Conditions: Breast Neoplasms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 103
Healthy volunteers: no

Brief summary:
The main objective of the trial is to assess the efficacy of xentuzumab in combination with everolimus and exemestane over everolimus and exemestane in patients with HR+/ HER2- advanced or metastatic breast cancer and non-visceral disease.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Xentuzumab intervention 2: Placebo intervention 3: Everolimus intervention 4: Exemestane
Intervention descriptions: intervention 1: Intravenous infusion intervention 2: Intravenous infusion intervention 3: Tablet intervention 4: Tablet

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c18323506-09
EudraCT No.: 
EU Trial No:
2017-003131-11
BI Trial No.:
1280-0022
BI Investigational 
Product:
Xentuzumab (BI 836845)
Title:
XeneraTM 1: A multi-centre, double-blind, placebo-controlled, 
randomised phase II trial to compare efficacy of xentuzumab in 
combination with everolimus and exemestane versus everolimus and 
exemestane in women with HR+ / HER2- metastatic breast cancer 
and non-visceral disease
Lay Title:
The XeneraTM 1 study tests xentuzumab in combination with 
everolimus and exemestane in women with hormone receptor 
positive and HER2-negative breast cancer that has spread
Clinical Phase:
II
Clinical Trial Leader:
Phone: 
, Fax:
Coordinating 
Investigators:
Phone: 
, Fax: 
Phone:
, Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 5))
Version and Date:
Version: 6.0
Date: 25 Nov 2021
Page 1 of 156
Proprietary confidential information.
2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Finished product name
N/A
Active ingredient name:
Xentuzumab (BI 836845)
Protocol date
03 Jan 2018
Revision date
25 Nov 2021
Trial number
1280-0022
Title of trial:
XeneraTM 1: A multi-centre, double-blind, placebo-controlled, 
randomised phase II trial to compare efficacy of xentuzumab in 
combination with everolimus and exemestane versus everolimus and 
exemestane in women with HR+ / HER2- metastatic breast cancer 
and non-visceral disease
Coordinating 
Investigator:
Phone: 
, Fax: 
Phone: 
, Fax: 
Trial site(s):
Multi-centre trial conducted in approximately 80 centres in 
approximately 15 countries
Clinical phase:
II
Objective(s):
The main objective of the trial is to assess the efficacy of xentuzumab 
in combination with everolimus and exemestane over everolimus and 
exemestane in patients with HR+/ HER2- advanced or metastatic 
breast cancer and non-visceral disease.
Methodology:
Double-blind, randomised, placebo-controlled phase II study with 
two parallel arms. Eligible patients will be randomised to receive 
therapy with either xentuzumab/everolimus/exemestane or 
placebo/everolimus/exemestane at a 1:1 ratio. Randomisation will 
be stratified by evidence of presence of baseline bone-only 
metastasis (Yes/No), and prior CDK4/6 inhibitor treatment 
(Yes/No).
Independent assessment of the primary endpoint progression free 
survival (PFS) according to RECIST 1.1 will be completed in a 
treatment-blinded manner.


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Number of patients 
entered:
Approximately 80 eligible patients
Number of patients on 
each treatment:
Xentuzumab in combination with everolimus and exemestane: 
Approximately 40 eligible patients
Placebo in combination with everolimus and exemestane: 
Approximately 40 eligible patients
Diagnosis:
Female patients with HR+ / HER2- advanced or metastatic breast 
cancer and non-visceral disease
Main in- and exclusion 
criteria
Main inclusion criteria
1. Documented histologically confirmed breast cancer with ER-
and/or PgR-positive and HER2-negative status
2. Locally advanced or metastatic breast cancer not deemed 
amenable to curative surgery or curative radiation therapy
3. Archival tumour sample available prior to recruitment. 
Patients must provide a formalin-fixed paraffin embedded 
tissue biopsy sample preferably taken at the time of 
presentation with recurrent or metastatic disease (provision of 
a biopsy sample taken from the bone is not acceptable). If 
archival tissue is not available, provision of detailed 
information from the original histology report may be agreed 
with the sponsor on a case by case basis.
4. Patients must satisfy the following criteria for prior therapy:
•
Disease progression during treatment or within 12 
months of completion of endocrine adjuvant therapy 
OR
•
Disease progression while on or within 1 month after 
the end of endocrine therapy for advanced/metastatic 
breast cancer (Note: the endocrine therapy does not 
have to be the treatment immediately prior to trial 
entry)
5. Patients must be either:

Premenopausal on ovarian suppression with a 
gonadotropin-releasing hormone (GnRH) agonist 
with FSH and estradiol in postmenopausal range
(initiated at least 28 days prior to screening) OR 

Post-menopausal, defined as one of the following:
•
Age ≥ 60 years
•
Age < 60 years and amenorrheic for 12 or more 
months in the absence of chemotherapy, tamoxifen, 
toremifene, or ovarian suppression, and FSH and 
estradiol in the postmenopausal range.
•
If taking tamoxifen or toremifene, and age < 60 
years, then FSH and estradiol level in post-
menopausal range.
•
Surgical menopause with bilateral oophorectomy
6. Patients must have:

