Brightline-1: A Phase II/III, Randomized, Open-label, Multi-center Study of Brigimadlin (BI 907828) Compared to Doxorubicin as First Line Treatment of Patients With Advanced Dedifferentiated Liposarcoma
Phase: PHASE2
Conditions: Liposarcoma, Dedifferentiated
Sponsor: Boehringer Ingelheim

Clinical Trial Protocol
TITLE PAGE
Document Number:
c35654143-06
EudraCT No.
EU Trial No.
2021-002392-20
BI Trial No.
1403-0008
BI Investigational
Medicinal Products
BI 907828 (INN: Brigimadlin)
Title
Brightline-1: A Phase II/III, randomized, open-label, multi-center
study of brigimadlin (BI 907828) compared to doxorubicin as
first line treatment of patients with advanced dedifferentiated 
liposarcoma
Lay Title
Brightline-1: A study to compare brigimadlin (BI 907828) with 
doxorubicin in people with a type of cancer called 
dedifferentiated liposarcoma
Clinical Phase
Phase II/III
Clinical Trial Leader
Phone:
Email:
Coordinating 
Investigators
Phone 
Email:
Phone:
Email:
Current Version and 
Date
Version 6.0, 02 May 2024
Original Protocol 
Date
18 Nov 2021
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Proprietary confidential information.
2024 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
Original Protocol date
18 Nov 2021
Revision date
02 May 2024
BI trial number
EU CT number
1403-0008
2021-002392-20
Title of trial
Brightline-1: A Phase II/III, randomized, open-label, multi-center
study of brigimadlin (BI 907828) compared to doxorubicin as first 
line treatment of patients with advanced dedifferentiated 
liposarcoma
Coordinating 
Investigators
Phone
Email:
Phone:
Email:
Trial site(s)
Multi-center trial
Clinical phase
Phase II/III
Trial rationale
Brigimadlin (BI 907828) is an orally available MDM2-p53
antagonist that showed a manageable safety profile and preliminary 
signs of efficacy in Phase I studies especially in patients with 
dedifferentiated liposarcoma (DDLPS).
The trial will compare different doses of brigimadlin (investigational 
arms) to doxorubicin (control arm) as first line systemic treatment 
of patients with advanced or metastatic DDLPS.
Trial objective(s)
The primary trial objective is to evaluate whether brigimadlin is 
superior to doxorubicin as first line systemic therapy for advanced or
metastatic DDLPS.
Additional trial objectives are to select an optimal dose of 
brigimadlin and to evaluate whether brigimadlin improves the 
objective response rate, duration of responses, overall survival, 
disease control rate, as well as tolerability and has a favorable 
impact on quality of life, compared to doxorubicin.

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Trial endpoints
Primary endpoint
Progression-free survival (PFS), defined as the time interval from 
randomization until tumor progression according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (based 
on blinded central independent review) or death from any cause, 
whichever occurs first.
Secondary endpoints:

Objective response (OR), defined as a best overall response 
of confirmed complete response (CR) or confirmed partial 
response (PR) according to RECIST version 1.1 (based on 
blinded central independent review) from the date of 
randomization until disease progression, death, or last 
evaluable tumor assessment before start of subsequent anti-
cancer therapy, loss to follow-up, or withdrawal of consent, 
whichever occurs first.

Duration of objective response (DOR), defined as the time
interval from first documented confirmed OR until disease 
progression or death among patients with confirmed OR
(based on blinded central independent review), whichever 
occurs first.

Overall survival (OS) at the end of Phase III, defined as the 
time interval from randomization until death from any cause.

Disease control (DC), defined as a best overall response of 
CR, PR, or stable disease (SD) according to RECIST 
version 1.1 (based on blinded central independent review).

Health-Related Quality of Life (HRQoL), based on data 
collected through specific questionnaires (Patient Reported 
Outcome Measures, PROMs), analyzed from baseline to 
Week 6 and to Week 18. The HRQoL endpoints are defined 
as the scores calculated from data collected through selected 
EORTC QLQ-C30 domains (physical functioning, fatigue, 
pain, and global health status / quality of life), fatigue and 
pain based on items from the EORTC QLQ-C30 and the 
EORTC Item Library, and the EQ-5D5L.

Occurrence of treatment-emergent adverse events (AEs).

Occurrence of treatment-emergent AEs leading to study drug 
discontinuation.
Trial design
Active-controlled, open-label, randomized, seamless Phase II/III
parallel design comparison of 3 arms (Phase II) followed by 2 arms
(Phase III).
The Phase II part of the trial will start with 3 arms (2 investigational 

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Trial design (continued) arms, 1 control arm) that will compare 2 different doses of 
brigimadlin (30 mg and 45 mg) versus doxorubicin (standard of 
care). An interim analysis for dose selection will be performed in the 
Phase II part for dose optimization, where one of the 
2 investigational arms may be selected to continue full enrollment. 
Enrollment of patients to all 3 arms will continue while this interim 
analysis is conducted. The transition to Phase III is based on the 
number of patients enrolled. At the transition point from Phase II to 
Phase III, a total of 180 patients will have been randomized to the 
selected investigational arm and the control arm, and up to 90 
patients randomized to the unselected investigational arm.
An interim futility analysis of PFS will be performed after 
approximately 56 PFS events from the selected investigational arm 
and the control arm, which is expected to occur at approximately the 
same time as the end of Phase II. Enrollment of patients will 
continue whilst this analysis is performed. If the selected 
investigational arm passes the futility boundary, then the trial will 
continue to full enrollment. If enrollment is close to completion 
when the required number of 56 PFS events is reached, then the 
interim futility analysis of PFS may not be performed.
Total number of 
patients randomized 
The overall sample size is approximately 390 patients. Up to 
270 patients will be randomized 1:1:1 in Phase II. In Phase III, 
approximately 120 additional patients will be randomized 1:1 to 
either the selected investigational arm or the control arm.
Randomization will be stratified by ‘extent of disease’ (locally 
advanced vs. metastatic disease).
Number of patients per
treatment group
Phase II:
Brigimadlin at 30 mg:
Up to 90 patients
Brigimadlin at 45 mg:
Up to 90 patients
Doxorubicin:
90 patients
Phase III:
Brigimadlin (at the selected dose level):
Approximately 60 additional patients
Doxorubicin:
Approximately 60 additional patients
Diagnosis
Histologically proven locally advanced or metastatic
dedifferentiated liposarcoma

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Main inclusion and 
exclusion criteria
Main inclusion criteria:

Histologically proven locally advanced or metastatic,
unresectable (surgery morbidity would outweigh potential 
benefits), progressive or recurrent DDLPS. Locally performed 
histopathological diagnosis will be accepted for entry into this 
trial.

Written pathology report indicating the diagnosis of DDLPS
with positive MDM2 immunohistochemistry or MDM2 
amplification as demonstrated by fluorescence in situ
hybridization or NGS must be available.

Male or female patients ≥18 years old.

Formalin fixed paraffin embedded tumor blocks or slides must 
be available for retrospective histopathological central review.

Presence of at least one measurable target lesion according to 
RECIST version 1.1.

Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 or 1.

Patient willing to donate blood samples for the 
pharmacokinetics, pharmacodynamics, and tumor mutation 
analysis.

Patient willing to undergo a mandatory tumor biopsy.

Adequate organ function as defined by inclusion criteria detailed 
in the clinical trial protocol.
Main exclusion criteria:

Known mutation in the TP53 gene (screening for TP53 status is 
not required).

Major surgery (major according to the investigator’s assessment) 
performed within 4 weeks prior to randomization or planned 
within 6 months after screening.

Prior systemic therapy for liposarcoma in any setting (including 
adjuvant, neoadjuvant, maintenance, palliative).

Previous or concomitant malignancies other than DDLPS or 
WDLPS, treated within the previous 5 years, except effectively
treated non-melanoma skin cancers, carcinoma in situ of the 
cervix, ductal carcinoma in situ, or other malignancy that is 
considered cured by local treatment.

Previous treatment with anthracyclines in any setting (systemic 
treatment with other anti-cancer agents is allowed if completed at 
least 5 years prior to study entry with the exception of hormone 
therapy).

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Main inclusion and 
exclusion criteria
(continued)

Patients who must or intend to continue the intake of restricted 
medications or any drug considered likely to interfere with the 
safe conduct of the trial.
Test product
Brigimadlin (BI 907828)
dose
Single dose on Day 1 every 21 days
Starting dose will be 30 mg or 45 mg
Patients with pre-specified adverse events or abnormal laboratory 
values can delay or reduce their dose.
 
mode of 
administration
Oral
Comparator product
Doxorubicin
dose
75 mg/m2 on Day 1 every 21-days
mode of
administration
Intravenous
Duration of treatment
Treatment will be administered until documented disease 
progression, unacceptable adverse events, withdrawal of consent, or 
other reasons requiring treatment discontinuation, or for the 
doxorubicin arm for up to the maximum cumulative dose of 
450 mg/m2.
Patients randomized to doxorubicin after confirmed disease 
progression by blinded central independent review will be allowed 
to cross-over to treatment with brigimadlin.
Statistical methods
Phase II:
The interim analysis for dose selection will be conducted during the 
Phase II part based on the totality of safety data and PK/PD
parameters as surrogates of clinical efficacy. After dose selection, 
enrollment into the unselected investigational arm will be stopped, 
and the rest of the Phase II and Phase III parts of the trial will 
continue with the selected dose of the investigational arm and the 
control arm. No PFS analysis between investigational arms and 
control arm is planned during this interim analysis for dose 
selection.
The interim futility analysis of PFS will occur at the timepoint when 
about 56 PFS events occur from the selected investigational arm and 
the control arm using a stratified log-rank test (locally advanced vs. 
metastatic) as the primary analysis method. An alpha spending of 
0.0005 (one-sided) and a non-binding futility boundary of HR = 0.80 
for PFS are planned.

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Statistical methods
(continued)
If the selected investigational arm passes the futility boundary, then 
the trial will continue to full enrollment.
Phase III:
The primary PFS analysis will take place during Phase III at the time 
point when approximately 120 PFS events from the selected 
investigational arm and the control arm have occurred in patients 
enrolled in Phase II; and approximately 65 PFS events from the
selected investigational arm and the control arm have occurred in 
patients enrolled in Phase III.
The combination test approach as outlined by Lehmacher et al. will 
be applied for the primary analysis of PFS in the Phase III part to 
control the familywise error rate for the adaptive design of the trial.
If statistical significance is obtained for PFS, then selected
secondary endpoints (i.e. ORR and OS) will be tested following a 
hierarchical testing framework. The Cochran-Mantel-Haenszel 
method will be used to test for a difference between the selected 
investigational treatment arm and the doxorubicin control arm for 
ORR, and ORR will be tested at a one-sided alpha level of 0.0245 at 
the same time as the primary PFS analysis. The stratification factor 
will be adjusted for in the analysis (locally advanced vs. metastatic). 
If statistical significance is obtained for both PFS and ORR, then the 
alpha of one-sided level of 0.0245 will be carried over to the primary 
analysis and test of OS, occuring at the end of the Phase III part
when approximately 133 OS events from the selected investigational 
arm and the control arm have occurred in patients enrolled in 
Phase II; and approximately 82 OS events from the selected 
investigational arm and the control arm have occurred in patients 
enrolled in Phase III. 
If statistical significance is obtained for PFS but not for ORR, then 
OS will continue to be followed up until the pre-specified number of 
OS events are met at the end of Phase III and then analyzed without 
being formally tested.
The primary analysis of OS will be performed using the stratified 
log-rank test (locally advanced vs. metastatic), and OS would be 
tested at a one-sided level of 0.0245.

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FLOWCHARTS
The flowchart in Table 1 gives details about brigimadlin (BI 907828) treatment, Table 2 provides details for the doxorubicin arm, and Table 3
gives details for the cross-over to treatment with brigimadlin.
Table 1
Flowchart brigimadlin treatment / trial 1403-0008
Brigimadlin arm
Screening
Cycles 1 and 2 1
Cycles 3 and 4 1
Cycle ≥5 1
EOT 2
EOR 3
FU for 
PD
FU for 
survival
Time point
Day
-28 to -
1
Day
-5 to 1
Day 1 22
Day 8
(±1 d)
Day 15
(±1 d)
Day 1
(+3 d) 
Day 15
(±2 d)
Day 1
(+3 d)
Within 7 days 
after EOT 
decision
Day 30 
(+5 d) after
last dose 4
Every 
6 weeks
(± 7 d)
Every 
12 weeks 21
(± 7 d)
Informed consent 5
X
Demographics / Medical 
history
X
Review of inclusion and 
exclusion criteria 6
X
Randomization
X
Physical examination, vital 
signs, ECOG PS 7
X
X
X
X
X
X
X
Hematology, biochemistry 
(safety laboratory 8)
X
X
X
X
X
X
X
X
X
X
Coagulation, urinalysis 
(safety laboratory 8)
X
X
X
X
X
X
X
Pregnancy test 9
X
X
X
X
X
X
X
X
Single 12-lead ECG 10
X
X
X
X
X
X
Echocardiogram / MUGA 
scan 11
X
X (C6)
Archival tumor material / 
fresh biopsy 12
X
Fresh biopsy during
treatment (mandatory) 12
X (C2D2-4) 12
Blood sample for circulating 
proteins 14
X
X (C2)
X
X
X

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Brigimadlin arm
Screening
Cycles 1 and 2 1
Cycles 3 and 4 1
Cycle ≥5 1
EOT 2
EOR 3
FU for 
PD
FU for 
survival
Time point
Day
-28 to -
1
Day
-5 to 1
Day 1 22
Day 8
(±1 d)
Day 15
(±1 d)
Day 1
(+3 d) 
Day 15
(±2 d)
Day 1
(+3 d)
Within 7 days 
after EOT 
decision
Day 30 
(+5 d) after
last dose 4
Every 
6 weeks
(± 7 d)
Every 
12 weeks 21
(± 7 d)
Blood sample for GDF-15 14
X
X
X 14
X
X
X
Blood sample for miRNA 
analysis 14
X
X
X
X
Blood samples for PBMCs /
MDSCs 14
X
X 14
X 14
X
Blood sample for tumor 
mutation analysis (ctDNA) 
14
X
X
X
X
Blood sample for PGx 
(mandatory)
X (C1)
PROMs: QLQ-C30, items 
pain & fatigue 15
From C1D1 to Week 48 or PD, whichever occurs first, every 3 weeks; and from PD (or Week 48) onwards annually
PROMs: EQ5D, PGIC,
PGIS 15
At C1D1; at Week 15; from Week 15 to Week 48 or PD, whichever occurs first, every 12 weeks; and from PD (or Week 48) onwards annually
PRO-CTCAE 16
From C1D1 until Week 15 weekly; from Week 15 to Week 48 or PD, whichever occurs first, every 3 weeks; no assessments after PD (or Week 48)
Concomitant therapy 17
X
X
X
X
X
Analgesic quantification 
algorithm (AQA)
X
X
X
X
X
Adverse events 18
X
X
X
X
X
X
X
X
X
X
Study treatment 
administration 19
X
X
X
Tumor assessment 20
X
Every 6 weeks starting 6 weeks after C1D1
X 20
Termination of trial 
medication
X
Patient status 21
X
1.
All cycles are 21 days in duration and may be extended if subsequent dosing is delayed e.g. due to toxicity. No new cycle should be started before at least 21 days have 
elapsed since the last treatment administration on Day 1 of the previous cycle. Patients may continue on treatment until any criteria for stopping medication are met 
(see Section 3.3.4.1). In general, Cycles 1 and 2 include visits on Days 1, 8, and 15; Cycles 3 and 4 include visits on Days 1 and 15; from Cycle 5 onwards visits are 
scheduled for Day 1.

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2.
EOT = End Of Treatment. All patients should undergo the EOT visit as soon as possible after permanent discontinuation of trial treatment (within 7 days of decision to 
stop treatment). An EOT visit beyond 21 days is possible for patients who delayed their next dose due to toxicity and only then decided to stop treatment. If the decision 
to permanently discontinue trial medication is taken during a scheduled visit, the EOT visit should be performed instead of the scheduled visit. Please see Section 3.3.4.
After the EOT visit, the investigator should report only any cancers of new histology, trial drug related SAEs and trial drug related AESIs of which the investigator may 
become aware of and only via the BI SAE form, please see Section 5.2.6.2.1.
3.
EOR = End Of Residual effect period.
4.
The residual effect period (REP) for brigimadlin is 30 days. The EOR visit must occur 30 days (+5 days) after last treatment. For patients who discontinue for a reason 
other than confirmed progression by central independent review, follow-up visits continue until confirmed disease progression by central independent review per the 
imaging schedule (refer to Section 5.1), lost to follow up, start of subsequent anti-cancer treatment, withdrawal of consent, or completion of the entire trial as specified in 
Section 8.6.
5.
Written informed consent must be obtained before any protocol-specific screening assessments are performed. Re-consenting may become necessary when new relevant 
information becomes available and should be conducted according to the sponsor’s instructions. The consent to collection of a blood sample for pharmacogenetics is 
mandatory (Section 5.4) unless precluded by local regulations.
6.
Inclusion / exclusion criteria should be re-confirmed before treatment start. Safety laboratory tests do not need to be repeated if performed within 10 days prior to 
treatment start and there is no clinical reason to repeat laboratory tests.
7.
The physical examination includes measurement of height (only at screening) and weight. Vital signs include systolic and diastolic blood pressure and pulse rate 
(electronically or by palpation count for 1 minute) in a seated position after 5 minutes of rest. Additional physical examinations including vital signs may be conducted as 
clinically indicated at the investigator’s discretion. Refer to Sections 5.2.1 and 5.2.2.
8.
Safety laboratory assessments including hematology, serum biochemistry, coagulation, and urinalysis will be performed locally and should be performed or repeated 
within 10 days prior to treatment initiation (Cycle 1 Day 1) then within 72 h prior to each treatment administration (Day 1 of each cycle). On Day 1 of each treatment 
cycle the results must be available prior to treatment and evaluated to ensure that the patient is eligible to receive the next dose. Refer to Section 5.2.3.
Hematology and serum biochemistry laboratory tests must be performed weekly during the first 2 cycles, on Days 1 and 15 of Cycles 3 and 4, then within 72 h 
prior to Day 1 of each subsequent cycle.
Coagulation and urinalysis must be performed within 72 h prior to Day 1 of each cycle.
All safety laboratory tests can be repeated at any other time point, if clinically indicated, at the investigator’s discretion. 
After trial treatment discontinuation, all safety laboratory tests will be performed at EOT and at EOR. They may be repeated during FU if clinically indicated.
In case of any elevation of ALT/AST and bilirubin, please see Section 5.2.6.1.4.
9.
A serum pregnancy test is mandatory for female patients of childbearing potential at screening. A urine or serum pregnancy test must be conducted within 72 hours prior
to start of study treatment on Day 1 of Cycle 1, prior to treatment on Day 1 of every cycle from Cycle 2 Day 1 onwards, at EOT, and then monthly until 6 months after 
the last dose of treatment (refer to Sections 5.2.3 and 4.2.2.3 regarding restrictions for women of childbearing potential). Pregnancy testing after EOT can be performed 
remotely or at the clinic.
10. Electrocardiogram (ECG): Standard 12-lead (I, II, III, aVR, aVL, aVF, V1 - V6) resting ECGs will be recorded (detailed timing see Appendix 10.1). To not confuse ECG 
recordings, PK samples should be taken after performing the ECG, and patient should rest in supine position for at least 10 minutes before starting ECG recordings (refer
to Section 5.2.4). ECGs may be repeated as clinically indicated.
11. Echocardiograms or MUGA scans are to be performed prior to treatment start and in Cycle 6. Scans may be repeated during treatment if clinically indicated.

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12. Archival tumor tissue MUST be provided for all patients to retrospectively test TP53 mutation status and MDM2 amplification by a central pathology laboratory. 
A block is preferred but slides are acceptable. The total volume of material provided (l×b×d) should not be less than 5 mm3. If archival tissue is not available (or 
insufficient), a biopsy must be performed for collection of fresh tissue. In addition, 1 on-treatment biopsy is required in Cycle 2 (Day 2-4). Patients under anticoagulation 
treatment or patients with thrombocytopenia of CTCAE Grade 3 or 4 are not required to undergo the on-treatment tumor biopsy. See Section 5.4.2 for details.
13.
14. Blood samples for biomarker analysis are mandatory. Details of blood sampling for all biomarker analyses are described in Section 5.4 and the detailed sampling 
schedule is available in Appendix 10.1.
Blood samples for GDF-15 will be collected as described in Appendix 10.1.
Blood samples for circulating protein biomarkers and miRNAs will be collected on Day 1 (pre-treatment) of all cycles and at EOT. An additional sample for
circulating protein biomarkers will be collected at Cycle 2 Day 8.
Blood samples for peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) for flow cytometry analysis will only be collected
for patients enrolled in the Phase II part.
Collection of blood samples for tumor mutation analysis (ctDNA) must be obtained at C1D1 prior to first drug administration, Day 1 of each treatment cycle, and at 
the time of progressive disease (at the EOT visit). Refer to Section 5.4.
15.
16.
17. For concomitant therapy and restrictions on concomitant therapy, refer to Sections 4.2.1 and 4.2.2.1.
18. Includes the review of safety laboratory tests if applicable. For details on Adverse Event reporting after treatment discontinuation, refer to Sections 5.2.6.2 and 6.2.3. 
Early and proactive management of side effects is essential to retention and the site is recommended to call the patient a few days after starting treatment to discuss 
whether the patient has side effects and how these can be treated. In addition, phone calls at any time are recommended e.g. in case of severe myelosuppression, and the 
patients should be instructed to contact the sites if applicable.

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19. Brigimadlin will be dispensed on Day 1 of each cycle by investigator or authorized designee. Refer to Section 4.3.
20. Tumor assessment will be performed according to RECIST version 1.1. Tumor assessments should include computed tomography (CT) or magnetic resonance imaging
(MRI) scans of chest and abdomen/pelvis. If clinically indicated, imaging of any other known or suspected sites of disease (e.g. bone) using an appropriate method (CT
scan, MRI, or bone scan) should be performed. The same radiographic procedure must be used throughout the study. If bone lesions are already known or confirmed at 
screening, correlative imaging (X-ray, CT scan, MRI, or bone scan) should be performed and repeated at each tumor assessment.
Assessments will be performed at the following time points, irrespective of scheduled protocol visits, until confirmed progressive disease by central independent review,
or start of subsequent anti-cancer treatment:
Screening visit (within 28 days prior to first drug intake). A scan performed as part of routine clinical practice and prior to provision of informed consent and within 
the screening timeframe can be used if it meets the requirements described by the imaging laboratory and imaging manual.
Every 6 weeks ±7 days, relative to the C1D1 date. From Week 36 onwards every 12 weeks ±7 days.
In case of discrepancy between investigator and central independent review, refer to Section 5.1 for handling.
Assessment schedule should not be changed for any reason, including interruption / delay of treatment.
All imaging scans / timepoints (scheduled and unscheduled) are to be submitted for central independent review. Whenever the investigator assesses that a patient 
has progressive disease, the relevant scans must be flagged and submitted immediately for central independent review. The investigator should await the results of 
central independent review before permanent discontinuation of treatment. Refer to Section 5.1 and the imaging manual for additional details.
21. During FU for survival, patient visits to the clinic are not required unless required for pregnancy testing. Information may be collected from the patient notes, via 
telephone contact or through an edevice for PROMs. Patient status will be collected until death, lost to follow-up, withdrawal of consent, or end of the whole trial. In the 
case of death, date of death and cause of death will be collected. Patient death information can be collected from the patient’s medical records, etc. if the patient had not 
withdrawn consent for trial participation.
22. Cycle 1 Day 1 assessments (physical examination, ECOG performance status, vital signs, ECG, safety laboratory blood tests, urinalysis, pregnancy test, weight) do not 
need to be performed if done during screening within 72 h prior to treatment administration and in the opinion of the investigator a repeat is not required. In this case the 
latest value prior to start of treatment will be considered the baseline.
A window (+3 d) is acceptable for scheduling Cycle 2 Day 1.

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Table 2
Flowchart doxorubicin arm / trial 1403-0008
Doxorubicin arm
Screening
Cycles 1 and 2 1
Cycles 3 to 6 1
EOT 2
EOR 3
FU for PD
FU for 
survival
Time point
Day
-28 to -1
Day
-5 to 1
Day 1 20
Day 8
(±1 d)
Day 15
(±1 d)
Day 1
(+3 d)
21 days (±3 d) 
after last Cycle 
Day 1
Day 30 (+5 d)
after last dose
Every 
6 weeks
(± 7 d)
Every 
12 weeks 19
(± 7 d)
Informed consent 4
X
Demographics / Medical history
X
Review of inclusion and exclusion 
criteria 5
X
Randomization
X
Physical examination, vital signs, 
ECOG PS 6
X
X
X
X
X
X
Hematology, biochemistry (safety 
laboratory 7)
X
X
X
X
X
X
Coagulation, urinalysis (safety 
laboratory 7)
X
X
X
X
X
X
Pregnancy test 8
X
X
X
X
X
X
X
Single 12-lead ECG 9
X
X
X
X
X
Echocardiogram / MUGA scan 10
X
X (C6)
Archival tumor material / fresh 
biopsy 11
X
Fresh biopsy during treatment 
(mandatory) 11
X (C2D2-4)
Blood sample for circulating 
proteins 12
X
X
X
Blood sample for miRNA analysis 
12
X
X
X
Blood samples for PBMCs /
MDSCs 12
X
X 12
X 12
X
Blood sample for tumor mutation 
analysis (ctDNA) 12
X
X
X
Blood sample for PGx (mandatory)
X (C1)
PROMs: QLQ-C30, items pain & 
fatigue 13
From C1D1 to Week 48 or PD, whichever occurs first, every 3 weeks; and from PD (or Week 48) onwards annually
PROMs: EQ5D, PGIC, PGIS 13
At C1D1; at Week 15; from Week 15 to Week 48 or PD, whichever occurs first, every 12 weeks; and from PD (or Week 48) onwards 
annually

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Doxorubicin arm
Screening
Cycles 1 and 2 1
Cycles 3 to 6 1
EOT 2
EOR 3
FU for PD
FU for 
survival
Time point
Day
-28 to -1
Day
-5 to 1
Day 1 20
Day 8
(±1 d)
Day 15
(±1 d)
Day 1
(+3 d)
21 days (±3 d) 
after last Cycle 
Day 1
Day 30 (+5 d)
after last dose
Every 
6 weeks
(± 7 d)
Every 
12 weeks 19
(± 7 d)
PRO-CTCAE 14
From C1D1 until Week 15 weekly; from Week 15 to Week 48 or PD, whichever occurs first, every 3 weeks; no assessments after PD (or 
Week 48)
Concomitant therapy 15
X
X
X
X
Analgesic quantification algorithm 
(AQA)
X
X
X
X
Adverse events 16
X
X
X
X
X
X
X
X
Pre-treatment 17
X
X
Study treatment administration 17
X
X
Tumor assessment 18
X
Every 6 weeks starting 6 weeks after C1D1
X 18
Termination of trial medication
X
Patient status 19
X
1.
All cycles are 21 days in duration and may be extended if subsequent dosing is delayed e.g. due to toxicity. Patients may continue on treatment with doxorubicin for up 
to the maximum cumulative dose of 450 mg/m2 (approximately 6 cycles), or until any criteria for stopping medication are met (see Section 3.3.4.1). Patients who 
complete doxorubicin treatment will complete the EOT and EOR visit and will be followed until PD by central independent review and thereafter per local institutional 
guidelines/standards. In rare cases patients may receive more than 6 cycles of doxorubicin treatment. If this occurs, the study visits for the additional cycles will follow 
the same schedule as for Cycle 6. In general, Cycles 1 and 2 include visits on Days 1, 8, and 15; Cycles 3 to 6 include visits on Day 1.
2.
EOT = End Of Treatment. This refers to completion of study treatment (as scheduled) as well as premature treatment withdrawal. Patients who received the maximum 
cumulative dose of doxorubicin should have the EOT visit 21 days (±3 d) after the last cycle Day 1. Patients who discontinue trial treatment prematurely should undergo 
the EOT visit as soon as possible (within 7 days of the decision to stop treatment). An EOT visit beyond 21 days is possible for patients who delayed their next dose due 
to toxicity and only then decided to stop treatment. If the decision to permanently discontinue trial medication is taken during a scheduled visit, the EOT visit should be 
performed instead of the scheduled visit. Please see Section 3.3.4. After the EOT visit the investigator should report only any cancers of new histology, trial drug related 
SAEs, trial drug related AESIs. Reporting is to be done only via the BI SAE form, please see Section 5.2.6.2.1. Patients being considered for the cross-over arm may use 
the EOT visit assessments as “screening” (i.e. C1D1). 
3.
EOR = End Of Residual effect period. The residual effect period (REP) for doxorubicin is 30 days. For patients who discontinue for a reason other than confirmed 
progression by central independent review, continue with follow-up visits until confirmed disease progression by central independent review per the imaging schedule 
(refer to Section 5.1), lost to follow up, start of subsequent anti-cancer treatment, withdrawal of consent, or completion of the entire trial as specified in Section 8.6. 
Patients with confirmed PD by central imaging do not need to complete the EOR visit if they cross-over to treatment with brigimadlin.
4.
Written informed consent must be obtained before any protocol-specific screening assessments are performed. Re-consenting may become necessary when new relevant 
information becomes available and should be conducted according to the sponsor’s instructions. The consent to collection of a blood sample for pharmacogenetics is 
mandatory (Section 5.4) unless precluded by local regulations.

