changed
Description of 
change

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Rationale for 
change
Section to be 
changed
3.1 Overall Study design Plan
Description of 
change
Changed from:
The eligible patient population will be CPI naïve and experienced 
patients with locally advanced or metastatic non - squamous NSCLC 
who progressed during or after first line platinum-based chemotherapy 
or CPI monotherapy treatment or the combination of CPI and 
chemotherapy. The trial will consist in 2 Parts; Part 1 and part 2:
The eligible patient population will be CPI naïve and experienced 
patients with locally advanced or metastatic non - squamous NSCLC 
who progressed during or after first line platinum-based chemotherapy 
or CPI monotherapy treatment or the combination of CPI and 
chemotherapy. The trial will consist in 2 Parts; Part 1 and part 2:
To:
The eligible patient population will be CPI naïve and experienced
patients with locally advanced or metastatic non - squamous NSCLC
who progressed during or after first line platinum-based chemotherapy 

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or CPI monotherapy treatment or the combination of CPI and 
chemotherapy in Part 1. Part-2 will have additional expansion cohorts.
Additional was the information regarding the new cohort added and 
two trial design overview graphics adapted and information was
changed to:
It is foreseen to enroll up to 230 patients of full age (according to local 
legislation, usually ≥ 18 years) at screening in different indications:
Patients with locally advanced or metastatic 2nd or 3rd line CPI 
resistant non-squamous Non-Small Cell Lung Cancer (NSCLC)  and 
≥2nd line Small Cell Lung Cancer (SCLC) and recurrent glioblastoma 
and IO failure metastatic melanoma,1st line HCC patients or HCC 
patients who were intolerant or progressed during or after standard 
first line treatment with sorafenib or lenvatinib. Patients who received 
2nd line treatment with anti-PD1 therapy (but not other therapy) after 
failure of sorafenib or lenvatinib are also eligible (see image below –
please note the cohorts will run in parallel, not sequential) (see 
Figure 3.1: 1). 1st line HCC cohort will be implemented only in 
countries UK, Korea, Taiwan, Hong Kong, Poland, Ukraine, Russia, 
Spain, USA, Australia.
Additional added:
As described in Section 6.1 of the protocol, the period of surveillance 
during the treatment phase after administration of BI 836880 and BI 
754091 is at the investigator´s discretion. Management guidelines 
have been provided for infusion related reactions (Section 5.2.7.1) and 
hypertension episodes (Appendix 10.2.1).
Rationale for 
change
The study design was adapted regarding the additional cohort D and 
the increase number of patients.
Section to be 
changed
3.2 Discussion of trial design, including the choice of control Groups
Description of 
change
Information was adapted to:
Part 2 is an open-label expansion phase to assess efficacy and safety of 
BI 836880 in combination with BI 754091 in pretreated or naïve check 
point inhibitor patients with locally advanced or metastatic non-
squamous NSCLC, small cell lung cancer, recurrent glioblastoma, 
malignant melanoma and 1st and 2nd line hepatocellular carcinoma.
Once RP2D is determined in Part 1, it is planned to randomize up to
230 patients as described in Section 3.1 for Part 2

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Rationale for 
change
HCC patient cohorts were adapted according to the needs
Section to be 
changed
3.3 Selection of trial population 
Description of 
change
Change from:
Approximately 80 patients will be enrolled in the NSCLC cohort and 
30 patients each in the SCLC, metastatic melanoma, recurrent 
glioblastoma and HCC cohorts.
To:
Approximately 80 patients will be enrolled in the NSCLC cohort and 
30 patients each in the SCLC, metastatic melanoma, recurrent 
glioblastoma, 1st and 2nd line HCC cohorts. 1st line HCC will be 
implemented only in countries UK, Korea, Taiwan, Hong Kong, 
Poland, Ukraine, Russia, Spain, USA, Australia.
Rationale for 
change
Adaption regarding additional HCC cohort G
Section to be 
changed
3.3.1 man diagnosis for trial entry – Part2
Description of 
change
Change from:
For the part 2 we look for patients with locally advanced or metastatic 
2nd line CPI resistant NSCLC and 2nd line SCLC, recurrent 
glioblastoma, IO failure metastatic melanoma and HCC pts who are 
intolerant or failed the first line treatment with sorafenib or lenvatinib.  
Patients who received 2nd line treatment with anti-PD1 therapy (but 
not other therapy) after failure of sorafenib or lenvatinib are also 
eligible.
Please refer to Section 8.3.1 (Source Documents) for the 
documentation requirements pertaining to the in- and exclusion 
criteria.
For the part 2 we look for patients with locally advanced or metastatic 
2nd line CPI resistant NSCLC and 2nd line SCLC, recurrent 
glioblastoma, IO failure metastatic melanoma and HCC pts who are 
intolerant or failed the first line treatment with sorafenib or lenvatinib.  
Patients who received 2nd line treatment with anti-PD1 therapy (but 
not other therapy) after failure of sorafenib or lenvatinib are also 
eligible.
Please refer to Section 8.3.1 (Source Documents) for the 
documentation requirements pertaining to the in- and exclusion 
criteria.
To
For the part 2 we look for patients with locally advanced or metastatic 
2nd  and 3rd line CPI resistant NSCLC and 2nd line SCLC, recurrent 
glioblastoma, IO failure metastatic melanoma, 1st line HCC patients 
and HCC patients who are intolerant or failed the first line treatment 

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with sorafenib or lenvatinib. HCC patients who received 2nd line 
treatment with anti-PD1 therapy (but not other therapy) after failure of 
sorafenib or lenvatinib are also eligible.
Please refer to Section 8.3.1 (Source Documents) for the 
documentation requirements pertaining to the in- and exclusion 
criteria.
Rationale for 
change
Adaption regarding additional HCC cohort
Section to be 
changed
3.3.2 Inclusion Criteria Part 1 -  # 13
Description of 
change
Change from:
Male or female patients. Women of childbearing potential (WOCBP) 
and men able to father a child must be ready and able to use highly 
effective methods of birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and 
correctly, starting with the screening visit and through 150 days after 
the last dose of BI 836880 and BI 754091 treatment, respectively. A 
list of contraception methods meeting these criteria is provided in the 
patient information. For further detail refer to Section 4.2.2.3.
Note: Female patients of childbearing potential must have a negative 
urine or serum pregnancy test within 72 hours prior to taking study 
medication. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. The serum 
pregnancy test must be negative for the patient to be eligible.
To:
Male or female patients. Women of childbearing potential (WOCBP) 
and men able to father a child must be ready and able to use highly 
effective methods of birth control per ICH M3 (R2) that result in a low 
failure rate of less than 1% per year when used consistently and 
correctly, starting with the screening visit and through 6 months after 
the last dose of BI 836880 and BI 754091 treatment, respectively. A 
list of contraception methods meeting these criteria is provided in the 
patient information. For further detail refer to Section 4.2.2.3.
Note: Female patients of childbearing potential must have a negative 
serum pregnancy test within 72 hours prior to taking study medication
during the screening period. At the following visits according to the 
flowchart a urine and/or serum pregnancy test is required. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. The serum pregnancy test must be negative for 
the patient to be eligible.
Rationale for 
change
Correction of wrong information

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Section to be 
changed
3.3.2 main Inclusion criteria for all Cohorts – Part 2
Description of 
change
Changed from:
2. At least one measurable untreated lesion according to RECIST 
v1.1
3. ECOG performance status ≤ 1   
4.Adequate organ function as all of the following (all screening labs 
should be performed at local lab within 10 days prior to treatment 
initiation)
To:
2: At least one measurable target lesion outside the brain (excluding 
the glioblastoma patients), that can be accurately measured per 
RECIST v 1.1
3.
ECOG performance status ≤ 1 (For glioblastoma cohort 
Karnofsky status is applicable; see below)
4.
Adequate organ function as all of the following (all screening 
labs should be performed at local lab within approximately 72 
hours prior to treatment initiation):
Change from: #9 
      Male or female patients. Women of childbearing potential 
(WOCBP) and men able to father a child must be ready and able to 
use highly effective methods of birth control per ICH M3 (R2) that 
result in a low failure rate of less than 1% per year when used 
consistently and correctly, starting with the screening visit and 
through 150 days after the last dose of BI 836880 and BI 754091 
treatment, respectively. A list of contraception methods meeting 
these criteria is provided in the patient information. For further 
detail refer to Section 4.2.2.3.
Note: Female patients of childbearing potential must have a 
negative urine or serum pregnancy test within 72 hours prior to 
taking study medication. If the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required. 
The serum pregnancy test must be negative for the patient to be 
eligible.
To:
9. Male or female patients. Women of childbearing potential 
(WOCBP) and men able to father a child must be ready and
able to use highly effective methods of birth control per ICH
M3 (R2) that result in a low failure rate of less than 1% per 
year when used consistently and correctly, for the entire 
duration of the trial treatment intake and for 6 months after the 
end of the trial treatment. A list of contraception methods 

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meeting these criteria is provided in the patient information. 
For further detail refer to Section 4.2.2.3.
Note: Female patients of childbearing potential must have a 
negative serum pregnancy test within 72 hours during the 
screening period. At the following visits according to the 
flowchart, a urine and/or serum pregnancy test is required. If 
the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. The serum pregnancy 
test must be negative for the patient to be eligible Change for 
the different cohorts to:
Section to be 
changed
3.3.2 Inclusion criteria Part 2 Cohort A
Description of 
change
Change from:
Cohort A (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
IIIB/IV non-squamous NSCLC 
-
Prior Check-point inhibitor monotherapy either as 1st or 
2nd line as the last therapy before entering trial.  No more 
than one regimen of prior chemotherapy.
-
Approximately 10 patients will be recruited who have primary 
resistance to CPI based therapy which is defined as those 
advanced or metastatic IIIB/IV non-squamous NSCLC patients 
who previously received at least 2 cycles of CPI treatment 
without achieving benefit (RECIST v1.1 SD <6 months or 
progressive disease in <6 months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined as 
those advanced or metastatic IIIB/IV non-squamous NSCLC 
patients who had a documented minimum duration of benefit 
of (minimum of stable disease) 6 months and minimum 
treatment duration of 2 months on the previous CPI treatment 
without experiencing disease progression during that period.
-
Patients with NSCLC known to harbor an ALK rearrangement, 
or EGFR mutation are only eligible after experiencing disease 
progression (during or after treatment) or intolerance to EGFR 
TKI or ALK TKI therapy.
To:
Inclusion for:
Cohort A (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
IIIB/IV non-squamous NSCLC 
-
Prior Check-point inhibitor monotherapy either as 1st or 2nd 
line. Patient must also have received treatment with a 

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platinum-based chemotherapy regimen and have progressed or 
be intolerant, or ineligible, as per applicable local practice. 
-
Approximately 10 patients will be recruited who have primary 
resistance to CPI based therapy which is defined as those 
advanced or metastatic IIIB/IV non-squamous NSCLC patients 
who previously received at least 2 cycles of CPI treatment and 
progressed without achieving benefit (RECIST v1.1 SD <4 
months or progressive disease in <4 months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined as 
those advanced or metastatic IIIB/IV non-squamous NSCLC 
patients who had a documented minimum duration of benefit 
of (minimum of stable disease) 4 months and minimum 
treatment duration of 2 cycles on the previous CPI treatment 
without experiencing disease progression during that period.
-
Patients with NSCLC known to harbor an ALK rearrangement, 
or EGFR mutation, or other genomic aberrations (e.g., ROS 
rearrangement, BRAF V600E mutation), are only eligible after 
experiencing disease progression (during or after treatment) or 
intolerance to approved targeted therapy for respective 
genomic aberrations, as applicable per local country 
guidelines.
-
No more than one prior line of targeted therapy or 
chemotherapy regimen is allowed.
Rationale for 
change
Adaption to requests from the authorities in different countries
Section to be 
changed
3.3.2
Inclusion criteria Part 2 Cohort B
Description of 
change
Change from:
-
Cohort B (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
IIIB/IV non-squamous NSCLC 
-
1st line Platinum-based chemotherapy and a check-point 
inhibitor combination treatment as the most recent therapy 
before entering trial 
-
Approximately 10 patients will be recruited who have primary 
resistance to the combination therapy which is defined as those 
advanced or metastatic IIIB/IV non-squamous NSCLC patients 
who previously received at least 2 cycles of platinum-based 
chemotherapy and CPI treatment without achieving benefit 
(RECIST v1.1 SD < 8 months or progressive disease in < 8 
months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined as 
those advanced or metastatic IIIB/IV non-squamous NSCLC 

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patients who had a documented minimum duration of benefit 
(minimum of stable disease) of 8 months who received CPI 
and platinum-based chemotherapy in a first line setting.
-
Patients with NSCLC known to harbor an ALK rearrangement, 
or EGFR mutation are only eligible after experiencing disease 
progression (during or after treatment) or intolerance to EGFR 
TKI or ALK TKI therapy.
To:
-
Cohort B (NSCLC):
-
Pathologically confirmed locally advanced or metastatic 
IIIB/IV non-squamous NSCLC 
-
1st line Platinum-based chemotherapy and a check-point 
inhibitor combination treatment as the most recent therapy 
before entering trial 
-
Approximately 10 patients will be recruited who have primary 
resistance to the combination therapy which is defined as those 
advanced or metastatic IIIB/IV non-squamous NSCLC patients 
who previously received at least 2 cycles of platinum-based 
chemotherapy and CPI treatment and progressed without
achieving benefit (RECIST v1.1 SD < 4 months or progressive 
disease in < 4 months).
-
Approximately 30 patients will be recruited who have 
secondary resistance to CPI based therapy which is defined as 
those advanced or metastatic IIIB/IV non-squamous NSCLC 
patients who had a documented minimum duration of benefit 
(minimum of stable disease) of 4 months when previously 
treated with at least 2 cycles of the CPI and platinum-based 
chemotherapy in a first line setting without experiencing 
disease progression during that period.
-
Patients with NSCLC known to harbor an ALK rearrangement, 
or EGFR mutation, or other genomic aberrations (e.g., ROS 
rearrangement, BRAF V600E mutation), are only eligible after 
experiencing disease progression (during or after treatment) or 
intolerance to approved targeted therapy for respective 
genomic aberrations, as applicable per local country 
guidelines. No more than one line of targeted therapy is 
allowed.
Rationale for 
change
Adaption to requests from the authorities in different countries
Section to be 
changed
3.3.2 Inclusion criteria Part 2 Cohort C
Description of 
change
Changed from:
Cohort C (SCLC):
-
Pathologically confirmed locally advanced or metastatic SCLC 

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-
No more than one line of chemotherapy with or without 
combination with CPI
-
Documented disease progression during or after first line 
standard chemotherapy regimen with or without combination 
with anti-PD (L)1
To:
Cohort C (SCLC):
-
Pathologically confirmed locally advanced or metastatic 
SCLC.
-
Documented intolerance to platinum-based chemotherapy or 
refractory to platinum-based chemotherapy (progression during 
treatment or during < 90 days of the last dose of platinum-
based chemotherapy). Patients who are platinum-sensitive 
(progression ≥ 90 days of the last dose of platinum-based 
chemotherapy) must also have received at least one other prior 
line of platinum-based chemotherapy, if eligible, with or 
without combination with CPI as per applicable local treatment 
country guidelines.
Rationale for 
change
Adaption to requests from the authorities in different countries
Section to be 
changed
3.3.2 Inclusion criteria Part 2 Cohort D
Changed from:
Cohort D (recurrent glioblastoma):
-
Histologically confirmed denovo glioblastoma (primary) 
-
No more than one line of chemotherapy (concurrent and 
adjuvant temozolomide based chemotherapy including in 
combination with another investigational agent is considered 
one line of chemotherapy). 
-
Documented first progression after radiotherapy (RT) and 
concurrent/adjuvant chemotherapy 
-
An interval of at least 12 weeks from the completion of 
radiation therapy to start of study drug unless there is a new 
area of enhancement consistent with recurrent tumor outside 
the radiation field or there is unequivocal histologic 
confirmation of tumor progression
-
Patient may have been operated for recurrence. If operated: 
residual and measurable disease after surgery is required; 
surgical site must be adequately healed free of drainage or 
cellulitis, and the underlying cranioplasty must appear intact at 
the time of randomization
To:
Cohort D (recurrent glioblastoma):