At least one measurable non-visceral lesion according to 


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RECIST version 1.1 in either lymph nodes, soft tissue, skin 
AND/OR

At least one measurable non-visceral lesion according to 
RECIST version 1.1 as lytic or mixed (lytic + blastic) in 
bone

AND/OR

At least one non-measurable (lytic, mixed lytic +blastic, or 
blastic) bone lesion according to RECIST version 1.1
7. Eastern Cooperative Oncology Group (ECOG) performance
score 0 or 1.
8. Adequate organ function
Main exclusion criteria
1. Previous treatment with agents targeting the IGF pathway, 
AKT, or mTOR pathways
2. Prior treatment with exemestane (except adjuvant exemestane 
stopped >12 months prior to start of study treatment as long as 
the patient did not recur during or within 12 months after the
end of adjuvant exemestane)
3. Evidence of visceral metastasis/es (i.e. liver, lung, peritoneal, 
pleural metastases, malignant pleural effusions, malignant 
peritoneal effusions) at screening. NOTE: Patients with a past 
history of visceral metastases are eligible if visceral 
metastases have completely resolved at least 3 months prior to 
screening.
4. History or evidence of metastatic disease to the brain
5. Leptomeningeal carcinomatosis
6. More than 1 prior line of chemotherapy for metastatic breast
cancer
7. Radiotherapy within 4 weeks prior to the start of study 
treatment
8. Use of concomitant systemic sex hormone therapy (e.g. 
Megace) within 2 weeks prior to start of trial treatment. 
NOTE: Ovarian suppression with GnRH agonists is permitted 
in premenopausal patients.
9. History or presence of cardiovascular abnormalities
10. Known pre-existing interstitial lung disease
11. More than 1 prior treatment line with a CDK4/6 inhibitor
12. Pregnant or nursing (lactating) women
13. Women of child-bearing potential unless they are using 
highly effective non-hormonal methods of contraception 
that achieve a failure rate of less than 1% per year when 
used consistently and correctly during dosing of study 
treatment and for at least 1 month after the last dose of 
exemestane, 8 weeks after the last dose of everolimus and 6 
months after the last dose of xentuzumab/placebo
(whichever is the longest).


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Test product(s):
Xentuzumab (BI 836845)
dose:
1000 mg weekly
mode of 
administration:
i.v.
Combination product 1:
Everolimus in accordance with the SmPC/PI
dose:
10 mg per day
mode of 
administration:
p.o.
Combination product 2:
Exemestane in accordance with the SmPC/PI
dose:
25 mg per day
mode of 
administration:
p.o.
Comparator product:
Placebo
dose:
Not applicable
mode of 
administration:
i.v.
Duration of treatment:
Treatments will be given continuously in both treatment arms until 
progression of disease, unacceptable adverse events or other reasons 
requiring treatment discontinuation. Treatment may continue 
beyond progression in case of clinical benefit.
Endpoints
Primary endpoint:

PFS* 
Secondary endpoints:

Overall survival (OS)

Disease control (DC)*

Duration of DC*

Objective response (OR)*

Time to pain progression or intensification of pain 
palliation
*Tumour response will be assessed according to RECIST 1.1, 
independent assessments will be considered primary with the 
investigator assessment as supportive.
Safety criteria:
Incidence and severity of adverse events according to Common 
Terminology Criteria for Adverse Events (CTCAE) (Version 5.0)


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Statistical methods:
A comparison between the treatment groups with respect to the 
primary endpoint of PFS (independent assessment) will be madevia 
a log-rank test, stratified by baseline bone-only metastases, prior 
CDK4/6 inhibitor treatment and menopause status. In addition a 
stratified Cox proportional hazards model will be used to estimate 
the hazard ratio and corresponding 95% confidence interval (CI). 
OS and time to pain progression or intensification of pain palliation 
will be analysed using a similar methodology. Logistic regression 
models, adjusted for the presence of baseline bone-only metastases,
prior CDK4/6 inhibitor treatment and menopause status will be 
used to compare the treatment groups with respect to DC and OR. 
Kaplan-Meier estimates will be used to calculate median duration 
of DC for each treatment group.
If at the time-point of the primary PFS analysis for this Phase II trial 
the hazard ratio is below a pre-defined criterion (to be defined in the 
DMC charter, prior to study initiation), in favour of the xentuzumab 
arm, then the trial will be expanded into a confirmatory Phase III trial. 
No formal hypothesis testing will be performed if the trial is not 
expanded. However, if the trial is expanded PFS and OS will be 
formally tested in a hierarchical manner controlling for the overall 
alpha-error of 2.5% (one-sided).