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5.
Inclusion / exclusion criteria should be re-confirmed before treatment start. Safety laboratory tests do not need to be repeated if performed within 10 days prior to 
treatment start and there is no clinical reason to repeat laboratory tests.
6.
The physical examination includes measurement of height (only at screening) and weight. Vital signs include systolic and diastolic blood pressure and pulse rate 
(electronically or by palpation count for 1 minute) in a seated position after 5 minutes of rest. Additional physical examinations including vital signs may be conducted as 
clinically indicated at the investigator’s discretion. Refer to Sections 5.2.1 and 5.2.2.
7.
Safety laboratory assessments including hematology, serum biochemistry, coagulation, and urinalysis will be performed locally and should be performed or repeated 
within 10 days prior to treatment initiation (Cycle 1 Day 1) then within 72 h prior to each treatment administration (Day 1 of each cycle). On Day 1 of each treatment 
cycle the results must be available prior to treatment and evaluated to ensure that the patient is eligible to receive the next dose. Refer to Section 5.2.3.
Hematology and serum biochemistry laboratory tests must be performed within 72 h prior to Day 1 of each cycle.
Coagulation and urinalysis must be performed within 72 h prior to Day 1 of each cycle.
All safety laboratory tests can be repeated at any other time point or post treatment, if clinically indicated, at the investigator’s discretion. 
After trial treatment discontinuation, all safety laboratory tests will be performed at EOT and at EOR and may be repeated during FU if clinically indicated.
In case of any elevation of ALT/AST and bilirubin, please see Section 5.2.6.1.4.
8.
A serum pregnancy test is mandatory for female patients of childbearing potential at screening. A urine or serum pregnancy test must be conducted within 72 hours prior 
to Cycle 1 Day 1 before start of study treatment, prior to treatment on Day 1 of every cycle from Cycle 2 Day 1 onwards, at EOT, and then monthly until 6 months after 
the last dose of treatment (refer to Sections 5.2.3 and 4.2.2.3 regarding restrictions for women of childbearing potential). Pregnancy testing after EOT can be performed 
remotely or at the clinic.
9.
Electrocardiogram (ECG): Standard 12-lead (I, II, III, aVR, aVL, aVF, V1 - V6) resting ECGs will be recorded. Patient should rest in supine position for at least 
10 minutes before starting ECG recordings. Refer to Section 5.2.4. Single 12-Lead ECGs are done at screening, pre-treatment on Day 1 of every treatment cycle, at EOT 
and EOR. ECGs may be repeated at the investigator’s discretion following local guidelines for doxorubicin treatment, or as clinically indicated.
10. Echocardiograms or MUGA scans are to be performed prior to treatment start and in Cycle 6. After Cycle 6 (for patients with resting LVEF >50%), perform 
echocardiograms or MUGA scans every 3 months (±2 weeks) or per local guidelines until the patient completes the trial, including cross-over treatment and follow up if 
applicable. For patients with LVEF <50% or with another cardiac dysfunction, scans should be performed more frequently, if clinically indicated. Patients who stop 
doxorubicin prior to Cycle 6 will undergo the same cardiac monitoring frequency as described above.
11. Archival tumor tissue MUST be provided for all patients to retrospectively test TP53 mutation status and MDM2 amplification by a central pathology laboratory. 
A block is preferred but slides are acceptable. The total volume of material provided (l×b×d) should not be less than 5 mm3. If archival tissue is not available (or 
insufficient), a biopsy must be performed for collection of fresh tissue. In addition, 1 on-treatment biopsy is required in Cycle 2 (Day 2-4). Patients under anticoagulation 
treatment or patients with thrombocytopenia of CTCAE Grade 3 or 4 are not required to undergo the on-treatment tumor biopsy. See Section 5.4.2 for details.
12. Blood samples for biomarker analysis are mandatory. Details of blood sampling for all biomarker analyses are described in Section 5.4.
Blood samples for circulating protein biomarkers and miRNAs will be collected on Day 1 (pre-treatment) of all cycles and at EOT.
Blood samples for peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) for flow cytometry analysis will only be collected 
for patients enrolled in the Phase II part. Sampling time points are C1D1 prior to first drug administration, C1D8, C1D15, C2D1, and at EOT.
Collection of blood samples for tumor mutation analysis (ctDNA) must be obtained at C1D1 prior to first drug administration, Day 1 of each treatment cycle, and at 
the time of progressive disease (at the EOT visit). Refer to Section 5.4.

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13. PROM = Patient Reported Outcome Measures; QLQ = Quality of Life Questionnaire QLQ; PGIC = Patient Global Impression of Change; PGIS = Patient Global 
Impression of Severity.
QLQ-C30, items pain and fatigue will be assessed from C1D1 to Week 48 or PD, whichever occurs first, every 3 weeks (+2 days); and from PD (or Week 48) onwards 
annually.
EQ5D, PGIC, PGIS will be assessed at C1D1; at Week 15; from Week 15 to Week 48 or PD, whichever occurs first, every 12 weeks (+2 days); and from PD (or Week 
48) onwards annually. Please note that the PGIC assessment is not required at C1D1.
Patients without PD who start subsequent anti-cancer treatment prior to Week 48, will switch to annual PROM assessment.
Patients may complete the assessments either on provided edevices or access to PROMs/QoL remotely with their own devices. Patients are not required to attend the 
clinic on non-dosing days to complete the questionnaires. On clinic days, it is recommended that patients complete the questionnaires prior to seeing the clinician, prior 
to clinical assessment, prior to any treatment at the clinic, and before provision of any new information about their disease status.
14. Patient assessments of pre-specified AEs will be collected starting on C1D1 and continued weekly (+2 days) through Week 15; from Week 15 to Week 48 or PD,
whichever occurs first, every 3 weeks (+2 days); there will be no assessments after PD (or Week 48).
Patients without PD who start subsequent anti-cancer treatment prior to Week 48 do not need any further PRO-CTCAE assessments.
Patients may complete self-assessments on provided edevices or access to PROMs/QoL remotely with their own devices. Patients are not required to attend the clinic on 
non-dosing days to complete the questionnaires. On clinic days, it is recommended that patients complete the questionnaires prior to seeing the clinician, prior to clinical 
assessment, prior to any treatment at the clinic, and before provision of any new information about their disease status.
15. For concomitant therapy and restrictions on concomitant therapy, refer to Sections 4.2.1 and 4.2.2.1.
16. Includes the review of safety laboratory tests if applicable. For details on Adverse Event reporting after treatment discontinuation, refer to Sections 5.2.6.2 and 6.2.3. 
Early and proactive management of side effects is essential to retention and the site is recommended to call the patient a few days after starting treatment to discuss 
whether the patient has side effects and how these can be treated. In addition, phone calls at any time are recommended e.g. in case of severe myelosuppression, and the 
patients should be instructed to contact the sites if applicable.
17. Doxorubicin will be given as standard-of-care dose of 75 mg/m2 for up to the maximum cumulative dose of 450 mg/m2 (approximately 6 cycles). For the prevention of 
cardiotoxicity, patients may be pre-treated with e.g. dexrazoxane at the investigator’s discretion, following institutional guidelines / clinical practice and prescribing 
information (see Section 4.1.2).
18. Tumor assessment will be performed according to RECIST version 1.1. Tumor assessments should include computed tomography (CT) or magnetic resonance imaging 
(MRI) scans of chest and abdomen/pelvis. If clinically indicated, imaging of any other known or suspected sites of disease (e.g. bone) using an appropriate method (CT
scan, MRI, or bone scan) should be performed. The same radiographic procedure must be used throughout the study. If bone lesions are already known or confirmed at 
screening, correlative imaging (X-ray, CT scan, MRI, or bone scan) should be performed and repeated at each tumor assessment.
Assessments will be performed at the following time points, irrespective of scheduled protocol visits, until confirmed progressive disease by central independent review, 
or start of subsequent anti-cancer treatment:
Screening visit (within 28 days prior to first drug intake). A scan performed as part of routine clinical practice and prior to provision of informed consent and within 
the screening timeframe can be used if it meets the requirements described by the imaging laboratory and imaging manual.
Every 6 weeks ±7 days, relative to the C1D1 date. From Week 36 onwards every 12 weeks ±7 days.
In case of discrepancy between investigator and central independent review, refer to Section 5.1 for handling.

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Assessment schedule should not be changed for any reason, including interruption / delay of treatment. All imaging scans / timepoints (scheduled and unscheduled) 
are to be submitted for central independent review. Whenever the investigator assesses that a patient has progressive disease, the relevant scans must be flagged and 
submitted immediately for central independent review. The investigator should await the results of central independent review before permanent discontinuation of 
treatment. Patients who do not have a confirmed PD by central independent review will not be offered to cross-over to brigimadlin treatment. Refer to Section 5.1
and the imaging manual for additional details.
19. During FU for survival, patient visits to the clinic are not required unless required for pregnancy testing. Information may be collected from the patient notes, via 
telephone contact or through an edevice for PROMs. Patient status will be collected until death, lost to follow-up, withdrawal of consent, or the end of the whole trial. In 
the case of death, date of death and cause of death will be collected. Patient death information can be collected from the patient’s medical records, etc. if the patient had 
not withdrawn consent for trial participation.
20. Cycle 1 Day 1 assessments (physical examination, ECOG performance status, vital signs, ECG, safety laboratory blood tests, urinalysis, pregnancy test, weight) do not 
need to be performed if done during screening within 72 h prior to treatment administration and in the opinion of the investigator a repeat is not required. In this case the 
latest value prior to start of treatment will be considered the baseline.
A window (+3 d) is acceptable for scheduling Cycle 2 Day 1.

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Table 3
Flowchart cross-over to brigimadlin treatment / trial 1403-0008
Cross-over to brigimadlin
Screening 1
Cycles 1 and 2 2
Cycles 3 and 4 2
Cycle ≥5 2
EOT 3
EOR 4
FU for 
PD 4
FU for 
survival
Time point
Day
-21 to -1
Day 1 22
Day 8
(±1 d)
Day 15
(±1 d)
Day 1
(+3 d)
Day 15
(±2 d)
Day 1
(+3 d)
Within 7 days 
after EOT 
decision
Day 30 
(+5 d) after
last dose
Every 
6 weeks
(± 7 d)
Every 
12 weeks 21
(± 7 d)
Re-consent 5
X
Review of inclusion and exclusion 
criteria 6
X
Physical examination, vital signs, 
ECOG PS 7
X
X
X
X
X
X
X
Hematology, biochemistry (safety 
laboratory 8)
X
X
X
X
X
X
X
X
X
X
Coagulation, urinalysis (safety 
laboratory 8)
X
X
X
X
X
X
X
Pregnancy test 9
X
X
X
X
X
X
X
X
Single 12-lead ECG 10
X
X
X
X
X
X
Echocardiogram / MUGA scan 11
X
X 11
Fresh biopsy during treatment 
(mandatory) 12
X (C2D2-4) 12
Blood sample for GDF-15 14
X
X
X
X
Blood sample for circulating 
proteins 14
X
X (C2)
X
X
X
Blood sample for miRNA analysis 14
X
X
X
X
Blood samples for PBMCs / MDSCs 
14
X
X
X
X
Blood sample for tumor mutation 
analysis (ctDNA) 14
X
X
X
X
PROMs: QLQ-C30, items pain & 
fatigue 15
From C1D1 to Week 48 or PD, whichever occurs first, every 3 weeks; and from PD (or Week 48) onwards annually
PROMs: EQ5D, PGIC,
PGIS 15
At C1D1; at Week 15; from Week 15 to Week 48 or PD, whichever occurs first, every 12 weeks; and from PD (or Week 48) onwards annually
PRO-CTCAE 16
From C1D1 until Week 15 weekly; from Week 15 to Week 48 or PD, whichever occurs first, every 3 weeks; no assessments after PD (or Week 48)
Concomitant therapy 17
X
X
X
X
X

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Cross-over to brigimadlin
Screening 1
Cycles 1 and 2 2
Cycles 3 and 4 2
Cycle ≥5 2
EOT 3
EOR 4
FU for 
PD 4
FU for 
survival
Time point
Day
-21 to -1
Day 1 22
Day 8
(±1 d)
Day 15
(±1 d)
Day 1
(+3 d)
Day 15
(±2 d)
Day 1
(+3 d)
Within 7 days 
after EOT 
decision
Day 30 
(+5 d) after
last dose
Every 
6 weeks
(± 7 d)
Every 
12 weeks 21
(± 7 d)
Analgesic quantification algorithm 
(AQA)
X
X
X
X
X
Adverse events 18
X
X
X
X
X
X
X
X
X
X
Study treatment administration 19
X
X
X
Tumor assessment 20
X
Every 6 weeks starting 6 weeks after the first dose of brigimadlin
X 20
Termination of trial medication
X
Patient status 21
X
1.
Patients randomized to the doxorubicin arm will be eligible to cross-over to receive brigimadlin following confirmed PD by central independent review and if eligibility 
criteria are met. Patients crossing over can use either their EOT, EOR or FU-PD visit assessments as part of screening or can have a complete screening visit. Patients 
who are screened but do not meet the criteria for cross-over must complete the required follow-up assessments for the doxorubicin arm (Table 2), including EOR and FU 
survival.
2.
All cycles are 21 days in duration and may be extended if subsequent dosing is delayed e.g. due to toxicity. Patients will retain their originally assigned patient number 
and will start once again at Cycle 1. No new cycle should be started before at least 21 days have elapsed since the last treatment administration on Day 1 of the previous 
cycle. Patients may continue on treatment until any criteria for stopping medication are met (see Section 3.3.4.1). In general, Cycles 1 and 2 include visits on Days 1, 8, 
and 15; Cycles 3 and 4 include visits on Days 1 and 15; from Cycle 5 onwards visits are scheduled for Day 1.
3.
EOT = End Of Treatment. All patients should undergo the EOT visit as soon as possible after permanent discontinuation of trial treatment (within 7 days of decision to 
stop treatment). An EOT visit beyond 21 days is possible for patients who delayed their next dose due to toxicity and only then decided to stop treatment. If the decision 
to permanently discontinue trial medication is taken during a scheduled visit, the EOT visit should be performed instead of the scheduled visit. Please see Section 3.3.4. 
After the EOT visit the investigator should report only any cancers of new histology, trial drug related SAEs and trial drug related AESIs of which the investigator may 
become aware of and only via the BI SAE form, please see Section 5.2.6.2.1.
4.
EOR = End Of Residual effect period. The residual effect period (REP) for brigimadlin is 30 days. The REP visit must occur 30 days (+5 days) after last treatment. For 
patients who discontinue for a reason other than confirmed progression, follow-up for PD visits continue per the imaging schedule (refer to Section 5.1), until disease 
progression, lost to follow up, start of subsequent anti-cancer treatment, withdrawal of consent, or completion of the entire trial as specified in Section 8.6. Wherever 
possible, follow-up for PD visits should continue until disease progression confirmed by central independent review.
5.
Patients must re-consent prior to starting treatment with brigimadlin. Assessments for screening may be completed prior to re-consent as they have been collected during 
participation in the doxorubicin arm. Re-consenting while on study may become necessary when new relevant information becomes available and should be conducted 
according to the sponsor’s instructions.
6.
Inclusion / exclusion criteria need to be re-confirmed before treatment start. Safety laboratory tests do not need to be repeated if performed within 10 days prior to 
treatment start and there is no clinical reason to repeat laboratory tests.

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7.
The physical examination includes measurement of weight. Vital signs include systolic and diastolic blood pressure and pulse rate (electronically or by palpation count 
for 1 minute) in a seated position after 5 minutes of rest. Additional physical examinations including vital signs may be conducted as clinically indicated at the 
investigator’s discretion. Refer to Sections 5.2.1 and 5.2.2.
8.
Safety laboratory assessments including hematology, serum biochemistry, coagulation, and urinalysis will be performed locally and should be performed or repeated 
within 10 days prior to treatment initiation (Cycle 1 Day 1) then within 72 h prior to each treatment administration (Day 1 of each cycle). On Day 1 of each treatment 
cycle the results must be available prior to treatment and evaluated to ensure that the patient is eligible to receive the next dose. Refer to Section 5.2.3.
Hematology and serum biochemistry laboratory tests must be performed weekly during the first 2 cycles, on Days 1 and 15 of Cycles 3 and 4, then within 72 h 
prior to Day 1 of each subsequent cycle.
Coagulation and urinalysis must be performed within 72 h prior to Day 1 of each cycle.
All safety laboratory tests can be performed at any other time point or post treatment, if clinically indicated, at the investigator’s discretion.
After trial treatment discontinuation, all safety laboratory tests will be performed at EOT and at EOR and may be repeated during FU if clinically indicated.
In case of any elevation of ALT/AST and bilirubin, please see Section 5.2.6.1.4.
9.
A serum pregnancy test is mandatory for female patients of childbearing potential at screening. A urine or serum pregnancy test must be conducted within 72 hours prior 
to Cycle 1 Day 1 before start of study treatment, prior to treatment on Day 1 of every cycle from Cycle 2 Day 1 onwards, at EOT, and then monthly until 6 months after 
the last dose of treatment (refer to Sections 5.2.3 and 4.2.2.3 regarding restrictions for women of childbearing potential). Pregnancy testing after EOT can be performed 
remotely or at the clinic.
10. Electrocardiogram (ECG): Standard 12-lead (I, II, III, aVR, aVL, aVF, V1 - V6) resting ECGs will be recorded (detailed timing see Appendix 10.1). To not confuse ECG 
recordings, PK samples should be taken after performing the ECG, and patient should rest in supine position for at least 10 minutes before starting ECG recordings (refer 
to Section 5.2.4). ECG may be repeated as clinically indicated.
11. Echocardiograms or MUGA scans are to be performed following the schedule from doxorubicin treatment and per local guidelines for post-doxorubicin treatment. Scans 
may be repeated during treatment if clinically indicated.
12. One on-treatment biopsy is required in Cycle 2 (Day 2-4), unless exemption applies. Patients under anticoagulation treatment or patients with thrombocytopenia of 
CTCAE Grade 3 or 4 are not required to undergo the on-treatment tumor biopsy. See Section 5.4.2.2 for details.
13.
14. Blood samples for biomarker analysis are mandatory. Details of blood sampling for all biomarker analyses are described in Section 5.4 and Appendix 10.1.
Blood samples for GDF-15 will be collected as described in Appendix 10.1.
Blood samples for circulating protein biomarkers and miRNAs will be collected on Day 1 (pre-treatment) of all cycles and at EOT. An additional sample for
circulating protein biomarkers will be collected at Cycle 2 Day 8.
Blood samples for peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) for flow cytometry analysis will only be collected 
for patients enrolled in the Phase II part.
Collection of blood samples for tumor mutation analysis (ctDNA) must be obtained at C1D1 prior to first drug administration, Day 1 of each treatment cycle, and at 
the time of progressive disease (at the EOT visit). Refer to Section 5.4.

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15. PROM = Patient Reported Outcome Measures; QLQ = Quality of Life Questionnaire QLQ; PGIC = Patient Global Impression of Change; PGIS = Patient Global 
Impression of Severity.
QLQ-C30, items pain and fatigue will be assessed from C1D1 to Week 48 or PD, whichever occurs first, every 3 weeks (+2 days); and from PD (or Week 48) onwards 
annually.
EQ5D, PGIC, PGIS will be assessed at C1D1; at Week 15; from Week 15 to Week 48 or PD, whichever occurs first, every 12 weeks (+2 days); and from PD (or Week 
48) onwards annually. Please note that the PGIC assessment is not required at C1D1.
Patients without PD who start subsequent anti-cancer treatment prior to Week 48, will switch to annual PROM assessment.
Patients may complete the assessments either on provided edevices or access to PROMs/QoL remotely with their own devices. Patients are not required to attend the 
clinic on non-dosing days to complete the questionnaires. On clinic days, it is recommended that patients complete the questionnaires prior to seeing the clinician, prior 
to clinical assessment, prior to any treatment at the clinic, and before provision of any new information about their disease status.
16. Patient assessments of pre-specified AEs will be collected starting on C1D1 and continued weekly (+2 days) through Week 15; from Week 15 to Week 48 or PD, 
whichever occurs first, every 3 weeks (+2 days); there will be no assessments after PD (or Week 48).
Patients without PD who start subsequent anti-cancer treatment prior to Week 48 do not need any further PRO-CTCAE assessments.
Patients may complete self-assessments on provided edevices or access to PROMs/QoL remotely with their own devices. Patients are not required to attend the clinic on 
non-dosing days to complete the questionnaires. On clinic days, it is recommended that patients complete the questionnaires prior to seeing the clinician, prior to clinical 
assessment, prior to any treatment at the clinic, and before provision of any new information about their disease status.
17. For concomitant therapy and restrictions on concomitant therapy, refer to Sections 4.2.1 and 4.2.2.1.
18. Includes the review of safety laboratory tests if applicable. For details on Adverse Event reporting after treatment discontinuation, refer to Sections 5.2.6.2 and 6.2.3. 
Early and proactive management of side effects is essential to retention and the site is recommended to call the patient a few days after starting treatment to discuss
whether the patient has side effects and how these can be treated. In addition, phone calls at any time are recommended e.g. in case of severe myelosuppression, and the 
patients should be instructed to contact the sites if applicable.
19. Brigimadlin will be dispensed on Day 1 of each cycle by investigator or authorized designee. Refer to Section 4.3.
20. Tumor assessment will continue according to RECIST version 1.1. Tumor assessments should include computed tomography (CT) or magnetic resonance imaging (MRI) 
scans of chest and abdomen/pelvis. If clinically indicated, imaging of any other known or suspected sites of disease (e.g. bone) using an appropriate method (CT scan, 
MRI, or bone scan) should be performed. The same radiographic procedure must be used throughout the study. If bone lesions are already known or confirmed at 
screening, correlative imaging (X-ray, CT scan, MRI, or bone scan) should be performed and repeated at each tumor assessment.
Assessments will be performed at the following time points, irrespective of scheduled protocol visits, until confirmed disease progression, or start of subsequent anti-
cancer treatment. Wherever possible assessments should continue until confirmed progressive disease by central independent review:
Baseline (screening) scans of all anatomical regions as described above are required if more than 6 weeks have passed since the last set of scans.
Every 6 weeks ±7 days, relative to the date of the first administration of brigimadlin. From Week 36 onwards every 12 weeks ±7 days.
In case of discrepancy between investigator and central independent review, refer to Section 5.1 for handling.
Assessment schedule should not be changed for any reason, including interruption / delay of treatment.
All imaging scans / timepoints (scheduled and unscheduled) are to be submitted for central independent review. Refer to Section 5.1 and the imaging manual for 
additional details.

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21. During FU for survival, patient visits to the clinic are not required unless required for pregnancy testing. Information may be collected from the patient notes, via
telephone contact or through an edevice for PROMs. Patient status will be collected until death, lost to follow-up, withdrawal of consent, or end of the whole trial. In the 
case of death, date of death and cause of death will be collected. Patient death information can be collected from the patient’s medical records, etc. if the patient had not 
withdrawn consent for trial participation.
22. Cycle 1 Day 1 assessments (physical examination, ECOG performance status, vital signs, ECG, safety laboratory blood tests, urinalysis, pregnancy test, weight) do not 
need to be performed if done during screening within 72 h prior to treatment administration and in the opinion of the investigator a repeat is not required. In this case the 
latest value prior to start of treatment will be considered the baseline.
A window (+3 d) is acceptable for scheduling Cycle 2 Day 1.