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-
Histologically confirmed denovo glioblastoma (primary) at 
first or second recurrence after initial standard, control or 
experimental therapy that includes at a minimum RT.
-
Unequivocal evidence of progressive disease on contrast-
enhanced brain CT or MRI as defined by RANO Criteria, or 
have documented recurrent glioblastoma on diagnostic biopsy.
-
No more than two lines of prior chemotherapy (concurrent 
and adjuvant temozolomide based chemotherapy including in 
combination with another investigational agent is considered 
one line of chemotherapy). 
-
Only first and second recurrences of GBM are eligible.
-
An interval of at least 12 weeks from the completion of 
radiation therapy to start of study drug unless there is a new 
area of enhancement consistent with recurrent tumor outside 
the radiation field or there is unequivocal histologic 
confirmation of tumor progression
-
Patient may have been operated for recurrence. If operated: 
residual and measurable disease after surgery is required;
surgical site must be adequately healed free of drainage or 
cellulitis, and the underlying cranioplasty must appear intact at 
the time of randomization1
-
Karnofsky performance status ≥ 70
-
MRI within 14 days prior to start of study drug.
-
Patients should be immunocompetent (i.e. no concomitant 
treatment with Description of change dexamethasone (or 
equivalent), or receive stable/decreasing steroid levels not 
exceeding 2 mg/day dexamethasone (or equivalent) during the 
last 3 days prior to clinical screening; no severe lymphopenia)
Rationale for 
change
Adaption regarding adequate way to evaluate this population 
Section to be 
changed
3.3.2 Inclusion criteria Part 2 Cohort E
Description of 
change
Change from:
Cohort E (Melanoma):
-
Histologically confirmed, unresectable, Stage IV metastatic 
melanoma
-
At least one line of any kind of CPI based regimen as last 
treatment before entering the study
-
Documented progression during or after CPI therapy based 
regimen
To:
Cohort E (Melanoma):
-
Histologically confirmed, unresectable, Stage IV metastatic 
melanoma

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-
Patients with a BRAF mutation must have received targeted 
treatment, or were not eligible, with a BRAF and MEK 
inhibitor as per applicable local country guidelines. In such a 
case no more than one line of targeted therapy is allowed.
-
At least one line of any kind of CPI based regimen as last 
treatment before entering the study
Rationale for 
change
Adaption to requests from the authorities in different countries
Section to be
changed
3.3.2 Inclusion criteria Part 2 Cohort F
Description of 
change
Change from:
To Cohort F (Hepatocellular Carcinoma):
-
Patients must have diagnosis of locally advanced or metastatic 
and/or unresectable histologically confirmed advanced 
hepatocellular carcinoma, not eligible for surgical and/or 
locoregional therapies
-
Patients should have progressed or discontinued first line 
treatment with sorafenib or lenvatinib, due to lack of 
tolerability. Patients who received 2nd line treatment with anti-
PD1 therapy (but not other therapy) after failure of sorafenib 
are also eligible. 
-
Child-Pugh score class A
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody to 
hepatitis B core antigen (anti-HBc), and/or anti-hepatitis C 
virus (anti-HCV)
-
Anti-viral therapy per local standard-of-care if active hepatitis 
B virus (HBV)
To:
Cohort F (2nd line HepatocellularCarcinoma):
-
Patients must have diagnosis of locally advanced or metastatic 
and/or unresectable histologically confirmed advanced 
hepatocellular carcinoma, not eligible for surgical and/or 
locoregional therapies
-
Patients should have progressed on or after first line treatment 
with sorafenib or lenvatinib or discontinued sorafenib or 
lenvatinib due to lack of tolerability after receiving at least 
two weeks of treatment. Reason for discontinuation must be 
documented. 
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody to 
hepatitis B core antigen (anti-HBc), HBV DNA, anti-hepatitis 
C virus (anti-HCV) and HCV RNA as applicable.
-
Child-Pugh score class A

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-
Anti-viral therapy per local standard-of-care if active hepatitis 
B virus (HBV). HBV DNA to be <500IU/ml and patients on 
anti HBV therapy for >4 weeks before entering the study.
Rationale for 
change
Adaption regarding the differentiation from the cohort G and request 
from local authorities
Section to be 
changed
3.3.2 Inclusion criteria Part 2 Cohort G
Description of 
change
Added new cohort G:
Cohort G (1st line Hepatocellular Carcinoma): To be 
implemented only in countries UK, Korea, Taiwan, Hong Kong, 
Poland, Ukraine, Russia, Spain, USA, Australia.
-
The subject should have have diagnosis of  locally advanced 
or metastatic and/or unresectable histologically confirmed 
advanced hepatocellular carcinoma that is not amenable to a 
curative treatment approach (eg, transplant, surgery, ablation 
therapy) or locoregional therapy (eg, TACE).
-
No prior systemic therapy for HCC. Previous use of herbal 
therapies/traditional Chinese medicines with anti-cancer 
activity included in the label is allowed, provided that these 
medications are discontinued prior to randomization.
-
Child-Pugh Score of A.
-
Documented virology status of hepatitis, as confirmed by 
screening hepatitis B surface antigen (HBsAg), antibody to 
hepatitis B core antigen (anti-HBc), HBV DNA, anti-hepatitis 
C virus (anti-HCV) and HCV RNA as applicable.
-
Anti-viral therapy per local standard-of-care if active hepatitis 
B virus (HBV). HBV DNA to be <500IU/ml and patients on 
anti HBV therapy for >4 weeks before entering the study.
Rationale for 
change
Additional population to the trial
Section to be 
changed
3.3.3 Exclusion Criteria Part 2
Description of 
change
Change from:
2.) Not more than one CPI based treatment regimen prior to 
entering study (eg. anti-Programmed Death receptor-1 (PD-1), 
anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or 
anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-
4) antibody); Exception is for Melanoma cohort (Cohort E)
4.) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection (exception for patients in HCC cohort).
6.)Immunosuppressive corticosteroid doses (> 10 mg prednisone 
daily or equivalent) within 4 weeks prior to the first dose of 
trial medication.

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7.)Current or prior treatment with any systemic anti-cancer 
therapy either within 28 days or a minimum of 5 half-lives, 
whichever is longer before start of treatment.
17.) No Vitamin K antagonist and other anticoagulation allowed; 
LMWH allowed only for prevention not for curative 
treatment.
23.) Women who are pregnant, nursing, or who plan to become 
pregnant in the trial
24.) Uncontrolled pleural effusion, pericardial effusion, or ascites
To:
2.) Not more than one CPI based treatment regimen prior to 
entering study (eg. anti-Programmed Death receptor-1 (PD-
1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, 
or anti-cytotoxic T lymphocyte associated antigen-4 (anti-
CTLA-4) antibody) unless combination CPIs approved by the 
local regulatory agencies; For eg., Melanoma cohort (Cohort 
E).
4.) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) 
infection (exception for patients in HCC cohorts; Cohorts F& 
G).
6.) Immunosuppressive corticosteroid doses (> 10 mg prednisone 
daily or equivalent) within 4 weeks prior to the first dose of 
trial medication except for control of cerebral edema in case 
of recurrent glioblastoma (cohort D).
7.) Current or prior treatment with any systemic anti-cancer 
therapy (including radiotherapy) either within 28 days or a 
minimum of 5 half-lives, whichever is shorter before start of 
treatment 
17.) History of pneumonitis (non-infectious) within the last 5 
years
23.) Symptomatic pleural effusion, pericardial effusion, or ascites
24.) Prior treatment with any antiangiogenic treatment (e.g. 
bevacizumab, cediranib, aflibercept, vandetanib, XL-184, 

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sunitinib, etc) except for sorafenib and lenvatinib in 2nd line 
HCC cohort (Cohort F)
Rationale for 
change
Changes required to new cohort definition 
Section to be 
changed
3.3.3 Exclusion Criteria
Description of 
change
Added information:
Exclusion criteria for Glioblastoma cohort:
3. Is known to have IDH mutant variety of recurrent glioblastoma.
4. Any prior treatment with prolifeprospan 20 with carmustine wafer.
5. Any prior treatment with an intracerebral agent.
Rationale for 
change
Additional request needed for Gliobastoma population
Section to be 
changed
3.3.3 Exclusion Criteria
Description of 
change
Change from:
Exclusion criteria for HCC cohort:
1. Co-infection with HBV and HCV or HBV and hepatitis D 
virus (HDV)
2. Known fibrolamellar HCC, sarcomatoid HCC, or mixed 
cholangiocarcinoma and HCC
3. History of hepatic encephalopathy
To:
Exclusion criteria for HCC cohorts (cohorts F & G):
1. Co-infection with HBV and HCV or HBV and hepatitis D 
virus (HDV)
2. Known fibrolamellar HCC, sarcomatoid HCC, or mixed 
cholangiocarcinoma and HCC
3. Untreated active Hepatitis B virus (HBV)
Rationale for 
change
Changes required for HCC population cohort F and G
Section to be 
changed
4.1.2.2 
Part 2

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Description of 
change
Change from:
Once at least 6 patients have received at least 1 cycle at the maximum 
dose level, a safety evaluation of all patients treated in Part 1 will be 
performed. Based on all this safety data, the SMC may approve the 
selected BI 836880 dose (RP2D) to be used in combination with BI 
754091 for Part 2 of the trial. This data will be supported with the PK 
and PD analysis of at least 3 patients in each dose cohort.
To:
Once at least 6 patients have received at least 1 cycle at the maximum 
dose level in Part 1, a safety evaluation of all patients treated in Part 1 
will be performed. Based on all available data, the SMC may approve 
the selected BI 836880 dose (RP2D) to be used in combination with 
BI 754091 for Part 2 of the trial. The RP2D assessment will be 
supported with the PK and PD analysis of at least 3 patients in each 
dose cohort.
Update after SMC decision:
The SMC selected the dose BI 836880 720 mg and for BI 754091 240 
mg as dose for the Part 2 of this trial.
Rationale for 
change
Added information regarding Part 2 dase according to SMC decision
Section to be 
changed
4.1.4 
Description of 
change
Change from:
If symptoms of an infusion-related reaction CTCAE grade 2 or higher, 
but not qualifying as DLT according to Section 5.3.1 occur, the 
infusion should be temporarily stopped. Upon recovery, it should be 
infused at 50% of the rate at which the reaction occurred. 
To:
If symptoms of an infusion-related reaction CTCAE grade 2 or higher, 
the infusion should be temporarily stopped. The intensity and 
prolongation of vital sign monitoring should be considered. Upon 
recovery, the study drug should be infused at 50% of the rate at which 
the reaction occurred.
Rationale for 
change
Adaption regarding new available data.
Section to be 
changed
4.1.4
Description of 
change
Re-treatment criteria – was renamed to:
Drug re-administration criteria after the first cycle has been 
completed for Part 1:

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And information regarding Part 2 was added:
Drug re-administration criteria after the first cycle has been 
completed in Part 2: 
Before initiating a new treatment cycle the current health status of the 
patient will be assessed according to the Flow Chart. 
To continue treatment with further cycles, all of the following criteria 
must be met:
1. Pre-infusion SBP should be < 160 mmHg and pre-infusion DBP 
should be < 100 mmHg; study drug administration of both study 
drugs should be temporarily delayed until BP < 160/100. Please see 
Table 10.2.1:1 in Appendix 10.2.1, which describes the guidelines 
for BP management and study drug administration. 
2. QTcF <=480 ms (according to Exclusion-Criterion #8) 
3. Echocardiography if clinically indicated (based on investigators 
judgment) with Left Ventricular Ejection Fraction (LVEF) ≥ 50%
4. Acceptable tolerability (in case of an adverse event at the planned 
start of a treatment cycle patients may continue therapy only after 
recovery to a level which would allow further therapy in the 
opinion of investigator).
In case the above mentioned criteria 2, 3, and 4 are not fulfilled the 
patient should be re-evaluated as needed. Any case of a delay in 
treatment cycle should be communicated to the Clinical Monitor at 
Boehringer Ingelheim. The investigator in agreement with the 
Clinical Monitor will decide about further treatment of individual 
patient, based on known risk/benefit of BI 836880 and BI 754091. 
Rationale for 
change
Changes refers to feedback from authorities and CTP development
Section to be 
changed
4.1.4 Dose reduction guidelines Part 2
Description of 
change
Information was changed to:
Part 2:
Dose escalations of BI 836880 or BI 754091 in any patient is not 
allowed. 
Dose reductions are not allowed for BI 754091 in any patient.

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In the dose expansion study, only dose reductions are allowed for BI 
836880.
Table 4.1.4: 3 Dose reduction recommendations for BI 836880 in Part 
2
BI 836880 received dose 
BI 836880 reduced dose 
720 mg
480 mg
A dose reduction of BI 836880 from 720 mg to 480 mg is allowed, if 
investigator can attribute the AE unequivocally to the BI 836880 (for 
eg., hypertension). If the reduced dose is still intolerable, the dose 
maybe delayed (please see below the sub-section “Delay of 
treatment”) . Where deemed in the best interest of the patient, the 
investigator may restart at the originally assigned dose of 720 mg of 
BI 836880 as soon as deemed clinically appropriate.
Delay of Treatment:
During combination therapy, if treatment is held or discontinued due 
to an AE(s), both BI 836880 and BI 754091 will be held or 
discontinued together. If treatment is to be restarted after resolution (≤ 
Grade 1 or baseline) of the AE, both BI 836880 and BI 754091 must 
be started together. The combination therapy may be delayed for up to 
6 weeks because of AEs, following discussion with the sponsor.
Rationale for 
change
Changes refer to the possibility to down dithrate the dose for the 
patients in case of AEs.
Section to be 
changed
4.2.2 Restrictions
Description of 
change
Changed from:

Concomitant anti-cancer therapy is not allowed. Radiotherapy 
for local symptom control of non-target lesions can be allowed 
after consulting the investigator and sponsor.
To:
Concomitant anti-cancer therapy is not allowed. Radiotherapy for 
local symptom control of non-target lesions can be allowed after 
consulting the investigator and sponsor. Palliative radiotherapy will 
not be allowed during the first cycle for any lesion. Palliative 
radiotherapy is allowed only for non-target lesions, following 
discussion with the Medical Monitor, provided that the reason for 
radiotherapy does not reflect PD and does not interfere with response 
assessment. Lesions that have been exposed to radiotherapy are no 
longer evaluable, and may not be included in the assessment of the 
non-target lesions and the overall assessment. Unless in emergency 

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situations, the Medical Monitor should be contacted prior to the 
administration of palliative radiotherapy in the expansion phase.
Rationale for 
change
Clarification to explain the specific restrictions
Section to be 
changed
4.2.2.3 Restrictions regarding women of childbearing potential
Description of 
change
Change to:
4.2.2.3 
Restrictions regarding women of childbearing potential 
Women of childbearing potential must use the contraception methods 
described in the patient information. Due to the advanced stage of 
disease of Phase I trial patient populations and the high medical need, 
females of childbearing potential can be included in this trial provided 
that they agree to use a highly-effective contraception method. These 
are methods of birth control per the International Committee on 
Harmonisation (ICH) M3 (R2) that result in a low failure rate of less 
than 1% per year when used consistently and correctly. 
Highly-effective methods of contraception include: 

Combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation, Oral,
intravaginal, transdermal 

Progestogen-only hormonal contraception associated with 
inhibition of ovulation: oral, injectable, implantable

Intrauterine device 

Intrauterine hormone-releasing system 

Bilateral tubal occlusion 

Vasectomised partner o provided that partner is the sole sexual 
partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the 
surgical success.

Sexual abstinence o defined as refraining from heterosexual 
intercourse during the entire period (stated above) of risk 
associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the 
subject. 
Details of these contraception methods are described in the patient 
information in the ICF.
Women of childbearing potential must follow these methods during 
the trial and for at least 6 months after the end of the trial treatment. 
Although use of a contraceptive pill is considered a highly-effective 
method of birth control, women of childbearing potential taking a 
contraceptive pill must use an additional barrier method for the entire 
duration of the trial treatment intake and for 6 months after the end of 
the trial treatment intake. 