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FLOW CHART -No longer applicable per CTPv6.0
Screening
Treatment Cycle 1**
Treatment 
Cycle 2-20
**
Treatment 
Cycle 2
Treatment 
Cycle 21 and 
subsequent 
cycles**
End of 
Treatment
***
End of residual 
effect period 
and
follow-up 1****
Further 
Follow-up for 
progression 
(FU-PD)****
Follow-up 
for survival 
(FU-OS)
*****
Visit abbreviation
SV*
C1V1
C1V2 C1V3
C1V4
Cx(2-20)V1a
C2V3
Cx(21+)V1a
     EOT
EOR/ FU1
FUx-PDb
FUx-OSc
Days
≤ 28 
days
≤ 14 
days
Day 1
Day 8
(± 2
days)
Day 
15
(± 2
days)
Day 
22
(± 2
days)
Day 1
every 28 
days
(± 2 days)
Day 15 (± 
2
days)
Day 1
every 56 days
(± 2 days)
0-14 days after 
permanent trial 
medication
discontinuation
42 days after 
permanent trial   
medication 
discontinuation 
(+ 7 days)
FU2-PD 56 or 
112 days****
after EOT and 
then every 56 
days (± 7 days)
Every 84 
days after 
last follow-
up visit
(± 15 days)
Informed Consent (1)
X
Demographics
X
Medical History
X
Provision of archival 
tumour tissue  for 
HR/HER2 analysis and
biomarker analysis (2)
X
Collection of information 
on available molecular 
breast cancer signatures 
(22)
X
Full physical exam (3)
X
X
Limited physical
exam (4)
X
X
X
X
X
Vital Signs (5)
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
X
X
Questionnaires (6)
X
X
X
X
X
X
Health care resource use (23)
X
X
X
X
X
X
ECG (7)
X
X
Echocardiography or MUGA 
(8)
X
X


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Screening
Treatment Cycle 1**
Treatment 
Cycle 2-
20**
Treatment 
Cycle 2
Treatment 
Cycle 21 and 
subsequent
cycles**
End of 
Treatment
***
End of 
residual effect 
period and
follow-up 1****
Further 
Follow-up for 
progression
(FU-PD)****
Follow-up 
for survival 
(FU-OS
*****
Visit abbreviation
SV*
C1V1
C1V2
C1V3
C1V4
Cx(2-20)V1a
C2V3
Cx(21+)V1a
    EOT
EOR/ FU1
FUx-PDb
FUx-OSc
Days
≤ 28 
days
≤ 14 
days
Day 1
Day 8
(± 2
days)
Day 15
(± 2
days)
Day 
22
(± 2
days)
Day 1
every 28 
days
(± 2 days)
Day 15 (± 2
days)
Day 1
every 56 days
(± 2 days)
0-14
days after 
permanent trial 
medication 
discontinuation
42 days after 
permanent trial   
medication 
discontinuation 
(+ 7 days)
FU2-PD 56 or 
112 days****
after EOT and 
then every 56 
days (± 7 days)
Every 84 
days after 
last follow-
up visit
(± 15 days)
Safety lab (9)
X
X
X (9)
X (9)
X
X
Hormone levels, pregnancy 
test  (if applicable) (25)
X(25)
X(25)
X(25)
X(25)
X(25)
X(25)
X(25)
X(25)
Tumour assessment (10)
X
See schedule below (10)
Review of In-/Exclusion
X
X
Randomisation (11)
X
Dispense
xentuzumab/placebo (12)
X
X
X
X
X
X
X
Dispense everolimus and 
exemestane (13)
X
X (13)
X (13)
Issue patient diary (14)
Continuous
Study treatment (24)
Continuous
Review study medication 
compliance (14)
X (14)
X
X
X
Blood sample for PK
analysis (15)
X
X
X (15)
X
X
X
Blood samples for ADAs and 
nAbs (15)
X
X
X (15)
X
X
X
Blood samples for 
cytokines (15)
X
X (15)
Blood samples for free and 
total IGF-1, total IGF-2 (16)
X
X (16)
Blood samples for cfDNA 
(17)
X
X (17)
X
X (17)
Blood and Urine samples for 
Bone remodelling markers 
(18)
X
X (18)
X
X