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOWCHARTS.......................................................................................................................8
TABLE OF CONTENTS ......................................................................................................23
ABBREVIATIONS AND DEFINITIONS...........................................................................29
1.
INTRODUCTION...............................................................................................33
1.1
MEDICAL BACKGROUND.............................................................................33
1.2
DRUG PROFILE................................................................................................34
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................35
1.4
BENEFIT - RISK ASSESSMENT.....................................................................35
1.4.1
Benefits.................................................................................................................35
1.4.2
Risks .....................................................................................................................36
1.4.3
Discussion.............................................................................................................38
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................39
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........39
2.1.1
Main objectives....................................................................................................39
2.1.2
Primary endpoint(s)............................................................................................40
2.1.3
Secondary endpoint(s) ........................................................................................40
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................42
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................43
3.3
SELECTION OF TRIAL POPULATION .......................................................45
3.3.1
Main diagnosis for trial entry ............................................................................45
3.3.2
Inclusion criteria .................................................................................................46
3.3.3
Exclusion criteria ................................................................................................47

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3.3.3.1
Eligibility criteria for cross-over to brigimadlin treatment............................50
3.3.4
Discontinuation of patients from treatment or assessments ...........................50
3.3.4.1
Discontinuation of trial treatment.....................................................................51
3.3.4.2
Withdrawal of consent to trial participation....................................................52
3.3.4.3
Discontinuation of the trial by the sponsor.......................................................52
4.
TREATMENTS...................................................................................................53
4.1
INVESTIGATIONAL TREATMENTS ...........................................................53
4.1.1
Identity of the investigational medicinal products...........................................53
4.1.2
Selection of doses in the trial and dose modifications......................................54
4.1.3
Method of assigning patients to treatment groups...........................................54
4.1.4
Drug assignment and administration of doses for each patient......................55
4.1.4.1
Administration of study medications ................................................................55
4.1.4.2
Guidance for dose delays and dose reductions for brigimadlin......................56
4.1.4.3
Guidance for treatment with brigimadlin after selection of Phase III dose..58
4.1.4.4
Guidance for dose delays, modifications, and discontinuation of 
doxorubicin..........................................................................................................58
4.1.5
Blinding and procedures for unblinding...........................................................59
4.1.5.1
Blinding................................................................................................................59
4.1.5.2
Unblinding and breaking the code ....................................................................59
4.1.6
Packaging, labelling, and re-supply...................................................................59
4.1.7
Storage conditions...............................................................................................59
4.1.8
Drug accountability.............................................................................................59
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................60
4.2.1
Other treatments and emergency procedures..................................................60
4.2.2
Restrictions ..........................................................................................................62
4.2.2.1
Restrictions regarding concomitant treatment ................................................62
4.2.2.2
Restrictions on diet and lifestyle........................................................................65
4.2.2.3
Contraception requirements..............................................................................66
4.3
TREATMENT COMPLIANCE........................................................................67
5.
ASSESSMENTS..................................................................................................67

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5.1
ASSESSMENT OF EFFICACY........................................................................67
5.1.1
Imaging ................................................................................................................67
5.2
ASSESSMENT OF SAFETY.............................................................................68
5.2.1
Physical examination ..........................................................................................68
5.2.2
Vital signs.............................................................................................................69
5.2.3
Safety laboratory parameters ............................................................................69
5.2.4
Electrocardiogram ..............................................................................................70
5.2.5
Other safety parameters.....................................................................................71
5.2.5.1
Left Ventricular Ejection Fraction....................................................................71
5.2.6
Assessment of adverse events.............................................................................72
5.2.6.1
Definitions of AEs................................................................................................72
5.2.6.1.1
Adverse event.......................................................................................................72
5.2.6.1.2
Serious adverse event..........................................................................................72
5.2.6.1.3
AEs considered “Always Serious”.....................................................................73
5.2.6.1.4
Adverse events of special interest ......................................................................73
5.2.6.1.5
Intensity (severity) of AEs..................................................................................75
5.2.6.1.6
Causal relationship of AEs.................................................................................75
5.2.6.2
Adverse event collection and reporting.............................................................76
5.2.6.2.1
AE Collection.......................................................................................................76
5.2.6.2.2
Vital Status Data Collection...............................................................................76
5.2.6.2.3
AE reporting to the sponsor and timelines.......................................................77
5.2.6.2.4
Pregnancy ............................................................................................................77
5.2.6.2.5
Exemptions to AE/SAE reporting .....................................................................77
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................79
5.4.1
Handling of samples and biomarker results.....................................................79

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5.4.2
Tumor tissue samples..........................................................................................80
5.4.2.1
Tumor tissue samples at screening....................................................................80
5.4.2.2
Fresh biopsies on treatment ...............................................................................80
5.4.2.3
Tumor tissue sample processing and storage ...................................................81
5.4.3
Circulating biomarkers ......................................................................................81
5.4.3.1
Circulating tumor DNA......................................................................................81
5.4.3.2
Circulating micro RNA ......................................................................................82
5.4.3.3
Circulating proteins............................................................................................82
5.4.4
Flow cytometry....................................................................................................82
5.4.5
Pharmacogenetics................................................................................................83
5.5
BIOBANKING ....................................................................................................83
5.6
OTHER ASSESSMENTS...................................................................................83
5.6.1
Patient reported outcomes..................................................................................83
5.6.2
Analgesic quantification algorithm ...................................................................85
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................85
6.
INVESTIGATIONAL PLAN.............................................................................85
6.1
VISIT SCHEDULE.............................................................................................86
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................86
6.2.1
Screening..............................................................................................................87
6.2.2
Treatment period(s)............................................................................................88
6.2.3
Follow-up period and trial completion..............................................................88
6.2.3.1
End of Treatment visit (EOT)............................................................................88
6.2.3.2
Safety follow-up visit (End of Residual Effect period, EOR)..........................89
6.2.3.3
Follow-up period .................................................................................................89
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE .....................................................................................................................90
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................91
7.2
PLANNED ANALYSES.....................................................................................92
7.2.1
General considerations .......................................................................................92
7.2.2
Handling of intercurrent events.........................................................................92
7.2.3
Primary objective analyses.................................................................................94

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7.2.4
Secondary objective analyses.............................................................................96
7.2.6
Safety analyses...................................................................................................100
7.2.8
Interim analyses ................................................................................................101
7.4
RANDOMIZATION.........................................................................................104
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ......107
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT .........................................................................................................107
8.2
DATA QUALITY ASSURANCE ....................................................................108
8.3
RECORDS.........................................................................................................109
8.3.1
Source documents .............................................................................................109
8.3.2
Direct access to source data and documents...................................................110
8.3.3
Storage period of records .................................................................................110
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................110
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......110
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.....................................................................................................................111
8.6
TRIAL MILESTONES.....................................................................................111
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................112
9.
REFERENCES..................................................................................................114
9.1
PUBLISHED REFERENCES..........................................................................114
9.2
UNPUBLISHED REFERENCES....................................................................118
10.
APPENDICES...................................................................................................119

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10.2
STATISTICAL DETAILS ...............................................................................122
10.2.1
Combination test approach..............................................................................122

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ABBREVIATIONS AND DEFINITIONS
AE
Adverse event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
ALT/WDLPS
Atypical Lipomatous Tumor / Well-Differentiated Liposarcoma
AQA
Analgesic Quantification Algorithm
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BLRM
Bayesian Logistic Regression Model
C1D1
Cycle 1 Day 1
CA
Competent Authority
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
COVID
Coronavirus disease 2019
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as 
“eCRF”)
CRO
Contract Research Organization
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTR
Clinical Trial Report
CYP
Cytochrome P
DBL
Database Lock
DC
Disease Control
DCR
Disease control rate
DDI
Drug-drug interaction
DDLPS
Dedifferentiated Liposarcoma
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DOR
Duration of Objective Response
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EEA
European economic area 

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EOR
End of residual effect period
EORTC
European Organization for Research and Treatment of Cancer
EOT
End of Treatment
ESMO
European Society for Medical Oncology
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
EWOC
Escalation With Overdose Control
FACT-GP5
Functional Assessment of Cancer Therapy - Global Physical item #5
FUP
Follow-up
GCP
Good Clinical Practice
GIST
Gastrointestinal stromal tumors
GMP
Good Manufacturing Practice
HA
Health Authority
HR
Hazard ratio
HRQoL
Health-Related Quality of Life
i.v.
Intravenous
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council on Harmonization
IEC
Independent Ethics Committee
INR
International normalized ratio
INN
International non-proprietary name
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LMS
Leiomyosarcoma
LPLT
Last patient last treatment
LPS
Liposarcoma
LVEF
Left ventricular ejection fraction
MDM2
Mouse double minute 2 homolog
MDSC
Myeloid-Derived Suppressor Cell
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRI
Magnetic resonance imaging
mRNA
Messenger RNA
MUGA
Multiple gated acquisition
NCI
National Cancer Institute
NGS
Next Generation Sequencing
OATP
Organic Anion Transporting Polypeptide

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OPU
Operative Unit
OR
Objective response
ORR
Overall response rate
OS
Overall survival
p53
Tumor protein P53
PBMC
Peripheral Blood Mononuclear Cell
PD
Progressive disease
PET
Positron Emission Tomography
PFS
Progression-Free Survival
PFS2
Progression-free survival 2
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PK
Pharmacokinetics
PR
Partial Response
PRO
Patient Reported Outcome
PROM
Patient Reported Outcome Measure
PS
Performance status
q3w
Once every 3 weeks
QLQ
Quality of Life Questionnaire
RA
Regulatory Authority
RCI
Repeated Confidence Interval
RDE
Recommended dose for expansion
RECIST
Response Evaluation Criteria In Solid Tumors
REP
Residual effect period
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SC
Steering Committee
SD
Stable Disease
SmPC
Summary of product characteristics
SNP
Single Nucleotide Polymorphism
SOP
Standard Operating Procedure
STS
Soft tissue sarcoma
SUSAR
Suspected Unexpected Serious Adverse Reactions
SVR
Sustained Viral Response
tmax
Timepoint of maximum plasma concentration
TMF
Trial Master File
TP53
Tumor protein 53
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
UPS
Undifferentiated pleiomorphic sarcoma

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WDLPS
Well-differentiated liposarcoma
WHO
World Health Organization
WOCBP
Woman of childbearing potential

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Sarcomas are a rare and heterogeneous group of malignant tumors of mesenchymal origin 
that comprise <1% of all adult malignancies and 12% of paediatric cancers. Approximately 
80% of sarcomas originate from soft tissue, and the rest originate from bone. More than 
100 histologically and biologically distinct subtypes of sarcoma are recognized with the 
majority being soft tissue sarcomas (STS). The most common STS subtypes in adults are 
undifferentiated / unclassified STS, undifferentiated pleiomorphic sarcoma (UPS), 
leiomyosarcoma (LMS), gastrointestinal stromal tumors (GIST) and liposarcoma (LPS). 
Some 13,000 new patients with STS are reported each year in the US [R21-0706; R21-0712;
R21-0693; R21-0694]. The RARECARE project involving 76 population-based cancer 
registries reported an estimated 23,574 new cases of STS in the EU each year, with age-
standardized incidence rates per 100,000 ranging from 3.3 in Eastern Europe to 4.7 in 
Northern Europe [R21-1225]. A recent report by Orphanet in January 2021 estimated the 
prevalence of STS in Europe to be 30.0 per 100,000 and the incidence to be 4.74 per 100,000 
[R21-1251].
While surgical management remains the mainstay of the treatment of localized STS, several 
different chemotherapy regimens are used in advanced or metastatic STS. First line systemic 
therapy has not changed substantially for the last 45 years and is still based on doxorubicin-
containing chemotherapy. The latest trials enrolling patients with STS showed a median 
progression-free survival of 7 months and a median overall survival of around 18 months. 
However, since patients’ prognosis varies from one histology to another, PFS and OS can be 
quite different depending on the specific STS histology [R21-0713; R21-0720; R21-0721].
LPS represents 20% of STS and includes 4 different subtypes, among which well-
differentiated and dedifferentiated subtypes display MDM2 (Mouse Double Minute 2)
amplification in over 90% of the cases. Interestingly, early genetic studies in LPS revealed 
that mutations in the TP53 gene are not observed in tumors carrying MDM2 amplification 
[R21-1630], suggesting these events are mutually exclusive, thus providing a strong 
molecular rational for sensitivity to treatment with a MDM2-p53 antagonist.
The dedifferentiated LPS subtype (DDLPS) represents 15-20% of all LPS cases. DDLPS is 
typically a high-grade tumor that metastasizes in more than 20% of cases (lungs, liver, bone, 
skin, or brain). The mainstay of first line therapy for advanced DDLPS remains an 
anthracycline-based regimen despite its moderate efficacy in this setting (ORR <15%;
median PFS: 2 to 4 months; median OS: 8 to 12 months [R21-0711; R21-0715; R21-0716;
R21-0720]). In addition, doxorubicin yields many side effects among them irreversible 
cardiac toxicity [R21-1309; R21-1310; R21-1311; R21-1312].
No evidence of added benefit in terms of overall survival was shown for the doxorubicin-
based combination compared to doxorubicin monotherapy in studies with mixed types of STS 
[R21-1533; R21-1534; R21-1535] and there are, to our knowledge, no studies demonstrating 
the potential added benefit in terms of OS for a doxorubicin-based combination over 
doxorubicin monotherapy in patients with DDLPS. Considering the above-mentioned 
reasons, doxorubicin monotherapy is considered the standard of care for DDLPS in the first
line setting.

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Brigimadlin is an orally available MDM2-p53 antagonist that showed a manageable safety 
profile and preliminary signs of efficacy in Phase I studies especially in patients with 
DDLPS. Given the heterogeneity of STS with different oncogenic drivers and diverse 
outcomes, it is considered that histotype-specific and biomarker-directed studies in sarcomas 
may better define the efficacy of novel therapies in this population.
1.2
DRUG PROFILE
Mode of action
The MDM2-p53 antagonist brigimadlin is a new small molecule that inhibits the interaction 
between the tumor suppressor TP53 and its negative regulator MDM2. Inhibition of this 
protein-protein interaction leads to stabilization of TP53 followed by target gene induction, 
which may result in cell cycle arrest or apoptosis in tumors with TP53 wild type status. For 
further details, please refer to the Investigator’s Brochure (IB [c15936970]).
Key pharmacokinetic characteristics
Brigimadlin has a tmax 
Brigimadlin has a low clearance/F (4.5 to 11 mL/min) and a low volume of distribution 
(23.6 to 35.1 L). Inter-individual variability in exposure is medium to high. The human 
bioavailability and metabolism profile are not known to date. Based on animal data, 
brigimadlin is excreted via the bile with very low renal excretion of parent or metabolites. 
Drug interactions
Brigimadlin reduces
and may therefore increase the 
exposure of drugs that are 
 substrates. Therefore, coadministration of any known 
 substrates are not allowed. 
Residual Effect Period
The Residual Effect Period (REP) is the period after the last administration of trial
medication with measurable drug levels and/or pharmacodynamics effects still likely to be 
present.

REP for brigimadlin will be 30 days

REP for doxorubicin will be 30 days
Data from nonclinical studies
Nonclinical data suggest that the anti-tumor efficacy of brigimadlin in tumors harboring wild-
type TP53 is based on 2 modes of action: (1) direct anti-tumor activity via activation of wild-
type TP53 function and induction of apoptosis in cancer cells, and (2) immunomodulatory 
activity. Detailed non-clinical results are available in the IB [c15936970] and show that

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brigimadlin is a potent MDM2-p53 antagonist
 and a high
bioavailability in several species. Available data support clinical investigation of brigimadlin 
in various malignancies with TP53 wild-type status, including tumors with MDM2
amplification.
Genotoxicity studies showed that brigimadlin was not mutagenic in the bacterial reverse 
mutation (Ames) test; but was clastogenic in the in vitro chromosomal aberration test. It was 
negative in the rat bone marrow assay, but induced DNA damage in the liver and duodenum 
of rats as assessed by the comet assay.
Data from clinical studies
There are currently several ongoing clinical trials of brigimadlin in patients with advanced or 
metastatic solid tumors. Trial 1403-0001 is a Phase Ia/Ib, open-label, multicenter, dose-
escalation study of brigimadlin monotherapy. Trial 1403-0002 is a Phase Ia/Ib, open-label, 
dose-escalation study of the combination of brigimadlin with ezabenlimab.
For a detailed description of the brigimadlin profile, please refer to the IB [c15936970] and 
for doxorubicin to the Summary of Product Characteristics (SmPC) or US Package Insert.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Dedifferentiated liposarcoma (DDLPS) represents 15-20% of liposarcoma and represents a 
high-grade MDM2-amplified tumor with low responsiveness to doxorubicin, the standard of 
care approved in first line treatment (that showed a median PFS between 2 and 4 months, and 
a median OS between 8 and 12 months; see [R21-0715; R21-0716; R21-0720]). In addition, 
doxorubicin yields many side effects which include irreversible cardiac toxicity [R21-1309, 
R21-1310, R21-1311, R21-1312]. Therefore, a treatment with a manageable safety profile 
that is superior to doxorubicin as first line systemic therapy for advanced or metastatic 
DDLPS is needed.
Brigimadlin is an orally available MDM2-p53 antagonist that showed a manageable safety 
profile and preliminary signs of efficacy in Phase I studies (1403-0001 and 1403-0002) 
especially in patients with DDLPS; an MDM2-driven malignancy fitting brigimadlin’s
mechanism of action.
To bring new treatments faster to a patient population with a high unmet medical need, a 
seamless Phase II/III study design is proposed. In accordance with the latest regulatory 
authority guidance [R21-3031], dose optimization of brigimadlin will be performed in the 
Phase II part and the chosen dose will be taken forward for comparison with the control arm 
in the Phase III part of the study.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
MDM2-p53 antagonists provide the opportunity to target the key tumor suppressor p53 
(tumor protein p53). Brigimadlin is a tumor-targeting agent that leads to p53 activation, 
which triggers cell cycle arrest or apoptosis in cancer cells. Pharmacology data support that 

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the compound can also modulate the immune response. Overall, brigimadlin-induced p53 
activation may trigger an adaptive immunity in TP53 wild type tumors.
Several MDM2-p53 protein-protein interaction inhibitors are currently being evaluated in 
clinical trials [P20-06431; R17-0975]. Reported clinical data with other MDM2-p53 
antagonists showed both, a pharmacodynamic target activity, 
Brigimadlin is a highly potent MDM2-p53 antagonist with efficacy in preclinical mouse 
models of human cancer with intermittent dosing [P20-03237]. Brigimadlin is orally 
available and showed high exposures in patients in trial 1403-0001
. The compound characteristics mentioned above allow an 
intermittent dosing schedule that mitigates serious adverse events.
Brigimadlin showed preliminary signs of efficacy in Phase I studies (1403-0001 and 
1403-0002) especially in patients with DDLPS (see Section 1.2). The durable disease 
stabilizations seen in 12 patients with DDLPS (median PFS approximately 10.8 months) were 
noticeable as DDLPS has a reported median PFS between 2 and 4 months after doxorubicin 
first line therapy.
A clinically meaningful benefit in terms of prolonged PFS and an improved quality of life for 
these patients with locally advanced or metastatic DDLPS is expected with brigimadlin 
versus doxorubicin. Doxorubicin (standard of care) induces limited efficacy and shows many 
side effects including irreversible cardiac toxicity [R21-0711; R21-0715; R21-0716; R21-
0720; R21-1309; R21-1310; R21-1311; R21-1312].
1.4.2
Risks
Brigimadlin has been administered to about 160 patients in the ongoing clinical trials. Based
on safety data from these trials and data from in-class competitors, the following potential 
treatment-induced side effects were identified, i.e. myelosuppression and gastrointestinal 
AEs:
1) Myelosuppression
Myelosuppression, particularly thrombocytopenia and neutropenia, is the main toxicity 
associated with brigimadlin. Current data show that myelosuppression is dose dependent. 
Most of these AEs (neutropenia, thrombocytopenia, anemia) are of CTCAE Grade 3 or lower. 
Grade 3 or higher events were manageable with appropriate treatment and dose modification. 
The mean duration (median 1 – 2 weeks) for myelosuppressive events was 2 – 3 weeks; 
recovery periods >90 days were reported in some cases.
To mitigate and manage the AEs related to myelosuppression, the following measures have 
been implemented:

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
Safety laboratory assessments at appropriate intervals to monitor the degree of 
myelosuppression and allow the investigators to properly treat the patients

General recommendations for the management of AEs related to myelosuppression 
are detailed in Sections 4.1.4.2 and 4.2.1.

Dose modification is allowed (see Section 4.1.4.2)
2) Gastrointestinal AEs
Data from the ongoing trials show that gastrointestinal AEs were common among treated 
patients: nausea (>75%), vomiting (>45%), and diarrhea (>35%). However, these AEs were 
predominantly of CTCAE Grade 1 or Grade 2. Less than 2% of the patients discontinued due 
to nausea and less than 3% of the patients had a dose reduction due to nausea. 
General recommendations for the management of treatment-induced gastrointestinal AEs are 
detailed in Section 4.2.1.
Preliminary data suggest that brigimadlin has a moderate emetogenic risk level. Primary anti-
emetic prophylaxis before Cycle 1 and before treatment on subsequent cycles are 
recommended in accordance with established national, international, and institutional 
guidelines based on the emetogenic risk level of brigimadlin (see Section 4.2.1).
Other risks and measures to reduce risks are described below:

As with all blood sampling, there is a risk of mild pain, local irritation, or bruising 
(a black or blue mark) at the puncture site. Furthermore, there is a small risk of 
lightheadedness and/or fainting. In rare cases, the puncture site can also become 
infected or nerves may be damaged, inducing long-lasting abnormal sensations 
(paresthesia), impaired sensation of touch and persistent pain. These risks will be 
addressed by careful safety monitoring and risk mitigation measures such as
(a) compression
(b) close clinical monitoring for AEs
(c) selection of experienced sites and site staff
(d) Safety recommendations provided in laboratory manual

Although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Patients treated with brigimadlin should be 

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monitored for signs of liver injury according to guidelines specified in 
Section 5.2.6.1.4.

Tumor biopsies will be taken during the treatment period or after disease progression. 
There is an added risk for pain, swelling, and bleeding for those patients who will 
undergo tumor biopsies. For this reason, biopsies will only be performed when 
deemed safe by the investigator and if the platelet count is sufficient to allow for 
hemostasis. The biopsy results will provide valuable information and will assist 
clinical decisions for future patients. Hence, the benefit is assumed to outweigh the 
risks associated with the biopsy.

Clinical imaging will expose the patient to a certain radiation burden. The imaging 
schedule is kept to the minimum in this trial. National regulations must be complied 
regarding the CT exposure for the purpose of this clinical trial.

A data-monitoring committee (DMC) that is independent of the sponsor will review 
unblinded efficacy and safety analyses prepared by the sponsor [R21-3662]. Further 
details about the planned analyses are given in Section 7.2.8. Details about the DMC 
are provided in Section 8.7 and will also be provided in a DMC charter.

A steering committee (SC) will act as an advisory body. It will consist of independent 
experts, sponsor representatives, and investigator representatives. Details about the
SC are provided in Section 8.7 and will also be provided in an SC charter.
For patients treated with doxorubicin, the following risk has been identified:
Infusion-related reaction: doxorubicin will be administered intravenously. The anticipated 
adverse effect for this route of administration is a hypersensitivity reaction. Typical 
compound-related signs and symptoms of hypersensitivity reactions of mild to severe grading 
could include flushing, shortness of breath, facial swelling, headache, chills, chest pain, back 
pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, 
bronchospasm, asthma, apnea, and hypotension.
In case of systemic hypersensitivity reactions including anaphylactic reaction emerging 
during or after administration of doxorubicin, the investigator should, in accordance with the 
severity of the reaction and the local standard of care, consider interrupting the infusion and 
treating the condition. Emergency medicines must be available, and the personnel must be 
aware how to handle such reactions.
1.4.3
Discussion
The nature of the target and the mechanism of action of brigimadlin are sufficiently
understood.
In the context of the unmet medical need and the anticipated benefit of brigimadlin treatment, 
the benefit risk evaluation of the compound is favorable, based upon the available preclinical 
and clinical information. The expected benefit outweighs the potential risks.
Guidance related to COVID-19 infection
Patients in clinical trials with brigimadlin have advanced, late-stage cancer with limited 
treatment options. Given the life-threatening nature of the underlying disease, the approach 

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recommended by professional oncology organizations (e.g. ASCO, ESMO) remains to treat 
patients with cancer as under normal circumstances. No consensus on recommendations 
exists regarding holding or delaying anti-cancer treatments in patients with or susceptible to 
COVID-19. Withdrawing treatment in a patient with cancer who may have few or no 
alternative treatment options requires a careful, individual evaluation.
To date, there is no evidence suggesting an association between an increased susceptibility to 
COVID-19 infection and MDM2-p53 inhibition by brigimadlin. Considering the limited data 
on immune activation and the role of inflammation as well as other underlying factors that 
may increase the severity and mortality of COVID-19 infection, there may be unknown risk 
factors associated with brigimadlin monotherapy. Information regarding relevant risk factors 
and recommendations from professional medical oncology organizations will be monitored.
There are no interactions expected between approved COVID-19 vaccines and the use of 
brigimadlin monotherapy. Patients treated with brigimadlin should be carefully monitored for 
myelosuppressive side effects before COVID-19 vaccination is started as guided by the 
vaccine labels. Interactions with COVID-19 therapeutics cannot be excluded, and restrictions 
should be considered (Section 4.2.2.1).
The inclusion of additional patients with cancer in trials with brigimadlin is evaluated on a 
single case basis, taking into account the totality of information related to each individual 
patient and the local COVID-19 situation. The sponsor, where required, will support the 
investigator in their decision finding.
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The trial will assess the efficacy and safety of brigimadlin compared to doxorubicin as first 
line systemic therapy for advanced or metastatic DDLPS.
The primary objective of the trial is to evaluate whether brigimadlin is superior to
doxorubicin as first line systemic therapy for advanced or metastatic DDLPS.
The secondary objectives of the Phase II part of the trial are to select an optimal dose of 
brigimadlin and to evaluate prior to the Phase III part whether the expected benefits of 
brigimadlin as first line systemic therapy for advanced or metastatic DDLPS outweigh any 
risks. The secondary objectives of the Phase III part of the trial are to evaluate whether 
brigimadlin as first line systemic therapy for advanced or metastatic DDLPS improves the 
objective response rate, duration of responses, overall survival, disease control rate, 
tolerability and has a favorable impact on quality of life, compared to doxorubicin. Safety of 
brigimadlin will be investigated in both parts of the trial.
The primary comparison will be made for randomized patients, regardless of the extent of 
adherence to the protocol and regardless of premature discontinuation of trial medication due 
to any reason; however, the primary comparison will exclude effects of any subsequent anti-

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cancer therapy started before documented progression. In other words, in primary analyses of 
PFS, any PFS events occurring after subsequent anti-cancer therapy begins will be censored.
2.1.2
Primary endpoint(s)
The primary endpoint of the trial is progression-free survival (PFS). PFS based on central 
independent review will be assessed at the interim futility analysis at approximately the same 
time as the end of Phase II, and the primary PFS analysis will take place during the Phase III 
part. For each patient, PFS is defined as the time interval from randomization until tumor 
progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 (solely based on blinded central independent review) or death from any cause, 
whichever occurs first.
2.1.3
Secondary endpoint(s)
The secondary endpoints in this trial are:

Objective response (OR), defined as a best overall response of confirmed complete 
response (CR) or confirmed partial response (PR) according to RECIST version 1.1 
(based on blinded central independent review) from the date of randomization until 
disease progression, death, or last evaluable tumor assessment before start of 
subsequent anti-cancer therapy, loss to follow-up, or withdrawal of consent, 
whichever occurs first.

Duration of objective response (DOR), defined as the time interval from first 
documented confirmed OR until disease progression or death among patients with 
confirmed objective response (based on blinded central independent review), 
whichever occurs first.

Overall survival (OS) will be assessed at the end of the Phase III part of the trial. OS 
is defined as the time interval from randomization until death from any cause.

Disease control (DC), defined as a best overall response of CR, PR, or stable disease 
(SD) according to RECIST version 1.1 (based on blinded central independent review).

Health-Related Quality of Life (HRQoL), based on data collected through specific 
questionnaires (Patient Reported Outcome Measures, PROMs), analyzed from 
baseline to Week 6 and to Week 18. The HRQoL endpoints are defined as the scores 
calculated from data collected through selected EORTC QLQ-C30 domains (physical 
functioning, pain, fatigue, and global health status / quality of life), fatigue and pain 
based on items from the EORTC QLQ-C30 and the EORTC Item Library, and the 
EQ-5D5L.

Occurrence of treatment-emergent adverse events (AEs).