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Male patients with partners of childbearing potential must agree to use 
condoms and ensure their partner is using an additional highly-
effective method of birth control, during the trial and until at least 6 
months after the end of the trial treatment.
Rationale for 
change
Adaption to clarify the information regarding restrictions regarding 
women of childbearing potential.
Section to be 
changed
5.1 Assessment of Efficacy 
Description of 
change
Added information:
The same method of assessment and the same technique should be 
used also in follow up of identified and reported lesions. Lesions in 
previously irradiated areas may not be used as target lesions (except 
recurrent glioblastoma after a period of 12 weeks). Baseline evaluation 
must be performed as close as possible to the treatment start and no 
more than 28 days before start of treatment. 
Efficacy endpoints will be assessed every 2 cycles (6 weeks) as 
specified in the FC. An additional evaluation at EoT is only 
applicable; when patient has no PD documented, will not continue 
with regular imaging in Follow-up period and did not have imaging 
within the last 4 weeks before EoT. At Safety Follow-up visit, in case 
a patient has discontinued due to PD one additional tumor assessment 
should be done in case no other cancer treatment has been initiated. 
All measurements must be recorded in metric notation.
All tumor imaging performed in this trial will be collected by authorized 
CRO and stored until shipment to Boehringer Ingelheim. The CRO will 
not be implicated in tumor response evaluation. This collected data may
be considered for central review at a later time point.  
Additionally added:
5.1.1 Tumor response assessments using RECIST 1.1
5.1.2 Tumor response assessments using RANO
Including the RANO criteria
Rationale for 
change
To address the evaluation regarding the Glioblastoma cohort 
Section to be 
changed
5.2.1 Physical examination
Description of 
change
Change from:
A complete physical examination (including cardiac, neurological, 
dermatological, pulmonological etc.), record of height (only at 
screening visit), weight and ECOG performance score will be 
performed at screening and before start of treatment and EoT and 
EoR. At further time points specified in the FC not a complete PE 
must be done, but at minimum the actual health status of the patient 

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should be assessed (incl. evaluation of BP, ECG, lab values, AE, 
Concomitant Treatments, ECOG as applicable). During the physical 
examination, the patient should be assessed for possible AEs.
To:
A complete physical examination (including cardiac, neurological, 
dermatological, pulmonological etc.), record of height (only at 
screening visit), weight and ECOG /Karnofsky performance score will 
be performed at screening and before start of treatment and EoT and 
Safety Follow-up. At further time points specified in the FC not a 
complete PE must be done, but at minimum the actual health status of 
the patient should be assessed (incl. evaluation of BP, ECG, lab 
values, AE, Concomitant Treatments, ECOG/Karnofsky as 
applicable). During the physical examination, the patient should be 
assessed for possible AEs.
Rationale for 
change
Updating the information regarding Gliostoma cohort evaluation and 
the re-wording of the EoR to Saftey Follow-up visit.
Section to be 
changed
5.2.2 Vital signs
Description of 
change
Adapted to:
Vital signs (blood pressure, heart rate and body temperature) will be 
recorded at every visit indicated in the FC.
In Part 1, on days of study drug administration, blood pressure and 
heart rate will be evaluated at three time points:
1. Pre-dose (-60 min. to -5 min.), before infusion of BI 754091
2. 5 to 10 minutes before infusion of BI 836880,
3. 5 to 10 minutes after infusion of BI 836880.In case of an 
infusion-related reaction, the Investigator should decide 
whether to intensify or prolong monitoring of vital signs of the 
patient.
In Part 2, on days of study drug administration, blood pressure and 
heart rate will be evaluated at two time points:
1. Pre-dose (-60 min. to -5 min.), before infusion of BI 754091; 
the results should be assessed using the BP management and 
study drug administration guidelines in Appendix 10.3
2. 5 to 10 minutes after infusion of BI 836880.
In case of an infusion-related reaction, the Investigator should decide 
whether to intensify or prolong monitoring of vital signs of the patient.
Frequency of blood pressure measurements at each time point 

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Systolic and diastolic blood pressure as well as pulse rate 
(electronically or by palpation, count for 1 minute) will be measured 
after 5 minutes of rest in the seated position.
In Part 1, the blood pressure measurement should be performed three 
times at each time point and the values of these measurements will be 
entered in the eCRF. In Part 2, only a single blood pressure 
measurement is required at each time point.
Further details on the procedure for blood pressure measurements are 
given in Appendix 10.2.
Rationale for 
change
Information specified for Part1 and Part2 and adapted for the new 
settings
Section to be 
changed
5.2.3 Safety laboratory parameters
Description of 
change
Changed from:
…Therefore it’s possible to take blood sample a valuable time ahead 
(usually the day before treatment). Safety laboratory examinations will 
include hematology, biochemistry, coagulation and urine analysis:
To:
Therefore it’s possible to take blood sample a valuable time ahead 
(usually the day before treatment but possible up to approximately 72 
hours before). Safety laboratory examinations will include 
hematology, biochemistry, coagulation and urine analysis:
Change from:
Biochemistry
Glucose, sodium, potassium, 
calcium, magnesium, inorganic
phosphate, creatinine, AST, ALT,
alkaline phosphatase (AP), lactate 
dehydrogenase (LDH), bilirubin, 
urea, total protein, albumin, uric 
acid, CK, CK-MB
Serum immunoglobulin levels 
(IgG, IgM, IgA; IgE) and direct 
antiglobulin test have to be 
measured at Screening and at
occurrence of infusion related 
reactions.
To
Biochemistry
Glucose, sodium, potassium, 
calcium, magnesium, inorganic

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phosphate, creatinine, AST, ALT,
alkaline phosphatase (AP), lactate 
dehydrogenase (LDH), bilirubin, 
serum urea nitrogen (or urea), 
thyroid panel [TSH, free T4, and 
free T3]), urinalysis total protein,
albumin, uric acid, CK, In case of 
pathological CK elevated, then 
CK-MB, additional troponin, and 
myoglobin as available should be 
reactively tested and the findings 
documented.
Serum immunoglobulin levels (IgG, IgM, IgA; IgE) and direct 
antiglobulin test have to be measured at Screening and at occurrence
of infusion related reactions.
Change from:
Pregnancy test
A serum pregnancy test needs to be 
obtained at the time 
points indicated in the Flow Chart in 
patients of childbearing 
potential.
To:
Pregnancy test                              A pregnancy test needs to be 
obtained at the time points 
indicated in the Flow Chart in 
patients of child bearing 
potential. A beta human 
chorionic gonadotropin (β-HCG) 
pregnancy test in serum will be 
performed for women of 
childbearing potential (WOCBP) 
at screening. Thereafter, this test 
may be done in serum or urine 
on Day 1 of each cycle, at the 
EOT visit. If the urine test is 
positive or cannot be confirmed 
as negative, a serum pregnancy 
test will be required.
Added information:
Screening for Infections             HIV-1 and HIV-2 antibody 
(qualitative, as per applicable 

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local regulations, at the 
discretion of the Investigator 
where clinically indicated).
Hepatitis B serology (HBsAg, 
anti-HBc qualitative) and 
Hepatitis C serology (anti-HCV 
qualitative) for screening active 
Hepatitis B and Hepatitis C. For 
HCC cohorts (cohorts F & G) 
additional tests may include 
HBV DNA (if needed), HCV 
RNA (if needed) and Hepatitis D 
(anti-HDV qualitative).
Rationale for 
change
To clarify needed safety lab parameters
Section to be 
changed
5.2.4 Electrocardiogram
Description of 
change
Changed from:
For the part 2:
1.        1st cycle pre and post treatment. Cycle 2,3 and 4 only one 
ECG pre treatment and then on ECG at pre treatment performed 
every second cycle (cycle 6,8, 10…etc)
2.
shortly before the end of the infusion of trial medication 
(only at cycle 1).
To:
For the part 2:
1.
Cycle 1 to 4 pre and post treatment (within 60 min after 
completion of administration of BI 836880)
and 
thereafter ECG at pre- and post treatment of BI 836880 
performed every second cycle (cycle 6,8, 10…etc)
Rationale for 
change
Clarification to the Part 2 ECGs
Section to be 
changed
5.2.5 Echocardiography
Description of 
change
Change from:
Echocardiography have to be conducted at screening (not older than 7 
days) and at EoT-visit.
During treatment phase it has only to be done when clinically 
indicated.
To:

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Echocardiography have to be conducted at screening (not older than 
21 days before treatment start) and at EoT-visit. During treatment 
phase it has only to be done when clinically indicated.
Rationale for 
change
More relaxed time window was introduced to help the sites in multiple 
countries manage Echocardiography based on their local practices. 
Based on data from Part 1 there are no concerns to having a relaxed 
window.
Section to be 
changed
5.2.6.1 Dose limiting toxicities (DLTs)
Description of 
change
Added:
Once the dose escalation part of the study has been completed (Part 1), 
DLTs no longer need to be reported (i.e. Part 2). 
Rationale for 
change
To clarify of no DLTs in Part 2 of the trial.
Section to be 
changed
5.2.7 Assessment of adverse events
Description of 
change
Different changes in the wording:
From:
Dose Limiting Toxicities
All DLTs are considered to be AESIs, and must be reported as such. 
The definition of DLT is presented in Section 5.2.6.1.
Severe Hypertension
A hypertensive episode will be considered an AESI if:

SBP >= 140 mmHg or DBP >= 90 mmHg which persists
longer than 2 days despite either he initiation of 
antihypertensive agent(s) in a patient without prior history of 
hypertension, or the intensification / addition of new 
antihypertensive agents in a patient with prior history of 
hypertension. 
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. Although all irAEs are to be reported as 
AEs, only clinically important irAEs need to be reported as AESIs as 
defined by the sponsor in Appendix 10.3. If an Investigator determines 
that a Grade 3 AE that is not included in Appendix 10.3 is an irAE, 
that event should also be reported as an AESI.

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Recommendations for the management of irAEs are presented in 
Appendix 10.4. 
Infusion-related reactions
In the event of an infusion-related reaction ≥ Grade 2, the infusion rate 
of BI 836880 or 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 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 4 or higher in severity at any 
point during the study, treatment with BI 836880 or BI 754091 will be 
permanently discontinued.
As with any mAb, allergic reactions to BI 754091 administration are 
possible. Appropriate drugs and medical equipment to treat acute 
anaphylactic reactions must be immediately available, and trial 
personnel must be trained to recognize and treat anaphylaxis. The trial 
site must have immediate access to emergency resuscitation teams and 
equipment in addition to the ability to admit patients to an intensive 
care unit if necessary.
The following events describe those events that are to be considered 
potential infusion-related AEs. Regardless of grade, these events are 
considered as AESIs and must be reported within 24 hours of the 
event:

Allergic reaction

Anaphylaxis

Cytokine-release syndrome

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 must report that 
event as an AESI.
Potential Hepatic injury

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A potential hepatic injury is defined by the following alterations of 
hepatic laboratory

Parameters:

For patients with normal aminotransferase levels at 
baseline: 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 without evidence 
of cholestasis, OR aminotransferase elevations ≥10 fold ULN

For patients with abnormal aminotransaminase levels at 
baseline >1 and <2.5 x ULN at baseline: An elevation of 
AST and/or ALT ≥3 fold the baseline value combined with an 
elevation of bilirubin ≥2 fold ULN and the baseline value in 
the same blood sample; OR Aminotransferase elevations ≥5 
fold the baseline value.

For patients with abnormal aminotransaminase levels at 
baseline >=2.5 and <=5 x ULN at baseline (patients with 
liver metastases only): An elevation of AST and/or ALT ≥2 
fold the baseline value combined with an elevation of bilirubin 
≥2 fold ULN and the baseline value in the same blood 
sample; OR Aminotransferase elevations ≥3 fold the baseline 
value.
These lab findings constitute a hepatic injury alert and the patients 
showing these lab abnormalities need to be followed up according to 
the “DILI checklist” provided in the ISF. 
In case of clinical symptoms of potential 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 analyzed, if necessary in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the 
procedures described in the DILI checklist should be followed
To:
Dose Limiting Toxicities
All DLTs are considered to be AESIs, and must be reported as such. 
The definition of DLT is presented in Section 5.2.6.1. DLTs are no 
longer applicable in Part 2 of the study, therefore are no longer AESIs 
in Part 2. 
Persistent hypertension despite treatment 
A hypertensive episode will be considered an AESI if:

SBP >= 140 mmHg or DBP >= 90 mmHg which persists
longer than 2 days despite either he initiation of 

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antihypertensive agent(s) in a patient without prior history of 
hypertension, or the intensification / addition of new 
antihypertensive agents in a patient with prior history of 
hypertension. 
Immune-related adverse events (irAE)
Although all irAEs are to be reported as AEs, only clinically important 
irAEs need to be reported as AESIs as defined by the sponsor in
Appendix 10.3. Non-clinically important irAEs, such as mild to 
moderate rash and hypothyroidism, for example, do not need to be 
reported as AESIs. If an Investigator determines that a severe irAE or 
other clinically significant irAE that is not included in Appendix 10.3
is medically significant, the investigator may, also report this irAE as 
an AESI.
Recommendations for the management of irAEs are presented in 
Appendix 10.4. 
Infusion-related reactions
All infusion-related reactions need to be reported as AESIs.
In the event of an infusion-related reaction ≥ Grade 2, the infusion rate 
of BI 836880 or 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 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 4 or higher in severity at any 
point during the study, treatment with BI 836880 or BI 754091 will be 
permanently discontinued.
As with any mAb, allergic reactions to BI 836880 and BI 754091 
administration are possible. Appropriate drugs and medical equipment 
to treat acute anaphylactic reactions must be immediately available, 
and trial personnel must be trained to recognize and treat anaphylaxis.
The trial site must have immediate access to emergency resuscitation 
teams and equipment in addition to the ability to admit patients to an 
intensive care unit if necessary.
The following events describe those events that are to be considered 
potential infusion-related AEs. Regardless of grade, these events are 

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considered as AESIs and must be reported within 24 hours of the 
event:

Allergic reaction

Anaphylaxis

Cytokine-release syndrome

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 must report that 
event as an AESI.
Potential DILI 
A potential DILI is defined by the following alterations of hepatic 
laboratory

Parameters:

For patients with normal aminotransferase levels at 
baseline: 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 without evidence 
of cholestasis, OR aminotransferase elevations ≥10 fold ULN

For patients with abnormal aminotransaminase levels at 
baseline >1 and <2.5 x ULN at baseline: An elevation of 
AST and/or ALT ≥3 fold the baseline value combined with an 
elevation of bilirubin ≥2 fold ULN and the baseline value in 
the same blood sample; OR Aminotransferase elevations ≥5 
fold the baseline value.

For patients with abnormal aminotransaminase levels at 
baseline >=2.5 and <=5 x ULN at baseline (patients with 
liver metastases only): An elevation of AST and/or ALT ≥2 
fold the baseline value combined with an elevation of bilirubin 
≥2 fold ULN and the baseline value in the same blood 
sample; OR Aminotransferase elevations ≥3 fold the baseline 
value.
These lab findings constitute a potential DILI alert and the patients 
experiencing these lab abnormalities need to be followed up according 
to the “DILI checklist” provided in the ISF, unless an underlying other 
than study drug(s) cause has been determined 
Rationale for 
change
Adapted wording to the part 2 and the clarification of DILI and 
infusion related reactions.

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Section to be 
changed
5.2.7.2 
Adverse event collection and reporting
Description of 
change
Change from:
…

After the end of the REP until individual patient’s end of trial: any 
new occurrence of cancer of new histology, all related SAEs and 
all related AESIs.
…
The Residual Effect Period (REP) is defined as 42 days after the last 
trial medication administration
….
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs 
which are relevant for the reported SAE or AESI, on the BI SAE form 
via fax immediately (within 24 hours ) to the sponsor’s unique entry 
point (country specific contact details will be provided in the ISF).
To:

After the end of the REP (Safety Follow up visit) until individual 
patient’s end of trial: any new occurrence of cancer of new 
histology, all related SAEs and all related AESIs.
…
The Residual Effect Period (REP) is defined as 30 days after the last 
trial medication administration
….
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs 
which are relevant for the reported SAE or AESI, on the BI SAE form 
immediately (within 24 hours ) to the sponsor’s unique entry point 
(country specific reporting process will be provided in the ISF). 
Rationale for 
change
Updating the SAE collection information, reducing the REP from 42 
to 30 days.
Section to be 
changed
5.3.2 Methods of sample collection
Description of 
change
Change from:
For quantification of analyte plasma concentrations, samples will be 
drawn at the time points listed in the Flow Chart under PK sampling 
and specified in PK time schedules in Appendix 10.4. Plasma will be 
divided into duplicate aliquots for each analyte (in total 4 aliquots) and 
stored frozen at about -70°C at the participating sites or logistics CRO 
until shipment on dry ice to the bioanalytical laboratory of Boehringer 
Ingelheim or a Boehringer Ingelheim selected and authorized CRO.
To:

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For quantification of analyte plasma concentrations, samples will be 
drawn at the time points listed in the Flow Chart under PK sampling 
and specified in PK time schedules in Apendix 10.5. The provided 
sampling timepoints are depicted as planned timepoints, however 
according to Section 4.1.4, the infusion time may be adapted. In this 
case, the PK sampling referring to the “end” time of the infusion 
should be performed shortly after the end of infusion including 
flushing of the tubes, no matter the duration of the infusion.
The subsequently requested PK sampling should be drawn as planned.
Do not adapt the time because of the variation of the duration of the 
infusion schema.
Rationale for 
change
Clarifictaion to the PK sample collections timepoints
Section to be 
changed
5.4 ASSESSMENT OF BIOMARKER(S)
Description of 
change

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Rationale for 
change
Clarification regarding biopsies and biomarker assessment
Section to be 
changed
5.4.1.Methods of sample collection –Part 2
Description of 
change

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Rationale for 
change
Clarification on needed Biopsy material.
Section to be 
changed
Description of 
change
Rationale for 
change
Section to be 
changed
Description of 
change

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Section to be 
changed
Section to be 
changed
5.5.1 Immunogenicity assessments
Description of 
change
Change from:
Methods of ADA sample collection
For the determination of anti-drug antibodies (ADA), approximately 3 
mL of blood will be taken from a forearm vein in a K2 EDTA 
(ethylendiaminetetraacetic acid) anticoagulant blood drawing tube at 
those time points specified in the Flow Chart and in Appendix 10.4. 
EDTA plasma will be divided into duplicate aliquots into 2 mL 
cryovials and stored frozen at approximately -70oC or below at the 
investigator sites or logistics CRO until shipment on dry ice to the 
bioanalytical laboratory. The second aliquot will be shipped only after 
the acknowledgement of receipt of the first aliquot. Details about 
sample collection, preparation, storage and shipment are described in 
the laboratory manual.