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Screening
Treatment Cycle 1**
Treatment 
Cycle 2-20
**
Treatment 
Cycle 2
Treatment 
Cycle 21 
and 
subsequent
cycles**
End of 
Treatment
***
End of 
residual effect 
period and
follow-up 1****
Further 
Follow-up 
for 
progression
(FU-PD)****
Follow-up 
for 
survival 
(FU-
OS)*****
Visit abbreviation
SV*
C1V1
C1V2
C1V3
C1V4
Cx(2-20)V1a
C2V3
Cx(21+)V1a
    EOT
EOR/ FU1
FUx-PDb
FUx-OSc
Days
≤ 28 
days
≤ 14 
days
Day 1
Day 8
(± 2
days)
Day 15
(± 2
days)
Day 22
(± 2
days)
Day 1
every 28 
days
(± 2 days)
Day 15 (± 2
days)
Day 1
every 56 days
(± 2 days)
0-14
days after 
permanent trial 
medication 
discontinuation
42 days after 
permanent trial   
medication 
discontinuation 
(+ 7 days)
FU2-PD 56 or 
112 days ****
after EOT and 
then every 56 
days (± 7 
days)
Every 84 
days after 
last follow-
up visit
(± 15 days)
Blood sample for genomic 
DNA 
X
Adverse events (19)
X
X
X
X
X
X
X
X
X
X
X (19)
X (19)
Concomitant medications 
(20)
X
X
X
X
X
X
X
X
X
X
X (20)
Termination of study
medication
X
Collection of vital status 
information (21)
X
X
X
X (21)
*
Screening: Documented HR/HER2 analyses results are required for the analysis of HR+ and HER2- status. If HR and HER2 status are unknown the patient is not eligible for 
screening.
  **
Treatment: From Cycle 1 to the end of Cycle 20 treatment cycles are 4 weeks in duration (28 days) with weekly visits for infusions and AE/concomitant medication 
documentation in addition to the CxV1 visits. From cycle 21 until the end of treatment cycles are 8 weeks in duration (56 days) with weekly visits for infusions and
AE/concomitant medication documentation in addition to the CxV1 visits. Everolimus and exemestane should be dispensed every 4 weeks. Pregnancy testing (where applicable) 
to continue to be performed every 4 weeks (see footnote 25 below). Patients may continue on treatment for an unlimited number of cycles, until the criteria for stopping medication are 
met (see Section 3.3.4). Note: from cycle 3 onwards those patients that have discontinued xentuzumab/placebo, but remain on everolimus/exemestane will only be required to attend visits 
on day 1 (V1) of each cycle until the end of cycle 20 and on day 1 (V1) and day 29 (V5) of each cycle from the start of cycle 21.
***
End of Treatment: If the decision to permanently discontinue all study medication is taken during a scheduled visit, the EOT visit should be performed instead of the scheduledvisit.
****
End of Residual Effect Period/Follow up: An EOR/FU1 visit must be conducted 42 days (+7 days) after the permanent discontinuation of treatment. 
If a patient has not progressed nor started further anti-cancer treatment prior to EOR/ FU1, the patient will continue to have regular follow-up visits for PD. FUx-PD visits will take 
place (i) every 8 weeks (56 days) after EOT for patients who did not yet reach the end of cycle 20 and (ii) every 16 weeks (112 days) for patients who received treatment past cycle 20. 
These visits should be aligned with the imaging schedule. The FU-PD period will end at the time point of disease progression or start of further anti-cancer treatment. 
***** Follow-up for Survival: When a patient has either progressed or started a new anti-cancer treatment, the follow period up for overall survival (FU-OS) starts. FU-OS ends when the 
patient dies, is lost to follow up or withdraws consent for collection of overall survival data (see Section 6.2.3.3). These visits can be conducted as phone calls.
a
x is the number of the treatment cycle
b
x is the number of the follow-up visit starting with FU2-PD
c
x is the number of the follow-up survival assessment


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1
Written informed consent must be obtained before any protocol-specific screening assessments are performed. Informed Consent must include consent to collection of demographic 
data. Re-consenting may become necessary when new relevant information becomes available and should be conducted according to the Sponsor’s instructions.
2
Archival tumour tissue (either tissue block or 20 slides) to be provided (preferably from the time point closest to trial entry) at SV for retrospective analysis of HR/HER2 at the central 
laboratory. Results from central laboratory are not required prior to randomisation. Bone biopsy samples are not acceptable (see Section 5.4.1).
3
Full physical examination (Section 5.2.1): Cardiopulmonary examination, clinical tumour assessment, examination of regional lymph nodes and the abdomen, assessment of mental and 
neurological status. Post baseline: Additional symptoms which were not previously reported should be clarified. Includes height (only at SV) and weight.
4
Limited physical examination (Section 5.2.1): Cardiopulmonary examination, clinical tumour assessment, examination of regional lymph nodes and the abdomen. Includesweight.
5
Vital signs include respiratory rate, pulse, temperature and blood pressure
6
PRO questionnaires will be completed by the patient as their first activity when attending a study visit at the visits indicated in the flow chart.
7
12-lead resting electrocardiograms (ECG) are recorded locally. ECG will be performed at SV and EOT, and if clinicallyindicated.
8
Echocardiography or MUGA will be performed at SV and EOT, and if clinically indicated. LVEF assessment does not need to be repeated during screening if there is valid result available 
from an assessment which was performed as part of routine clinical practice within 28 days prior to start of trial treatment.
9
Includes haematology, biochemistry, and urinalysis (Section 5.2.3). To be performed every 4 weeks for cycles 1-5 (C1V1, C2V1, C3V1, C4V1 and C5V1), and then every 8 weeks
from cycle 5 (C7V1, C9V1, C11V1 etc.). Reminder: when cycle duration is extended to 8 weeks, i.e. after completion of cycle 20 (week 80), safety lab will be done at Day 1 of each 
cycle (every 8 weeks). Patients must be in a fasted state for safety bloods. See Section 5.2.3 for details.
10
Tumour assessments will include CT scans of the chest, abdomen, pelvis and a brain CT/MRI as well as a bone scan at screening. If clinically indicated, imaging of any other known or 
suspected site of disease (e.g. breast) using an appropriate method (CT scan, MRI etc.) will be performed. Imaging assessments do not need to be repeated during screening if there is 
valid result available from an assessment which was performed as part of routine clinical practice within 28 days prior to start of trial treatment.
The same radiographic procedure must be used throughout the study. If bone lesions are already known or confirmed at screening, bone scans must be performed together with every 
other CT scan but with an additional bone scan at week 8 (49-56 days after randomisation). If mammography is additionally conducted during clinical routine, it should also be sent to 
the central imaging assessment together with any correlative images. Breast- ultrasound and biopsy data, if available, will be provided to the central imaging CRO for independent 
review (see Appendix 10.4 for more detail). Skin lesions will be documented as photographs as described in Appendix 10.4. All images and photos will be sent to a central imaging 
CRO.
Assessments will be performed every 8 weeks at following time points until week 80, irrespective of scheduled visits, until progression or start of further treatment for mBC;
SV, images taken within 28 days prior to start of trial treatment (C1V1) and compliant with central imaging 
requirements 
During week 8 (49-56 days after randomisation) (including bone scan if applicable)
During week 16 (105-112 days after randomisation) (including bone scan if applicable)
During week 24 (161-168 days after randomisation)
During week 32 (217-224 days after randomisation) (including bone scan if applicable)
During week 40 (273-280 days after randomisation)
For patients continuing beyond week 80 the imaging schedule will change to q12 weeks (bone scans q24 weeks).
For patients in FU-PD (i) (who came off trial treatment before the end of Cycle 20) imaging every 8 weeks (56 days) and (ii) (who received treatment beyond cycle 20) every 12 
weeks (84 days). Imaging procedures will be performed until progression or start of further anti-cancer therapy. For patients starting further anti-cancer therapy without objective 
progression, imaging should be performed prior to starting the new therapy if no image has been performed within the last 4 weeks. If patients continue treatment beyond 
progression, imaging must also be continued and sent to a central imaging CRO.
In the event of early discontinuation or an interruption/delay to treatment the tumour assessment schedule should not be changed.