Occurrence of treatment-emergent AEs leading to study drug discontinuation.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A randomized, open-label, seamless Phase II/III parallel design was considered most 
appropriate to assess the efficacy, safety, and tolerability of brigimadlin versus doxorubicin 
as first line systemic therapy for advanced or metastatic DDLPS. A seamless Phase II/III 

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design was chosen to bring new treatments faster to a patient population with a high unmet 
medical need.
The mainstay of first line therapy for advanced DDLPS remains an anthracycline-based 
regimen. In studies with mixed types of STS, no evidence of added benefit in terms of overall 
survival was shown for the doxorubicin-based combination compared to doxorubicin 
monotherapy [R21-1533; R21-1534; R21-1535]. In patients with DDLPS, there are no known 
studies demonstrating the potential added benefit in terms of OS for a doxorubicin-based 
combination over doxorubicin monotherapy; doxorubicin monotherapy is considered to be an 
appropriate comparator representing clinical practice and standard of care for the treatment of 
DDLPS in the first line setting.
The trial has an open-label design due to the doxorubicin-specific cumulative cardiac toxicity 
potential and the requirement to discontinue doxorubicin once the maximum cumulative dose 
is reached. These distinctive features of doxorubicin make the use of blinding in the trial 
design unfeasible. The open-label nature of the design should not alter the data quality, as the 
outcome is based on objective endpoints which are assessed by blinded independent 
reviewers.
PFS was chosen as primary endpoint of the trial due to its wide acceptance as a primary 
endpoint in STS and its capacity to show clinical benefit. This is supported by 2 recent meta-
analyses conducted on trials in first- and second-line STS. A meta-analysis of 33 randomized 
clinical trials performed between 1995 and 2014 in patients with STS found that PFS was the 
predominant selected primary endpoint (70% of the cases), while OS was the primary 
endpoint in only 6% of the trials [R21-1540]. A second meta-analysis of 52 randomized 
clinical trials of mixed first line or pre-treated settings [R21-1540] reported a highly 
significant correlation between PFS and OS (R = 0.61), the highest among any other 
measurements correlated with OS including ORR, 3-month PFS, and 6-month PFS. In 
addition, since treatment with brigimadlin will be allowed after objective PD is observed 
among patients in the doxorubicin arm of this trial, and because receipt of subsequent anti-
cancer therapy is expected to occur at a high rate, OS may not be an appropriate primary
endpoint in the first line setting of DDLPS. Details about the cross-over from the doxorubicin 
arm to treatment with brigimadlin are available in Section 4.1.3.
Cross-over to treatment with brigimadlin is provided for eligible patients who have disease 
progression following doxorubicin treatment. The purpose is to give access to the 
investigational treatment for a population with high unmet need where available therapies 
have limited benefit.
A central imaging vendor will conduct blinded reads (‘central independent review’) on a 
regular basis to support the interim and final analysis of efficacy endpoints based on 
RECIST; real-time reads will be performed to assess patients’ tumor response and to 
independently document disease progression if applicable. The imaging vendor’s roles and 
responsibilities will be described in an imaging charter.
During this open-label trial, a DMC independent of the sponsor will be established to review 
unblinded efficacy and safety analyses prepared by the sponsor [R21-3662]. Further details 

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about the DMC are in Section 8.7 and will also be provided in a DMC charter. Further details 
about the planned interim analyses are given in Section 7.2.8.
3.3
SELECTION OF TRIAL POPULATION
The Phase II part of the trial will be conducted in about 125 sites in multiple countries and 
regions. For the Phase III part of the trial, additional sites might be added as needed to fulfill
the planned enrollment. If site(s) are unable to recruit patients, additional sites may be 
opened, and non-enrolling sites may be closed.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial. Patients already in screening at this time will be allowed to continue to 
randomization if eligible.
Assessments may be repeated within the screening period if patients do not initially meet the 
inclusion / exclusion criteria. Eligibility must always be assessed using the latest results 
available. In addition, up to 2 re-screenings of patients who have previously failed screening 
will be permitted.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If retrospectively it is found that a patient has been randomized in error (= did not meet all 
inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be 
contacted immediately. Based on an individual benefit-risk assessment, a decision will be 
made whether continued trial participation is possible or not.
3.3.1
Main diagnosis for trial entry
The trial will include patients with histologically proven locally advanced or metastatic
dedifferentiated liposarcoma.
Criteria to assist with the differentiation of locally advanced vs. metastatic disease are 
provided below (randomization in this trial will be stratified by ‘extent of disease’ as 
described in Section 4.1.4, i.e. locally advanced vs. metastatic disease):

Locally advanced DDLPS is defined here for the purpose of this trial as DDLPS
without metastatic spread via the blood vessels or the lymphatic system. A huge, 
inoperable retroperitoneal DDLPS or DDLPS elsewhere in the body should be 
considered locally advanced disease.

Metastatic DDLPS is defined here for the purpose of this trial as DDLPS with 
metastatic spread via the blood vessels or the lymphatic system. A relapse of 
retroperitoneal DDLPS after earlier surgery with or without radiotherapy should be 
considered metastatic disease.

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Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
Patients will only be included in the trial if they meet all the following criteria:
1. Provision of signed and dated, written informed consent form ICF in accordance with 
ICH-GCP and local legislation prior to any trial-specific procedures, sampling, or 
analyses.
2. Male or female patients ≥18 years old at the time of signature of the ICF. Women of 
childbearing potential (WOCBP; for a definition see Section 4.2.2.3) and men able to 
father a child must be ready and able to use 2 medically acceptable 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 beginning at screening, during trial participation, and until 
6 months and 12 days after last dose. A list of contraception methods meeting these 
criteria is provided in the patient information.
3. Histologically proven locally advanced or metastatic, unresectable (surgery morbidity 
would outweigh potential benefits), progressive or recurrent DDLPS *. Locally 
performed histopathological diagnosis will be accepted for entry into this trial but will be 
confirmed by independent pathological review while the patients receive treatment in this 
trial.
4. Written pathology report indicating the diagnosis of DDLPS with positive MDM2 
immunohistochemistry or MDM2 amplification as demonstrated by fluorescence in situ
hybridization or NGS must be available.
5. Formalin fixed paraffin embedded tumor blocks or slides must be available for 
retrospective histopathological central review.
6. Presence of at least one measurable target lesion according to RECIST version 1.1. In 
patients who only have one target lesion, the baseline imaging must be performed at least 
2 weeks after any biopsy of the target lesion.
7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
8. Patient must be willing to donate blood samples for the pharmacokinetics, 
pharmacodynamics, and tumor mutation analysis.
9. Patient willing to undergo a mandatory tumor biopsy at the time point specified in the 
flowchart unless exempt (see Section 5.4.2.2 for details).
10. Adequate organ function, defined as meeting all criteria in Table 3.3.2: 1.
* Histology of DDLPS according to the WHO classification of tumors [R21-3615]: transition 
from atypical lipomatous tumor / well-differentiated liposarcoma (ALT/WDLPS) to non 
lipogenic sarcoma with a variable extent of dedifferentiation; the transition can be abrupt or 

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gradual and the well-differentiated lipomatous component can be easily or hardly identifiable.
Patients with purely well-differentiated liposarcomas are excluded from trial participation.
Table 3.3.2: 1
Screening reference laboratory values
System
Laboratory Value
Hematological
   Absolute neutrophil count
≥1.5×109/L (or ≥1.5×103/µL or ≥1500/mm3)
   Platelets
≥100×109/L (or ≥100×103/μL or ≥100×103/mm3)
   Hemoglobin
≥8.5 g/dL or ≥5.3 mmol/L or ≥85 g/L
Hepatic
   Total bilirubin
≤1.5×upper limit of normal (ULN), (patients with Gilbert’s 
syndrome, total bilirubin must be ≤3×ULN)
   AST and ALT
≤2.5×ULN OR ≤5×ULN for patients with liver metastases
Renal
   Creatinine * 
≤1.5×ULN
Patients may enter if creatinine is >1.5×ULN provided 
that the estimated glomerular filtration rate (eGFR) is
>50 mL/min (assessed by Chronic Kidney Disease 
Epidemiology [CKD-EPI] creatinine equation); 
confirmation of eGFR is only required when creatinine is 
>1.5×ULN
Coagulation
   International Normalized Ratio
  (INR) or Prothrombin Time
  (PT)
   Activated Partial
  Thromboplastin Time (aPTT)
≤1.5×institutional ULN
Patients taking low dose warfarin must have their INR 
followed closely and according to institutional guidelines
* Creatinine can be assessed by any of these methods: CREE (enzymatic serum creatinine assay), 
CREJIDMS (IDMS standardized Jaffe), or CREJ (non-IDMS standardized Jaffe).
3.3.3
Exclusion criteria
Patients will be excluded from the trial if they meet any of the following criteria:
1. Known mutation in the TP53 gene (screening for TP53 status is not required).
2. Major surgery (major according to the investigator’s assessment) performed within 
4 weeks prior to randomization or planned within 6 months after screening.
3. Prior systemic therapy for liposarcoma in any setting (including adjuvant, neoadjuvant, 
maintenance, palliative).
4. Previous or concomitant malignancies other than DDLPS or WDLPS, treated within the 
previous 5 years, except effectively treated non-melanoma skin cancers, carcinoma in situ
of the cervix, ductal carcinoma in situ, or other malignancy that is considered cured by 
local treatment.
5. Previous treatment with anthracyclines in any setting (systemic treatment with other anti-
cancer agents is allowed if completed at least 5 years prior to study entry with the 
exception of hormone therapy).

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6. Patients who must or intend to continue the intake of restricted medications (see 
Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the 
trial.
7. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s) or receiving other 
investigational treatment(s).
8. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition 
that, in the investigator’s opinion, makes the patient an unreliable trial participant).
9. Women who are pregnant, nursing, or who plan to become pregnant while in the trial; 
female patients who do not agree to the interruption of breast feeding from the start of 
study treatment until 6 months and 12 days after last dose of study treatment.
10. Patients with known history of human immunodeficiency virus (HIV) infection who meet 
one or more of the following criteria:
o
CD4+ count <350 cells/µL
o
Viral load >400 copies/mL (local laboratory assessment)
o
Not receiving antiretroviral therapy
o
Receiving established antiretroviral therapy for <4 weeks prior to the start of study 
treatment
o
History of AIDS-defining opportunistic infections within 12 months prior to start 
of study treatment
Patients with a history of HIV who do not meet any of the criteria above are eligible to 
participate but the patient must be under the care of a HIV/Infectious Diseases specialist 
or a HIV/Infectious Diseases specialist must be consulted prior to inclusion.
11. Patients with a history of HCV infection who meet any of the following criteria:
o
Currently receiving curative antiviral treatment or not yet achieved sustained viral 
response (SVR)
o
HCV viral load is above the limit of quantification (HCV RNA positive)
12. Patients with chronic HBV infection with active disease who meet the criteria for anti-
HBV therapy (according to local / institutional standard) and who have not been treated 
with suppressive antiviral therapy prior to initiation of study treatment.
13. Any history or presence of uncontrolled gastrointestinal disorders that could affect the 
intake and/or absorption of the trial drug (e.g. nausea, vomiting, Crohn’s disease, 
ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion of the investigator.
14. Known hypersensitivity or contraindication to the trial drugs or their excipients.
15. Active major infection requiring systemic treatment (antibacterial, antiviral, or antifungal 
therapy) at treatment start in this trial.
16. History or presence of cardiovascular abnormalities such as uncontrolled hypertension, 
congestive heart failure NYHA classification of ≥III or IV, unstable angina or poorly 
controlled arrhythmia which are considered as clinically relevant by the investigator. 
Myocardial infarction or stroke within 6 months prior to randomization.

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17. Any of the following cardiac criteria:
-
Mean resting corrected QT interval (QTcF) >470 msec
-
Any clinically important abnormalities (as assessed by the investigator) in rhythm, 
conduction, or morphology of resting ECGs, e.g. complete left bundle branch block, 
third degree heart block
-
Any factor that increases the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, congenital long QT syndrome, family history of 
long QT syndrome or unexplained sudden death under 40 years-of-age, or any 
concomitant medication known to prolong the QT interval
-
Patients with an ejection fraction (EF) <50% or the lower limit of normal of the 
institutional standard
18. Patients with brain metastasis, unless they meet all below criteria:
-
Patients with treated or stable CNS metastasis:
o
Therapy for CNS metastasis was completed at least 4 weeks prior to first 
administration of trial drug.
o
No evidence of CNS metastatic progression (based on CNS imaging) 
following therapy for CNS metastasis (patients manifesting progression in 
lesions previously treated with stereotactic radiosurgery might still be eligible 
if pseudoprogression can be demonstrated by appropriate means).
o
Any CNS metastasis is asymptomatic.
o
Without corticosteroids or on a stable dose of corticosteroids for at least 
14 days prior to first administration of trial medication, (except for 
physiological/replacement doses of about 5 mg per day prednisolone or 
equivalent).
o
Without antiepileptic drugs (for malignant disease) or on a stable dose of 
antiepileptic drugs (for malignant disease) for at least 14 days prior to first 
administration of trial medication.
19. Active bleeding, significant risk of haemorrhage (e.g. previous severe gastrointestinal 
bleeding, previous haemorrhagic stroke at any time), or current bleeding disorder (e.g. 
haemophilia, von Willebrand disease).
20. Any history of, or concomitant condition that, in the opinion of the investigator, would 
compromise the patient’s ability to comply with the trial or interfere with the evaluation 
of the safety and efficacy of the trial drug.

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3.3.3.1
Eligibility criteria for cross-over to brigimadlin treatment
Patients randomized to the doxorubicin arm will be offered the option to receive brigimadlin 
as subsequent therapy upon PD by central independent review (for more information please 
refer to Sections 4.1.3 [assigning patient to treatment group] and 6.2.1 [details about 
screening]). For cross-over to brigimadlin, patients need to fulfill all of the following 
inclusion and exclusion criteria:
Inclusion criteria:
1. Received a minimum of 1 dose of doxorubicin.
2. PD according to RECIST version 1.1 based on central independent review after receiving 
a minimum of 1 dose of doxorubicin.
3. Adequate organ function, defined as meeting all criteria in Table 3.3.2: 1.
4. Recovered from any doxorubicin-related toxicity to CTCAE Grade 1 or baseline (except 
for alopecia and peripheral neuropathy which must be ≤CTCAE Grade 2, and amenorrhea 
/ menstrual disorders which can be any grade).
Exclusion criteria:
1. In the judgment of the investigator, any serious condition affecting compliance with trial 
requirements or considered relevant for the evaluation of safety of brigimadlin.
2. Intake of restricted medications (see Section 4.2.2.1) or any drug considered likely to 
interfere with the safe conduct of the trial.
3.3.4
Discontinuation of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
However, if the patients agree, they should stay in the trial. Even if continued trial treatment 
is not possible, they should attend further trial visits to ensure their safety and 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 trial enrollment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Section 5.2.6.2).

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3.3.4.1
Discontinuation of trial treatment
The patient must attend all remaining visits including follow-up for progression assessments 
if discontinued from treatment prior to confirmed progression by the central independent 
review. Should the patient not agree, at least phone contacts should occur at the scheduled 
visit time points. Should that not be acceptable, a phone contact once a year or at the end of 
the planned observation period should occur to collect the most relevant information: vital 
status (please see Section 5.2.6.2.1), outcome events, adverse events, or last contact date in 
case of lost to follow-up. 
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment. The patient will be asked to explain the
reasons but has the right to refuse to answer.

The patient has repeatedly shown to be non-compliant with important trial procedures
and, in the opinion of both the investigator and sponsor representative, the safety of the
patient cannot be guaranteed as he / she is not willing or able to adhere to the trial
requirements in the future.

The patient needs to take concomitant medication that interferes with the safety of the
investigational medicinal product or other trial treatment.

The patient can no longer receive trial treatment for medical reasons such as surgery,
adverse events, other diseases, or pregnancy. This includes specified adverse events
requiring discontinuation as described in Section 4.1.4.2.

The patient has radiological documentation of progressive disease by central independent
review on the current treatment (see Section 5.1) with the exception of patients receiving
doxorubicin, who may be offered cross-over to treatment with brigimadlin. If the patient
has radiological progression by investigator assessment while tolerating trial treatment,
the treatment should be continued. The decision to withdraw treatment must be based on
documentation of progressive disease according to RECIST version 1.1 based on central
independent review.

If a patient becomes pregnant during the trial, treatment with brigimadlin or doxorubicin
must be stopped immediately. The patient will be followed up until delivery or
termination of pregnancy.
In case of a temporary reason for pausing treatment, trial treatment should be restarted if 
medically justified; please see Section 4.1.4.
After completion of the final OS analysis (see Section 7), the sponsor may remove patients on 
treatment with brigimadlin from the trial if the patient has access to brigimadlin via an 
alternative clinical trial, marketed product, an expanded access program, named patient use 
program, compassionate use protocol or other means based on local regulation. The cost of 
any ongoing supply of brigimadlin will be incurred by the sponsor until disease progression 
or any other reason for treatment discontinuation occurs. If a patient is removed from the trial 
treatment in these circumstances, an end of treatment and follow-up visit will be performed to 
ensure all adverse events are followed up and then the patient will be considered to have 

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completed the trial. Follow-up for overall survival may continue if required by the sponsor 
(see Section 6.2).
An interim analysis for dose selection will be performed in Phase II, and an interim futility 
analysis will be performed at approximately the same time as the end of Phase II (see 
Section 7.2.8 for details). If the trial is stopped for futility or an investigational arm is 
discontinued, ongoing patients will be informed of this, and the possibility to continue 
receiving their assigned treatment will be discussed with the investigator.
If new efficacy or safety information becomes available, BI will review the benefit-risk-
assessment and, if needed, pause or discontinue the trial treatment for all patients or take any 
other appropriate action to guarantee the safety of the trial patients. 
Even if the trial treatment is discontinued, the patients remain in the trial and will undergo the 
procedures for early treatment discontinuation and follow-up as outlined in the flowchart and 
Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a patient wants to withdraw consent, the investigator should be 
involved in the discussion with the patient and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, 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 enrollment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see Section 3.3.4.1.
3. Deviations from GCP, the clinical trial protocol, or the contract impairing the appropriate 
conduct of the trial.
4. All efficacy analyses (see Section 7) are complete and all patients have either ended trial 
treatment or are eligible to receive brigimadlin under the conditions listed in 
Section 3.3.4.1.
Further treatment and follow up of patients affected will occur as described in 
Section 3.3.4.1. 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
This trial investigates brigimadlin (BI 907828) monotherapy and doxorubicin monotherapy.
Brigimadlin (BI 907828)
Table 4.1.1: 1 
Brigimadlin (BI 907828)
Substance:
Brigimadlin (BI 907828)
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Posology:
Single dose on Day 1 every 21 days
Starting dose will be 30 mg or 45 mg
Mode of administration:
Oral
Doxorubicin
Table 4.1.1: 2
Doxorubicin
Substance:
Doxorubicin
Pharmaceutical formulation:
Concentrate for solution for infusion
Source:
Commercial supply provided by BI
Unit strength:
2 mg/mL:
200 mg per 100 mL vial
Posology:
75 mg/m2 on Day 1 of each 21-day cycle
Maximum cumulative dose of 450 mg/m2
Mode of administration:
Intravenous infusion / injection

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4.1.2
Selection of doses in the trial and dose modifications
Selected doses of brigimadlin (investigational arms) for the Phase II/III trial are derived from
the Phase I monotherapy trial (1403-0001). The dose escalation part of trial 1403-0001 has 
recently been completed. Based on exploratory safety and efficacy analyses, 60 mg q3w
(once every 3 weeks) was determined as the maximum tolerated dose (MTD) and 45 mg q3w 
was selected as the recommended dose for expansion (RDE).
The 2 doses of brigimadlin proposed for dose optimization in trial 1403-0008 are 45 mg and 
30 mg q3w. The 45 mg dose was determined as the highest dose fulfilling the EWOC 
(escalation with overdose control) criterion from a Bayesian Logistic Regression Model 
(BLRM) analysis, taking into account the AEs of interest during the entire treatment period 
(and not only during the MTD evaluation period); the AEs considered for the BLRM 
sensitivity analysis were analyzed for all cycles and included the following: hematologic 
DLTs, hematologic AEs Grade 4, hematologic AEs leading to dose delay / dose reduction /
discontinuation, time for platelet count recovery (to over 100,000/mm3) >21 days, time for 
neutrophil count recovery (to over 1,500/mm3) >21 days. The 30 mg dose was selected as the 
next lower and potentially efficacious dose. An interim analysis for dose selection in Phase II 
will enable the selection of 1 of the 2 investigational arms for further enrollment.
The dose for doxorubicin is 75 mg/m2 given as intravenous infusion on Day 1 of each 21-day 
cycle. Patients will continue receiving doxorubicin for up to the maximum cumulative dose 
of 450 mg/m2. Investigators should consult the approved package insert for complete 
prescribing information and follow institutional procedures / clinical practice for the 
administration of doxorubicin. 
The sponsor will determine the optimal Phase III dose based on the Phase II data, taking into 
consideration any recommendations from the Steering Committee and the Data Monitoring 
Committee. More details about the interim analysis for dose selection are provided in 
Section 7.2.8.
4.1.3
Method of assigning patients to treatment groups
Patients will be randomized to one of the available treatment groups using an Interactive 
Response Technology (IRT) system. The company that provides the IRT system will receive 
the randomization list from Boehringer Ingelheim Clinical Trial Support Group or a CRO 
appointed by the sponsor. The BI standard validated random number generating system will 
be used to generate the randomization schedules.
Patient numbers will be assigned at enrollment (screening) via the IRT system. Note that the 
medication number is different from the patient number (the latter is generated during 
screening via the IRT system). Initial medication number(s) will be assigned at time of the 
randomization call. If a patient withdraws from the trial, then the enrollment code cannot be 
re-used.

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Cross-over to treatment with brigimadlin
Patients randomized to the doxorubicin arm will be offered the option to receive brigimadlin 
as subsequent therapy upon confirmed PD by central independent review. Patients must not 
have received any other anti-cancer therapy since commencing trial treatment with 
doxorubicin. Palliative radiotherapy is permitted; however, the irradiated area cannot be used 
for further tumor response assessment. These patients will be randomized 1:1 to receive 
either 30 mg or 45 mg brigimadlin until a dose for Phase III is selected, after which all 
patients assigned to one of the brigimadlin dose groups will be allowed to continue on the 
same dose (unless there are toxicity concerns) or change to the selected dose (if different 
from the current dose at the investigator’s discretion), with the exception that patients who 
have previously had a dose reduction due to toxicity are not allowed to change to a higher 
dose.
The crossed over patients will re-consent, be re-assessed for inclusion and exclusion criteria 
and undergo assessments as described in the cross-over Flowchart prior to being registered in 
the IRT for the new treatment arm. Patients crossing over from the doxorubicin arm will not 
contribute to the total number of required patients needed in the investigational arm(s) as 
noted in the trial design. 
4.1.4
Drug assignment and administration of doses for each patient
After the assessment of all inclusion and exclusion criteria, each eligible patient will be 
randomized to treatment groups according to a randomization plan in a 1:1:1 ratio at Cycle 1 
Day 1 (-5 days) via an IRT. Randomization will be stratified by ‘extent of disease’ (locally 
advanced vs. metastatic disease). After the interim analysis for dose selection, patients will be 
randomized in a 1:1 ratio at Cycle 1 Day 1 (-5 days).
All trial medication will be prepared and handled according to the ‘Medication Handling 
Instruction’, which will be filed in the ISF. Upon notification that a patient will be treated in 
the trial, the pharmacy will prepare the trial medication at the assigned dosage for 
administration to the patient.
4.1.4.1
Administration of study medications
Administration of brigimadlin
Brigimadlin film-coated tablets are developed in 3 dosage strengths:
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.
Brigimadlin will be stored at each investigational site. 

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In all treatment cycles, brigimadlin should only be administered if all of the following criteria 
are met:

Absolute neutrophil count is ≥1.5×109/L

Platelet count is ≥100×109/L (in case of platelet transfusion after the last drug 
administration, this criterion must be met in a measurement taken at least 72 hours 
after the last platelet transfusion)

Haemoglobin is ≥8.5 g/dL

Any related SAE/AE which required a dose delay (see Section 4.1.4.2) has recovered
to ≤CTCAE Grade 1 or to baseline value.
Brigimadlin will be administered at a fixed dose of either 30 mg or 45 mg, independent of the 
patient’s body surface area (weight and height). 
The medication will be administered in the clinic, as a single oral dose, with about 240 mL 
(approximately 8 U.S. ounces) water, in the standing or sitting position, under supervision of 
the investigating physician or an authorized designee in the morning of Day 1 of each cycle. 
Patients with emesis should not take a replacement dose. Any occurrence of vomiting within 
12 hours of brigimadlin administration should be documented in the medical record and the 
eCRF.
Pre-dose laboratory samples will be collected ≤72 hours prior to receiving each single dose.
Administration of doxorubicin
Doxorubicin will be administered intravenously at a dose of 75 mg/m2 on Day 1 every 
21 days, for up to the maximum cumulative dose of 450 mg/m2. Doxorubicin will be 
administered according to institutional guidelines and SmPC/US Package Insert as an 
intravenous injection or as an infusion. Route as well as administration start and end times 
will be recorded in the eCRF.
4.1.4.2
Guidance for dose delays and dose reductions for brigimadlin
Adverse events requiring discontinuation
Treatment will be permanently discontinued if the following events related to brigimadlin 
occur:

CTCAE Grade 4 AEs with the exception of myelosuppressive AEs of CTCAE 
Grade 4 (e.g. neutropenia, thrombocytopenia, anaemia) for which treatment options 
and blood transfusion are available (Section 4.2.1).

Adverse events which cause a dose delay and do not recover within the allowed time 
window, as described in the sections below.

Patient requires more than 2 dose reductions.

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Guidance for dose delays of brigimadlin due to low platelet and/or neutrophil count
Platelet and neutrophil count are assessed on the planned Day 1 of (or within 72 hours prior 
to) each treatment cycle. Recovery days and treatment pause should be counted from the 
planned Day 1 of the treatment cycle.

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Brigimadlin dose reduction guidelines

Any dose reduction will be permanent (i.e. dose re-escalation is NOT allowed). 

Up to 2 dose reductions of brigimadlin are allowed. For patients who require more 
than 2 dose reductions, brigimadlin should be permanently discontinued. 
4.1.4.3
Guidance for treatment with brigimadlin after selection of Phase III dose
During the Phase II part of the trial, a dose of either 30 mg or 45 mg brigimadlin will be 
selected for Phase III (see Section 3.1). From then on, all new patients who enter the trial and 
are randomized to brigimadlin will receive the selected brigimadlin dose.
If the 45 mg dose of brigimadlin is selected for Phase III, then all patients who at that time 
are already on treatment with brigimadlin at the 30 mg dose, and did not reduce their dose,
will be offered to increase their dose to 45 mg brigimadlin but may also choose to continue 
on the 30 mg dose.
If the 30 mg dose of brigimadlin is selected for Phase III, patients on the 45 mg dose may 
continue (assuming there are no safety concerns) or may switch to the 30 mg dose.
4.1.4.4
Guidance for dose delays, modifications, and discontinuation of doxorubicin
Doxorubicin will be administered according to the current SmPC or US Package Insert of the 
supplied medication and according to institutional guidelines.

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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
In this open-label trial, treatment allocation will not be concealed throughout the trial. The 
eCRF will contain information on randomized treatment.
For a discussion explaining the rationale for why this controlled trial is open-label, please see 
Section 3.2.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labeled 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. Investigator information is omitted 
from the labels due to use of an IRT system.
For details of packaging and the description of the label, refer to the ISF.
Due to potential regional restriction for locally sourcing doxorubicin, doxorubicin will be 
sourced, packaged, labeled, and provided to the sites. Should BI supply become unavailable, 
sites will be allowed to use local source supply. Investigator information is omitted from the 
labels due to use of an IRT system. The visit number is not relevant for the label of 
doxorubicin as the product will remain at the clinical site.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate CRA (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor or 
delegate 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 or delegate
and the investigational site,

Approval / notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

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
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 clinical trial 
protocol. They must not be forwarded to other investigators or clinics.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or 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 medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the clinical trial protocol and reconcile all 
investigational medicinal products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
For patients treated with doxorubicin, supportive reatment should be given as needed and in 
accordance with current SmPC or US Package Insert of the supplied medication.
Rescue medications to reverse the actions of brigimadlin are not available. Therefore, 
potential side effects must be treated symptomatically or as specifically noted below.

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For patients with thrombocytopenia of CTCAE Grade 3 or 4 who are under treatment with 
anticoagulants, weekly controls of the blood counts and coagulation parameters should be 
performed.
Patients under anticoagulation treatment or patients with thrombocytopenia of CTCAE 
Grade 3 or 4 are not required to undergo the on-treatment tumor biopsy.
The use of the medications or therapies listed below is allowed, as clinically indicated:

Erythropoietic therapy when used in accordance with the American Society of 
Clinical Oncology (ASCO)/American Society of Hematology or the National 
Comprehensive Cancer Network (NCCN) guidelines. In Japan, erythropoietic therapy 
is not approved for anemia caused by cancer chemotherapies.

Colony-stimulating factor (granulocyte colony-stimulating factor or granulocyte 
macrophage colony-stimulating factor) when used in accordance with the ASCO 
guidelines. 