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To:
For ADA assessments (BI 836880 and BI 754091), the specified blood 
volume will be drawn into blood-drawing tubes at the time points 
listed in the flow chart and Appendix 10.5.
Details on sample characteristics, processing, handling, and shipment 
are provided in the Laboratory Manual.
Rationale for 
change
Clarification regarding the us e of ADAs in this trial.
Section to be 
changed
6.1 Visit Schedule
Description of 
change
Added information:
During the treatment phase of Part 2, hospitalization is not required, 
and the period of surveillance is left at the discretion of the 
investigator. Investigators should consider that although infusion 
reactions to any monoclonal antibody typically develops within 30 
minutes to two hours after the initiation of drug infusion, symptoms 
may be delayed for up to 24 hours. Some patients may also develop 
severe hypertensive episodes, and treatment should be considered 
accordingly. Please see Section 4.1.4 for the required criteria to 
administer study drugs after the first cycle. Please see Section 5.2.7.1
for guidelines on how to report and
manage infusions related reactions, and Appendix 10.2.1 for BP 
management and study administration guidelines
Rationale for 
change
Clarification regarding hospitalization in the Part 2.
Section to be 
changed
6.2.1 Screening and run-in period(s
Description of 
change
Changed from:
The examinations required for the screening visit may be conducted 
within a time interval of 21 days prior to the first study drug 
administration. Prior to any other study related procedure, written 
informed consent must be obtained from the patient.
CT/MRI images obtained prior to study participation can be used 
within the study as long as they are not older than 28 days at day of 
first treatment.

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Echocardiography must be obtained within 7 days before start of 
treatment.
If for administrative or medical reasons, the patient is not entered 
within the defined screening period, re-assess of eligibility parameter 
could be allowed after discussion with Clinical Monitor. This should 
be considered as exceptional situation and not a general rule. 
If the patient has been determined eligible by the investigator to enter 
the trial (refer to Section 3.3), the investigator will assign one or more 
medication number(s) to the patient through the IRT system at Visit 1 
(Section 4.1.3). First dose of BI 836880+ BI 75091 will be 
administered at the beginning of Visit 1 at the trial site (Day 1, cycle 
1).
To:
The examinations required for the screening visit may be conducted 
within a time interval of 21 days prior to the first study drug 
administration. Prior to any other study related procedure, written 
informed consent must be obtained from the patient.
CT/MRI images obtained prior to study participation can be used 
within the study as long as they are not older than 28 days at day of 
first treatment.
For Glioblastoma patient only, MRI 14 days before treatment start is 
required
Echocardiography must be obtained within 7 days before start of 
treatment.
I possible to take blood sample a valuable time ahead (usually the day 
before treatment but possible up to 72 hours before).
For cohort D (Glioblastoma) patient the base line status on IDH and 
MGMT methylation need to be captured in the eCRF if available.
If for administrative or medical reasons, the patient is not entered 
within the defined screening period, re-assess of eligibility parameter 
could be allowed after discussion with Clinical Monitor. This should 
be considered as exceptional situation and not a general rule. 
If the patient has been determined eligible by the investigator to enter 
the trial (refer to Section 3.3), the investigator will assign one or more 
medication number(s) to the patient through the IRT system at Visit 1 
(Section 4.1.3). First dose of BI 836880+ BI 754091 will be 
administered at the beginning of Visit 1 at the trial site (Day 1, cycle 
1)

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Rationale for 
change
Clarification and adding of Cohort D specific procedures.
Section to be 
changed
6.2.2.Treatment period
Description of 
change
Change from:
For Part 2 tumour assessment should be done every 6 weeks (in 
accordance to local requirements). Assessments are always done prior 
to the start of the new treatment cycle. At EOT and EOR only when
applicable (see Section 5.1)
To:
For Part 2 tumour assessment should be done every 6 weeks (in 
accordance to local requirements with a window of minus 7days). 
Assessments are always done prior to the start of the new treatment 
cycle. At EOT and Safety Follow-up visit only when applicable (see 
Section 5.1)
Rationale for 
change
Adapted wording to the change of the EOR visit to Safety Follow-up 
visit
Section to be 
changed
6.2.4 Residual effect period (REP)
Description of 
change
Changed from:
The REP is defined in Section 5.2.7.2. The End of REP (EoR) visit 
should not be performed earlier than 42 days after permanent 
discontinuation of the trial medication. In case the patient 
discontinued due to PD by RECIST 1.1, one additional tumour 
assessment should be done at EOR visit. The information collected at 
this visit should include all new AEs that occurred after EOT and a 
follow-up of adverse events ongoing at EOT. Any subsequent anti-
cancer therapy administered between EoT and EoR should be reported
To:
The REP is defined in Section 5.2.7.2. The End of REP the Safety 
Follow-up visit should not be performed earlier than 30 days after 
permanent discontinuation of the trial medication (last day medication 
was administered). In case the patient discontinued due to PD by 
RECIST 1.1/RANO, one additional tumor assessment should be done 
at the Safety Follow-up visit or time close according to requested 6 
weeks interval for images. The information collected at this visit 
should include all new AEs that occurred after EOT and a follow-up 
of adverse events ongoing at EOT. Any subsequent anti-cancer 
therapy administered between EoT and EoR should be reported.
Rationale for 
change
Adaption, to wording, new RANO assessment and different time 
window. 

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Section to be 
changed
7.3 Planned Analyses
Description of 
change
Changed from:
For the determination of the MTD, only MTD-evaluable patients will 
be considered. For the analysis of secondary and further endpoints, 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
To:
For the determination of the MTD, only MTD-evaluable patients will 
be considered. For the analysis of secondary and further endpoints in 
Part 1, all patients in the treated set (i.e., patients treated with at least 
one dose of trial medication) will be included in the analysis. All 
analyses planned in Part 2 will be based on the treated set.
Rationale for 
change
Adapted wording regarding Part 2.
Section to be 
changed
7.3.1.2 Primary endpoint analyses for Part 2
Description of 
change
Change from:
The primary endpoint for Part 2 of the trial is OR defined by 
confirmed CR or PR according to RECIST 1.1 as assessed by the 
Investigator. Overall response will be analyzed in terms of the 
shrinkage estimator of the OR rate (ORR) based on BHM.
To:
The primary endpoint for Part 2 of the trial is OR defined by 
confirmed CR or PR according to RECIST 1.1 for all cohorts except 
GBM as assessed by the Investigator. OR in GBM cohort will be 
evaluated using RANO criteria. Overall response will be analyzed in 
terms of the shrinkage estimator of the OR rate (ORR) based on BHM.
Rationale for 
change
Adaption for the Glioblastoma Cohort D and the RANO criteria
Section to be 
changed
7.3.2.2 Secondary endpoint analyses for Part 2
Description of 
change
Change From:
Disease control (DC) will be analyzed in terms of DC rate (DCR), 
defined as the proportion of patients with best overall response of CR, 
PR, or SD according to RECIST 1.1. Proportions will be presented 
with 95% two-sided confidence interval using the exact Clopper-
Pearson method.
Duration of objective response (DoR) - for all patients with an OR, the 
duration of OR is defined as time from first documented CR or PR to 
the earliest of disease progression or death among patients with OR.  
If a patient did not die or progress until the last visit in the study, this 

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patient will be censored at the last time point known to be alive and 
progression-free. 
The outcome will be assessed according to RECIST 1.1.
To:
Disease control (DC) will be analyzed in terms of DC rate (DCR), 
defined as the proportion of patients with best overall response of CR, 
PR, or SD according to RANO for GBM & RECIST1.1 for all other 
cohorts. Proportions will be presented with 95% two-sided confidence 
interval using the exact Clopper-Pearson method.
Duration of objective response (DoR) - for all patients with an OR, the 
duration of OR is defined as time from first documented CR or PR to 
the earliest of disease progression or death among patients with OR.  
If a patient did not die or progress until the last visit in the study, this 
patient will be censored at the last time point known to be alive and 
progression-free. The outcome will be assessed according to RANO 
for GBM & RECIST1.1 for all other cohorts.
Rationale for 
change
Adaption for the Glioblastoma Cohort D and the RANO criteria
Section to be 
changed
Description of 
change
Rationale for 
change
Section to be 
changed
7.4 Interim Analysis – Part 2
Description of 
change
Change from:
In Part 2 we are randomizing 200 patients. 40 patients for the each of 
the cohorts A and B, and 30 patient for each of the cohorts C, D, E and 
F. An interim futility analysis will be performed for cohort C, D, E 
and F in Part 2. Until any decision from the futility analysis is done, 

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the enrolment of next patient will not be stopped. The two-stage 
design is planned to stop further recruitment of patient if the defined 
efficacy boundary (see Table 7.7.2: 1) is not met at the first stage. 
The interim analyses for each cohort will be conducted after 15th
patients in that cohort have completed their two on-treatment imaging 
assessment (i.e. end of cycle 4). 
In addition, if considered necessary interim analysis may be 
performed for evaluation of the efficacy and safety aspects as each 
cohort is finished.
To:
In Part 2, 230 patients are planned to be treated. 40 patients each are 
planned for cohorts A and B, and 30 patients each are planned for 
cohorts C, D, E, F, and G. An interim futility analysis will be 
performed for cohorts C, D, E, F, and G in Part 2. The interim 
analyses for each cohort are planned to be conducted after 15 patients 
in that cohort have completed their two on-treatment imaging 
assessments (i.e., end of cycle 4). For each cohort, timing of the 
interim analysis may be adjusted according to actual recruitment rate 
to facilitate or avoid delay of the trial conduct. Until any decision from 
the futility analysis is done, the enrollment of next patient will not be 
stopped. The two-stage design is planned to stop further recruitment of 
patients if the defined efficacy boundary (see Table 7.7.2: 1) is not met 
at the first stage. 
Section to be 
changed
Adaptions regarding new cohort
Section to be 
changed
7.7.2 Determination of sample size for Part 2
Description of 
change
Change from:

Cohort F: patients with locally advanced or metastatic and/or 
unresectable Hepatocellular Carcinoma (HCC) who were intolerant 
or progressed during 1st line sorafenib or lenvatinib treatment; 
subsequent CPI therapy is allowed as the most recent anticancer 
treatment.
…..
For cohort D (GBM), around 25% ORR with Bevacizumab is 
assumed. In AVF3708 (R11-2708), which is an open-label study in 
patients with glioblastoma who had progressed following initial 
treatment with temozolomide and radiation, the ORR was 28% 
[95%CI, 19-40] (N=85). Based on above results, the futility boundary 
for cohort D is set as 25% at planned interim futility analysis timing.

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For cohort F (HCC), around 15% ORR with anti-PD-1 antibody 
monotherapy is assumed. In Checkmate-040 (R17-3829) which is an 
open label phase I/II trial of Nivolumab in patients with advanced 
hepatocellular carcinoma, the ORR was 20% [95%CI, 15-26] (N=50) 
in dose expansion phase and 15% [95% CI, 6-28] (N=10) in the dose 
escalation phase. In KEYNOTE-224 (R19-0168) which is a phase 2 
study of Pembrolizumab in patients with advanced hepatocellular 
carcinoma previously treated with sorafenib , the ORR was 17% [95% 
CI, 11-26] (N=104). Based on above result, the futility boundary for 
cohort F is set as 15% at planned interim futility analysis timing.
Different homogeneous scenarios and heterogeneous scenarios as well 
as different sample sizes are considered in the simulations to assess 
the operating characteristics of the BHM approach. The simulation 
results as shown in Table 7.7.2: 2 below show that, with the proposed 
cohort size, the BHM approach has reasonable probability of reaching 
the pre-specified response rate under a wide range of scenarios.
To:
Cohort F (2nd line HCC): patients with locally advanced or metastatic 
and/or unresectable Hepatocellular Carcinoma who were intolerant or 
progressed during 1st line sorafenib or lenvatinib treatment; subsequent 
CPI therapy is allowed as the most recent anticancer treatment.

Cohort G (1st line HCC): patients with locally advanced or 
metastatic and/or unresectable HCC with no prior systemic 
treatment
A total of approximately 230 patients will be enrolled for these 7 
cohorts. 40 patients each are planned for cohorts A and B, and 30 
patients each are planned for cohorts C to G
….
For cohort D (GBM), around 20% ORR with Bevacizumab is 
assumed. In a recent phase II study (R22-0513) comparing standard 
dose bevacizumab versus low dose bevacizumab plus lomustine, in 
patients with recurrent glioblastoma following standard radiation and 
temozologmide, the ORR was 19% [95% CI, 8-36] (N = 36) based on 
RANO criteria for the standard dose bevacizumab arm. Based on 
above results, the futility boundary for cohort D is set as 20% at 
planned interim futility analysis timing.
For cohort F (2nd line HCC), around 15% ORR with anti-PD-1 
antibody monotherapy is assumed. In Checkmate-040 (R17-3829) 
which is an open label phase I/II trial of Nivolumab in patients with 
advanced hepatocellular carcinoma, the ORR was 20% [95% CI, 15-
26] (N=50) in dose expansion phase and 15% [95% CI, 6-28] (N=10) 
in the dose escalation phase. In  KEYNOTE-224 (R19-0168) which is 

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a phase 2 study of Pembrolizumab in patients with advanced 
hepatocellular carcinoma previously treated with sorafenib, the ORR 
was 17% [95% CI, 11-26] (N=104). Based on above result, the futility 
boundary for cohort F is set as 15% at planned interim futility analysis 
timing.
For cohort G (1st line HCC), around 20% ORR with target 
monotherapies is assumed. In REFLECT (R20-3051), which is a 
Phase 3 study comparing Lenvatinib vs. Sorafenib, the ORR was 19% 
[95%, CI 17-21] (N = 478) for Lenvatinib and 7% [95%, CI 6-8] (N = 
476) for Sorafenib. In IMbrave150 (R22-0533), which is a Phase III 
trial comparing Atezolizumab plus Bevacizumab vs. Sorafenib, the 
ORR for Sorafenib arm observed was 12% [95% CI, 7-17] (N = 165). 
In Checkmate-459 (R22-0532), which is a phase III study comparing 
Nivolumab vs. Sorafenib, the observed ORR was 7% [95% CI, 4-10] 
(N = 372)). Based on above result, the futility boundary for cohort G 
is set as 20% at planned interim futility analysis timing.
Proposed sample size will provide accumulative safety and tolerability 
data for the investigational combination across different tumor types. 
Different homogeneous scenarios and heterogeneous scenarios as well 
as different sample sizes are considered in the simulations to assess 
the operating characteristics of the BHM approach. The simulation 
results as shown in Table 7.7.2: 2 below show that, with the proposed 
cohort size and interim futility analysis in SCLC, MLN, GBM and 
HCC cohorts, the BHM approach has reasonable probability of 
reaching the pre-specified response rate under a wide range of 
scenarios. The probability of observing a > 15% increase in the 
shrinkage estimator of the ORR under negative scenario is well 
controlled on cohort level (< 1%). Desirable true positive probabilities 
(~> 60%) and false negative probabilities (<2%) are also demonstrated 
under nugget scenarios for each cohort on proposed sample size. 
Additional update of:
Table 7.7.2: 1
Early stopping probabilities at interim for cohorts C-G 
based on observed ORR under different scenarios
Table 7.7.2: 2
Operating characteristics of the Bayesian Hierarchical 
Modelling approach for final analysis under different 
scenarios with futility evaluation at the interim
Rationale for 
change
Adaptions regarding new cohort and patient numbers.
Section to be 
changed
9.1
Description of 
change
Added information:

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R11-0753 
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, 
Sorensen AG, Galanis E, DeGroot J, Wick W, Gilbert 
MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, 
Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum 
MA, Bent MJ van den, Chang SM. Updated response 
assessment criteria for high-grade gliomas: Response 
Assessment in Neuro-Oncology Working Group. J Clin 
Oncol 2010 ; 28(11) ; 1963-1972.
R22-0513
Weathers S-P, Han X, Liu DD, Conrad CA, Gilbert MR, 
Loghin ME, et al. A randomized phase II trial of standard 
dose bevacizumab versus low dose bevacizumab plus 
lomustine (CCNU) in adults with recurrent glioblastoma. 
J Neurooncol 129 (3), 487 - 494 (2016)
R20-3051
Kudo, M, Finn RS, Qin S, Han K-H, Ikeda K, Piscaglia 
F, et al. Lenvatinib versus sorafenib in first-line 
treatment of patients with unresectable hepatocellular 
carcinoma: a randomised phase 3 non-inferiority trial. 
The Lancet 391 (10126), 1163 - 1173 (2018)
R22-0533
ESMO 2019 oncology news: atezolizumab in 
combination with bevacizumab provides superior 
outcome compared with sorafenib in unresectable HCC 
(date: 23 Nov 2019). esmo.org/oncology-
news/atezolizumab-in-combination-with-bevacizumab-
provides-superior-outcome-compared-with-sorafenib-in-
unresectable-hcc (access date: 28 Jan 2020) 2019
R22-0532
ESMO 2019 press release: clinical benefit with first-line 
immunotherapy in advanced hepatocellular carcinoma 
(date: 27 Sep 2019). esmo.org/newsroom/press-
office/esmo-congress-hepatocellular-carcinoma-cancer-
checkmate459-yau (access date: 28 Jan 2020) 2019
R20-0571 
Okada H, Weller M, Huang R, Finocchiaro G, Gilbert 
MR, Wick W, et al. Immunotherapy response assessment 
in neuro-oncology: a report of the RANO working group. 
Lancet Oncol 2015 ; 16; e534-e542.
Rationale for 
change
New available information
Section to be 
changed
10.2 BLOOD PRESSURE MEASUREMENT PROCEDURE
Description of 
change
Change from:
In Part 2, only a single blood pressure measurement is required per 
scheduled time point measurement. 