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11
Patients will be randomised after all SV procedures have been completed and eligibility is confirmed. Treatment must commence as soon as possible after randomisation, but within 
7 days at the latest.
12
Xentuzumab/placebo will be dispensed weekly. Drug holidays of up to 14 calendar days will be allowed for xentuzumab/placebo as described in Section 4.3.1. In case of drug holidays 
please also refer to footnote 14.
13
From Cycles 1 to 20 everolimus and exemestane will be dispensed at V1 of each cycle. After cycle 20 (week 80), dispensation will take place at V1 and V5 of eachcycle.
14
A patient diary will be given to the patient for continuous use through the trial. It should be given to the patient at the start of each cycle. The diary collects information about 
medication taken at home and provides reminders about fasting bloods and urine samples. After one week on study medication, treatment compliance should be discussed with the 
patient, to ensure that the medication is being taken correctly (no compliance calculation has to be performed). Then at Visit 1 of each cycle and at EOT treatment compliance needs 
to be checked including compliance calculations.
15
Pharmacokinetic, ADA/nAb and cytokine sampling will take place as described in Appendix 10.1. If a patient misses xentuzumab/placebo infusions due to drug holidays 
replacement samples for PK, ADAs, nAbs should be drawn at -0:05 timepoint, before the next infusion.
16
Biomarker blood sampling will take place at pre-dose at C1V1, C2V1. At C2V1 an additional sample will be taken 15 min. (±5 min.) after end of xentuzumab/placeboinfusion as described 
in Appendix 10.1.
17
A blood sample from which the plasma needs to be separated and isolated within approx. 4 hours after blood collection. Plasma will be used for cfDNA isolation and further molecular 
analysis as described in Section 5.4. Sample collection has to be performed (pre-dose) at baseline on C1V1, C3V1, EoT and at time of disease progression during FU-PD if applicable 
(Appendix 10.1).
18
Samples for bone remodelling markers in blood and urine will be taken (pre-dose) at C1V1, C2V3, C4V1, and EoT as described in Appendix 10.1. Subsequent specimens for 
comparison should be collected at the same time of day as C1V1 sample. Urine samples must be provided by patient using second morning void (note: this may occur at home)
19
After the EOR/FU1 visit, only drug-related SAEs and AESIs need to be reported. For details refer to Section 5.2.6.2.
20
Analgesic intake will be assessed and completed using Analgesic Quantification Algorithm (AQA) as part of concomitant medications assessment. During FU-PD only concomitant 
medications for treatment of a drug-related SAE or AESI will be recorded in the CRF.
21
Collection of information on progression, further anti-cancer treatment, pregnancy (if applicable – see footnote 25) and death. Information should be collected from the patient 
notes or by telephone contact with the patient. A formal study visit is not required.
22
In the case that prior information regarding the patient’s genomic breast cancer signature is available, an anonymized copy of the report will be collected for the trial database and 
results will also be recorded in the CRF.
23
Information on caregiver support (home care), general practitioner, outpatient and hospital visits (other than scheduled visits) will be collected in the CRF and as part of AE reporting to 
inform on healthcare resource use required. For details refer to section 5.6.3.
24
Everolimus and exemestane should be taken once a day at approximately the same time of day, following a meal. The tablets may be taken at home or in the clinic. 
25
Pre-menopausal women:
Serum pregnancy testing to be performed at screening followed by serum or urine testing on Day 1 of each cycle until the end of Cycle 20. From Cycle 21 onwards, serum or urine 
pregnancy testing to be performed every 4 weeks (i.e. on Day 1 and Day 29 of 56 day cycle) until the end of treatment. Serum or urine pregnancy testing to be performed at end of treatment 
visit and then during the follow up phase every 4 weeks until either 1 month after the last dose of exemestane, 8 weeks after the last dose of everolimus, or 6 months after the last dose of 
xentuzumab/placebo, whichever is longer. During the follow up period urine pregnancy tests may be done at home, in which case multiple tests should be provided at end of treatment 
period to ensure that patient has enough to cover the follow up phase. Patient should be advised to contact the blinded team immediately on result of a positive test, otherwise results of tests
will be collected at either the EOR/FU1, FU-PD or FU-OS visits. 
Hormone testing to include Estradiol and FSH to be performed at screening followed by estradiol only on Day 1 of every odd number cycle starting at Cycle 3 and end of treatment. See 
Section 5.2.3.
Post-menopausal women: If under 60, and not had a bilateral oophorectomy, hormone testing to include Estradiol and FSH at screening. See section 5.2.3.