Blood transfusions are allowed at any time during the trial when clinically indicated. 

Corticosteroids.

Bisphosphonates for patients with lytic bone metastases. 

Anti-diarrheal agents e.g. loperamide.

After study enrollment, palliative radiotherapy may be given for bone pain or for 
other reasons (e.g. bronchial obstruction, skin lesions), provided that the total dose 
delivered is in a palliative range according to institutional standards. The irradiated 
area cannot be used for further tumor response assessment. During palliative 
radiotherapy, study treatment should be delayed and may be resumed once the patient 
has recovered from any radiation associated toxicity. If medication is delayed for 
more than 14 days, the decision to continue will be made by the sponsor in agreement 
with the investigator.

Gonatropin-releasing hormone or luteinizing hormone-releasing hormone analogs for 
patients with prostate adenocarcinoma or breast cancer can be continued but should 
not be initiated during trial.

Prevention and treatment of gastrointestinal adverse events
Preliminary data suggest that brigimadlin has a moderate emetogenic risk level. 
Primary anti-emetic prophylaxis before Cycle 1 and on subsequent treatment days is 
recommended in accordance with established national, interna
al 
guidelines based on the emetogenic risk levels of brigimadlin.
 
-
The recommendations for prevention and management of nausea and 
vomiting are as follows:

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 in addition to 
continuing the standard antiemetic regimen (ASCO / MASCC / ESMO /
NCCN [P22-02579; P22-05918; P22-05968])
o
Continue or modify anti-emetic strategy based on clinical judgement, patients’ 
condition, and response.
Auxiliary Medicinal Product
Supportive treatment for doxorubicin should be given as needed and in accordance with the 
SmPC, package insert, and institutional guidelines.
Dexrazoxane may be administered for the prevention of cardiotoxicity associated with 
doxorubicin. The dosing and administration are at the discretion of the investigator and/or 
according to institutional guidelines.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Concomitant therapy, with reasons for the treatment, must be recorded in the CRF during the 
screening and treatment periods, starting at the date of signature of informed consent and 
ending after the residual effect period (REP). After the REP, only concomitant therapy 
indicated for treatment of a related AE has to be reported. If a new anti-cancer treatment is 
started, it will be documented in the CRF, on a separate page of follow-up therapy, different 
from the concomitant therapy pages.

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
Brigimadlin is an inhibitor of P-gp and BCRP in in vitro studies with IC50 values of 
8.6 μM and 7.2 μM, respectively. Assessment of the DDI likelihood according to 
FDA guidelines suggest that the inhibition of intestinal P-gp and BCRP would likely 
occur at brigimadlin dose levels exceeding 12 mg and 10 mg, respectively. P-gp or 
BCRP substrates with a narrow therapeutic window or index (NTI) are prohibited 
during the trial. P-gp or BCRP substrates without a narrow therapeutic index may be 
used with caution or should be replaced with alternatives wherever possible. For a list 
of P-gp substrates with an NTI see Table 4.2.2.1: 1.

Based on clinical data brigimadlin can be considered a weak, transient CYP3A4 
inducer at the clinically relevant dose and dosing schedule (45 mg q3w). 
Coadministration of brigimadlin with CYP3A4 sensitive substrates, for which 
minimal concentration changes may lead to therapeutic failures of the substrate, 
should be avoided. If coadministration cannot be avoided, follow recommendations 
for CYP3A4 inducers provided in their approved product label.

Brigimadlin is a potential inducer of CYP1A2, based on in vitro studies. Drugs that 
are known CYP1A2 substrates may have reduced exposure and therefore reduced 
efficacy when given together with brigimadlin. Alternatives with less potential for 
CYP1A2-based interactions or concomitant drug dose adjustment should be 
considered if possible.

Brigimadlin is in part metabolized by CYP3A4 according to in vitro hepatocyte data. 
Thus, the exposure of brigimadlin might be influenced by concomitant medications 
that are inducers and inhibitors of CYP3A4. Concomitant medications that are 
inhibitors or inducers of CYP3A4 should be administered with care and the patient 
should be more closely monitored.

Brigimadlin reduces CYP2C9 mRNA and CYP2C19 enzyme activity in vitro. Drugs 
that are known CYP2C9 and CYP2C19 substrates may have increased exposure and 
therefore increased risk for side effects when given together with brigimadlin. 
Specifically, sensitive substrates and substrates with narrow therapeutic window or 
index (NTI) e.g. warfarin, should be used with caution or should be replaced with 
alternatives with less potential for CYP2C9 and CYP2C19-based interactions.

Brigimadlin is a substrate of the OATP1B1 and OATP1B3, hence inhibitors for both 
transporters are not allowed as concomitant therapies. Inhibitors of OATP1B1 and 
OATP1B3 are listed in Table 4.2.2.1: 1.
Anti-viral treatments have recently been approved for use in some countries for the treatment 
of mild to moderate COVID-19 infection.
. Other treatments are allowed taking into consideration 
the restrictions detailed in this section and in Section 4.2.1.
In addition to the restrictions detailed above, the following concomitant medications are 
prohibited:

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
Live attenuated vaccines are prohibited during the trial and until 30 days after the last 
dose of brigimadlin.
Herbal preparations / medications and nutritional supplements are allowed throughout the 
trial at the discretion of the investigator. Potential interactions described above should be 
taken into consideration.

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For restrictions during treatment with doxorubicin, please refer to the current SmPC or US 
Package Insert of the supplied medication. Table 4.2.2.1: 2 provides on overview.
Table 4.2.2.1: 2
Examples of restricted comedications during treatment with 
doxorubicin
Strong CYP3A4 inhibitors
Not Permitted
Boceprevir, ritonavir, indinavir, 
nelfinavir, saquinavir, clarithromycin, 
telithromycin, chloramphenicol, 
ketoconazole, itraconazole, 
posaconazole, voriconazole, nefazodone, 
cobicistat 
Strong CYP2D6 inhibitors
Not Permitted
Fluoxetine, paroxetine, bupropion, 
quinidine, quinine, cinacalcet, ritonavir
Strong P-glycoprotein 
inhibitors
Not Permitted
Amiodarone, carvedilol, clarithromycin, 
dronedarone, itraconazole, lapatinib, 
lopinavir, ritonavir, propafenone, 
quinidine, ranolazine, saquinavir 
telaprevir, tipranavir, verapamil
COVID-19 vaccine
It is recommended that the treating physician consider vaccination against SARS-CoV-2 
using the vaccines that have been authorized by the regulatory agencies for the patients 
participating in these BI clinical trials, provided that a benefit-risk assessment by the treating 
physician is favorable. Given the mode of action of brigimadlin, it is not anticipated that it 
would adversely interfere with the response to the vaccines. 
This recommendation is consistent with the recommendation by professional oncology 
organizations (e.g. ASCO, ESMO, and SITC).
4.2.2.2
Restrictions on diet and lifestyle
Patients treated with brigimadlin should be instructed to avoid consumption of 
and their products on days when brigimadlin is administered, as these 
are CYP3A4 inhibitors.
For all cycles, 
.
For restrictions during treatment with doxorubicin, please refer to the current SmPC or US 
Package Insert of the supplied medication.

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4.2.2.3
Contraception requirements
A woman is considered of child-bearing potential (WOCBP), i.e. fertile, following menarche 
and until becoming postmenopausal, unless permanently sterile. Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Tubal 
ligation is NOT a method of permanent sterilization. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause.
WOCBP and men able to father a child must use 2 medically approved methods of birth 
control throughout the trial. They must use one barrier method, i.e. condom or occlusive cap 
with spermicide, and one highly effective non-barrier method including oral, injected, or 
implanted hormonal contraceptives, intrauterine device or system. These requirements also 
apply regardless of whether the male is vasectomized.
Male patients: 
Men receiving brigimadlin whose partner is a WOCBP must use a condom (regardless of 
whether the male is vasectomized) and their female partner must use a highly effective form 
of contraception, during the study and until 102 days after the last dose of brigimadlin
(calculated as the period of relevant systemic exposure (5 half-lives plus 90 days).
Men receiving doxorubicin whose partner is a WOCBP must use a condom (regardless of 
whether the male is vasectomized) and their female partner must use a highly effective form 
of contraception, during the study and until 3 months and 10 days after the last dose of 
doxorubicin.
Female patients: 
WOCBP must use a highly effective method of birth control (as outlined in the patient 
information) per ICH M3 (R2) that results in a low failure rate of less than 1% per year when 
used consistently and correctly beginning at screening, during trial participation, and until 
6 months and 12 days after the last dose of brigimadlin (calculated as the period of relevant 
systemic exposure (5 half-lives plus 6 months) or until 6 months and 10 days after the last 
dose of doxorubicin.
Acceptable methods of birth control for this trial are:

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal).

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable).

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion
Alternatively, patients must abstain from male-female sex. This is defined as being in line 
with the preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, 
ovulation, symptothermal, post-ovulation methods; declaration of abstinence for the duration 
of exposure to study drug; and withdrawal are not acceptable.
The efficacy of oral hormonal contraceptives may be compromised by vomiting and/or 
diarrhoea or other conditions where the absorption may be affected. Women taking oral 

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hormonal contraceptives and experiencing these conditions should be advised to use an 
alternative highly effective contraceptive measure.
Treatment in this trial carries a potential risk of reduced fertility in both male and female 
participants, which could be permanent. Prior to treatment initiation, investigators must 
advise trial participants (men and WOCBP) on the conservation of gametes. Additionally, 
ovum or sperm donation is not permitted during the periods of contraception.
4.3
TREATMENT COMPLIANCE
The investigational product should only be used as directed in this clinical trial protocol. 
Brigimadlin will be administered orally and only if considered safe by the investigator.
Brigimadlin will be taken at the investigational site under the supervision of the investigator 
and/or an authorized and trained designee. Therefore, actual dosing is expected to precisely 
follow the assigned dose. Dosing will be recorded in the eCRF.
Doxorubicin will be administered by intravenous infusion / injection at the investigational 
site under the supervision of the investigator and/or an authorized and trained designee, 
according to the current SmPC or US Package Insert of the supplied medication. Therefore, 
actual dosing is expected to precisely follow the assigned doses. Missed or interrupted doses 
will be recorded in the eCRF with the associated reasons.
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
Imaging
Tumor response will be evaluated according to RECIST version 1.1 [R09-0262].
Baseline imaging should include imaging of all known or suspected sites of disease using an 
appropriate method. The investigator (or a designee) will record the target and non-target 
lesions in the eCRF. Lesions in previously irradiated areas may not be considered measurable 
at baseline unless the lesions occurred after irradiation. The same method of assessment and 
the same imaging technique must be used at each subsequent time point to characterize each 
reported lesion throughout treatment and during follow-up.
All imaging-related endpoints will also be assessed by central independent review (in a 
blinded fashion) according to RECIST version 1.1. All decisions in this trial will be taken 
based on central independent review. Instructions for obtaining images and the shipment /
transfer of image data will be provided in the imaging manual located in the ISF.
Tumor assessment will be performed at the time points indicated in the flowchart and must
continue until confirmation of disease progression by central independent review. Wherever 
possible, the assessment schedule should not be changed. Additional unscheduled tumor 
assessments may be performed at the investigator’s discretion. If the patient stops trial 
medication for a reason other than disease progression by central independent review, tumor 

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assessment according to RECIST version 1.1 will continue until progression by central 
independent review (or until death, lost to follow-up, or end of the trial).
Management of imaging discrepancies
If there is a discrepancy in the assessment of PD between investigator and central 
independent evalution, this will be handled as follows:

If the patient has PD according to investigator assessment, but not according to central 
independent review, the patient must continue treatment and be re-assessed at the next 
scheduled time point. The patient must be kept on trial until central independent 
review concludes that the patient has progressive disease. Patients receiving 
doxorubicin will only be eligible for cross-over to treatment with brigimadlin after PD 
based on central independent review.

If the patient is receiving doxorubicin and has PD according to central independent 
review, but not according to investigator assessment, the patient must stop 
doxorubicin. The patient is eligible for cross-over to treatment with brigimadlin.

If the patient is receiving brigimadlin and has PD according to central independent 
review, but not according to investigator assessment, the patient must stop
brigimadlin. Further treatment outside of the trial will be at the discretion of the 
investigator.
For patients in the cross-over arm, assessments should, wherever possible, continue until 
confirmed PD by central independent review.
The assessment schedule will be as follows:

Every 6 weeks (42 days ±7 days), relative to the C1D1 date (for patients after cross-
over to brigimadlin: relative to the date of the first administration of brigimadlin). 
From Week 36 onwards every 12 weeks ±7 days
Clinical imaging data acquired in this trial might be analyzed further for changes in tumor
texture features, e.g. using radiomics, and assessment tumor growth kinetics using lesion 
volumes. If such exploratory analyses are conducted, then the exploratory analyses may be 
performed in collaboration with an independent third party nominated by the sponsor.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the 
flowchart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. Additional physical examinations may be conducted, as 
clinically indicated, at the investigator’s discretion.

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Measurement of height (in cm) and body weight (in kg) and the evaluation of the ECOG 
performance score will be performed at the time points specified in the flowchart. The results 
must be included in the source documents available at the site.
Body weight measurements should be done on the same scale for each patient. To get 
comparable body weight values, body weight measurements should be performed as follows:

shoes and coat or jackets should be taken off

pockets should be emptied of heavy objects (i.e. keys, coins etc.)
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flowchart, prior to blood 
sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must be 
included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. For the sampling time 
points, please refer to the flowchart.
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Instructions regarding sample collection, sample handling / processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
It is the responsibility of the investigator to evaluate the laboratory reports. Clinically relevant 
abnormal findings as judged by the investigator will be reported as adverse events (please 
refer to Section 5.2.6.1.1).
If the criteria for hepatic injury are fulfilled, a number of additional measures may need to be 
performed (please see Section 5.2.6.1.4 and the DILI Checklist provided in the ISF and EDC 
system). The amount of blood taken from the patient concerned will be increased due to this 
additional sampling.

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Table 5.2.3: 1 
Safety laboratory tests
Category
Parameters
Hematology
Hemoglobin, red blood cell count, hematocrit, mean corpuscular volume, 
white blood cell count, and differential blood count (preferably expressed in 
absolute values), and platelets.
Biochemistry
Glucose, sodium, potassium, chloride, calcium, phosphate, venous 
bicarbonate HCO3, total protein, albumin, uric acid and creatinine kinase 
(CK; if CK is elevated, then patient should be further evaluated according to 
local standard of care).
If symptoms of pancreatitis are observed, amylase and lipase should be 
tested at the discretion of the investigator.
Liver function 
AST, ALT, alkaline phosphatase, lactate dehydrogenase, bilirubin (direct 
and indirect bilirubin in case of elevated total bilirubin values)
Renal function
Blood urea or blood urea nitrogen, and creatinine.
Note: Creatinine can be assessed by any of these methods: CREE 
(enzymatic serum creatinine assay), CREJIDMS (IDMS standardized Jaffe), 
or CREJ (non-IDMS standardized Jaffe).
Coagulation
Activated partial thromboplastin time (aPTT) and prothrombin time (PT) 
(expressed either in seconds or as percentage) or International Normalized 
Ratio (INR)
Urinalysis
pH, glucose, erythrocytes (hemoglobin / blood), leukocytes, protein, and 
nitrite analyzed by dipstick (semi-quantitative measurements)  
Pregnancy
Beta human chorionic gonadotropin (β-HCG) pregnancy test in serum 
performed for women of childbearing potential at Screening 
Urine or serum test performed within 72 h prior to start of study treatment, 
prior to treatment on Day 1 of every cycle from Cycle 2 Day 1 onwards, at 
EOT, and then monthly until 6 months after the last dose of treatment. 
All screening laboratory assessments should be performed or repeated within 10 days prior to 
treatment initiation, except for the pre-treatment urine or serum pregnancy test which should 
be conducted within 72 hours of treatment start; all other screening assessments are 
performed within 28 days of treatment start (Day 1). On-treatment laboratory assessments 
can be performed up to 72 hours prior to Day 1 of each cycle.
5.2.4
Electrocardiogram
Recording
Standard 12-lead (I, II, III, aVR, aVL, aVF, V1 - V6) resting ECGs will be digitally recorded 
at various time points (see the flowchart and Appendix 10.1). In addition, safety ECGs will 
be performed as single measurements.
All ECG recordings will be obtained after the patient has rested in supine position for at least 
10 minutes prior to the indicated time points. All ECGs should be recorded with the patient in 
the same physical position.

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To avoid disruption of ECG recordings, blood samples for a particular time point should be 
taken after performing the ECG.
ECG recordings may be repeated for quality reasons, e.g. due to alternating current artefacts, 
muscle movements, or electrode dislocation. 
Additional ECGs may be recorded for safety reasons. These ECGs are single recordings and 
will be assigned to the most previous scheduled time point in the sponsor’s database.
All ECG recordings must be analyzed and checked for abnormalities by the investigator (or a 
designated physician) who will calculate the QTcF value for each time point. Abnormal 
findings, if deemed clinically relevant by the investigator, will be reported either as baseline 
condition (if identified at the screening visit) or otherwise as adverse events and will be 
followed up and/or treated as medically appropriate. CTCAE version 5.0 will be used for the 
grading of prolonged QTcF intervals, T wave flattening or unspecific ST segment changes.
In case of QTcF prolongation of >500 msec after receiving therapy, the investigator will 
initiate further ECG monitoring and diagnostics (e.g. check electrolytes and check 
concomitant therapy that may be contributing to QTcF prolongation per local standards) and, 
if required, provide adequate treatment according to medical standards.
In case of occurrence of symptoms suggestive of arrhythmia related to QTcF prolongation, a 
cardiologic evaluation will be performed, and treatment will be provided according to 
medical standards at the discretion of the investigator.
5.2.5
Other safety parameters
5.2.5.1
Left Ventricular Ejection Fraction
Left Ventricular Ejection Fraction (LVEF) as measured by echocardiography or Multiple 
Gated Acquisition (MUGA) scan will be assessed at the time points specified in the 
flowchart. The same method of measurement must be used throughout the trial. LVEF 
assessment does not need to be repeated at the screening visit if there is valid result available 
from an assessment which was performed as part of routine clinical practice within 28 days 
prior to treatment start.
Echocardiography
Echocardiography will be performed to assess the LVEF according to the standard guidelines 
of the American Society of Echocardiography [R06-1414].
MUGA scan
MUGA scan is recommended for the assessment of diseases of the heart muscle. It is used for 
the monitoring of the ejection fraction of the cardiac ventricles, especially the LVEF.
Patients randomized to doxorubicin and who have completed their treatment will continue to
undergo monitoring for cardiotoxicity following local guidelines / clinical practice for 
cardiotoxicity post doxorubicin treatment. Results will be captured in the eCRF. In addition,

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those patients who cross-over to brigimadlin treatment will continue to have LVEF monitored 
following local guidelines.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An 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 considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease if certain conditions are met – refer to 
Section 5.2.6.2.5

Worsening of pre-existing conditions other than the underlying disease
Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least 1 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 prolongation of existing hospitalization
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
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: An event that possibly leads to disability will be handled as ‘deemed serious 
for any other reason’ and, therefore, reported as an SAE.

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5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in Section 5.2.6.2.
Every occurrence of cancer of new histology must be classified as a serious event regardless 
of the time since the discontinuation of the trial medication and must be reported as described 
in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (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 
Section 5.2.6.2.3. AESIs need to be reported only for patients receiving brigimadlin.
In this trial, hepatic injury, hematological AEs, gastrointestinal AEs, and fatigue are 
considered as AESIs. Details are provided below:
1. Hepatic injury
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined by 
the following alterations of hepatic laboratory parameters: 

For patients with normal aminotransaminase levels:
o
An elevation of AST (Aspartate Aminotransferase) and / or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other
OR
o
ALT and / or AST elevations ≥10-fold ULN.

For patients with abnormal aminotransaminase levels,
ALT and AST are both between >1 and <3×ULN at baseline: 
o
An elevation of AST and/or ALT ≥3×the baseline value combined with an 
elevation of bilirubin ≥2×ULN (if bilirubin is normal at baseline) or ≥2×the 
baseline value (if bilirubin is elevated at baseline), measured in the same blood 
sample, or in samples drawn within 30 days of each other
OR
o
Aminotransferase elevations (ALT and/or AST ≥5×the baseline value). 

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
For patients with abnormal aminotransaminase levels,
ALT and/or AST between ≥3 and <5×ULN at baseline: 
o
An elevation of AST and/or ALT ≥2×the baseline value combined with an 
elevation of bilirubin ≥2×ULN (if bilirubin is normal at baseline) and/or 
≥2×the baseline value (if bilirubin is elevated at baseline) measured in the 
same blood sample or in samples drawn within 30 days of each other
OR
o
Aminotransferase elevations (ALT and/or AST ≥3×the baseline value).
For further details, see the figure below:
Figure 5.2.6.1.4: 1 Potential severe DILI reporting
These laboratory findings constitute a hepatic injury alert and the patients showing these 
laboratory abnormalities need to be followed up according to the “DILI checklist” 
provided in the EDC system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without laboratory 
results (ALT, AST, total bilirubin) available, the investigator should make sure these
parameters are analyzed, if necessary, in an unscheduled blood test. If the results meet the 
criteria of hepatic injury alert, the procedures described in the DILI checklist should be 
followed.

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2. Hematological AEs

Thrombocytopenia of CTCAE Grade ≥3

Neutropenia of CTCAE Grade ≥3

Thrombocytopenia or anemia requiring transfusion per local or international 
guidelines
3. Gastrointestinal AEs

Nausea of CTCAE Grade ≥3

Vomiting of CTCAE Grade ≥3

Diarrhoea/colitis of CTCAE Grade ≥3
4. Fatigue

Fatigue of CTCAE Grade 3 if it lasts for ≥7 days despite adequate medical 
interventions and if baseline fatigue was of CTCAE Grade ≤1
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the CRF
according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
If the CTCAE grade of an AE changes, a new separate AE should be recorded in the eCRF.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, 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 trial 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 reduced).

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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 trial 
drug concerned).

Continuation of the event despite the withdrawal of the medication, considering 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.

There is an 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.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of 
treatment, including the Residual Effect Period (REP): 
all AEs (serious and non-serious) and all AESIs. 
•
After the end of treatment (including the REP) until the individual patient’s end of trial: 
cancers of new histology, all trial drug related SAEs and all trial drug related AESIs.
•
After the individual patient’s end of the trial: 
the investigator does not need to actively monitor the patient for new AEs but should 
report any occurrence of cancer and trial drug related SAEs and trial drug related AESIs 
of which the investigator may become aware of by any means of communication, e.g. 
phone call. Those AEs should be reported on the BI SAE form (see Section 5.2.6.2.3), but 
not on the CRF.
The rules for Adverse Event Reporting exemptions still apply, please see Section 5.2.6.2.5.
5.2.6.2.2
Vital Status Data Collection
Patients who discontinue trial treatment prematurely, who agree to be contacted further but 
do not agree to physical visits, should be followed up as described in Section 3.3.4.1, 
withdrawal from trial treatment. From then on until the individual patient’s end of the trial the 
investigator must report any occurrence of cancer, report all deaths / fatal AEs regardless of 
relationship, and trial drug related SAEs and trial drug related AESIs the investigator 
becomes aware of. 

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5.2.6.2.3
AE reporting to the 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 to the sponsor’s unique entry point within 
24 hours of becoming aware of the event, the country specific process will be specified 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 the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form must be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained.
5.2.6.2.4
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 written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The 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 Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (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 Studies 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.
5.2.6.2.5
Exemptions to AE/SAE reporting
The outcome “progressive disease (PD)” is used to assess trial endpoints for the analysis of 
efficacy and will be recorded on the appropriate page of the eCRF.
If the disease progression does not meet standard seriousness criteria (see Section 5.2.6.1.2), 
then it is exempt from AE/SAE reporting, and will only be recorded on the appropriate page 
of the eCRF. For example, asymptomatic disease progression detected on a routine scan
would be exempt from AE/SAE reporting, even if disease progression is on the “always 
serious” list.

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However, if there is evidence suggesting a causal relationship between the investigational 
drug and the progression of the underlying malignancy, the event must be recorded as an 
SAE on the AE page in the eCRF and reported as an SAE on the SAE form.
If disease progression meets the standard seriousness criteria (see Section 5.2.6.1.2) it will be 
recorded on the AE page in the eCRF and on the SAE form and the SAE reporting process 
will be followed.
Laboratory values meeting the potential severe DILI definition in Section must always be 
reported as AESI, even if the most likely cause is disease progression. No exemption in AE 
reporting applies.
Clinical symptoms and/or signs of PD will be recorded on the AE page in the eCRF. If 
signs and symptoms of disease progression of the patient’s underlying malignancy meet 
standard seriousness criteria, they will additionally be reported as SAEs on the SAE form 
and the SAE reporting procedures will be followed. If signs and symptoms are attributable 
to a diagnosis, reporting the diagnostic term is preferable, e.g. pulmonary embolism rather 
than dyspnoea, intestinal obstruction rather than abdominal pain.
Exempted events are reviewed at appropriate time intervals by an independent DMC and the 
sponsor. The objectives of the DMC are described in Sections 3.2, 8.7 and in the DMC 
charter.

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5.4
ASSESSMENT OF BIOMARKER(S)
This section refers to exploratory biomarkers. Planned exploratory analyses of biomarkers 
during the trial may be reduced or stopped based on new information in the literature or early 
analyses.
5.4.1
Handling of samples and biomarker results
Detailed instructions for handling, storage, and shipment of the biomarker samples will be
provided in the laboratory manual included in the ISF. All required materials and labels will

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be provided. If local regulations allow, any excess materials at the central laboratory will be 
shipped and stored at BI’s central laboratory until all required validations have taken place or 
until it is decided that there is no requirement for validation. Samples will be destroyed no 
later than 5 years after trial completion.
A brief description of the biomarker analyses to be performed is provided below. All tumor 
and blood samples will be obtained at the time points specified in the flowchart. The results 
of the biomarker analyses performed by the central screening laboratory will be reported to
investigators, upon request.
5.4.2
Tumor tissue samples
5.4.2.1
Tumor tissue samples at screening
Patients with a written pathology report indicating the diagnosis of DDLPS with positive 
MDM2 immunohistochemistry and/or MDM2 amplification are eligible for enrollment into 
the trial (see Section 3.3.2). Patients may be enrolled based on local testing of tumor tissue 
which establishes the MDM2 gene amplification status of their tumor. Test results from a 
liquid biopsy are not acceptable. If there is a local test result from tumor tissue and from 
liquid biopsy, the test result from the tumor tissue must be used to determine eligibility.
If a fresh biopsy is conducted for the baseline (Screening) assessment of TP53 and MDM2 
amplification, a sample from the same procedure may be used as baseline (pre-treatment)
sample for other biomarker analyses.
A sample of archival tumor tissue must be provided for every randomized patient for the 
retrospective testing of the TP53 and MDM2 gene status in a central pathology laboratory 
nominated by the sponsor. As central laboratory testing is conducted retrospectively for 
patients deemed eligible per local testing, if test results are inconsistent, the investigator will 
be informed, and the patient will continue at the investigator’s discretion, taking into 
consideration the patient’s clinical benefit.
A fresh biopsy taken for the patient’s primary or a metastatic lesion is preferred for
biomarker testing but archival sample from a tumor biopsy taken at disease diagnosis is 
acceptable.
Tumor samples should be provided in the form of a formalin-fixed paraffin embedded 
(FFPE) block (preferred). Please refer to the laboratory manual for further details on sample 
preparation.
5.4.2.2
Fresh biopsies on treatment
The use of freshly taken biopsies will enable to generate correlative biomarker data from 
tumor tissue which help to better understand the treatment benefit but also contributes to the 
better understanding of the mechanism of action of brigimadlin. Tissue-based biomarker 
analyses may also be used to support the dose selection. However, the retrospective 
correlative studies are exploratory and will not be powered to demonstrate statistical 
significance.