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In case of a suspected “white coat effect” it is recommended to repeat
the measurement in a pleasant condition after sufficient rest. Values
from self-blood pressure measurements (SBPM) communicated from
patient to investigator are not considered valuable for study related
decisions.
To:
In Part 2, only a single blood pressure measurement is required per 
scheduled time point, i.e. one measurement before the study drugs 
have been administered, and one measurement after the study drugs 
are administered. Please see Section 5.2.2 for further details, and 
Appendix 10.2.1 for management guidelines.
In case of a suspected “white coat effect” it is recommended to repeat
the measurement in a pleasant condition after sufficient rest. Values
from self-blood pressure measurements (SBPM) communicated from
patient to investigator are not considered valuable for study related
decisions.
Table was added:
Table 10.2.1: 1 BP management and study drug administration guidelines 
following completion of cycle 1, based on pre-infusion SBP and DBP 
measured on study drug administration visits. 
Rationale for 
change
Adaption to the new blood pressure measurement guideline for this 
trial
Section to be 
changed
10.3
Description of 
change
Change of chapter title:
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL 
INTEREST
To:
IMMUNE-RELATED ADVERSE EVENTS AS ADVERSE 
EVENTS OF SPECIAL INTEREST
Rationale for 
change
To specify the immune related events regarding events of special 
interest.
Section to be 
changed
10.5.1 Time Schedule for Pharmacokinetic (PK) and 
Pharmacodynamic Blood Sampling
Description of 
change
Added information:
According to Section 4.1.4 of the protocol, the infusion time may be 
adapted. In this case, the PK sampling referring to the “end” time of 
the infusion should be performed shortly after the end of infusion
including flushing of the tubes, no matter the duration of the infusion.

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The subsequently requested PK sampling should be drawn as planned.
Do not adapt the time because of the variation of the duration of the 
infusion schema.
Table 10.5.1:1 was modified
Change from:
According to Section 4.1.4 of the protocol, the infusion time may be 
adapted. In this case, the PK sampling referring to the” start” and 
“end” time of the infusion should be performed shortly after the end of 
infusion, no matter the duration of the infusion.
The subsequently requested PK sampling should be drawn as planned.
Do not adapt the time because of the variation of the duration of the 
infusion schema.
To:
The time for PK plasma sampling in Table 10.5.1: 1 and 10.5.1: 2 are 
nominal times and should be adhered if possible. However, as actual 
sampling times will be recorded and used for the determination of 
pharmacokinetic parameters, there is some flexibility. A guidance for 
allowed time windows for PK plasma sample collection is provided in 
Table 10.5.1: 3. 
Table 10.5.1: 3
Allowed time windows for PK plasma sample 
collection
Samples 
Time Windows
Explanation 
pre-dose Cycle 1
Before start of first infusion
1:00, 2:15
Within 15 min 
after end of 
each infusion
This time point refers to 
suggested infusion time of 1 
hour for each compound. If 
the infusion time is adapted 
please collect the sample 
within 15 min after the end of 
the infusion + flushing, when 
the full dose was 
administered 
6:00
± 1 h 
24:00, 168:00, 
336:00
± 5 h
-0:05 (pre-dose) 
all other Cycle 
besides Cycle 1
- 5 h
But before start of next 
infusion
Rationale for 
change
Windows for the PK sample collection have been added

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Section to be 
changed
10.7APPENDIX - PERFORMANCE STATUS CRITERIA
Description of 
change
Added information:
10.7APPENDIX - PERFORMANCE STATUS CRITERIA
ECOG Performance Status 
Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
0
Normal activity. Fully 
active, able to carry 
on all pre-disease 
performance without 
restriction.
100
Normal, no 
complaints, no 
evidence of disease.
90
Able to carry on 
normal activity; minor 
signs or symptoms of 
disease.
1
Symptoms, but 
ambulatory.
Restricted in 
physically strenuous 
activity, but 
ambulatory and able 
to carry out work of a 
light or sedentary 
nature (e.g., light 
housework, office 
work).
80
Normal activity with 
effort; some signs or 
symptoms of disease.
70
Cares for self, unable 
to carry on normal 
activity or to do active 
work.
2
In bed <50% of the 
time. Ambulatory and 
capable of all self-
care, but unable to 
carry out any work 
activities. Up and 
about more than 50% 
of waking hours.
60
Requires occasional 
assistance, but is able 
to care for most of 
his/her needs.
50
Requires considerable 
assistance and 
frequent medical care.
3
In bed >50% of the 
time. Capable of only 
limited self-care, 
confined to bed or 
chair more than 50% 
of waking hours.
40
Disabled, requires 
special care and 
assistance.
30
Severely disabled, 
hospitalization 
indicated. Death not 
imminent.
4
100% bedridden.
Completely disabled.
Cannot carry on any 
self-care. Totally 
20
Very sick, 
hospitalization 
indicated. Death not 
imminent.

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confined to bed or 
chair.
10
Moribund, fatal 
processes progressing 
rapidly.
5
Dead.
0
Dead.
Rationale for 
change
Clarifying the performance status criteria regarding the Cohort D and 
the Karnofsky Performance scale
11.5
GLOBAL AMENDMENT 5
Date of 
amendment
18 Nov 2020
EudraCT 
number
EU number
2017-001378-41
BI Trial 
number
1336-0011
BI 
Investigational 
Product(s)
BI 836880
BI 754091
Title of 
protocol
An open label phase Ib dose finding study of BI 836880 in 
combination with BI 754091 to characterize safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy in patients with 
locally advanced or metastatic non-squamous Non-Small Cell Lung
Cancer and in other solid tumors
Global Amendment due to urgent safety reasons
Global Amendment
Section to be 
changed
Synopsis – Study Design and Main in- and exclusion criteria
Description of 
change
Change from:
Cohort C (SCLC):
Patient with pathologically confirmed locally advanced or metastatic 
Small Cell Lung Cancer (SCLC) with documented intolerance to 
platinum-based chemotherapy or refractory to platinum-based 
chemotherapy (progression during treatment or during < 90 days of the 
last dose of platinum-based chemotherapy). Patients who are platinum-
sensitive (progression ≥ 90 days of the last dose of platinum-based 
chemotherapy) must also have received at least one other prior line of 
platinum-based chemotherapy, if eligible, with or without combination 
with CPI as per applicable local treatment country guidelines.
To:
Cohort C (SCLC):
Patient with pathologically confirmed locally advanced or metastatic 
Small Cell Lung Cancer (SCLC) with documented intolerance to 
platinum-based chemotherapy or refractory to platinum-based 

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chemotherapy (progression during treatment or during < 90 days of the 
last dose of platinum-based chemotherapy). Patients who are platinum-
sensitive (progression ≥ 90 days of the last dose of platinum-based 
chemotherapy) must also have received one additional prior line of 
platinum-based chemotherapy, if eligible, with or without combination 
with CPI as per applicable local treatment country guidelines
Rationale for 
change
Clarification to understand the inclusion criteria of cohort C SCLC 
better.
Section to be 
changed
Synopsis - Number of patients entered:
Description of 
change
Change from:
A total of 315 patients (22 part 1 plus 293 part 2) approximately will 
be entered
(Part 1 and Part2)
To:
A total of approximately 315 patients (22 in Part 1 plus 293 in Part 2)
will be entered.
Rationale for 
change
Clarification of the wording.
Section to be 
changed
Synopsis - Number of patients on each treatment
Description of 
change
Change from:
Part 1: 12 to 18 evaluable patients
Part 2: 80 evaluable locally advanced or metastatic non-squamous 
NSCLC patients (Cohort A and B; 40 patients per cohort) and 30 
evaluable patients in each of the other 5 cohorts. In total 230 patients
To:
Part 1: 12 to 18 evaluable patients 
Part 2: 80 evaluable locally advanced or metastatic non-squamous 
NSCLC patients (Cohort A and B; 40 patients per cohort) and 30 
evaluable patients in each of the other 5 cohorts for a total of 230 
patients.
Rationale for 
change
Clarification of the wording.
Section to be 
changed
Synopsis - Main in- and exclusion criteria
Description of 
change
Change from:
Exclusion Criteria:
Part 2:
1
Not more than one CPI based treatment regimen prior to 
entering study (eg. anti-Programmed Death receptor-1 (PD-1), 

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anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or 
anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-
4) antibody) unless combination CPIs approved by the local 
regulatory agencies; For eg.,  Melanoma cohort (Cohort E) 
To:
1
Not more than one CPI based treatment regimen prior to 
entering study (e.g., anti-Programmed Death receptor-1 (PD-
1), anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or 
anti-cytotoxic T lymphocyte associated antigen-4 (anti-CTLA-
4) antibody). In case of CPIs combination, they need to be 
approved by the local regulatory agencies (e.g., Melanoma 
cohort (Cohort E)).
Rationale for 
change
Clarification for a better understanding of the exclusion criteria.
Section to be 
changed
Flowchart Part2
Description of 
change
Change of Safety Follow-up visit period from 30 to 42 day
Change the Disease response assessment field
Addding to footnote $:
HCC cohorts (cohorts F & G) additional tests may include HBV DNA (if needed), HCV RNA 
(if needed) and Hepatitis D (anti-HDV qualitative).
HIV-1 and HIV-2 Ab and r local applicable guidelines. HBsAg, anti-HBc qualitative, 
anti-HCV qualitative. If positive: test HBV DNA + HCV RNA, anti HDV qualitative
Rationale for 
change
The change of the residual period was an requirement of the MHRA. 
The change of the Disease response field is a clarification for a better 
understanding of the CTP requirements.
The adding of the additional wording should clarify the already 
required hepatitis testing.
Section to be 
changed
1.1 Medical Backgrounds
Description of 
change
Added:
The planned inclusion of a cohort of patients with locally advanced or 
metastatic and/or
unresectable hepatocellular carcinoma (HCC) with no prior systemic 
treatment is based on an
understanding of the mechanisms involved in the proposed 
combination therapy, and the
available evidence supporting the expectation of enhanced activity 
with the added inhibition of Ang2 signaling. Hepatocellular carcinoma 
(HCC) is a vascular tumor and angiogenesis is believed to play an 

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important role in its progression. The role of anti-VEGF is well 
established in HCC.
Multikinase inhibitors targeting VEGFR like sorafenib and lenvatinib 
have been approved as
a first-line treatment in HCC. Given its high immunogenicity, immune 
checkpoint inhibitors (ICI), targeting the programmed cell death-1 
(PD-1) axis have been approved either as monotherapies or in 
combination with other ICI, such as cytotoxic T lymphocyte antigen-4 
(CTLA-4).
Combination therapies involving antiangiogenics and ICI show 
improved response over antiangiogenic monotherapy (IMbrave 150 
trial). It is hypothesized that this is due to the complementary 
mechanisms involved.
The phase III IMbrave150 study conducted in the previously untreated 
HCC patients supported the combination of atezolizumab (anti-PDL1) 
with Bevacizumab (anti-VEGF). Overall response rate was 27% with 
atezolizumab plus bevacizumab vs 12% compared to sorafenib based 
on independent assessment using RECIST 1.1 criteria. Median 
progression-free survival (PFS) was also significantly increased 
(median 6.8 vs 4.3 months, HR = 0.59; 95% CI = 0.47– 0.76, P < 
.0001).
The combination therapy being investigated in this trial addresses both 
mechanisms described above. It combines an anti-PD-1 agent (BI 
754091) with a bispecific nanobody (BI 836880) that blocks VEGF 
and in addition Ang2. Data suggests that this added activity against 
Ang2 may add to the overall response seen with the combination of 
ICI and anti-VEGF alone. The rationale for this is described below. 
Ang2 leads to immune suppression by distinct mechanisms compared 
to VEGF. VEGF plays a key role in suppressing tumor immune 
response by negatively affecting the antigen presenting cells (APCs)1 
and effector T-cells2,3 while augmenting the effects of immune 
suppressive cells such as T-regulatory cells (T-regs)4 and myeloid 
derived suppressor cells (MDSCs)5.
Ang-2 increases the neutrophil recruitment and adhesion of both 
neutrophils and TEMs to endothelium6 and increases the conversion to 
M2-like macrophage phenotype7. Ang-2 further can stimulate TEMs 
to secrete IL-10, which can promote the expansion of T-regs and the 
inhibition of effector T-cells. The Sorafenib HCC Assessment 
Randomized Protocol (SHARP) trial demonstrated that angiogenesis 
biomarkers Ang2 and VEGF were independent predictors of survival 
in patients with advanced HCC8. Furthermore, treatment with CTLA-4 
and PD-1 blockade in patients with high pre-treatment serum Ang-2 
and increased Ang-2 titers post-treatment were found to have worse 
clinical outcomes compared to patients with lower pre-treatment titers 
and treatment with immune checkpoint inhibitors can induce 

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functional Ang-2 antibodies especially in patients who derive clinical 
benefits from ICIs9,10.
Based on the distinct role of Ang-2 in immune suppression of the 
tumor microenvironment and its role in conferring resistance to 
therapy targeting only VEGF, we believe selective triple inhibition of 
anti-VEGF, anti-Ang2 and PD-1 may confer a distinct advantage in 
the treatment of HCC patients. This is supported by preclinical data 
from a LL/2 (lewis lung) syngeneic tumour pre-clinical study (please 
refer to section 5.1.1.4 “Combining BI 836880 with immune 
checkpoint inhibition” of the IB).
Rationale for 
change
Adding of new information which supports the medical background of 
the study.
Section to be 
changed
1.4.1 Benefit-Risk Assessment in context of COVID-19 pandemic 
for patients participating in clinical trials investigating BI 
836880 in combination with BI 754091 
Description of 
change
Adding of:
1.4.1 Benefit-Risk Assessment in context of COVID-19 pandemic 
for patients participating in clinical trials investigating BI 
836880 in combination with BI 754091 
Considering the mechanism of action of VEGF/Ang2 inhibition and 
PD-1receptor blockade, there is no evidence to suggest an increased 
risk of infection.  Based on available data, treatment with BI 836880 
alone and in combination with a PD-1 inhibitor is not anticipated to 
pose a higher risk of acquiring a COVID-19 infection in cancer 
patients.  Overlapping toxicity with VEGF/Ang2 combined with PD1 
with an increased risk of infection has not been observed.
Considerations around drug-drug interactions are not included in this 
benefit-risk assessment – this information is provided in the protocol, 
Investigator’s Brochure and the most recent label of the respective 
medication(s) used for treatment of COVID-19 infection.
BENEFITS AND RISKS CONCLUSIONS AND 
RECOMMENDATIONS
Patients in clinical trials with BI 836880 and BI 754091 have 
advanced late stage cancer with limited treatment options. Given the 
life threatening nature of the underlying disease, the approach 
recommended by professional oncology organizations (e.g. ASCO, 
ESMO) remains to treat patients with cancer as under normal 
circumstances. No consensus on recommendations exist regarding 
holding chemotherapy or immunotherapy or delaying adjuvant therapy 