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FLOW CHART- Reduced schedule per CTP v6.0 – Ongoing patients
  *
Treatment cycles are 4 weeks in duration (28 days) with a clinic visit on day 1 (V1) of each cycle. Patients may 
continue on treatment for an unlimited number of cycles, until the criteria for stopping medication are met (see Section
3.3.4). 
**
End of Treatment, End of Residual Period & End of Study: This combined visit should be scheduled 7-14 days 
after all trial medications are permanently stopped, to account for the residual periods for everolimus (7 days) and 
exemestane (5 days).
a           x is the number of the treatment cycle 
1.
Tumour assessments will be performed according to institutional practices. Based on DBL primary analysis, images 
no longer need to be sent to central CRO and reviewed independently. The overall response only will be collected 
in the electronic CRF. 
2.
A patient diary will be given to the patient for continuous use through the trial. It should be given to the patient at
the start of each cycle. The diary collects information about medication taken at home and provides reminders 
about fasting bloods and urine samples. At Visit 1 of each cycle and at EOT treatment compliance needs to be 
checked including compliance calculation
3.
All serious adverse events, AESI and study drug related adverse events still ongoing at the end of treatment will 
be followed until resolution/stabilization 
4.
Everolimus and exemestane should be taken once a day at approximately the same time of day, following a meal. The 
tablets may be taken at home or in the clinic. 
5.
Pre-menopausal women:
Serum and/or urine pregnancy testing to be performed on Day 1 of each cycle until the end of treatment and after EOT
per institutional practice Hormone testing to include estradiol only on Day 1 of every odd number cycle starting at 
Cycle 3 and end of treatment. See Section 5.2.3.
Treatment Cycle 2 and 
subsequent cycles*
End of Treatment, End of 
residual period & End of 
Study**
Visit abbreviation
CxV1a
     EOT/ EOR/ EOS
Days
Day 1, every 28 days
(± 2 days)
7-14 days after permanent 
trial medication 
discontinuation
Physical exam and Vital Signs 
                                      Per institutional practice 
Safety lab 
                                       Per institutional practice 
Tumour assessment (1)
                                       Per institutional practice
Issue patient diary (2)
X
Review study medication compliance (2)
X
X
Adverse events (3)
X
X
Dispense everolimus and exemestane (4)
X 
Pregnancy test and hormone testing (if 
applicable) (5)
                                       Per institutional practice


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TABLE OF CONTENTS
TITLE PAGE ............................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ......................................................................2
FLOW CHART -No longer applicable per CTPv6.0 ............................................................7
FLOW CHART- Reduced schedule per CTP v6.0 – Ongoing patients.............................12
TABLE OF CONTENTS .......................................................................................................13
ABBREVIATIONS.................................................................................................................17
1.
INTRODUCTION................................................................................................21
1.1
MEDICAL BACKGROUND..............................................................................21
1.2
DRUG PROFILE .................................................................................................24
1.2.1
Xentuzumab..........................................................................................................24
1.2.2
Everolimus ............................................................................................................25
1.2.3
Exemestane ...........................................................................................................26
1.3
RATIONALE FOR PERFORMING THE TRIAL ..........................................26
1.4
BENEFIT - RISK ASSESSMENT......................................................................27
2.
TRIAL OBJECTIVES AND ENDPOINTS.......................................................28
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS.........28
2.1.1
Main objectives.....................................................................................................28
2.1.2
Primary endpoint.................................................................................................28
2.1.3
Secondary endpoints............................................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION ..........................31
3.1
OVERALL TRIAL DESIGN AND PLAN ........................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) .......................................................................................32
3.3
SELECTION OF TRIAL POPULATION ........................................................33
3.3.1
Main diagnosis for trial entry .............................................................................33
3.3.2
Inclusion criteria ..................................................................................................34
3.3.3
Exclusion criteria .................................................................................................35
3.3.4
Withdrawal of patients from therapy or assessments ......................................37
3.3.4.1 
Withdrawal from trial treatment ............................................................................37
3.3.4.2
Withdrawal of consent for trial participation.........................................................38
3.3.4.3
Discontinuation of the trial by the Sponsor............................................................38
4.
TREATMENTS....................................................................................................40
4.1
INVESTIGATIONAL TREATMENTS ............................................................40
4.1.1
Identity of the Investigational Medicinal Product (IMP) and Comparator...40
4.1.2
Background medication.......................................................................................41
4.1.3
Selection of doses in the trial...............................................................................42
4.1.4
Method of assigning patients to treatment groups............................................43
4.1.5
Drug assignment and administration of doses for each patient.......................43
4.1.5.1 
Drug assignment and administration......................................................................43
4.1.5.2
Temporary treatment pauses and dose reduction...................................................44
4.1.6
Blinding and procedures for unblinding............................................................45
4.1.6.1
Blinding..................................................................................................................45
4.1.6.2
Unblinding and breaking the code .........................................................................45