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At Cycle 2 Day 2-4, patients will be required to undergo a biopsy (see flowchart) for 
assessment of the biomarkers listed below. This is a mandatory assessment; however, if in the 
judgment of the investigator, the biopsies are not feasible (e.g. considering tumor 
accessibility, patient safety) for a particular patient, the fresh biopsy procedure will not be 
conducted.
Patients with only one measurable target lesion are not required to undergo the on-treatment 
biopsy. This is because of the potential effects of a biopsy on the assessment of the lesion and 
thus the efficacy endpoints.
5.4.2.3
Tumor tissue sample processing and storage
Refer to the laboratory manual for additional detail 
5.4.3
Circulating biomarkers
5.4.3.1
Circulating tumor DNA
The isolation of DNA from blood originating from the tumor (circulating tumor DNA, or
ctDNA) provides a minimally invasive means of monitoring changes in the biology of the
tumor resulting from the trial medication.

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The plasma will also be used to analyze changes in tumor- derived circulating microRNAs, or
circulating markers such as cytokines, chemokines, and other circulating protein markers,
which may be affected by the therapy. Plasma samples will be destroyed no later than 5 years 
after study completion.
5.4.3.2
Circulating micro RNA
The p53 pathway also controls the expression of short length RNA species called microRNAs 
(miRNA) 
5.4.3.3
Circulating proteins 
Circulating proteins such as cytokines, chemokines and hormones will be measured to 
determine the potential predictive or pharmacodynamic impact of these biomarkers of the 
treatment benefit.
5.4.4
Flow cytometry
Flow cytometry studies will be carried out to measure or monitor drug-related changes on 
circulating immune cells such as T cells, dendritic cells, and myeloid-derived suppressor cells
(MDSCs).

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5.4.5
Pharmacogenetics
Pharmacogenetics (PGx) investigates genetic variations in patients to explain and to predict
their individual response to drugs. The pharmacogenetic analysis is mandatory but a whole
genome sequencing is excluded.
5.5
BIOBANKING
Not applicable for this trial.
5.6
OTHER ASSESSMENTS
5.6.1
Patient reported outcomes
Patient-reported outcomes (PRO) will be measured throughout the trial using the below 
multidimensional questionnaires. Patients will use digital devices to complete the 
questionnaires. During the conduct of the trial, the sponsor may decide to implement paper 
questionnaires.

EORTC QLQ-C30 v3, European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire (QLQ-C30) [R07-2064; R99-1213].

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
EQ-5D5L health status self-assessment questionnaire [R96-2382]

Fatigue: A selection of items from the EORTC PRO item library.

Pain: A selection of items from the EORTC PRO item library.

Patient Global Impression of Change (PGIC) and Patient Global Impression of Severity 
(PGIS) [R21-2016]
The questionnaires will be completed at the time points specified in the flowchart. To 
minimize the possibility of bias, on clinic days it is recommended that patients should 
complete the questionnaires prior to seeing the clinician, prior to clinical assessment, prior to 
any treatment at the clinic, and before provision of any new information about their disease 
status. The responses recorded on the questionnaires will not be recorded as adverse 
events. Adverse events are collected during protocol specified study visits with the clinician.
The questionnaires generally take about 15 to 30 minutes to complete. Validated translations 
exist for all questionnaires for all countries participating in the trial, and patients will receive 
the questionnaires in their native language. 
The patient perspective is considered a supportive contribution to inform physicians on the 
clinical utility of brigimadlin compared to doxorubicin in patients with DDLPS. In addition, 
the EQ-5D5L, HRQoL assessment will inform a later health economic (cost-effectiveness) 
analysis.
EORTC QLQ-C30 
The QLQ-C30 comprises 30 questions. The QLQ-C30 incorporates both multi-items scales 
and single-item measures. These include 1 global health status/QoL scale, 5 functional scales, 
3 symptoms scales and 6 single items to assess dyspnea, insomnia, appetite loss, constipation, 
diarrhoea and financial difficulties. Each of the multi-item scales includes a different set of 
items – no item occurs in more than one scale [R07-2064].
PROMs for fatigue and pain symptoms
A selection of Likert scale items from the EORTC item library will be used to assess pain and 
fatigue. These items are selected based on patient preferences and are considered relevant and 
specific for patients with soft-tissue sarcoma, including liposarcoma.
Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change 
(PGIC) are FDA-recommended anchors to detect meaningful change. Both single item 
PROMs are scored through a Likert response scale: the PGIS is scored on a 4-point Likert 
scale (1 = none, 4 = severe) while the PGIC is scored on a 5-point Likert scale (1 = much 
better, 5 = much worse).
EQ-5D5L
The EQ-5D5L is a disease-generic instrument that has been widely used and has been found 
to capture HRQoL changes in soft-tissue sarcoma, including liposarcoma [R21-2293]. The 
EQ-5D5L comprises the following 2 components:

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1. The EQ-5D5L comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression). Each dimension comprises 5 levels (no problems,
slight problems, moderate problems, severe problems, unable to/extreme problems).
2. The EQ-VAS records the respondents self-rated health status on a vertical graduated 
(0-100) visual analogue scale.
For the EQ-5D5L, the respondent is asked to indicate his/her health state by placing a cross in 
the box against the most appropriate statement in each of the 5 dimensions. Additional 
instructions are provided in the ISF.
PRO-CTCAE
The PRO-CTCAE was previously developed to elicit symptomatic toxicity information 
directly from participants in cancer clinical trials. The PRO-CTCAE has demonstrated 
favorable validity, reliability, and responsiveness in a sample of 975 patients who had 
received cancer-directed therapy in the prior 2 weeks. PRO-CTCAE exhibited acceptable 
test-retest reliability across the subset of items tested. There is also evidence that the 1-week 
recall corresponds most closely to daily reporting, supporting the validity of the 7-day recall 
period [R21-2312].
The PRO-CTCAE Item Library is comprised of 78 symptomatic adverse events, assessed by 
124 items. It has been linguistically validated in more than 30 languages. Items from this 
library were selected to assess the following pre-defined adverse events: abdominal pain, 
nausea, vomiting, diarrhea, mouth sores, decreased appetite, cough, fatigue. One item to 
assess the global experience of side effects (FACT-G item GP5) will be added to the PRO-
CTCAE items.
5.6.2
Analgesic quantification algorithm
The use of analgesic medications for pain will be assessed throughout the trial, at the same 
schedule as concomitant medication (see flowchart). The investigator (or a designee) will 
complete the AQA (Analgesic Quantification Algorithm), a measure of analgesic use. The 
AQA will be used as a component of the clinical trial secondary PRO endpoint (pain as a 
symptom of the disease), to determine whether changes in pain assessments are due to the 
intervention or due to changes in analgesic use.
5.7
APPROPRIATENESS OF MEASUREMENTS
All clinical assessments are standard measurements commonly used in studies of advanced 
solid tumors. 
The US National Cancer Institute (NCI) CTCAE is used in the assessment of adverse events 
in cancer patients. In the present trial, CTCAE version 5.0 will be used.
6.
INVESTIGATIONAL PLAN
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, the sponsor and investigator may agree on alternative, back-up or 

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rescue methodology which may include but will not be limited to: virtual patient visits and 
assessments, home healthcare nurse visits, and direct-to-patient shipments of trial treatment. 
The implementation of these measures will depend on the patient’s consent, operational 
feasibility, and local laws and regulations. If alternative methodology is implemented, the 
deviations from the original plan will be precisely documented.
6.1
VISIT SCHEDULE
Written informed consent must be obtained before any protocol specific screening 
assessments are performed. Informed consent may be signed by the patient prior to the 
screening visit. A separate written informed consent must be obtained for patients crossing 
over from the doxorubicin arm to treatment with brigimadlin. Imaging scans performed as 
part of routine clinical practice and prior to provision of informed consent and within the 
screening timeframe can be used if they meet the imaging requirements.
Eligible patients will be randomized to their trial medication and receive the assigned trial 
medication until any of the criteria for stopping medication is met (see Section 3.3.4.1), or the 
maximum cumulative dose of doxorubicin is met for the doxorubicin arm.
During the treatment phase, visits should be performed weekly during Cycles 1 and 2, and 
once or twice per cycle (as indicated in the flowchart) from Cycle 3 onwards, within 2 days 
of the scheduled date. The scheduled time interval for each visit is relative to the initiation of 
trial medication (C1D1). Following discontinuation of all trial medications, an EOT visit 
must occur as soon as possible (within 7 days after the EOT decision). An EOT visit beyond 
21 days is possible for patients who delayed their next dose due to toxicity and only then 
decided to stop treatment. After the EOT visit, the patient must undergo a follow-up safety 
evaluation (after the REP of the assigned trial medication). Then the patient will enter the 
follow-up period until trial completion. Please see the flowchart for the detailed visit 
schedule.
Unscheduled visits can be performed as necessary, and assessments will be performed as 
required at the discretion of the investigator. In case a patient missed a visit and the patient 
reports to the investigator between the missed visit and the next scheduled visit, the date of 
the report and the reason for the delayed visit should be noted in the patient’s chart. The next 
visit, however, should take place at the scheduled time. In the event of any interruption / 
delay of treatment, the imaging schedule should not be changed.
In COVID-19-related or similar exceptional situations, sites should adhere to the required
protocol procedures as close as possible while implementing measures to reduce the risk of
transmission of infections; however, where a patient is unable or unwilling to attend a clinic
visit, the investigator must assess the risk-benefit for the individual patient and may decide to
perform a visit remotely if this is in the best interests of the patient and if agreed with the
sponsor. Patient safety must be ensured when determining if a visit may be remote.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
An overview of all assessments to be performed at the respective visit is given in the 
flowchart; detailed explanations of procedures or observations are given in Section 5.

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6.2.1
Screening
The screening visit should be performed between 28 days and 1 day prior to first 
administration of treatment.
Before or during the screening visit, prior to any study procedures, all patients will need to 
sign the Informed Consent Form (ICF) for trial participation.
Examinations and assessments will be conducted as depicted in the flowchart. Patients’ 
medical history and demographic information will be collected, and inclusion and exclusion 
criteria must be assessed (see details below).
A tumor-tissue biopsy (archival or fresh) will be submitted to the central laboratory. This is a 
mandatory requirement for study enrollment.
Demographics
During the screening visit, demographics information will be collected. This includes:

Age on the day of informed consent (in years)

Sex (male, female to describe the subject’s sex at birth)

Gender identity (male, female, other to describe how the subject self-identifies 
regardless of their genotypic or phenotypic sex)

For women: of childbearing potential yes / no to characterize the patient population 
and as a basis for contraception requirements

Ethnicity and race to sufficiently characterize the patient population, to support 
possible subgroup analyses, unless not acceptable according to local regulations.
Baseline Conditions
Baseline conditions and concomitant therapies present during screening will be recorded in 
the eCRF.
Medical History
Medical history for each tumor type will be obtained during screening and documented in the 
eCRF, this includes:

Date of first histological diagnosis

Primary tumor site

Number and location of metastatic sites at screening (bone, brain, liver, pleural 
effusion, other)

Previous anti-cancer treatments including any surgery, radiotherapy, and or systemic 
therapy, including start and end dates as well as the outcome
Pre-existing tumor molecular marker information (e.g. Next Generation Sequencing data) 
will be collected where possible.
Baseline imaging
Imaging scans performed as part of routine clinical practice prior to provision of informed 
consent and within the screening timeframe can be used if they meet the imaging 

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requirements, provided it is clear from source documents that the imaging was not performed 
for the purpose of the present trial.
Cross-over to treatment with brigimadlin
Patients randomized to the doxorubicin arm will be offered the option to receive brigimadlin
as subsequent therapy (see Section 4.1.3 for further details). The crossed over patients will re-
consent, undergo a screening visit, and will be re-assessed for inclusion and exclusion criteria
(see Section 3.3.3.1).
Special rules apply for the screening visit of crossed over patients:

EOT, EOR, and FU for PD assessments from the doxorubicin arm can be used if they 
had been completed within 21 days of C1D1.

At maximum a 12-week window is permitted from the date of confirmed PD by 
central independent review to C1D1 of the cross-over arm.

Imaging scans do not need to be repeated and can be used as baseline if performed 
within 6 weeks prior to C1D1.

If the patient fails screening for the cross-over arm, the patient needs to complete the 
EOR visit and the follow-up assessments of the doxorubicin arm.
6.2.2
Treatment period(s)
Eligible patients will be randomized through IRT and will be administered trial medication in 
21-day treatment cycles until criteria for treatment discontinuation are met (see Section 3.3.4)
or the maximum cumulative dose of doxorubicin is met for the doxorubicin arm. Treatment 
visits are specified in the flowchart and must be conducted as scheduled and outlined there.
Eligible patients for the for the cross-over arm will either be randomized to the 30 mg or 
45 mg dose of brigimadlin during Phase II or be assigned to the selected brigimadlin dose in 
Phase III.
All procedures will be conducted on Day 1 of the cycle. Selected procedures, 
pharmacokinetics and pharmacodynamics sampling (refer to Appendix 10.1), as well as 
PROM / PRO-CTCAE assessment will also be performed on subsequent days (Days 8 
and 15). A treatment delay should not affect the imaging schedule – the imaging schedule 
continues, based on the randomization date or C1D1 date of the cross-over arm.
6.2.3
Follow-up period and trial completion
6.2.3.1
End of Treatment visit (EOT)
For patients in the doxorubicin arm who complete the maximum treatment, the EOT visit is 
performed 21 days (±3 days) after the last dose of doxorubicin. 
For all other patients, after permanent discontinuation of trial medication for any reason, the 
EOT visit must be performed as soon as possible and within 7 days after EOT decision. An 
EOT visit beyond 21 days is possible for patients who delayed their next dose due to toxicity 
and only then decided to stop treatment.

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If the decision to permanently discontinue trial medication is taken during a scheduled visit, 
the EOT (End of Treatment) visit should be performed instead of the scheduled visit. In the 
event of early discontinuation for reasons other than confirmed progressive disease, the tumor 
assessment schedule as outlined in Section 5.1.1 should continue to be followed.
After permanent discontinuation of trial medication, further therapy will be decided by the 
investigator.
6.2.3.2
Safety follow-up visit (End of Residual Effect period, EOR)
After the last administration of trial medication, all patients are required to attend the EOR 
visit to evaluate safety. The EOR visit is conducted as indicated in the flowchart. In cases 
where the EOT may be after the EOR period, the EOT and EOR can be done as a single visit. 
The purpose of this visit is primarily to collect all new AEs that occurred after last 
administration of trial medication and to follow-up on ongoing adverse events. The EOR visit 
should occur for all patients, including those patients with confirmed disease progression 
and/or start of subsequent anti-cancer treatment. For AE reporting after EOT, see 
Section 5.2.6.2.3.
6.2.3.3
Follow-up period
If a patient does not have documented progression by central independent review prior to or 
at the safety follow-up visit (EOR) he / she will continue to have regular follow-up visits 
(FU-PD) and tumor assessments in accordance with the trial schedule. Assessments will be 
performed as indicated on the flowchart. The end of FU-PD will occur at the timepoint of the 
earliest event of the following:

Disease progression

Start of further anti-cancer treatment

Loss to follow-up

Death

End of the whole trial as specified in Section 8.6
After disease progression the patient will continue to be followed-up for survival as described 
below.
The following will be obtained and/or performed every 6 weeks during the follow-up for PD:

For each reportable SAE/AESI, the investigator should provide the information about
concomitant medication and the medication administered to treat the AE on the 
appropriate CRF pages and the SAE form including trade name, indication, and dates 
of administration.

Perform tumor imaging and assessment.

Pregnancy testing as required according to the flowchart.

Treatment and date with any subsequent anti-cancer drug / therapy including the name
and type of the anti-cancer drug and/or best supportive care (if applicable).

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
Outcome (date and cause of death [if applicable]; for PD, the actual date of PD.
During this period, imaging scans will continue to be collected as per the imaging manual and 
submitted to central imaging laboratory.
Follow-up for survival:
After disease progression, the patient will enter the follow-up for survival. No visits will be 
performed for the purposes of the trial, but data on further anti-cancer treatment and survival 
will be collected from medical records or via telephone. Patients will also be asked to 
complete the PROMs. For WOCBP, pregnancy testing will continue as applicable and 
according to the flowchart. Survival data will be collected every 12 weeks (±7 days) starting 
from last contact (EOT and/or EOR) and may also be collected at additional timepoints when 
a snapshot of data is required (e.g. at the time of analysis). Data collection will continue until 
death, lost to follow-up, withdrawal of consent, or end of the whole trial (see Section 8.6).
The following information will be collected during the follow-up for OS period:

Date of contact

Subsequent anti-cancer therapy (if applicable)

Related SAE/AESI and concomitant medication

Outcome event (e.g. death; date of and reason for outcome event/death)
For patients who discontinue for a reason other than confirmed progression by central 
independent review, follow-up visits continue until confirmed disease progression per the 
imaging schedule (refer to Section 5.1.1), lost to follow up, start of subsequent anti-cancer 
treatment, withdrawal of consent, or completion of the entire trial as specified in Section 8.6. 
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The overall trial design is an active-controlled, randomized, open-label, seamless Phase II/III 
parallel design to evaluate whether brigimadlin is superior to doxorubicin as first line 
systemic therapy for advanced or metastatic DDLPS. The primary endpoint, progression-free 
survival (PFS), will be used to determine superiority. Randomization will be stratified by 
‘extent of disease’ (locally advanced vs. metastatic disease).
The selected investigational arm (brigimadlin at the 30 mg dose or at the 45 mg dose) will be 
compared with the control arm for the primary endpoint of PFS (based on blinded central 
independent review). The weighted inverse normal method described by Lehmacher and 
Wassmer [R14-1197] combining one-sided p-values from a stratified log-rank test (locally 
advanced vs. metastatic) will be the primary analysis method for PFS. The Lehmacher and 
Wassmer method is a generalization of the method described by Cui et al. [R08-2069].
Family-wise type I error rate will be strongly controlled under the level of 2.5% (one-sided) 
using the technique detailed in Section 10.2 and as described in [R14-2334; R15-5218; R20-
0234; R21-0907;]. Details regarding hypothesis testing, alpha-spending/control, and interim 
analyses are provided in the following sections. 

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7.1
NULL AND ALTERNATIVE HYPOTHESES
The primary endpoint PFS will be assessed and compared between the selected 
investigational arm and the doxorubicin control arm at an interim futility analysis (which is 
expected to occur at approximately the same time as the end of Phase II) and at the primary
analysis of PFS during Phase III.
The one-sided null hypothesis of the primary PFS endpoint is:
: 	
; () ≤	
;() for all  > 0,
versus the alternative hypothesis:
: 	
; () > 	
;() for some  > 0.
	
() is the probability that a patient passes time  without experiencing a PFS event. The 
further subscripts represent the 2 treatment arms, i.e. MDM2 denotes the selected 
investigational arm of brigimadlin, and Doxorubicin denotes the doxorubicin control arm.
The weighted inverse normal combination test approach will be applied to the primary
analysis of PFS. Details of the combination test approach can be found in Appendix 10.2.
For the primary endpoint PFS, a technical one-sided alpha of 0.0005 will be spent at the 
interim futility analysis and the rest one-sided alpha of 0.0245 will be spent at the primary 
analysis. There is no plan to test or claim for superiority at the interim futility analysis. If 
statistical significance is obtained for PFS at the primary PFS analysis during Phase III, then
selected secondary endpoints (i.e. ORR and OS) will be tested following a hierarchical 
testing framework. Due to the hierarchical testing procedure chosen, no alpha adjustment is 
required to account for multiple testing. ORR will be tested at one-sided level 0.0245 at the 
same time as the primary PFS analysis. If statistical significance is obtained for both PFS and 
ORR, then the alpha of one-sided level of 0.0245 will be carried over to the primary analysis
and test of OS, occuring at the end of Phase III. If statistical significance is obtained for PFS
but not for ORR, then OS will continue to be followed up until the pre-specified number of 
OS events are met at the end of Phase III and then analyzed without being formally tested.
For ORR, the Cochran-Mantel-Haenszel method will be used to test for a difference between 
the selected investigational treatment arm and the doxorubicin control arm. The one-sided p-
value to test ORR will be generated from the Cochran-Mantel-Haenszel test statistic. The 
stratification factor will be adjusted for in the analysis (locally advanced vs. metastatic). The 
one-sided null hypothesis of the ORR endpoint is:
:  ≤,
versus the alternative hypothesis:
:  > .
The subscripts represent the 2 treatment arms, i.e. MDM2 denotes the selected investigational 
arm of brigimadlin, and Doxorubicin denotes the doxorubicin control arm.
For OS, the primary analysis will be performed using the stratified log-rank test (locally 
advanced vs. metastatic). The one-sided null hypothesis of the OS endpoint is:
: !
; () ≤!
;() for all  > 0,

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versus the alternative hypothesis:
: !
; () > !
;() for some  > 0.
!
() is the probability that a patient passes time  without experiencing death. The further 
subscripts represent the 2 treatment arms, i.e. MDM2 denotes the selected investigational arm 
of brigimadlin, and Doxorubicin denotes the doxorubicin control arm.
The weighted inverse normal method described by Lehmacher and Wassmer [R14-1197]
combining one-sided p-values will be the analysis method for ORR and OS.
7.2
PLANNED ANALYSES
7.2.1
General considerations
The primary endpoint of PFS (based on central independent review) will be assessed and 
compared between the selected investigational arm and the doxorubicin control arm at an 
interim futility analysis (which is expected to occur at approximately the same time as the 
end of Phase II) and at the primary PFS analysis during Phase III. For more details about the 
interim futility analysis, see Section 7.2.8 below. Analysis of the primary endpoint of PFS 
will follow the intention-to-treat principle and will therefore include all randomized patients 
regardless of whether the patient is treated with trial medication or not.
If statistical significance is obtained for the primary analysis of PFS during Phase III, then the 
alpha will be carried over, and selected secondary endpoints ORR and OS will be tested 
following a hierarchical testing framework. These analyses would follow the intention-to-
treat principle and would therefore include all randomized patients regardless of whether the 
patient is treated with trial medication or not.
The final analysis of the secondary endpoint of OS will occur at the end of Phase III. The 
final analysis of OS will also follow the intention-to-treat principle and will therefore include 
all randomized patients regardless of whether the patient is treated with trial medication or 
not.
Safety analyses will include all patients in the treated set (TS), i.e. all patients treated with at 
least 1 dose of trial medication.
The PK set includes all patients in the TS who provide at least one observation for at least 
1 PK endpoint without important protocol deviations relevant to the evaluation of PK.
Any other analysis sets will be defined in the TSAP.
No per protocol set will be used in the analysis. However, important protocol deviations will 
be identified and listed in the Clinical Trial Report (CTR).
7.2.2
Handling of intercurrent events
The expected intercurrent events of interest in this trial are:

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
Start of subsequent anti-cancer therapy before a PFS event based on blinded central 
independent review

Treatment switching from doxorubicin to brigimadlin before a PFS event based on 
blinded central independent review

Start of a restricted medication (see Section 4.2.2.1)

Loss to follow-up

Withdrawal of informed consent by patient 

Missed visits, or 2 or more consecutively missed tumor assessments

Treatment discontinuation

Death
The strategies for handling intercurrent events in this trial are as follows:
Primary strategy
The primary strategy for the analysis of the primary endpoint PFS is to handle intercurrent 
events by studying the effect of randomizing patients to a treatment arm regardless of the 
actual treatment taken. Different strategies will be used for the expected intercurrent events. 
Start of subsequent anti-cancer therapy, cross-over from doxorubicin to brigimadlin, loss to 
follow-up, withdrawal of informed consent, missed visits, or 2 or more consecutively missed 
tumor assessments before the event of interest occurs will be handled using the “hypothetical 
approach” as defined in ICH E9 (R1). Use of the “hypothetical approach” considers the effect 
of what would have happened if the intercurrent event (e.g., start of subsequent therapy) did 
not occur.
Intercurrent events of treatment discontinuation and start of restricted medications will be 
handled using the “treatment policy” approach as defined in ICH E9 (R1). Use of the 
“treatment policy” approach disregards the intercurrent event and uses the value of the 
variable regardless of the occurence of the intercurrent event (e.g., start of a restricted 
medication).
The intercurrent event of death will be handled using the composite strategy as defined in 
ICH E9 (R1), where the intercurrent event becomes part of the endpoint.

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Table 7.2.2: 1
Handling of intercurrent events as per ICH E9 (R1) within the 
different strategies
Intercurrent event
Primary strategy
Start of subsequent anti-cancer therapy before a PFS 
event by blinded central independent review
Hypothetical (censored; 
see Section 7.3)
Cross-over from doxorubicin to brigimadlin before a PFS 
event by blinded central independent review
Hypothetical (censored)
Start of a restricted medication
Treatment policy
Loss to follow-up
Hypothetical (censored)
Withdrawal of informed consent by patient
Hypothetical (censored)
Missed visits or 2 or more consecutively missed tumor 
assessments
Hypothetical (censored)
Treatment discontinuation
Treatment policy
Death
Composite
Each analysis will reference the strategy for handling intercurrent events that it will be 
estimating. The estimand for each main analysis in this clinical trial protocol is the 
combination of the relevant detailed clinical objective from Section 2.1 and this strategy.
Any handling of intercurrent events not listed above will be decided during blinded review 
and documented in the TSAP.
7.2.3
Primary objective analyses
The primary endpoint of PFS is defined in Section 2.1.2.
The primary endpoint of PFS (based on central independent review) will be assessed and 
compared between the selected investigational arm and the doxorubicin control arm at an 
interim futility analysis (which is expected to occur at approximately the same time as the 
end of Phase II) and at a primary PFS analysis during Phase III. The interim futility analysis 
will be performed once the required number of approximately 56 PFS events have occurred
between the selected investigational arm and the control arm. The primary PFS analysis 
during Phase III will be performed once approximately 120 PFS events from the selected 
investigational arm and the control arm have occurred in patients enrolled in Phase II and 
approximately 65 PFS events have occurred in patients enrolled in Phase III according to 
option A (patient separation approach) in Jenkins et al. [R15-5218].
For patients with known date of progression based on blinded central independent review or 
death:
PFS [days] = earlier date of progression based on blinded central independent review or 
death – date of randomization + 1.

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For patients who will be censored:
PFS [days] = date of last imaging assessment without disease progression based on
blinded central independent review – date of randomization + 1.
Censoring rules for PFS are provided in Section 7.3.
The analysis of the primary endpoint PFS (based on blinded central independent review) will 
be performed using the weighted inverse normal method described by Lehmacher and 
Wassmer [R14-1197]. Stage 1 (Phase II) is defined as the time period until 180 patients have 
been enrolled between the selected investigational arm and the control arm, and Stage 2 
(Phase III) is defined as the time period after that (when 120 additional patients have been
enrolled between the selected investigational arm and the control arm). Two one-sided p-
values will be calculated, one for each stage. P-values for comparisons of PFS based on 
stratified log-rank tests are produced separately for those patients recruited to Stage 1 and 
those recruited to Stage 2. For the patients enrolled at the first stage, the p-value is based on 
the one-sided Dunnett test [R97-1269] adjusted p-value for dose selection, derived from the 
stratified log-rank test statistics for PFS. The follow up time of Stage 1 patients is
prespecified until 120 PFS events are observed from the selected investigational arm and the 
control arm. This Stage 1 adjusted p-value for primary PFS analysis can only be calculated 
when the prespecified number of events for patients enrolled at Stage 1 has been reached. For 
the patients enrolled at the second stage, the p-value is based on the one-sided p-value 
derived from the stratified log-rank test statistics for PFS. The follow up time of Stage 2 
patients is planned until 65 PFS events are observed from the selected investigational arm and 
the control arm. Patients who are randomized to the unselected dose level and change to the 
selected dose (after dose selection), will be censored at the time when dose change occurs (if 
there is no PFS event before that). The test for statistical significance at the primary PFS 
analysis will then be based on combining these p-values via the weighted inverse 
combination function. The above-mentioned process is based on independent, normally 
distributed stratified log-rank test statistics, which ensures control of the type I error rate 
[R15-0928]. Additional technical details of the combination test approach can be found in 
Appendix 10.2.
Kaplan-Meier estimates of the survival function of PFS, median PFS and the corresponding
95% confidence interval using Greenwood variance that is incorporated into the Brookmeyer 
and Crowley method [R09-6372] with a loglog transformation, as well as the p-value of 
stratified log-rank test (stratified by locally advanced vs. metastatic) on PFS will be provided. 
To estimate the HR for PFS, the median unbiased estimator [R14-2334] will be used as the 
primary estimator. The 95% confidence interval for the HR will then be calculated as 
repeated confidence interval (RCI) according to [R15-0928]. In addition, as a secondary 
estimator, the partial maximum likelihood estimator from the stratified Cox proportional 
hazards model (stratified by locally advanced vs. metastatic) will be used.