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or radiotherapy treatment in cancer patients with no signs of a 
COVID-19 infection. Withdrawing treatment in a cancer patient who 
may have few or any alternative treatment options requires a careful, 
individual evaluation. 
To date, there is no evidence suggesting a link between susceptibility 
to COVID-19 infections and the inhibition of VEGF-A and Ang2 
targeted by BI 836880. Also, there is no evidence suggesting a link 
between susceptibility to COVID-19 infections and the inhibition of 
PD-1/PDL-1. Available non-clinical and clinical data from completed 
clinical trials have not shown an increased risk of infections with BI 
836880 and BI 754091. 
Considering the limited and sparse data on immune activation and the 
role of inflammation as well as other underlying factors that may 
increase the severity and mortality from COVID-19 infection, there 
may be some factors representing the risk for using VEGF/Ang2 or 
PD1 that are currently still unknown. The information about the risk 
factors, the severity and the activity of immune response in patient 
with COVID-19 infections will be constantly monitored as it evolves. 
All up-to-date information about the investigational compounds 
(preclinical, clinical, clinical pharmacology) is included in the trial 
documentation, including IB, clinical trial protocol for the guidance of 
the investigator. The latter also outlines the pre-cautionary eligibility 
criteria, measures for management of associated AEs, required dose 
reductions etc. The protocol-defined trial procedures themselves do 
not impose any increased risk to study participants in developing 
COVID-19 infection. The risk mitigation measures currently in place 
within the clinical trial protocols are a sufficient safeguard, as patients 
are frequently monitored with comprehensive safety evaluations. 
Based on laboratory data and any adverse event that may occur, 
clinical trial protocols include guidance for the continuation, 
interruption, dose reduction, and discontinuation of study drugs. 
Therefore, assuming the protocol-defined requirements for continued 
study drug administration are met, the decision about concomitant use 
of experimental anti-cancer therapy with VEGF/Ang2 and PD1 with 
COVID-19 treatment in case of contracted COVID-19 infection will 
be left to the investigator’s benefit-risk assessment on a case-by-case 
basis.
The investigators will take the totality of information related to each 
single patient and the local COVID-19 situation into consideration 

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when performing the individual benefit-risk assessment on a case-by-
case basis. Considering all aspects, the investigator will decide upon 
each patient’s (continued) participation in the planned trials. BI as the 
sponsor, recommend to adhere to the trial protocol and where 
required, will support the investigator in their decision finding, where 
this protects the safety, wellbeing and/or is in the best interest of the 
patient. 
Rationale for 
change
Additing of the risk/ benefit assessment in context of the covid-19 
Section to be 
changed
Description of 
change
Rationale for 
change
Section to be 
changed
3.1. OVERALL TRIAL DESIGN AND PLAN – Part 2
Description of 
change
Change from:
It is foreseen to enroll up to 230 patients of full age (according to local 
legislation, usually ≥ 18 years) at screening in different indications:
Patients with locally advanced or metastatic 2nd or 3rd line CPI 
resistant non-squamous Non-Small Cell Lung Cancer (NSCLC)  and 
≥2nd line Small Cell Lung Cancer (SCLC) and recurrent glioblastoma 
and IO failure metastatic melanoma,1st line HCC patients or HCC 
patients who were intolerant or progressed during or after standard 
first line treatment with sorafenib or lenvatinib. Patients who received 
2nd line treatment with anti-PD1 therapy (but not other therapy) after 
failure of sorafenib or lenvatinib are also eligible (see image below –
please note the cohorts will run in parallel, not sequential) (see 
Figure 3.1: 1). 1st line HCC cohort will be implemented only in 

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countries UK, Korea, Taiwan, Hong Kong, Poland, Ukraine, Russia, 
Spain, USA, Australia
To:
It is foreseen to treat up to 230 patients of full age (according to local 
legislation, usually ≥ 18 years) at screening in different indications:
patients with locally advanced or metastatic 2nd or 3rd line CPI 
resistant non-squamous Non-Small Cell Lung Cancer (NSCLC), ≥2nd
line Small Cell Lung Cancer (SCLC), recurrent glioblastoma, IO 
failure metastatic melanoma, 1st line HCC patients or HCC patients 
who were intolerant or progressed during or after standard first line 
treatment with sorafenib or lenvatinib. Please note that the cohorts 
will run in parallel, not sequentially (see Figure 3.1: 1). The 1st line 
HCC cohort will be implemented only in countries: UK, Korea, 
Taiwan, Hong Kong, Poland, Ukraine, Russia, Spain, USA, Australia, 
Japan.
Figure 3.1:1 adapted
Rationale for 
change
Clarification of wording and adding of Japan as a country which 1st
line HCC will be implemented.
Section to be 
changed
3.3.1. Main diagnosis for trial entry
Description of 
change
Change from:
For the part 1 we look for patients with advanced/metastatic non 
squamous NSCLC who have progressed during or after first line (in 
case of naïve patients) of platinum-based therapy and patients who 
relapsed after completion of at least 2 cycles (in case of relapsed 
patients) of  
a CPI treatment alone or in combination with platinum-based 
chemotherapy (monotherapy or in combination with chemotherapy). 
Patients included in Part1 are not eligible to participate in Part 2.
For the part 2 we look for patients with locally advanced or metastatic 
2nd  and 3rd line CPI resistant NSCLC and 2nd line SCLC, recurrent 
glioblastoma, IO failure metastatic melanoma, 1st line HCC patients 
and HCC patients who are intolerant or failed the first line treatment 
with sorafenib or lenvatinib. HCC patients who received 2nd line 
treatment with anti-PD1 therapy (but not other therapy) after failure of 
sorafenib or lenvatinib are also eligible.
Please refer to Section 8.3.1 (Source Documents) for the 
documentation requirements pertaining to the in- and exclusion 
criteria.
To:
In Part 1, the following patients are allowed for trial entry: patients 
with advanced/metastatic non squamous NSCLC who have progressed 
during or after first line (in case of naïve patients) of platinum-based

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therapy and patients who relapsed after completion of at least 2 cycles 
(in case of relapsed patients) of a CPI treatment alone or in 
combination with platinum-based chemotherapy (monotherapy or in 
combination with chemotherapy). Patients included in Part 1 are not 
eligible to participate in Part 2.
In Part 2, the following patients are allowed for trial entry: patients 
with locally advanced or metastatic as 2nd  and 3rd line CPI resistant 
NSCLC and 2nd line SCLC, recurrent glioblastoma, IO failure 
metastatic melanoma, 1st line HCC patients and HCC patients who are 
intolerant or failed the first line treatment with sorafenib or lenvatinib.
Rationale for 
change
Clarification for a better understanding.
Section to be 
changed
3.3.2: Inclusion criteria – Part 2
Main Inclusion Criteria for all cohorts
Description of 
change
Change from:
2.
At least one measurable target lesion outside the brain 
(excluding the glioblastoma patients), that can be 
accurately measured per RECIST v 1.1
Cohort C (SCLC):
-
Pathologically confirmed locally advanced or metastatic 
SCLC. 
Documented intolerance to platinum-based chemotherapy or 
refractory to platinum-based chemotherapy (progression during 
treatment or during < 90 days of the last dose of platinum-based 
chemotherapy). Patients who are platinum-sensitive (progression ≥ 90 
days of the last dose of platinum-based chemotherapy) must also have 
received at least one other prior line of platinum-based chemotherapy, 
if eligible, with or without combination with CPI as per applicable 
local treatment country guidelines.
To:
3.
At least one measurable target lesion outside the brain 
(excluding the glioblastoma patients where brain 
lesions are allowed), that can be accurately measured 
per RECIST v 1.1 or RANO.
Cohort C (SCLC):
-
Pathologically confirmed locally advanced or metastatic 
SCLC. 
Documented intolerance to platinum-based chemotherapy or 
refractory to platinum-based chemotherapy (progression during 
treatment or during < 90 days of the last dose of platinum-based 
chemotherapy). Patients who are platinum-sensitive (progression ≥ 90 

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days of the last dose of platinum-based chemotherapy) must also have 
received one additional prior line of platinum-based chemotherapy, if 
eligible, with or without combination with CPI as per applicable local 
treatment country guidelines.
Adding of Japan for the countries where Cohort G- 1st line HCC will 
be implemented.
Rationale for 
change
Clarification of the main inclusion criteria #2 and the cohort C- SCLC 
and adding of Japan to the countries where Cohort G will be 
implemented.
Section to be 
changed
3.3.3 – Exclusion criteria Part 2 - #2
Description of 
change
Change from:
Not more than one CPI based treatment regimen prior to entering 
study (eg. anti-Programmed Death receptor-1 (PD-1), anti-
Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic 
T lymphocyte associated antigen-4 (anti-CTLA-4) antibody) unless 
combination CPIs approved by the local regulatory agencies; For eg., 
Melanoma cohort (Cohort E).
To:
Not more than one CPI based treatment regimen prior to entering 
study (eg. anti-Programmed Death receptor-1 (PD-1), anti-
Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic 
T lymphocyte associated antigen-4 (anti-CTLA-4) antibody).In case of 
CPIs combination, they need to be approved by the local regulatory 
agencies; for e.g., Melanoma cohort (Cohort E).
Rationale for 
change
Clarification of exclusion criteria #2 for a better understanding
Section to be 
changed
4.1.4. Drug assignment and administration of doses for each 
patient
Description of 
change
Change from:
The expected infusion time is 60 minutes for BI 754091 and same for 
BI 836880; BI 754091 will be administered first, then 15 minutes (+/-
10 min) after the end of this infusion BI 836880 will be administered. 
In case no relevant infusion reactions are observed, this can be shorten 
to about 30 minutes for BI836880 only but should not be prolonged to 
more than 6 hours for BI 836880 and should not be prolonged to more 
than 2 hours for BI 754091, also in case of technical issues. 
Appropriate drugs and medical equipment to treat anaphylactic 
reactions must be immediately available and study personnel must be 
trained to recognize and treat anaphylaxis.

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If symptoms of an infusion-related reaction CTCAE grade 2 or higher, 
the infusion should be temporarily stopped. The intensity and 
prolongation of vital sign monitoring should be considered. Upon 
recovery, the study drug should be infused at 50% of the rate at which 
the reaction occurred. Depending on the time of occurrence and the 
severity of the reaction, the investigator may consider administering 
additional supportive medication, e.g. corticosteroids for re-
introduction. Infusion rate and premedication for further treatment 
cycles should be adapted according to Investigator decision, but 
adaption of administration scheme need to be agreed with sponsor.
To:
The expected infusion time is 60 minutes for BI 754091 and same for 
BI 836880; BI 754091 will be administered first, then 15 minutes (+/-
10 min) after the end of this infusion BI 836880 will be administered. 
In case of technical issues or complications during infusion, the total 
infusion time (including stop time and flushing) for BI836880 should 
not exceed 360 minutes.
For BI 754091, in case of technical issues or complications during 
infusion, the total infusion time (including stop time) should not 
exceed 180 minutes.
Appropriate drugs and medical equipment to treat anaphylactic 
reactions must be immediately available, and study personnel must be 
trained to recognize and treat anaphylaxis.
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. Depending on the time of occurrence and the 
severity of the reaction, the investigator may consider administering 
additional supportive medication, e.g. corticosteroids for re-
introduction. Infusion rate and premedication for further treatment 
cycles should be adapted according to Investigator decision, but 
adaption of administration scheme need to be agreed with sponsor. If 
an infusion related reaction is Grade 3 or higher in severity at any 
point during the study, treatment with BI 754091 has to be 
permanently discontinued.
Adding of:

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Rescreening is generally not allowed. In individual cases, rescreening 
can be considered in alliance with the sponsor.
Rationale for 
change
Change of the administration time for BI 836880 and adding of 
wording regarding the new available information for infusion related 
reaction in line with the new wording for Appendix 10.4.
Adding for wording regarding rescreening of patients.
Section to be 
changed
4.2.2. Restrictions
Description of 
change
Adding of wordin G:
…For patients in the cohort D (Glioblastoma) higher doses of 
corticosteroids may be allowed as defined in the cohort-specific 
eligibility criteria. 
Rationale for 
change
Adding to use higher corticosteroids for Cohort D Glioblastoma 
patient-
Section to be 
changed
5.1 Assessment of efficacy 
Description of 
change
Change from:
…
Efficacy endpoints will be assessed every 2 cycles (6 weeks) as 
specified in the FC. An additional evaluation at EoT is only 
applicable; when patient has no PD documented, will not continue 
with regular imaging in Follow-up period and did not have imaging 
within the last 4 weeks before EoT. At Safety Follow-up visit, in case 
a patient has discontinued due to PD one additional tumor assessment 
should be done in case no other cancer treatment has been initiated. 
All measurements must be recorded in metric notation.
All tumor imaging performed in this trial will be collected by authorized 
CRO and stored until shipment to Boehringer Ingelheim. The CRO will 
not be implicated in tumor response evaluation. This collected data may 
be considered for central review at a later time point.  
To:
Efficacy endpoints will be assessed every 2 cycles (6 weeks) as 
specified in the FC. An additional evaluation at EoT is only 
applicable; when patient has no PD documented, will not continue 
with regular imaging in Follow-up period and did not have imaging 
within the last 4 weeks before EoT. In case a patient has discontinued 
due to PD one additional tumor assessment should be done according 
to iRECIST in case no other cancer treatment has been initiated
(confirming image should be done 4 – 6 weeks after the last image).
For Glioblastoma patients, an additional image according to iRANO 
should be taken 3 month after PD. All measurements must be recorded
in metric notation.

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All tumor imaging performed in this trial will be collected by 
authorized CRO and stored until shipment to Boehringer Ingelheim. 
The CRO will not be implicated in tumor response evaluation. This 
collected data might be considered for central review at a later time 
point.
Rationale for 
change
Calrification regarding the required use f iRANO and iRecist in the 
trial.
Section to be 
changed
5.2.3 Safety laboratory parameters – infection screening
Description of 
change
Adding of wording:
HIV-1 and HIV-2 Ab and HBsAg, anti-HBc qualitative, anti-HCV 
qualitative for all patients. as per local applicable guidelines. HBsAg, 
anti-HBc qualitative, anti-HCV qualitative. If positive: test HBV DNA 
+ HCV RNA, anti HDV qualitative.
Rationale for 
change
Clarification which parameters for the infection screening for which 
cohort are needed.
Section to be 
changed
Description of 
change
Change from:
Infusion-related reactions
All infusion-related reactions need to be reported as AESIs.
In the event of an infusion-related reaction ≥ Grade 2, the infusion rate 
of BI 836880 or 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 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 4 or higher in severity at any 
point during the study, treatment with BI 836880 or BI 754091 will be 
permanently discontinued.
To:
Infusion-related reactions
All infusion-related reactions need to be reported as AESIs.
In the event of an infusion-related reaction ≤Grade 2, the infusion 
rate of BI 836880 or 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 study, treatment with BI 836880 or BI 754091 will be 
permanently discontinued.
Rationale for 
change
Adapted wording because of new program related information.
Section to be 
changed
5.2.7.2 Adverse event collection and reporting
Description of 
change
Change from:
…
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs 
which are relevant for the reported SAE or AESI, on the BI SAE form 
immediately (within 24 hours ) to the sponsor’s unique entry point 
(country specific reporting process will be provided in the ISF). The 
same timeline applies if follow-up information becomes available. In 
specific occasions the investigator could inform the sponsor upfront 
via telephone. This does not replace the requirement to complete and 
fax the BI SAE form.
With receipt of any further information to these events, a follow-up 
SAE form has to be provided. For follow-up information the same 
rules and timeline apply as for initial information.
To:
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs 
which are relevant for the reported SAE or AESI, on the BI SAE form 
immediately (within 24 hours ) to the sponsor’s unique entry point 
(country specific reporting process will be provided in the ISF). The 
same timeline applies if follow-up information becomes available. In 
specific occasions, the investigator could inform the sponsor upfront 
via telephone. This does not replace the requirement to complete and 
send the BI SAE form.