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4.1.7
Packaging, labelling, and re-supply....................................................................46
4.1.8
Storage conditions................................................................................................46
4.1.9
Drug accountability..............................................................................................46
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS .................................................................................................47
4.2.1
Other treatments and emergency procedures ...................................................47
4.2.1.1
Rescue medication .................................................................................................47
4.2.1.2
Emergency procedures...........................................................................................47
4.2.1.3
Concomitant treatments .........................................................................................49
4.2.2
Restrictions ...........................................................................................................49
4.2.2.1
Restrictions regarding concomitant treatment .......................................................49
4.2.2.2
Restrictions on diet and life style...........................................................................50
4.3
TREATMENT COMPLIANCE .........................................................................50
4.3.1
Xentuzumab/Placebo ...........................................................................................50
4.3.2
Everolimus and exemestane................................................................................50
4.4
MANAGEMENT OF EXPECTED ADVERSE EVENTS...............................51
4.4.1
Management of stomatitis/mucosal inflammation............................................51
4.4.1.1
Treatment recommendations for the prophylaxis of stomatitis..............................51
4.4.1.2
Treatment recommendations for established stomatitis/mucositis ........................52
4.4.2
Management of hyperglycaemia.........................................................................54
4.4.3
Management of non-infectious pneumonitis/ILD .............................................54
4.4.4
Management of neutropenia ...............................................................................55
5.
ASSESSMENTS...................................................................................................56
5.1
ASSESSMENT OF EFFICACY.........................................................................56
5.2
ASSESSMENT OF SAFETY..............................................................................56
5.2.1
Physical examination ...........................................................................................56
5.2.2
Vital signs and ECOG Performance Status.......................................................57
5.2.3 
Safety laboratory parameters .............................................................................57
5.2.4
Electrocardiogram ...............................................................................................58
5.2.5
Left Ventricular Ejection Fraction.....................................................................59
5.2.6
Assessment of adverse events..............................................................................59
5.2.6.1
Definitions of AEs..................................................................................................59
5.2.6.2
Adverse event collection and reporting..................................................................61
5.2.6.3
Assessment of healthcare resource use ..................................................................64
5.2.7
Safety assessment as of 29 Sept 2021..................................................................64
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS ....................................................................................64
5.3.1
Assessment of pharmacokinetics ........................................................................64
5.3.2
Methods of sample collection ..............................................................................65
5.3.4
Pharmacokinetic – pharmacodynamic relationship .........................................65
5.4
ASSESSMENT OF BIOMARKER(S) ...............................................................65
5.4.1
Evaluation of molecular and biochemical biomarkers in tumour tissue:.......66
5.4.2
Molecular evaluation in blood:...........................................................................67
5.4.3
Protein biomarkers from blood and urine.........................................................67
5.4.4
Biobanking (Optional).........................................................................................68
5.4.5
Radiomics..............................................................................................................68


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5.5
ASSESSMENT OF IMMUNOGENICITY .......................................................69
5.5.1
Assessment of immunogenicity ...........................................................................69
5.5.2
Methods of sample collection ..............................................................................69
5.6
OTHER ASSESSMENTS....................................................................................70
5.6.1
Patient-reported outcomes ..................................................................................70
5.6.2
Analgesics use.......................................................................................................72
5.6.3
Health care resource utilisation..........................................................................73
5.7
APPROPRIATENESS OF MEASUREMENTS...............................................73
6
INVESTIGATIONAL PLAN..............................................................................74
6.1
VISIT SCHEDULE..............................................................................................74
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ..................74
6.2.1
Screening...............................................................................................................74
6.2.2
Treatment period .................................................................................................75
6.2.2.1
End of treatment visit and follow-up visit 1...........................................................75
6.2.2.2
Treatment beyond progression...............................................................................75
6.2.3
Follow up period and trial completion...............................................................75
6.2.3.1
Extended follow-up period.....................................................................................75
6.2.3.2
Follow-up for Overall Survival..............................................................................76
6.2.3.3
Trial completion for an individual patient ............................................................77
7
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE78
7.1
STATISTICAL DESIGN - MODEL..................................................................78
7.2
NULL AND ALTERNATIVE HYPOTHESES ................................................78
7.3
PLANNED ANALYSES......................................................................................79
7.3.1
Primary endpoint analyses ..................................................................................80
7.3.2
Secondary endpoint analyses Overall survival..................................................81
7.3.4
Safety analyses......................................................................................................85
7.4
INTERIM ANALYSES .......................................................................................86
7.5
HANDLING OF MISSING DATA ....................................................................87
7.6
RANDOMISATION ............................................................................................89
7.7
DETERMINATION OF SAMPLE SIZE ..........................................................89
8
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE..........92
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
................................................................................................................................92
8.2
DATA QUALITY ASSURANCE .......................................................................93
8.3
RECORDS ............................................................................................................93
8.3.1
Source documents ................................................................................................93
8.3.2
Direct access to source data and documents......................................................94
8.3.3
Storage period of records ....................................................................................94
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS....................................94
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY.........94
8.5.1
Collection, storage and future use of biological samples and corresponding 
data ........................................................................................................................95
8.6
TRIAL MILESTONES........................................................................................95
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ....................................96
9
REFERENCES.....................................................................................................98