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7.2.4
Secondary objective analyses
No key secondary endpoints are defined for the trial.
Secondary endpoints are defined in Section 2.1.3.
The hierarchical testing framework for testing selected secondary endpoints (i.e. ORR and 
OS) is described in Section 7.1.
In addition to the details described below, further details may be specified in the TSAP.
Objective response
Objective response (OR) is defined as a best overall response of confirmed complete 
response (CR) or confirmed partial response (PR) according to RECIST version 1.1 (based on 
blinded central independent review) from the date of randomization until disease progression,
death, last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to 
follow-up, or withdrawal of consent, whichever occurs first. Each patient will be assigned as 

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having a best overall response of one of the following RECIST categories: CR, PR, SD 
(stable disease), PD (progressive disease), or NE (not evaluable). 
A best overall response of CR or PR must be confirmed by a subsequent tumor assessment, 
i.e., a confirmed response requires a repeat observation at least 4 weeks apart. 
Unconfirmed PR or CR will be presented as a sub-category of confirmed SD. SD must last
for at least 42 days to be presented as SD. SD lasting less than 42 days and followed by PD 
will be presented as a sub-category of PD. SD lasting less than 42 days and without evaluable 
response thereafter will be listed as “Not evaluable”. Any assessments done in compliance 
with the pre-specified (-)7-day assessment window will also be accounted for as within the 
42-day duration.
Objective tumor response rate (ORR) gives the percentage of patients with objective tumor 
response. The Cochran-Mantel-Haenszel method will be used to test for a difference between 
arms for ORR. The stratification factor will be adjusted for in the analysis (locally advanced 
vs. metastatic). The two-sided p-value will be generated from the Cochran-Mantel-Haenszel 
test statistic. The one-sided p-value will then be inferred from the two-sided p-value. The 
weighted inverse normal method described by Lehmacher and Wassmer [R14-1197]
combining one-sided p-values from two stages will be the analysis method. The Stage 1 
p-value will be calculated only based on patients enrolled at Stage 1, and the Stage 2 p-value 
will be calculated only based on patients enrolled at Stage 2.
To estimate the odds ratio for ORR, the median unbiased estimator [R14-2334] will be used 
as the primary estimator. The 95% confidence interval for the odds ratio will then be 
calculated as repeated confidence interval (RCI) according to [R15-0928]. In addition, as a 
secondary estimator, an odds ratio and corresponding 95% confidence interval will be 
generated using the likelihood ratio confidence interval.
Overall survival
Overall survival (OS) will be assessed at the end of Phase III. OS is defined as the time 
interval from randomization until death from any cause.
For patients with known date of death of any cause:
OS [days] = date of death - date of randomization + 1.
For patients who died but with unknown date of death of any cause:
OS [days] = date of last contact when the patient is known to be alive - date of 
randomization + 1.
For patients who will be censored:
OS [days] = date of last contact when the patient is known to be alive - date of 
randomization + 1.
The primary analysis of OS will be assessed and compared between the selected 
investigational arm and the doxorubicin control arm at the end of Phase III once 
approximately 133 OS events have occurred in patients enrolled in Phase II and 
approximately 82 OS events have occurred in patients enrolled in Phase III, and the testing 
process will be similar to the analysis described for PFS.

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Kaplan-Meier estimates of the survival function of OS, median OS, and the corresponding 
95% confidence interval using Greenwood variance that is incorporated into the Brookmeyer 
and Crowley method [R09-6372] with a loglog transformation, as well as the p-value of 
stratified log-rank test (stratified by locally advanced vs. metastatic) on OS, will be provided.
To estimate the HR for OS, the median unbiased estimator [R14-2334] will be used as the 
primary estimator. The 95% confidence interval for the HR will then be calculated as 
repeated confidence interval (RCI) according to [R15-0928]. In addition, as a secondary 
estimator, the partial maximum likelihood estimator from the stratified Cox proportional 
hazards model (stratified by locally advanced vs. metastatic) will be used.
To address cross-over effects, a sensitivity analysis of OS is planned. Details will be provided 
in the TSAP.
Duration of objective response
Duration of objective response (DOR) is defined as the time interval from first documented 
confirmed OR until disease progression or death among patients with confirmed objective 
response (based on blinded central independent review), whichever occurs first. 
DOR can only be calculated for patients with confirmed objective response.
For patients with disease progression based on blinded central independent review or death:
DOR [days] = date of outcome - date of first assessment indicating objective response + 1.
For patients without disease progression based on blinded central independent review or 
death:
DOR (censored) [days] = date of outcome - date of first assessment indicating objective 
response + 1.
The censoring rules for DOR will be provided in the TSAP. Only radiological assessments 
after first assessment indicating objective response should be taken into consideration.
Kaplan-Meier methods will be used for the calculation of DOR.
Disease control
Disease control is defined as a best overall response of CR, PR, or SD according to RECIST 
version 1.1 (based on blinded central independent review). 
Disease control rate gives the percentage of patients with disease control. Logistic regression 
will be used to explore the difference between arms for disease control rate. The stratification 
factor will be included as a covariate in the logistic regression model (locally advanced vs. 
metastatic).
Health-Related Quality of Life
Health-Related Quality of Life (HRQoL), based on data collected through specific 
questionnaires (Patient Reported Outcome Measures, PROMs). Scores will be calculated 
from data collected through the QLQ-C30, EQ-5D5L, fatigue, pain, Patient Global 
Impression questionnaires, PRO-CTCAE, and FACT-GP5 as described in Section 5.6.1 at the 
time points specified in the flowchart. 

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Secondary HRQoL endpoints analyzed will be:

Mean change from baseline to Week 18 in the following QLQ-C30 scores:
o Physical functioning
o Pain
o Fatigue
o Global health status / quality of life

Mean change from baseline to Week 18 in the following scores obtained using items from 
the EORTC QLQ-C30 and Item Library 
o Fatigue
o Fatigability
o Pain
o Fatigue impact
o Pain impact

Mean change from baseline to Week 6 of all the EORTC QLQ-C30 scores listed above

Mean change from baseline to Week 6 of all the scores obtained using items from the 
EORTC QLQ-C30 and Item Library listed above
Piecewise linear mixed models will be used for the main analysis of secondary HRQoL 
endpoints. Responder analyses will complement the main analysis of HRQoL. In addition, 
PROMs will be analysed descriptively. Further details on the analyses of PROMs will be 
provided in the TSAP.
Analyses for the secondary safety endpoints
Please refer to Section 7.2.6 where the safety analyses are described.

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7.2.6
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 treatment start and end of the REP will be assigned to the on-treatment 
period for evaluation. The REP is the period after the last administration of trial medication
with measurable drug levels and/or pharmacodynamics effects still likely to be present. For 
more details about the REP, please refer to Section 1.2.
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 for safety 
analyses is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between treatment start and end of the REP.
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) at database lock.
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 summarized. 
Treatment groups will be compared descriptively regarding distribution parameters as well as 
regarding frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the trial, and at the end-of-trial evaluation will be assessed regarding possible 
changes compared to findings before treatment start.

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7.2.8
Interim analyses
Interim analysis for dose selection
The interim analysis for dose selection will be conducted during Phase II based on the totality 
of safety data and PK/PD parameters as surrogates of clinical efficacy. This interim analysis 
is estimated to take place approximately 8 months after the start of enrollment when PK/PD 
and safety data from at least 20 evaluable patients treated with 30 mg of brigimadlin and 
20 evaluable patients treated with 45 mg of brigimadlin become available. Patients must have 
received at least 1 dose of brigimadlin and have evaluable PK/PD data in Cycle 1 to be 
considered evaluable. If the overall safety profile is assessed to be tolerable and manageable 
(i.e. manageable gastrointestinal AEs and acceptable risk of hematological side effects) and at 
least
increase of PK/PD parameters are observed at the 45 mg dose as compared to the 
30 mg dose, then the brigimadlin 45 mg dose will be selected. Otherwise, the brigimadlin
30 mg dose will be selected. All available data (i.e safety, dose modification rates, PK/PD 
parameters, and preliminary anti-tumor activity) from all patients enrolled until the data lock 
point for this interim analysis will be used to support the final dose selection. Enrollment of 
both investigational arms will continue until the dose selection decision is made, which may 
be before or at the end of Phase II. Additional details will be provided in the TSAP.
Interim futility analysis
An interim futility analysis of the primary endpoint of PFS will take place when there are 
approximately 56 PFS events from the selected investigational arm and the control arm,
which is expected to occur at approximately the same time as the end of Phase II. Enrollment 
of patients will continue whilst this analysis is performed. Only PFS will be analyzed at the 
interim futility analysis; no other endpoints are planned to be tested at this timepoint. If the 
selected investigational arm passes the non-binding futility boundary of HR = 0.80 for PFS 
(based on blinded central independent review), then the study will continue to full 
enrollment. If enrollment is close to completion when the required number of 56 PFS events 
is reached, then the interim futility analysis of PFS may not be performed.
Primary PFS analysis
The primary PFS analysis will take place during Phase III at the time point when 
approximately 120 PFS events from the selected investigational arm and the control arm have 
occurred in patients enrolled in Phase II and approximately 65 PFS events from the selected 
investigational arm and the control arm have occurred in patients enrolled in Phase III. The 
primary PFS analysis is expected to take place around 
 after the trial starts. If 
statistical significance is obtained for PFS at this analysis, then the secondary endpoints will 
be tested following a hierarchical testing framework.

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DMC analyses
During this open-label trial, an independent DMC will review unblinded interim efficacy and 
safety analyses prepared by the sponsor.
Though the trial is open-label, a minimum number of sponsor internal team members will 
view unblinded data aggregated by treatment arm before the end of the trial as defined in 
Section 8.6. These precautions will be taken to reduce potential bias during trial conduct.
The independent DMC will review the unblinded analyses at the interim analysis for dose 
selection, at the interim futility analysis (which is expected to occur at approximately the 
same time as the end of Phase II), and as needed during the conduct of the trial.
For more details about the DMC, please see Section 8.7.

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7.4
RANDOMIZATION
The trial will use randomization for assignment of patients to the different trial arms. This is 
an open-label trial, and during trial conduct, treatment assignments will be available to all 
personnel in the trial.
As mentioned in Section 7.2.8 above, though the trial is open-label, a minimum number of 
sponsor internal team members will view unblinded data aggregated by treatment arm before 
the end of the trial as defined in Section 8.6. These precautions will be taken to reduce 
potential bias during trial conduct.
First, in the Phase II part, up to 270 patients will be randomized with a 1:1:1 ratio to 
brigimadlin at the 30 mg dose, brigimadlin at the 45 mg dose, or the doxorubicin control arm.
Patients randomized to the doxorubicin arm who receive brigimadlin as subsequent therapy 
(cross-over arm) will be randomized 1:1 to receive either 30 mg or 45 mg of brigimadlin until 
a dose for Phase III is selected, after which all crossed over patients will be offered the 
selected dose (see Section 4.1.3).
In the Phase III part, an additional 120 patients will be randomized with a 1:1 ratio to either 
the selected investigational arm or the doxorubicin control arm.
An IRT will be used to perform the randomization centrally across all study sites. The
randomization list will be generated by BI using a validated pseudo-random number 
generator, yielding reproducible and non-predictable results.

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Randomization will be stratified by ‘extent of disease’ (locally advanced vs. metastatic
disease).

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014, the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997) and other relevant regulations. Investigators and 
site staff must adhere to these principles. Deviation from the protocol, the principles of ICH 
GCP or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor or delegate 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
regarding 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 it
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 

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(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 or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial patient protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
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.

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8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. 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 the “ALCOA principles” 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 at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Copies of source documents necessary for tumor assessments will be provided to blinded 
central independent review. Before sending or uploading those copies, 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.
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 

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meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion / exclusion criteria does not make 
the patient eligible for the clinical trial.
For patient-reported outcomes that were provided via an edevice or remotely, the electronic 
record is the source document.
8.3.2
Direct access to source data and documents
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 or delegate will also monitor compliance with the protocol and GCP.
COVID-19 restrictions may limit the options for onsite source data verification and other 
onsite monitoring tasks. 
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 5.2.6.2.5.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage, and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:

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Personalized 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 at the site
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 and future use of 
biological samples and clinical data, in particular:

Sample and data usage must be in accordance with the 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 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 ICF
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 Completed”).The “Last Patient Last Treatment” (LPLT) date is defined as the 
date on which the last patient in the whole trial is administered the last dose of trial treatment
(as scheduled per protocol or prematurely). Individual investigators will be notified of 
SUSARs occurring with the trial medication until 30 days after LPLT 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 clinical trial 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.

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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). In EU/EEA countries, the trial is 
sponsored by Boehringer Ingelheim International GmbH,
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 steering committee (SC) will act as an advisory body and oversees the execution and the 
dissemination of the trial. It will consist of independent experts, sponsor representatives from 
different disciplines, and investigator representatives. The composition of the SC will be 
documented in the Trial Master File (TMF). The tasks and responsibilities will be agreed in 
contracts between the SC members and the sponsor and will also be summarized in an SC 
charter.
A DMC will be established for the trial. Voting members of the DMC are independent of BI; 
they are physicians with relevant expertise, and a statistician. The DMC will review 
unblinded efficacy and safety analyses prepared by the sponsor. The independent DMC will 
review the unblinded analyses at the interim analysis for dose selection, at the interim futility 
analysis around the end of Phase II, and as needed during the conduct of the trial. Further 
details about the planned interim analyses are given in Section 7.2.8. While DMC members 
are unblinded to treatment arm assignment, measures are in place to ensure that during trial 
conduct, a minimum number of sponsor internal team members will view unblinded data 
aggregated by treatment arm. The DMC will recommend continuation, modification, or 
termination of the trial as detailed in the DMC charter. DMC recommendations as well as the 
final BI decision will be reported to the appropriate Regulatory Authorities (RAs) / Health 
Authorities (HAs), IRBs / ECs, and to investigators as requested by local law. The tasks and 
responsibilities of the DMC are specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader responsible for coordinating all required activities,
-
to manage the trial in accordance with applicable regulations and internal SOPs,
-
to direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
to ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
In the participating countries, the trial will be performed by the respective local or regional 
BI-organization (Operating Unit, OPU) in accordance with applicable regulations and BI 

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SOPs, or by a Contract Research Organization (CRO) based on a contract. The CRO will 
perform project management, clinical field monitoring, medical monitoring, and reporting.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned to organize, 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, a central images service (responsible for the blinded central 
independent review), 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.
REFERENCES
9.1
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Konopleva M, Martinelli G, Daver N, et al. MDM2 inhibition: an important 
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patients with advanced liposarcoma in a tertiary referral center. Oncol Res 
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factors for outcome to first-line ifosfamide-containing chemotherapy for 
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(EORTC-STBSG). Eur J Cancer 2010; 46; 72-83
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9.2
UNPUBLISHED REFERENCES
c15936970
Investigator’s Brochure: BI 907828. Indication: Solid tumors 1403.P1. 
Current version.

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10.
APPENDICES

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10.2
STATISTICAL DETAILS
10.2.1
Combination test approach
This appendix provides the technical details of the methodology used for the primary analysis 
of PFS, especially to control the familywise type I error rate. Familywise type I error rate will 
be strongly controlled under level of 2.5% (one-sided) using the following technique as 
described in [R14-2334; R15-5218; R20-0234; R21-0907].
Step 1: Get the stage-wise unadjusted p-value.
For each analysis, the relevant stage-wise p-value " will be derived from the data available at 
the time of analysis. Stage 1 (Phase II) is defined as the time period until 180 patients have 
been enrolled between the selected investigational arm and the control arm, and Stage 2 
(Phase III) is defined as the time period after that (when 120 additional patients have been
enrolled between the selected investigational arm and the control arm). Here, # = 1, 2 for the 
two stages. "' and " are the stagewise one-sided p-values derived from the stratified log-
rank test statistics for PFS based on patient enrolled in each stage until the planned follow up 
time, respectively.
Step 2: Get the adjusted p-value "'
∗for Stage 1 based on the Dunnett test.
The Dunnett test is a multiple comparison procedure for the comparison of multiple 
investigational treatments with a single control. This adjustment will avoid any potential 
type I error inflation due to dose selection.
Step 3: Combine stage-wise p-values for  using inverse normal p-value combination 
function to generate the adjusted test statistics.
For the calculation of the final test statistics, an inverse-normal p-value combination 
approach will be used. The data of the two different stages will be combined to generate the 
adjusted test statistics z at the end of Stage 2:
z = *'+,'(1 −"'
∗) + *+,'(1 −")
based on patients enrolled at Stages 1 and 2
where * (i=1,2) are the predefined weights for Stages 1 and 2 with ∑
*
 = 1

0'
. 
Φ denotes the standard normal distribution function and +,' its inverse.
The weights are chosen to be proportional to the planned numbers of PFS events from
Stage 1 and Stage 2 patients. The planned number of PFS events from patients in Stage 1 is 
120 and the planned number of PFS events from patients in Stage 2 is 65. Thus, the fraction 
of PFS events for the first stage patients will be around 0.64. Therefore, the weights are 
chosen as:
*' = √0.64 and * = √0.36
To protect type I error, the weights are fixed and will not change. 

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Step 4: Hypothesis testing using a user-defined spending function.
In our two-stage setting,  will be tested at the primary PFS analysis during Phase III
(7 = 0.0245 one-sided); a technical 7' = 0.0005 one-sided will be used at the end of 
Stage 1. The data available at the time of analysis will be used to calculate the test statistic 
based on Step 1 and Step 2. There is no plan to claim superior efficacy at the interim futility 
analysis despite setting one-sided alpha spending of 0.0005. This alpha spending will only 
make the trial planning more conservative in type one error control. The trial will be claimed 
a success if the selected investigational arm has p-value that crosses the efficacy boundary at 
the primary analysis, i.e.
1 −+(z) < 7
All patients enrolled at Stage 1 and at Stage 2 will be included in the proposed combination 
test. The strong familywise type I error rate control has been established theoretically by 
[R14-1197].

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11.
DESCRIPTION OF GLOBAL AMENDMENTS
11.1
GLOBAL AMENDMENT 1
Date of amendment
17 Jan 2022
EudraCT number
EU number
2021-002392-20
BI Trial number
1403-0008
BI Investigational Medicinal 
Product(s)
BI 907828
Title of protocol
Brightline-1: A Phase II/III, randomized, open-
label, multi-center study of BI 907828 compared 
to doxorubicin as first line treatment of patients 
with advanced dedifferentiated liposarcoma
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Synopsis
Description of change
Instead of the likelihood ratio test based on 
logistic regression, the Cochran-Mantel-Haenszel 
test will be used as the primary analysis method 
for ORR.
Rationale for change
FDA request to use the Cochran-Mantel-Haenszel 
test as the primary analysis method for ORR.
Section to be changed
Flowchart
Description of change
In all flowcharts, in the footnote starting with the 
text “A serum pregnancy test is mandatory (…)” 
the sentence “Pregnancy testing after EOT can be 
performed remotely or at the clinic.” was added.
Rationale for change
More flexibility for the patient.
Section to be changed
Flowchart
Description of change
In all flowcharts, in the footnote starting with the 
text “Blood samples for biomarker analysis are 
mandatory. (…)”, “myeloid-deprived” was 
corrected to “myeloid-derived”.
Rationale for change
Typo corrected.
Section to be changed
Flowchart
Description of change
In all flowcharts, the column “FU for survival” 
had a reference to a non-existing footnote 22; this 
was corrected to refer to the footnote starting 
with the text “During FU for survival, (…)”.
Rationale for change
Reference to a non-existing footnote.

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Section to be changed
Flowchart
Description of change
Section to be changed
Flowchart
Description of change
In all flowcharts, in the line “PROMs: QLQ-C30, 
items pain & fatigue” as well as in the footnote 
starting with the text “PROM = Patient Reported 
Outcome Measures; (…)”, the frequency of the 
assessments was reduced.
Rationale for change
Less frequent assessments are sufficient.
Section to be changed
Flowchart
Description of change
In all flowcharts, in the line “PRO-CTCAE” as 
well as in the footnote starting with the text 
“Patient assessments of pre-specified AEs (…)”, 
the frequency of the assessments was reduced.
Rationale for change
Less frequent assessments are sufficient.
Section to be changed
1.4.2
Description of change
Update of numbers based on most recent data 
available with the new IB version 7.
Rationale for change
New IB version 7 is available.
Section to be changed
3.3.4.1
Description of change
Further details about the AEs that require 
treatment discontinuation is available in Section 
4.1.4.2; a cross-reference to this section was 
added.
Rationale for change
FDA request to to further specify the AEs.
Section to be changed
3.3.4.1
Description of change
Specification that ongoing patients will be 
informed about the impact of the interim analysis 
before discussing the possibility to continue their 
assigned treatment.
Rationale for change
FDA request to specify that if the trial is stopped 
for futility, patients must be informed of this 
before being offered the opportunity to continue 
treatment with their assigned drug.
Section to be changed
4.1.4.1
Description of change
Deletion of the paragraph that allowed patients at 
30 mg BI 907828 after confirmed PD to continue 
treatment at 45 mg BI 907828.

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Rationale for change
FDA request to discontinue treatment at the time 
of progressive disease, also for patients 
randomized to 30 mg BI 907828.
Section to be changed
4.1.4.2
Description of change
Further details about the AEs that require 
treatment discontinuation were added.
Rationale for change
FDA request to to further specify the AEs.
Section to be changed
4.1.4.2, Figure 4.1.4.2: 1
Description of change
Modified instruction for dose delays of 
BI 907828 due to low platelet and/or neutrophil 
count for patients who do not recover within 
14 days.
Rationale for change
FDA request to specify dose modifications for 
recurrent AEs and to shorten the maximum 
possible treatment delay.
Section to be changed
4.1.4.2
Description of change
Modified guidance for dose delays of BI 907828 
due to other AEs.
Rationale for change
FDA request to specify dose modifications for 
recurrent AEs, to shorten the maximum possible 
treatment delay, and to remove investigator’s 
considerations when re-exposure is clinically 
indicated.
Section to be changed
5.1.1
Description of change
For patients in the cross-over arm, the tumor 
assessment at EOT was removed (“At the EOT 
visit [if not performed within the previous 
4 weeks]”)
Rationale for change
The tumor assessment at EOT is not needed and 
was inconsistent with the flowchart.
Section to be changed
5.4.4
Description of change
“Myeloid-deprived” corrected to “myeloid-
derived”.
Rationale for change
Typo corrected.
Section to be changed
5.6.1
Description of change
Clarification on the information about the 
measurement of patient-reported outcomes was 
updated.
Rationale for change
Administrational change.
Section to be changed
7.1
Description of change
Instead of the likelihood ratio test based on 
logistic regression, the Cochran-Mantel-Haenszel 
test will be used as the primary analysis method 
for ORR.

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Rationale for change
FDA request to use the Cochran-Mantel-Haenszel 
test as the primary analysis method for ORR.
Section to be changed
7.2.1
Description of change
“Key secondary endpoints” corrected to “selected
secondary endpoints”.
Rationale for change
Typo corrected.
Section to be changed
7.2.4
Description of change
Instead of the likelihood ratio test based on 
logistic regression, the Cochran-Mantel-Haenszel 
test will be used as the primary analysis method 
for ORR.
Rationale for change
FDA request to use the Cochran-Mantel-Haenszel 
test as the primary analysis method for ORR.
Section to be changed
7.2.8
Description of change
Inclusion of a definition of patients considered 
“evaluable” for the interim analysis for dosage 
selection.
Rationale for change
FDA request to further specify patients
considered “evaluable” for the interim analysis 
for dosage selection.
Section to be changed
8.7
Description of change
Description of the DMC structure was modified.
Rationale for change
The details of the DMC composition will be 
described in the charter.
Section to be changed
10.1, Table 10.1: 1
Description of change
In the column “ECG”, an “X” was added for 
Cycle 2, Day 1, 4:00 h assessment.
Rationale for change
The ECG assessment at Cycle 2 Day 1 is needed 
and is now consistent with the flowchart.
Section to be changed
General
Description of change
Minor grammar, typographical errors were 
corrected throughout the document.
Rationale for change
The corrections were made throughout the 
document to ensure that grammar and spellings 
were corrected.

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11.2
GLOBAL AMENDMENT 2
Date of amendment
12 Sep 2022
EudraCT number
EU number
2021-002392-20
BI Trial number
1403-0008
BI Investigational Medicinal 
Product(s)
BI 907828
Title of protocol
Brightline-1: A Phase II/III, randomized, open-
label, multi-center study of BI 907828 compared 
to doxorubicin as first line treatment of patients 
with advanced dedifferentiated liposarcoma
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Title Page and Synopsis
Description of change
New phone number for one of the coordinating 
investigators was added.
Rationale for change
Update needed.
Section to be changed
Synopsis and 2.1.1
Description of change
Wording for HRQoL-related main objectives was 
modified to read “evaluate whether BI 907828 
(…) has a favorable impact on quality of life, 
compared to doxorubicin”.
Rationale for change
Make it clearer that the evaluation covers both 
worsening and improvement.
Section to be changed
Synopsis and 2.1.3
Description of change
Wording of a secondary endpoints was updated to 
read “Health-Related Quality of Life (HRQoL), 
based on data collected through specific 
questionnaires (Patient Reported Outcome 
Measures, PROMs), analyzed from baseline to 
Week 6 and to Week 18. The HRQoL endpoints 
are defined as the scores calculated from data 
collected through selected EORTC QLQ-C30 
domains (physical functioning, fatigue, pain, and 
global health status / quality of life), fatigue and 
pain based on items from the EORTC QLQ-C30 
and the EORTC Item Library, and the EQ-
5D5L.”
Rationale for change
Clarification of the HRQoL secondary endpoint.