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Rationale for 
change
Adaption needed as of new distribution possibilities in some countries.
Section to be 
changed
5.4 Assessment of Biomarkers
Description of 
change
Rationale for 
change
Wording needed to be adapted for the use of radiomics
Section to be 
changed
Description of 
change
Rationale for 
change
Section to be 
changed
Description of 
change

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Rationale for 
change
Section to be 
changed
6.2.1 Screening and run-in period(s)
Description of 
change
Change from:
The examinations required for the screening visit may be conducted 
within a time interval of 21 days prior to the first study drug 
administration. Prior to any other study related procedure, written 
informed consent must be obtained from the patient.
To:
The examinations required for the screening visit may be conducted 
within a time interval of 21 days prior to the first study drug 
administration. Prior to any other study related procedure, written 
informed consent must be obtained from the patient.
ECOG and Physical examination can be performed the day prior to the 
start of treatment cycle.
Rationale for 
change
Allowing a bigger window for certain pre-treatment assessments.
Section to be 
changed
6.2.4 Residual effect period (REP)
Description of 
change
Change from:
The REP is defined in Section 5.2.7.2. The End of REP the Safety 
Follow-up visit should not be performed earlier than 30 days after 
permanent discontinuation of the trial medication (last day medication 
was administered).

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To:
The REP is defined in Section 5.2.7.2. The End of REP the Safety 
Follow-up visit should not be performed earlier than 42 days after 
permanent discontinuation of the trial medication (last day medication 
was administered).
Rationale for 
change
MHRA requestde change back from 30 to 42 days. 
Section to be 
changed
7.4  Interim Analyse
Description of 
change
Change from:
Part 2:
In Part 2, 230 patients are planned to be treated. 40 patients each are 
planned for cohorts A and B, and 30 patients each are planned for 
cohorts C, D, E, F, and G. An interim futility analysis will be 
performed for cohorts C, D, E, F, and G in Part 2. The interim 
analyses for each cohort are planned to be conducted after 15 patients 
in that cohort have completed their two on-treatment imaging 
assessments (i.e., end of cycle 4). For each cohort, timing of the 
interim analysis may be adjusted according to actual recruitment rate 
to facilitate or avoid delay of the trial conduct. Until any decision from 
the futility analysis is done, the enrollment of next patient will not be 
stopped. The two-stage design is planned to stop further recruitment of 
patients if the defined efficacy boundary (see Table 7.7.2: 1) is not met 
at the first stage. 
In addition, if considered necessary, interim analysis may be 
performed for evaluation of the efficacy and safety aspects as each 
cohort is finished.
To:
Part 2:
In Part 2, 230 patients are planned to be treated. 40 patients each are 
planned for cohorts A and B, and 30 patients each are planned for 
cohorts C, D, E, F, and G. The Sponsor may pause enrollment in any 
cohort at any time to carefully evaluate the safety and efficacy data of 
patients already enrolled in a given cohort.
An interim futility analysis will be performed for cohorts C, D, E, F, 
and G in Part 2. The interim analyses for each cohort are planned to be 
conducted after 15 patients in that cohort have completed their two on-
treatment imaging assessments (i.e., end of cycle 4 or later depending 
on the cohort). For each cohort, timing of the interim analysis may be 
adjusted according to actual recruitment rate to facilitate or avoid 
delay of the trial conduct. The Sponsor may pause enrollment in a 

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cohort before making any decisions from the interim futility analysis.
The two-stage design is planned to stop further recruitment of patients 
if the defined efficacy boundary (see Table 7.7.2: 1) is not met at the 
first stage. 
Rationale for 
change
Adding possibility to pause a cohort before making any decision from 
the interim futility analysis.
Section to be 
changed
7.7.2 Determination of sample size for Part 2
Description of 
change
Change fropm:

Cohort C: 
- patients with locally advanced or metastatic Small Cell Lung 
Cancer, with no more than one line of chemotherapy

Cohort D: 
- patients with histologically confirmed recurrent glioblastoma 
(primary), with no more than one line of chemotherapy 
(concurrent and adjuvant temozolomide based chemotherapy)
To:

Cohort C: 
- patients with locally advanced or metastatic Small Cell Lung 
Cancer, with no more than one line of chemotherapy, except 
platinum sensitive patients.

Cohort D: 
- patients with histologically confirmed recurrent glioblastoma 
(primary), No more than two lines of prior chemotherapy
(concurrent and adjuvant temozolomide based chemotherapy 
including in combination with another investigational agent is 
considered one line of chemotherapy).
Rationale for 
change
Clarification of the CTP v5.0.
Section to be 
changed
10.4 MANAGEMENT OF IMMUNE-RELATED ADVERSE
EVENTS
Description of 
change
Change of the complete appendix section
Rationale for 
change
As of new available program information the section was accordantly 
adapted.
Section to be 
changed
Table 10.5.1: 2 change of footnote**
Description of 
change
Change from:
**For the HCC cohorts, only the Cycle 1 Day 1 sample will be 
collected for ANG/VEGF, but no on-treatment samples, and NO 
KYN:TRP samples
To:

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**For the HCC cohorts, only the Cycle 1 Day 1 pre-treatment sample 
will be collected for ANG/VEGF, but no on-treatment samples, and 
NO KYN:TRP samples
Rationale for 
change
Clarification for the collection of the biomarker samples.
Section to be 
changed
6. Investigational Plan
Description of 
change
Added wording:
In the event of force majeure or other disruptive circumstances (e.g. 
pandemic, war) the investigational plan as per this clinical trial 
protocol may not be feasible at a site. With the consent of the patient, 
sponsor and investigator may agree on alternative, back-up or rescue 
methodology. The implementation of these measures will depend on 
patient’s consent, operational feasibility, local law and regulations. If 
alternative methodology is implemented, the deviations from the 
original plan will be precisely documented.
Rationale for 
change
Adaption to handle crisis which may occur and affect the trial and 
patient safety.

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11.6
GLOBAL AMENDMENT 6
Date of 
amendment
16 Aug 2021
EudraCT 
number
EU number
2017-001378-41
BI Trial 
number
1336-0011
BI 
Investigational 
Product(s)
BI 836880 (anti-VEGF/Ang2)
Ezabenlimab (BI 754091 [anti-PD-1])
Title of 
protocol
An open label phase Ib dose finding study of BI 836880 in 
combination with ezabenlimab to characterize safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy in patients with 
locally advanced or metastatic non-squamous Non-Small Cell Lung
Cancer and in other solid tumors
Global Amendment due to urgent safety reasons
Global Amendment
Section to be 
changed
All sections
Description of 
change
Change from:
BI 754091
To:
Ezabenlimab
Rationale for 
change
Name registered for BI 754091.
Section to be 
changed
Cover page
Description of 
change
Change from:
BI 836880
BI 754091
To:
BI 836880 (anti-VEGF/Ang2)
Ezabenlimab (BI 754091 [anti-PD-1])
Rationale for 
change
Adding information regarding the molecules
Section to be 
changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
3.1 OVERALL TRIAL DESIGN AND PLAN
3.3 SELECTION OF TRIAL POPULATION
Description of 
change
Change from:

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Cohort G to be implemented only in countries UK, Korea, Taiwan, 
Hong Kong, Poland, Ukraine, Russia, Spain, USA, Australia.
To:
Cohort G to be implemented only in countries where this cohort is 
approved.
Rationale for 
change
Additional countries could be added to contribute to cohort G 
recruitment.
Section to be 
changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Flowchart Part 2
3.1 OVERALL DESIGN AND PLAN
3.3 SELECTION OF TRIAL POPULATION
5.2.3 Safety Laboratory Parameters
5.4.1 Methods of sample collection
7.4 INTERIM ANALYSES
7.7.2 Determination of sample size for Part 2
Description of 
change
Cohort H added, including number of patients to be enrolled, patient 
population, inclusion/exclusion criteria, applicable procedures and 
statistical considerations
Rationale for 
change
Adding cohort H for further exploration of preliminary efficacy and 
safety among 2nd line HCC patients
Section to be 
changed
CLINICAL TRIAL PROTOCOL SYNOPSIS (Primary endpoints):
Description of 
change
Change from:
The primary endpoint is the shrinkage estimator of objective response 
(OR) based on BHM. OR is defined as best overall response (RECIST
1.1) of complete response (CR) or partial response (PR) from first 
treatment infusion until the earliest of disease progression, death or 
last evaluable tumor assessment before start of subsequent anti-cancer 
therapy, lost to follow-up, or withdrawal of consent.
To:
The primary endpoint is Objective Response (OR) defined as best 
overall response (RECIST 1.1) of complete response (CR) or partial 
response (PR) from first treatment infusion until the earliest of disease 
progression, death or last evaluable tumor assessment before start of 
subsequent anti-cancer therapy, lost to follow-up, or withdrawal of 
consent.
Rationale for 
change
Consistency with Section 2.1.2
Section to be 
changed
CLINICAL TRIAL PROTOCOL SYNOPSIS (Secondary endpoints):

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Description of 
change
Change from:
PART 1:

Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the first
infusion cycle.
PART 2:

- Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the 
first and fourth infusion cycle.
To:
PART 1:

Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the first
and fourth infusion cycle.
PART 2:

Pharmacokinetic parameters Cmax, tmax, AUC0-504h after the first 
infusion cycle.
Rationale for 
change
Updated timepoints to be in line with section 2.
Section to be 
changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
3.1 OVERALL TRIAL DESIGN AND PLAN
3.3 SELECTION OF TRIAL POPULATION
7.4 INTERIM ANALYSES
7.7.2 Determination of sample size for Part 2
Description of 
change
Number of patients updated from 293 to 420 screened and from 230 to 
290 evaluable patients (treated) in Part 2.
Rationale for 
change
Number of patients updated due to the addition of cohort H and 30 
additional patients in cohort F.
Section to be 
changed
FLOW CHART (PART 2)
2.2.2 Further endpoints
6.2.5.2 Follow up for Overall Survival
Description of 
change
Adding Overall Survival as a further enpoint and the Follow up for 
Overall Survival status visit
Rationale for 
change
Data collection for new Further endpoint in Part 2
Section to be 
changed
FLOW CHART (PART 2)
10.5.1:2 Time schedule for PK blood sampling during treatment cycles
for Part 2
Description of 
change
PK, ADA and Biomarker sample collection timepoints have been 
updated (from visits 2 to 12 to visits 2 - onwards). 
Rationale for 
change
Further sample analysis planned for all treatment visits. 
Section to be 
changed
Flowchart (PART 2) - footnotes

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Description of 
change
Change from:
8 Tumour assessments should be done according to RECIST v1.1 and iRECIST for all cohorts 
except GBM. RANO/iRANO criteria to be followed for GBM cohort. Assessments should 
include computed tomography (CT) scans of the chest and abdomen only, 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. Baseline evaluation must be 
performed as close as possible to the treatment start and no more than 28 days before start of 
treatment (For GBM – 14 days prior to treatment). Tumour assessment should be done every 
6 weeks (in accordance to local requirements). Assessments are always done prior to the start 
of the new treatment cycle (window is up to minus 7 days).. 
To:
8 Tumour assessments should be done according to RECIST v1.1 and iRECIST for all cohorts 
except GBM. RANO/iRANO criteria to be followed for GBM cohort. Assessments should 
include computed tomography (CT) scans of the chest and abdomen only, 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. Baseline evaluation must be 
performed as close as possible to the treatment start and no more than 28 days before start of 
treatment (For GBM – 14 days prior to treatment). Tumour assessment should be done every 
6 weeks (± 7 days) (in accordance to local requirements). Assessments are always done prior 
to the start of the new treatment cycle. 
Rationale for 
change
Allowing a wider window for tumour assesments
Section to be 
changed
Flowchart (PART 2) 
5.4.1 Methods of sample collection
Description of 
change
Change from 14-16 G to 16G and 3 18G to 4 18 G needle biopsies to 
be obtained. Change from 26 to 20 archival 4 µm sections from 
archival block to be provided.
Rationale for 
change
Modifying needle size to have enough material for analysis.
Section to be 
changed
ABBREVIATIONS
Description of 
change
Adding EMA, FDA, EWOC, OS
Rationale for 
change
Inclusion of the new abbreviations used in the main text
Section to be 
changed
1.1 MEDICAL BACKGROUND
1.3 RATIONALE FOR PERFORMING THE TRIAL
Description of 
change
Addition of introduction and rationale to include HCC patients in 
second line (atezo-bev failures)
Rationale for 
change
Adding justification for the addition of cohort H.

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Section to be 
changed
1.4 BENEFIT – RISK ASSESSMENT
Description of 
change
Updated information regarding the number of treated patients and 
adverse events observed.
Rationale for 
change
Updating information according to the last Investigator Brochure
Section to be 
changed
Description of 
change
Rationale for 
change
Section to be 
changed
3.1 OVERALL TRIAL DESIGN AND TRIAL POPULATION
7.1.2 Statistical design – Part 2 (dose expansion cohorts)
7.2 NULL AND ALTERNATIVE HYPOTHESES
7.3.1 Primary endpoint analyses 
7.7.2 Determination of sample size for Part 2
7.7.3 Determination of additional sample size for stage II in cohort F
Description of 
change
Addition of 30 patients in cohort F: justification and statistical 
considerations and justification and statistical considerations for the 
adding of 30 patients to cohort H.
Rationale for 
change
Observed response rates in cohort F have triggered the decision to add 
30 more patients in the cohort F and to add the new cohort H for the 
same patient pool, but pretreated with the new standard of care, 
Section to be 
changed
4.1.4 Drug assignment and administration of doses for each patient
Description of 
change
Text added:
In some cases, in discussions with the Sponsor, treatment with one of 
the two investigational drugs can be allowed if there is an AE reported 
which can be clearly attributed to one of the two drugs and further 
warrants a temporary discontinuation of this drug in the interest of the 
patient.
Rationale for 
change
Allow certain flexibility to continue treatment with one drug only.
Section to be 
changed
5.3.1 Assessment of pharmacokinetics
7.4 INTERIM ANALYSES
Description of 
change
Change from:
Exploratory pharmacokinetic analyses can be performed as necessary 
for safety review as well as for dose selection in part 2 of the trial, but 
require sufficient lead time to collect samples, measure plasma 
concentrations, analyze data and prepare meaningful outputs.
…
In contrast to the final PK analysis, the exploratory analyses will be 
based on planned sampling times rather than on actual times; no 

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supplementary subject information, e.g. on adverse events of 
concomitant medication, will be used in these analyses, and the 
outputs will not be validated. Minor discrepancies between interim 
and final results may therefore occur.
To:
Exploratory pharmacokinetic and ADA analyses can be performed as 
necessary for safety review, for dose selection in part 2 of the trial as 
well as further project planning, but require sufficient lead time to 
collect samples, measure plasma concentrations, analyze data and 
prepare meaningful outputs. Exploratory data may also be used for 
modelling activities.
…
In contrast to the final PK analysis, the exploratory analyses will be 
based on planned sampling times rather than on actual times; the 
outputs will not be validated. Minor discrepancies between interim 
and final results may therefore occur.
Additional text:
Exploratory analyses of PK/PD may be additionally performed during 
Part 2 and if considered informative for the study
Rationale for 
change
Addition of ADA and allowing model set up for part 2 data.
Section to be 
changed
8.6 TRIAL MILESTONES
Description of 
change
Change from:
The end of the trial is defined as the date of the last visit of the last 
patient in the whole trial (“Last Patient Out”).
To:
The end of the trial is defined as the date of the last visit of the last 
patient in the whole trial (“Last Patient Out”), or when all patients 
have been discontinued from study treatment and followed up for 
overall survival for at least 12 weeks after treatment discontinuation.
Rationale for 
change
End of trial definition updated due to the addition of overall survival.
Section to be 
changed
9. PUBLISHED REFERENCES
Description of 
change
References added or updated 
Rationale for 
change
Adding references that support the protocol updates.

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Section to be 
changed
Minor editorial changes were done across the protocol
Description of 
change
Rationale for 
change
Clarification
Section to be 
changed
1.2 DRUG PROFILE
Description of 
change
Information for BI 836880 and Ezabenlimab was adapted.
Rationale for 
change
The CTP was adapted according to the latest available IB information 
regarding the profiles of the two IMP compounds.
11.7
GLOBAL AMENDMENT 7
Date of 
amendment
01 Mar 2022
EudraCT 
number
EU number
2017-001378-41
BI Trial 
number
1336-0011
BI 
Investigational 
Product(s)
BI 836880 (anti-VEGF/Ang2)
Ezabenlimab (BI 754091 [anti-PD-1])
Title of 
protocol
An open label phase Ib dose finding study of BI 836880 in 
combination with ezabenlimab to characterize safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy in patients with 
locally advanced or metastatic non-squamous Non-Small Cell Lung
Cancer and in other solid tumors
Global Amendment due to urgent safety reasons
Global Amendment
Section to be 
changed
Cover
Description of 
change
From:
Phone: 
Fax: 
To:

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Phone: 
Fax:  
Rationale for 
change
New CTL contact details updated
Section to be 
changed
Synopsis – Duration of treatment
Description of 
change
From:
Treatment will continue until disease progression, undue toxicity or 
Informed consent withdrawn
To:
Treatment may continue until disease progression, undue toxicity,
withdrawal of patient consent, or 53 cycles [approximately 3 years] 
from the start of first treatment administration, whichever occurs first. 
Patients will be allowed to stay on treatment also in the case of initial 
radiological PD, until progression is confirmed or up to 53 cycles from 
the start of first treatment administration if the investigator considers 
that the treatment is beneficial for the patient
Rationale for 
change
Treatment period limitation added due to the program discontinuation
Section to be 
changed
Flow chart Part 1 and Flow chart Part 2
Description of 
change
Total number of cycles limited to 53
Rationale for 
change
Treatment period limitation added due to the program discontinuation
Section to be 
changed
Flow chart Part 1 and Flow chart Part 2
Description of 
change
Central lab samples collection discontinuation
Rationale for 
change
To reduce patient burden due to the program discontinuation for the 
remaining visits
Section to be 
changed
Flow chart Part 1 and Flow chart Part 2 (footnotes)
Description of 
change
From:  
Tumour assessment every 6 weeks (in accordance to local requirements) starting from first trial
medication infusion. At EOT and EOR only when applicable (see Section 5.1).
To:
Tumour assessment can be performed according to institutional practices and SOC from the 
data cut-off date for interim database lock forward, starting from first trial medication 
infusion. 
Rationale for 
change
Imaging adjusted to standard of care to reduce patient burden after 
program discontinuation decision on December 2021.
Section to be 
changed
Flow chart Part 2

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Description of 
change
Biopsies removed
Rationale for 
change
To reduce patient burden after program discontinuation decision on 
December 2021.
Section to be 
changed
Flow chart Part 2
Description of 
change
FUP for survival status removed
Rationale for 
change
Program discontinuation decision from December 2021.
Section to be 
changed
ABBREVIATIONS
Description of 
change
Addition of SOC
Rationale for 
change
Inclusion of new abbreviation used in the main text.
Section to be 
changed
1.1 MEDICAL BACKGROUND
Description of 
change
Update in the number of treated patients.
Rationale for 
change
Updated information.
Section to be 
changed
1.1 MEDICAL BACKGROUND
Description of 
change
Last paragraph with preliminary responses removed:
Although available data from the ongoing clinical program for the 
ezabenlimab + BI 836880 combination indicate a positive benefit risk 
ratio, with signs of antitumor activity and manageable safety profile, 
BI decided in December 2021 to discontinue further development with 
this combination due to evolving standards of care in the indications 
under investigation. As a part of this decision, any patients still 
ongoing will be allowed to continue to receive treatment with the 
investigational regimen until progression or 53 cycles [approximately 
3 years] from the start of first treatment administration until treatment 
expires in early 2025, whichever comes first. 
Rationale for 
change
Information outdated.
Section to be 
changed
1.2. DRUG PROFILE
Description of 
change
Safety update according to IB BI 836880 version 17 Aug 2021 and 
ezabenlimab IB version 19 Jan 2022
Rationale for 
change
New safety information available.
Section to be 
changed
1.3 RATIONALE FOR PERFORMING THE TRIAL

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Description of 
change
Addition: 
DECISION TO TERMINATE THE TRIAL
Although a preliminary assessment of the available data from the 
ongoing clinical program for the ezabenlimab + BI 836880 
combination exhibit signs of antitumor activity and a manageable 
safety profile for an overall positive benefit risk ratio, careful 
review of the full data set performed in the context of the current 
standards of care for the indications under study has led to the 
decision taken by the sponsor in December 2021 to discontinue 
recruitment in study 1336.11, and terminate further expansion of 
the study. 
An important consideration in the review process was whether the 
investigational combination treatment under study, namely BI 
836880 plus ezabenlimab, had demonstrated benefit that delivered 
clear improvement over the current standards of care, some of 
which had evolved over the course of the study. The measure used 
to evaluate efficacy was the Objective Response Rate (ORR) which 
was the primary efficacy endpoint of the trial. It is important to 
note that at the time of this evaluation all cohorts had completed 
planned enrolment, and sufficient data had been collected to 
support a well-informed decision. Based on this evaluation, the 
efficacy observed in the different indications did not show clear 
improvement over the standards of care relative to published 
efficacy results in the different indications, with the one possible 
promising result in the 2L HCC cohort. This finding, however, was 
confounded by the population studied. The 2L HCC cohort enrolled 
patients that had received prior 1L treatment with monotherapy 
anti-angiogenic TKi (i.e., either sorafenib or lenvatinib). Given the 
evolution of the standard of care for 1L HCC, from monotherapy 
anti-angiogenic TKi treatment to combination treatment with 
immune checkpoint inhibitor plus an anti-angiogenic agent, it was 
determined that this cohort was not representative of what is 
expected to be the 2L HCC patient population moving forward. 
Based on this evaluation, the decision was taken to terminate the 
trial.
As a part of this decision, for patients still under active treatment, 
treatment with BI 836880 plus ezabenlimab may continue until disease 
progression, undue toxicity, withdrawal of patient consent, or 53 
cycles [approximately 3 years] from the start of first treatment 
administration, whichever occurs first (see Section 4.1.4, “Treatment 
duration” for full details). 

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Rationale for 
change
To include information regarding the program discontinuation 
decision.
Section to be 
changed
3.1 OVERALL TRIAL DESIGN AND PLAN
3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE 
OF CONTROL GROUP(S)
3.3 SELECTION OF TRIAL POPULATION
Description of 
change
Addition:
Rationale for 
change
As of the decision of Boehringer Ingelheim in Dec 2021 no additional 
patients will be further included to the trial.
Section to be 
changed
To include information regarding the program discontinuation 
decision.
Description of 
change
Deletion:
BI 836880 + ezabenlima will be administered (infusion every 3 weeks. 
In the case the patient shows a stable disease or response, the 
administration of BI 836880 and Ezabenlimab can be continued up o 
desease progression or until intolerable toxicity has been observed.
Rationale for 
change
Information moved to Section 4.1.4
Section to be 
changed
4.1 INVESTIGATIONAL TREATMENTS (tables 4.1.1: 1 and 4.1.1: 
2)
Description of 
change
From: 
BI836880. 
Duration of use: until progression or unacceptable toxicity
BI 754091
Duration of use: until progression or unacceptable toxicity
To:
BI836880. 
Duration of use: until progression, unacceptable toxicity, or up to a 
maximum of 53 cycles
BI 754091
Duration of use: until progression, unacceptable toxicity, or up to a 
maximum of 53 cycles
Rationale for 
change
Treatment period limitation added due to the program discontinuation
Section to be 
changed
4.1.4 Drug assignment and administration of doses for each patient
Description of 
change
From:

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Dose escalations of BI 836880 or ezabenlimab in any patient is not 
allowed. 
Dose reduction are not allowed for Ezabenlimab in any patient.
In the dose expansion study, only dose reductions are allowed for BI 
836880.
To:
Dose reductions or escalations are not allowed for ezabenlimab in any 
patient. 
In the dose expansion study, only dose reductions/re-escalations are 
allowed for BI 836880.
Rationale for 
change
Clarification: only BI 836880 dose can be reduced/re-escalated in part 
2.
Section to be 
changed
4.1.4 Drug assignment and administration of doses for each patient
Description of 
change
Addition:
Treatment duration:
Treatment with BI 836880 plus ezabenlimab may continue until 
disease progression, undue toxicity, withdrawal of patient consent, or 
53 cycles [approximately 3 years] from the start of first treatment 
administration, whichever occurs first. Patients will be allowed to stay 
on treatment also in the case of initial radiological PD, until 
progression is confirmed or up to 53 cycles from the start of first 
treatment administration if the investigator considers that the treatment 
is beneficial for the patient.
Investigators may consider discontinuing BI 836880 and continue 
therapy with ezabenlimab for up to 53 cycles from the start of the first 
treatment administration if the patient has been on therapy ≥ 6 months, 
has achieved at least SD by RECIST 1.1 and can tolerate the therapy, 
and if the investigator considers this to be in the best interest of the 
patient.
For any patient still on treatment with the investigational combination 
of BI 836880 plus ezabenlimab 53 cycles from the start of the first 
treatment administration, treatment extension will be considered on a 
case-by-case basis upon request by the investigator for a maximum 
additional 6 cycles, to complete no later than 30 April 2025, if the 
investigator considers this to be in the best interest of the patient. After 
this date treatment with the investigational combination BI 836880 
plus ezabenlimab will no longer be available.

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Investigators are requested to prepare for discontinuation of patients 
from the current investigational treatment of BI 836880 plus 
ezabenlimab and to switch them to alternative available treatment 
options outside of the current protocol no later than by the final 
availability date of 30 April 2025.
Rationale for 
change
Treatment period limitation added due to the program discontinuation
Section to be 
changed
5.1 ASSESSMENT OF EFFICACY
Description of 
change
From:
Efficacy endpoints will be assessed every 2 cycles (6 weeks) as 
specified in the FC. An additional evaluation at EoT is only 
applicable; when patient has no PD documented, will not continue 
with regular imaging in Follow-up period and did not have imaging 
within the last 4 weeks before EoT. In case a patient has discontinued 
due to PD one additional tumor assessment should be done according 
to iRECIST in case no other cancer treatment has been initiated
(confirming image should be done 4 – 6 weeks after the last image).
For Glioblastoma patients, an additional image according to iRANO 
should be taken 3 month after PD. All measurements must be recorded 
in metric notation
To:
Efficacy endpoints will be assessed according to institutional practices 
and SOC from data cut-off date for interim database lock (iDBL) 
forward as specified in the flowchart.
Rationale for 
change
To reduce patient burden after program discontinuation decision on 
December 2021.
Section to be 
changed
5.1.2 Tumour response assessments using RANO
Description of 
change
From:
Response assessments in GBM will be performed every 6 weeks using 
the objective status categories per RANO and iRANO criteria.
To:
Response assessment in GBM will be performed according to 
institutional practices and SOC from data cut-off date for interim 
database lock (iDBL) forward using the objective status categories per 
RANO and iRANO criteria.
Section to be 
changed
5.3.1 Assessment of pharmacokinetics
Description of 
change
Addition:
As of the decision of Boehringer Ingelheim in December 2021 no 
additional blood samples for pharmacokinetics will be collected

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Rationale for 
change
To reduce patient burden after program discontinuation decision on 
December 2021.
Section to be 
changed
5.4 ASSESSMENT OF BIOMARKER(S)
Description of 
change
From:
The list of biomarkers planned to be studied during the trial may 
change or based on new information in the literature or early analyses.
To:
Planned exploratory biomarker analyses during the trial may be 
changed or stopped based on new information in the literature or early 
analyses.
Rationale for 
change
Clarification
Section to be 
changed
5.4.1 Methods of sample collection
Description of 
change
Addition:
As of the decision of Boehringer Ingelheim in December 2021 no 
additional biopsies will be collected.
Rationale for 
change
To reduce patient burden after program discontinuation decision on 
December 2021.
Section to be 
changed
6.2.2 Treatment period(s)
Description of 
change
From:
For Part 1 disease response assessment by CT/MRI will be performed 
at the end of every other cycle (CT to be performed every 6 weeks 
starting from first trial medication administration).
Follow up period and trial completion
For Part 2 tumour assessment should be done every 6 weeks (in 
accordance to local requirements with a window of +/- 7 days).
Assessments are always done prior to the start of the new treatment 
cycle. At EOT and Safety Follow-up visit only when applicable (see 
Section 5.1).
To:
For Part 1 and Part 2 disease response assessment by CT/MRI will be 
performed according to institutional practices and SOC.
Rationale for 
change
To reduce patient burden after program discontinuation decision on 
December 2021.
Section to be 
changed
6.2.5.1 Follow-up for progression
Description of 
change
Deletion:
-
Sampes for PK, ADA and plasma biomarker at first Follow 
up (FU1)
Rationale for 
change
To reduce patient burden after program discontinuation decision on 
December 2021.

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Section to be 
changed
6.2.5.2 Follow up for Overall Survival
Description of 
change
Complete instruction removed and replaced with:
Sponsor has decided that as of this protocol amendment 
acknowledgement no further survival status follow-up will be 
collected.
Rationale for 
change
Overall survival follow-up will no longer be performed.
Section to be 
changed
8.6 TRIAL MILESTONES
Description of 
change
From:
The end of the trial is defined as the date of the last visit of the last 
patient in the whole trial (“Last Patient Out”), or when all patients 
have been discontinued from study treatment and followed up for 
overall survival for at least 12 weeks after treatment discontinuation.
To:
The end of the trial is defined as the date of the last visit of the last 
patient in the whole trial (“Last Patient Out”), or when all patients 
have been discontinued from study treatment and followed up for 
overall survival until the end of REP
Rationale for 
change
Clarification
Section to be 
changed
10.5.1 Time Schedule for Pharmacokinetic (PK) and 
Pharmacodynamic Blood Sampling
Description of 
change
Addition:
From December 2021, no further blood samples should be obtained 
for central lab shipments, and no biopsies should be performed.
Rationale for 
change
To reduce patient burden after program discontinuation decision on 
December 2021.
Section to be 
changed
Minor editorial changes were done across the protocol
Description of 
change
Rationale for 
change
Clarification
11.8
GLOBAL AMENDMENT 8
Date of 
amendment
03 May 2023
EudraCT 
number
EU number
2017-001378-41
BI Trial 
number
1336-0011

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BI 
Investigational 
Product(s)
BI 836880 (anti-VEGF/Ang2)
Ezabenlimab (BI 754091 [anti-PD-1])
Title of 
protocol
An open label phase Ib dose finding study of BI 836880 in 
combination with ezabenlimab to characterize safety, tolerability, 
pharmacokinetics, pharmacodynamics and efficacy in patients with 
locally advanced or metastatic non-squamous Non-Small Cell Lung
Cancer and in other solid tumors
Global Amendment due to urgent safety reasons
Global Amendment
Section to be 
changed
4.1.1 Identity of the Investigational Medicinal Products
Description of 
change
From:
Substance:
Ezabenlimab (BI 754091)
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH 
& Co. KG
Unit strength:
20 mg /mL (15 mL vial)
Posology
rate controlled infusion on Day 1 of 
each 3-week cycle
Route of administration:
i.v.
Duration of use: 
until progression, unacceptable 
toxicity, or up to a maximum of 53 
cycles
To:
Substance:
Ezabenlimab (BI 754091)
Pharmaceutical formulation:
Solution for Infusion or Concentrate 
for solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH 
& Co. KG
Unit strength:
20 mg /mL (15 mL vial) or 20 mg 
/mL (12 mL vial)
Posology
rate controlled infusion on Day 1 of 
each 3-week cycle
Route of administration:
i.v.

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001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
Duration of use: 
until progression, unacceptable 
toxicity, or up to a maximum of 53 
cycles
Rationale for 
change
Update new formulation of ezabenlimab.
Section to be 
changed
4.1.7 Storage conditions
Description of 
change
From:
BI 836880 vials (old and new formulation) and ezabenlimab vials must
be stored in their original packaging.
To:
BI 836880 vials (old and new formulation) and ezabenlimab vials
(solution and concentrate for solution) must be stored in their original 
packaging.
Rationale for 
change
Addition of the concentrate for solution

 
 
 
APPROVAL / SIGNATURE PAGE 
Document Number: 
 
Technical Version Number:
Document Name: 
                                                                                                                 
 
Title: 
                                                                                                                   
Signatures (obtained electronically) 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c16151514
12.0
clinical-trial-protocol-version-09
An open label phase Ib dose finding study of BI 836880 in combination with
ezabenlimab to characterize safety, tolerability, pharmacokinetics,
pharmacodynamics and efficacy in patients with locally advanced or metastatic
non-squamous Non-Small Cell Lung Cancer and in other solid tumors
Author-Trial Statistician
18 May 2023 15:51 CEST
Author-Clinical Trial Leader
18 May 2023 15:55 CEST
Approval-Clinical Program Leaders
22 May 2023 09:33 CEST
Approval-Clinical Trial Leader
22 May 2023 15:27 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c16151514
12.0