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Section to be changed
Synopsis and 2.1.3
Description of change
Safety was included as a secondary endpoint by 
adding “Occurrence of treatment-emergent 
adverse events (AEs).” and “Occurrence of 
treatment-emergent AEs leading to study drug 
discontinuation.” to the secondary endpoints.
Rationale for change
Safety is a secondary objective for both parts of 
this trial, there need to be secondary safety 
endpoints.
Section to be changed
Synopsis
Description of change
Exclusion criterion was modified to read 
“Previous or concomitant malignancies other than 
DDLPS or WDLPS, treated within the previous 
5 years, except effectively treated non-melanoma 
skin cancers, carcinoma in situ of the cervix, 
ductal carcinoma in situ, or other malignancy that 
is considered cured by local treatment.”
Rationale for change
Allow for more exceptions from this exclusion 
criterion.
Section to be changed
Synopsis and 3.1
Description of change
Alignment of both sections to get a consistent
description of the trial design and the statistical 
methods.
Rationale for change
The description was slightly inconsistent.
Section to be changed
Flowchart
Description of change
In Table 1, Cycles 1 and 2, Days 8 and 15, the 
entry for “Physical examination, vital signs, 
ECOG PS” was removed.
Rationale for change
These assessments are not needed.
Section to be changed
Flowchart
Description of change
In all flowcharts, the PROM and the PRO-
CTCAE schedule was modified from “until 
EOT” to “until “PD”. The related footnote 
starting with the text “PROM = Patient Reported 
Outcome Measures; (…)” was corrected with the 
new text “Please note that the PGIC assessment is 
not required at C1D1.” and the additional 
information that “Patients without PD who start 
subsequent anti-cancer treatment prior to 
Week 48, will switch to annual PROM 
assessment.”.
The related footnote starting with the text 
“Patient assessments of pre-specified AEs” was 
corrected with the additional information that 
“Patients without PD who start subsequent anti-

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cancer treatment prior to Week 48 do not need 
any further PRO-CTCAE assessments.”.
Rationale for change
Assessments until PD are sufficient. The PGIC 
assessment is not needed at C1D1. For patients 
without PD who start subsequent anti-cancer 
treatment, annual PROM assessments are 
sufficient, and no further PRO-CTCAE 
assessments are needed.
Section to be changed
Flowchart
Description of change
In all flowcharts, in the footnote starting with the 
text “EOT = End Of Treatment.”, the following 
sentence was added: “An EOT visit beyond 
21 days is possible for patients who delayed their 
next dose due to toxicity and only then decided to 
stop treatment.”
Rationale for change
Explain a special situation where an EOT visit 
could happen more than 21 days after the last 
cycle Day 1.
Section to be changed
Flowchart
Description of change
In Table 1 and Table 2, in the footnote starting 
with the text “Tumor assessment will be 
performed according to RECIST version 1.1.”, 
brain MRI at screening was removed.
Rationale for change
Brain MRI at screening is not needed.
Section to be changed
Flowchart
Description of change
In all flowcharts, a new footnote was added: 
“Cycle 1 Day 1 assessments (physical 
examination, ECOG performance status, vital 
signs, ECG, safety laboratory blood tests, 
urinalysis, pregnancy test, weight) do not need to 
be performed if done during screening within 
72 h prior to treatment administration and in the 
opinion of the investigator a repeat is not 
required. In this case the latest value prior to start 
of treatment will be considered the baseline.
A window (+3 d) is acceptable for scheduling 
Cycle 2 Day 1.”
Rationale for change
Make logistics less complex for the clinical site.
Section to be changed
Flowchart
Description of change
In Table 2, in the footnote about “Safety 
laboratory assessments”, the text was corrected to 
now read “Hematology and serum biochemistry 
laboratory tests must be performed within 72 h 
prior to Day 1 of each cycle.”
Rationale for change
Error corrected.

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Section to be changed
Flowchart
Description of change
Rationale for change
Section to be changed
Flowchart
Description of change
In Tables 1 and 3, wording of the footnote related 
to PK sampling for BI 907828 was modified to 
read “A more detailed overview of the exact 
timing for PK sample collection can be found in 
Appendix 10.1.
Rationale for change
The old wording was difficult to understand for 
the investigators.
Section to be changed
1.2
Description of change
Rationale for change
New data in the IB available.
Section to be changed
1.4.2
Description of change
1) Myelosuppression: information about 
hematological AEs was updated; guidance text on 
treatment options was moved.
2) Gastrointestinal AEs: information about 
gastrointestinal AEs was updated; guidance text 
on treatment options was moved to Section 4.2.1.
Rationale for change
New data available. Wrong location for treatment 
options – now available in Section 4.2.1.
Section to be changed
1.4.3
Description of change
Information on COVID-19 vaccines was updated.
Rationale for change
New information available.
Section to be changed
Description of change
Rationale for change
Section to be changed
3.3.1
Description of change
Criteria to assist with the differentiation of locally 
advanced vs. metastatic DDLPS were added.
Rationale for change
Unclarity about locally advanced vs. metastatic 
DDLPS was resolved.

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Section to be changed
3.3.2
Description of change
Inclusion criterion #2 was changed to state that 
birth control needs to be applied “until 6 months 
and 12 days after last dose.”.
Rationale for change
!"#$ 
%&'(&)* 
*+ )*,*& -. /-.& 0-*1 *1& 2345
6+% 
7+8+%(9-:-. *1,* *1& 7(%,*-+. +6 :+.*%,:&;*-+. 6+% 
3,/& ;,*-&.*) 3()* 9& < 3+.*1) ,6*&% 
*1& /,)* 
7+)&= >1& -.:/()-+. :%-*&%-+. 
1,) 9&&. (;7,*&7 *+ 
)*,*& (.*-/ < 3+.*1) ,.7 ?@ 7,A) ,6*&%
/,)* 7+)& ,) 
*1-) -) *1& /+.B&)* 3,.7,*&7 :+.*%,:&;*-+. ;&%-+7 
,) 7&):%-9&7 
-. 2&:*-+.C=@=@=D=
Section to be changed
>,9/& D=D=@E 
?
Description of change
F+% *1& /,9+%,*+%A 
G,/(& HH5%&,*-.-.&IIJ *1& (.-* 
0,) :+%%&:*&7 
*+ HH3KL3-. IIM *1& 6+%3(/, 0,) 
:+%%&:*&7 
*+ 5NO PQ4R HH:%&,*-.-.& &'(,*-+. II=
Rationale for change
Q%%+%
) 0 &%&
:+%%&:*&7=
Section to be changed
D=D=D
Description of change
Q8:/()-+. :%-*&%-+. 
SC was modified: “Previous 
or concomitant malignancies other than DDLPS 
or WDLPS, treated within the previous 5 years, 
except effectively treated non-melanoma skin 
cancers, carcinoma in situ of the cervix, ductal 
carcinoma in situ, or other malignancy that is 
considered cured by local treatment.”=
Q8:/()-+. :%-*&%-+. 
S?TE : +%%&:*-+. 
*+ 
HH:+;-&)L3KII=
Q8:/()-+. :%-*&%-+. 
S??E,77-*-+. +6 HHUVW or not 
yet achieved sustained viral response (SVR)II=
Q8:/()-+. :%-*&%-+. 
S?C 0,) 3+7-6-&7EHHN.+0. 
1A;&%)&.)-*-G-*A 
+% :+.*%,-.7-:,*-+. *+ *1& *%-,/ 
7%(B) UVWII=
Q8:/()-+. :%-*&%-+. 
S?<E ;(/3+.,%A &39+/-)3 
0-*1-. < 3+.*1) ;%-+% 
*+ %,.7+3-X,*-+. 0,) 
%&3+G&7 
,) ,. &8:/()-+. :%-*&%-+.=
Y&0 &8:/()-+. :%-*&%-+. 
S?ZE HH$:*-G& 9/&&7-.BJ 
)-B.-6-:,.* %-)[ +6 1,&3+%%1,B& 
U&=B= 
;%&G-+() 
)&G&%& 
B,)*%+-.*&)*-.,/ 
9/&&7-.BJ ;%&G-+() 
1,&3+%%1,B-: )*%+[& 
,* ,.A *-3&WJ 
+% :(%%&.* 
9/&&7-.B 7-)+%7&% U&=B= 1,&3+;1-/-,J G+. 
\-//&9%,.7 7-)&,)&W=
II
Y&0 &8:/()-+. :%-*&%-+. 
S@TEHH$.A 1-)*+%A 
+6J +% 
:+.:+3-*,.* :+.7-*-+. *1,*J -. *1& +;-.-+. +6 *1& 
-.G&)*-B,*+%J 
0+(/7 :+3;%+3-)& *1& ;,*-&.*I) 
,9-/-*A *+ :+3;/A 0-*1 *1& *%-,/ +% -.*&%6&%& 
0-*1 

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*1& &G,/(,*-+. +6 *1& ),6&*A ,.7 &66-:,:A +6 *1& 
*%-,/ 7%(B=II
Rationale for change
#4: Allow for more exceptions.
S?TE Q%%+% 
0,) :+%%&:*&7=
S??E "&;,*-*-) 5 *%&,*3&.* 
-) :+.)-7&%&7 
)(::&))6(/ 9,)&7 +. 2]# M )(:1 ;,*-&.*) ,%& 
&/-B-9/&
=
S?CE >1& -.G&)*-B,*+% 
)1+(/7 ,/)+ :1&:[ 6+% 
:+.*%,-.7-:,*-+.=
S?<E 4,*-&.*) 0-*1 ;(/3+.,%A &39+/-)3 0-*1-. 
< 3+.*1) ;%-+% 
*+ %,.7+3-X,*-+. ,%& &/-B-9/&=
S?ZEMyelosuppression, particularly 
thrombocytopenia and neutropenia, is the main 
toxicity associated with BI 907828. Patients with 
bleeding events are at risk.
S@TE$//+0 *1& -.G&)*-B,*+% 
*+ &8:/(7& ;,*-&.*) 
9,)&7 +.
 +;-.-+. =
Section to be changed
D=D=C=?
Description of change
New exception was added: “An individual patient 
will discontinue trial treatment if: (…) The 
patient has radiological documentation of 
progressive disease by central independent 
review on the current treatment (see Section 5.1) 
with the exception of patients receiving 
doxorubicin, who may be offered cross-over to 
treatment with BI 907828.”
Rationale for change
>1-) &8:&;*-+. -) ,;;/-:,9/&=
Section to be changed
4.1.4.2
Description of change
In the sentence “CTCAE Grade 4 AEs with the 
exception of myelosuppressive AEs of CTCAE 
Grade 4 (…) for which targeted treatment options
(…) are available”, the word “targeted” was 
deleted.
Rationale for change
The term “targeted treatment” is misleading in 
this context.
Section to be changed
4.1.4.2 and Figure 4.1.4.2: 1
Description of change
Algorithm for treatment pauses was clarified in 
the figure and in the describing paragraph below 
the figure.
Rationale for change
The old wording was difficult to understand for 
the investigators.

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Section to be changed
4.2.1
Description of change
In the guidance text on the use of colony-
stimulating factors, the sentence “However, their 
use as primary prophylaxis during the first 
treatment cycle in the dose escalation phase is 
prohibited.” was deleted.
Recommendations for prevention and treatment 
of nausea and vomiting were modified.
Blood transfusions are allowed at any time during 
the trial when clinically indicated. Further 
limitations were removed.
Rationale for change
Trial 1403-0008 is not a dose escalation trial, the 
restriction during Cycle 1 was incorrect. Colony-
stimulating factors can be used throughout the 
trial (including Cycle 1) in accordance with the 
ASCO guidelines.
Introduction of a 2-drug treatment for nausea and 
vomiting according to ACSO / ESMO / MASCC 
NCCN.
Allow for more flexibility concerning blood 
transfusions.
Section to be changed
4.2.2.1
Description of change
A new paragraph on anti-viral treatments for 
COVID-19 infection was added.
Herbal preparations / medications and nutritional 
supplements are now allowed throughout the trial 
at the discretion of the investigator.
Rationale for change
New information on treatment of COVID-19 
infection available.
Allowing herbal preparations / medications and 
nutritional supplements follows the patient-
centric approach.
The additional table was added based on a 
request by the Swedish health authority.

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Section to be changed
Table 4.2.2.1: 1
Description of change
Concerning concomitant ritonavir treatment, a 
footnote was added that it is allowed from 
72 hours after the administration of BI 907828 
until 72 hours prior to the next administration.
Rationale for change
Section to be changed
Table 4.2.2.1: 2
Description of change
Rationale for change
Cannabidiol is no longer a restricted 
comedication during treatment with doxorubicin.
Section to be changed
4.2.2.3
Description of change
Update to contraception requirements.
Rationale for change
!"#$
%&'(&)* 
*+ ,77 , ;+*&.*-,/ %-)[ +6 %&7(:&7 
6&%*-/-*A
-. 9+*1 3,/&) ,.7 6&3,/& ;,%*-:-;,.*)J 
01-:1 :+(/7 9& ;&%3,.&.*J ,.7 *+ )*,*& -. /-.& 
0-*1 *1& 2345
6+% 7+8+%(9-:-. *1,* *1& 7(%,*-+. 
+6 :+.*%,:&;*-+. 6+% 3,/& ;,*-&.*) 3()* 9& 
< 3+.*1) ,6*&% 
*1& /,)* 7+)&=
Section to be changed
^=C
Description of change
Y&0 *&8* 0,) ,77&7E HH4/,..&7 &8;/+%,*+%A 
,.,/A)&) +6 9-+3,%[&%) 7(%-.B *1& *%-,/ 3,A 9& 
%&7(:&7+% )*+;;&7 9,)&7 +. .&0 -.6+%3,*-+. -. 
*1& /-*&%,*(%& +% &,%/A ,.,/A)&)=
II
Rationale for change
4,*-&.* :&.*%-: ,;;%+,:1 *1,* ,//+0) *+ )*+; 
6(%*1&% 
), 3;/-.B -6 )(66-:-&.* 7,*, ,%& :+//&:*&7=
Section to be changed
5.6.1
Description of change
The list of pre-defined AEs assessed by the PRO-
CTCAE Item Library was corrected.
Rationale for change
Cough and fatigue were missing as pre-defined 
AEs, constipation and hair loss had to be deleted 
as pre-defined AEs.
Section to be changed
5.6.2
Description of change
Wording was changed to “The investigator (or a 
designee) will complete the AQA (…)”.
Rationale for change
Allow for more flexibility.

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Section to be changed
6.1 and 6.2.3.1
Description of change
A new sentence was added: “An EOT visit 
beyond 21 days is possible for patients who 
delayed their next dose due to toxicity and only 
then decided to stop treatment.”.
Rationale for change
Explain a special situation where an EOT visit 
could happen more than 21 days after the last 
cycle Day 1.
Section to be changed
7.2.4
Description of change
In the description of the planned analyses for 
HRQoL secondary endpoints, more details were 
added.
A reference to Section 7.2.6 was added, where 
the analyses of secondary safety endpoints are 
described.
Rationale for change
Provide more information about the planned 
analyses.
Make it easier to find the analyses for secondary 
safety endpoints.
Section to be changed
Tables 10.1: 1 and 10.1: 2
Description of change
Pre-dose ECG consistently added for all cycles, 
just before drug administration.
Footnote was modified to make clear that pre-
dose (planned time, PTM -0:05) is within 1 hour 
before drug administration.
Rationale for change
Some pre-dose ECG entries were missing.
The old text about the timing of pre-dose was 
difficult to understand for the investigators.
Section to be changed
10.3
Description of change
Rationale for change
The additional section contains a table that was 
added based on a request by the Swedish health 
authority.
Section to be changed
General
Description of change
Wording throughout the document was 
harmonized: the interim futility analysis will 
happen around the end of Phase II; the sample 
size re-estimation will happen around the end of 
Phase II; all patients numbers in the CTP are 
estimates.
Rationale for change
The time points and numbers are approximations.

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Section to be changed
General
Description of change
List of abbreviations was updated; list of 
references was updated; typos were removed, and 
grammar was corrected.
Rationale for change
Improve the readability of the document.
11.3
GLOBAL AMENDMENT 3
Date of amendment
26 Jan 2023
EudraCT number
EU number
2021-002392-20
BI Trial number
1403-0008
BI Investigational Medicinal 
Product(s)
BI 907828
Title of protocol
Brightline-1: A Phase II/III, randomized, open-
label, multi-center study of BI 907828 compared 
to doxorubicin as first line treatment of patients 
with advanced dedifferentiated liposarcoma
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Synopsis
Description of change
Trial design, number of patients, and statistical 
methods updated to reflect a higher overall 
sample size and PFS event rate.
Rationale for change
The trial is enrolling much faster than anticipated.
Section to be changed
1.2
Description of change
Changed “2” ongoing trials to “several” ongoing 
trials.
Rationale for change
New trials have started in the meantime.
Sections to be changed
2.1.2, 3.3.4.1, 4.1.2, 7.1, 7.2.1, 7.3
Description of change
Wording about the timing of the assessment of 
PFS at the interim futility analysis was modified 
to say that it will happen at approximately the 
same time as the end of Phase II.
Rationale for change
The trial is enrolling much faster than anticipated, 
this affects the timing of the analysis.
Section to be changed
3.1, 7.1, 7.2.3, 7.2.4, 7.2.8, 7.4, 7.5, 10.2.1
Description of change
Trial design, number of patients, and statistical 
methods updated to reflect a higher overall 
sample size and PFS event rate.
Rationale for change
The trial is enrolling much faster than anticipated.

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Section to be changed
4.2.2.1
Description of change
Rationale for change
New information available.
Section to be changed
4.2.2.3
Description of change
Text modified to read: “WOCBP must use a 
highly effective method of birth control (as 
outlined in the patient information) per ICH M3 
(R2) that results in a low failure rate of less than 
1% per year when used consistently and correctly 
beginning at screening, during trial participation, 
and until 6 months and 12 days after the last dose 
of BI 907828 (calculated as the period of relevant 
systemic exposure (5 half-lives plus 6 months) or 
until 6 months after the last dose of 
doxorubicin.”
Rationale for change
Clarification.
Section to be changed
5.2.3
Description of change
New text added in Table 5.2.3: 1: “pH, glucose, 
erythrocytes (hemoglobin / blood), leukocytes, 
protein, and nitrite analyzed by dipstick (semi-
quantitative measurements)”
Rationale for change
Clarification.
Section to be changed
7.2.4
Description of change
Corrected text:  “SD lasting less than 42 days and 
without evaluable response thereafter will be 
listed as “Not evaluable”.
Rationale for change
Correction.
11.4
GLOBAL AMENDMENT 4
Date of amendment
05 Dec 2023
EudraCT number
EU number
2021-002392-20
BI Trial number
1403-0008

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BI Investigational Medicinal 
Product(s)
BI 907828 (INN: brigimadlin)
Title of protocol
Brightline-1: A Phase II/III, randomized, open-
label, multi-center study of brigimadlin (BI 
907828) compared to doxorubicin as first line 
treatment of patients with advanced 
dedifferentiated liposarcoma
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
All sections
Description of change
Change from: BI 907828
To: 
Brigimadlin
Rationale for change
Introduction of the international nonpropietary 
name (INN) for BI 907828
Section to be changed
Title page, Synopsis 
Description of change
The coordinating investigator information was 
updated
Rationale for change
The coordinating investigator changed from
Section to be changed
Flowchart (Table 1) footnote 11
Flowchart (Table 2) footnote 11
Description of change
The requirement to have an echocardiography or 
MUGA scan assessment within 7 days prior to 
treatment was removed
Rationale for change
Deleted to be consistent with Section 5.2.5.1, 
which stated that the assessment does not need to 
be repeated at the screening visit if there is a 
valid result with 28 days prior to treatment start.
Section to be changed
Flowchart (Table 2)
Description of change
Addition of ±3 d window for the EOT visit
Rationale for change
Allow flexibility
Section to be changed
Flowchart (Table 3)
Description of change
Addition of sample for “Blood GDF-15” at the 
EOT visit
Rationale for change
Added to be consistent with the assessment 
schedule in Table 10.1: 2
Section to be changed
Description of change
Rationale for change
Section to be changed

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Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
3.3.3
Description of change
Changed from: 
Any factor that increases the risk of QTc 
prolongation or risk of arrhythmic events such as 
heart failure, hypokalaemia, congenital long QT 
syndrome, family history of long QT syndrome 
or unexplained sudden death under 40 years-of-
age, or any concomitant medication known to 
prolong the QT interval (see also Section 4.2.1).
To:
Any factor that increases the risk of QTc 
prolongation or risk of arrhythmic events such as 
heart failure, hypokalaemia, congenital long QT 
syndrome, family history of long QT syndrome
or unexplained sudden death under 40 years-of-
age, or any concomitant medication known to 
prolong the QT interval.
Rationale for change
The reference to Section 4.2.1 was irrelevant 
Section to be changed
3.3.4.1
Description of change
Statement added: 
If the patient has radiological progression by 
investigator assessment while tolerating trial 
treatment, the treatment should be continued. The 
decision to withdraw treatment must be based on 
documentation of progressive disease according
to RECIST version 1.1 based on central 
independent review.
Rationale for change
Clarification 
Section to be changed
4.1.3
Description of change
Statement added:
Palliative radiotherapy is permitted; however, the 
irradiated area cannot be used for further tumor 
response assessment.
Rationale for change
Clarification
Section to be changed
4.1.4
Description of change
Deletion of “pharmacy manual”
Rationale for change
Information is provided in the ‘Medication 
Handling Instruction’, not a pharmacy manual

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Section to be changed
4.1.4.1
Description of change
Changed from:
Doxorubicin will be administered according to 
institutional guidelines and the provided 
pharmacy manual as an intrvenous injection or as 
an infusion.
To: 
Doxorubicin will be administered according to 
institutional guidelines and SmPC/US Package 
Insert as an intravenous injection or as an 
infusion.
Rationale for change
There is no pharmacy manual for this trial
Section to be changed
4.1.4.2
Description of change
Statement added:
Recovery days and treatment pause should be 
counted from the planned Day 1 of the treatment 
cycle.
Rationale for change
Clarification
Section to be changed
4.1.6
Description of change
Statement added for brigimadlin: 
Investigator information is omitted from the 
labels due to use of an IRT system.
Statement added for doxorubicin: 
Investigator information is omitted from the 
labels due to use of an IRT system. The visit 
number is not relevant for the label of 
doxorubicin as the product will remain at the 
clinical site.
Rationale for change
Added to fulfill the requirements of Annex 6 
becoming effective with the new CTR process
Section to be changed
4.2.2.1 (Table 4.2.2.1: 1)
Description of change
Footnote added:
For fentanyl, transdermal patches are permitted
Rationale for change
Clarification
Section to be changed
4.2.2.3
Description of change
The contraception requirements for male patients 
on doxorubicin was changed from 6 months to 
3 months and 10 days. For female patients it was 
changed from 6 months to 6 months and 10 days 
Rationale for change
The change was made to reflect an update in the 
SmPC
Section to be changed
5.3.1
Description of change
Statement added: 
Plasma samples from the trial may be used for the 
measurement of unbound brigimadlin

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concentrations. For this purpose, pooled plasma 
samples may be used. Results may be included in 
a separate report.
Rationale for change
Clarification 
Section to be changed
6.2.3.2
Description of change
Statement added: 
In cases where the EOT may be after the EOR 
period, the EOT and EOR can be done as a single 
visit.
Rationale for change
Clarification 
Section to be changed
6.2.3.3 
Description of change
Changed from: 
Data will be collected every 12 weeks (±7 days) 
and may also be collected at additional timepoints 
when a snapshot of data is required (e.g. at the 
time of analysis).
To: 
Survival data will be collected every 12 weeks 
(±7 days) starting from last contact (EOT and/or 
EOR) and may also be collected at additional 
timepoints when a snapshot of data is required 
(e.g. at the time of analysis).
Rationale for change
Clarification
Section to be changed
Synopsis, 7.1
Description of change
Statement added:
If statistical significance is obtained for PFS but 
not for ORR, then OS will continue to be 
followed up until the pre-specified numbers of 
OS events are met at the end of Phase III and then 
analyzed without being formally tested.
Rationale for change
Clarification 
Section to be changed
Synopsis, 7.2.3, 7.2.8, 7.5 
Description of change
Rationale for change
The primary analysis of PFS will only be 
analyzed when the number of events has been 
reached.
Section to be changed
7.2.4
Description of change
Statement added:
Any assessments done in compliance with the 
pre-specified (-)7-day assessment window will 
also be accounted for as within the 42-day 
duration.
Rationale for change
Clarification 
Section to be changed
7.3 (Table 7.3: 1)
Description of change
Changed from:

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Patient without death or patient with death after 
second performed radiological assessment
To:
Patient without death or patient with death after 
second planned radiological assessment
Rationale for change
Correction
Section to be changed
7.3 (Table 7.3: 1)
Description of change
Changed from:
Date of last radiological assessment prior to 
missed assessments
To:
Date of last radiological assessment prior to 
missed radiological assessments 
Rationale for change
Correction
Section to be changed
8.7
Description of change
Statement added: 
In EU/EEA countries, the trial is sponsored by 
Boehringer Ingelheim International GmbH, 
Rationale for change
The clinical trial regulation requires trial protocol 
to state trial sponsor name and address, but the 
current protocol template does not include the 
information.
Section to be changed
General
Description of change
List of abbreviations was updated; typos were 
removed, and grammar was corrected.
Rationale for change
Improve the readability of the document.

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11.5
GLOBAL AMENDMENT 5
Date of amendment
02 May 2024
EudraCT number
EU number
2021-002392-20
BI Trial number
1403-0008
BI Investigational Medicinal 
Product(s)
BI 907828 (INN: brigimadlin)
Title of protocol
Brightline-1: A Phase II/III, randomized, open-
label, multi-center study of brigimadlin (BI 
907828) compared to doxorubicin as first line 
treatment of patients with advanced 
dedifferentiated liposarcoma
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Flowcharts (Tables 1, 2, and 3)
Description of change
Addition of (± 7 d) window for FU for PD
Rationale for change
Allow flexibility
Section to be changed
Flowcharts (Tables 1, 2, and 3)
Description of change
Addition of (± 7 d) window for FU for survival
Rationale for change
Visibility and consistency; the window was in 
place, but it was not in the column header of 
flowcharts. 
Section to be changed
1.4.2
Description of change
Rationale for change
Section to be changed
4.1.4.1
Description of change
Addition of: 
(in case of platelet transfusion after the last drug 
administration, this criterion must be met in a 
measurement taken at least 72 hours after the last 
platelet transfusion)
Rationale for change
Update of guidance
Section to be changed
4.2.1
Description of change
Removed:
In case of long-lasting thrombocytopenia (i.e. no 
recovery to ≥75.0×109/L after at least 4 weeks 
from the nadir), a hematology workup should be 
considered at the investigator’s discretion 
including bone marrow cytology, platelet volume, 
and hematologist advice for appropriate therapy 
and follow-up.

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Rationale for change
Update of guidance
Section to be changed
4.2.1
Description of change
Rationale for change
Update of guidance
Section to be changed
4.2.1
Description of change
Rationale for change
Update of guidance
Section to be changed
4.2.2.1
Description of change

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Rationale for change
Update of guidance
Section to be changed
4.2.2.1
Description of change
Rationale for change
Update of guidance
Section to be changed
4.2.2.3
Description of change
Addition of: 
The efficacy of oral hormonal contraceptives may 
be compromised by vomiting and/or diarrhoea or 
other conditions where the absorption may be 
affected. Women taking oral hormonal 
contraceptives and experiencing these conditions 
should be advised to use an alternative highly 
effective contraceptive measure.
Rationale for change
Update of guidance
Section to be changed
Table 5.2.3: 1 
Description of change
Change from: 
(if CK is elevated, then CK-MB [cardiac], 
Troponin I or T, and myoglobin should be 
reactively tested).
To: 
CK (if CK is elevated, then patient should be 
further evaluated according to local standard of 
care).
Rationale for change
Update of guidance 
Section to be changed
General
Description of change
List of abbreviations and references was updated; 
typos were removed, and grammar was corrected.
Rationale for change
Improve the readability of the document.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c35654143
6.0
clinical-trial-protocol-version-06
Brightline-1: A Phase II/III, randomized, open-label, multi-center study of
brigimadlin (BI 907828) compared to doxorubicin as first line treatment of patients
with advanced dedifferentiated liposarcoma
Approval-Clinical Trial 
03 May 2024 17:25 CEST
Approval-Clinical Program
03 May 2024 17:47 CEST
Author-Trial Statistician
06 May 2024 15:02 CEST
Verification-Paper Signature
Completion
06 May 2024 15:57 CEST

Boehringer Ingelheim 
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 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c35654143
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