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9.1
PUBLISHED REFERENCES.............................................................................98
9.2
UNPUBLISHED REFERENCES.....................................................................104
10
APPENDICES ....................................................................................................105
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK), 
PHARMACODYNAMIC (PD), BIOMARKER (BM) AND ANTI-DRUG-
ANTIBODY (ADA) AND NEUTRALIZING ANTIBODY (NAB) 
SAMPLING ........................................................................................................105
10.2
RECOMMENDATIONS FOR ADVERSE EVENT TREATMENT............108
10.2.1
Management of Diarrhoea ................................................................................108
10.2.2
Management of nausea/vomiting......................................................................109
10.3
ECOG PERFORMANCE STATUS.................................................................110
10.4
TUMOUR RESPONSE ASSESSMENT ACCORDING TO MODIFIED 
RECIST 1.1 CRITERIA....................................................................................111
10.5
HEALTH-RELATED QUALITY OF LIFE QUESTIONNAIRES ..............118
10.5.1
BPI-SF.................................................................................................................118
10.5.2
NFBSI-16.............................................................................................................120
10.5.3
EQ-5D-5L............................................................................................................121
10.5.4
PRO-CTCAE......................................................................................................122
10.6
COCKCROFT-GAULT FORMULA ..............................................................124
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) ........................................125
11.1
GLOBAL AMENDMENT 1 .............................................................................125
11.2
GLOBAL AMENDMENT 2 .............................................................................129
11.3
GLOBAL AMENDMENT 3 .............................................................................140
11.4
GLOBAL AMENDMENT 4 .............................................................................148
11.5
GLOBAL AMENDMENT 5 .............................................................................153
    


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ABBREVIATIONS
ADA
Anti-drug antibodies
ADL
Activities of daily living
AE
Adverse Event
AESI
Adverse Event of Special Interest
AI
Aromatase inhibitor
AKT
Protein kinase B-alpha
ALT
Alanine amino transferase
AMP
Auxiliary medicinal product
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
aPTT
Activated Partial Thromboplastin Time
AQA
Analgesic Quantification Algorithm
ASCO
American Society of Clinical Oncology
AST
Aspartate amino transferase
BI
Boehringer Ingelheim
BOLERO
Breast cancer trials of OraL EveROlimus
BPI-SF
Brief Pain Inventory– Short Form
BRS
Bone-only metastases randomized set
BUN
Blood urea nitrogen
C
Cycle x
CAP
College of American Pathologists
CCND1
Cyclin D1
CDK
Cyclin-dependent kinases
cf
Cell-free
CI
Confidence Interval
CPK
Creatine phosphokinase
Cpre
Pre-dose plasma concentration
CR
Complete response
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract research organisation
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events 
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450
DC
Disease control
DCR
Disease control rate
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiography
ECOG
Eastern Cooperative Oncology Group
eDC
Electronic Data Capturing
e.g.
Exempli gratia (for example)
ELISA
Enzyme Linked Immunosorbent Assay 


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EOR
End of residual effect period
EOT
End of treatment
EQ-5D-5L
EuroQoL 5-dimension health status self-assessment questionnaire
ER
Estrogen receptor
EU
European Union
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose positron-emission tomography
FFPE
Formalin fixed paraffin embedded
FGFR
Fibroblast growth factor receptor
FISH
Fluorescence in situ hybridisation
FSH
Follicle-stimulating hormone
FU
Follow-up
GCP
Good Clinical Practice
GGT
γ-glutamyltransferase
GMP
Good Manufacturing Practice
HbA1c
Glycated haemoglobin
HCRU
Health care resource utilisation
HDL
High-density lipoprotein
Hep
Hepatitis
HER2
Human epidermal growth factor receptor 2
Hgb
Haemoglobin
HIV
Human immunodeficiency virus
HR
Hazard ratio
HR
Hormone receptor
HRQOL
Health-related quality of life
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
i.e.
Id est (that is)
IEC
Independent Ethics Committee
IGF
Insulin-like growth factor
IGF-1R
IGF1 receptor
IGFBP3
IGF-binding protein 3
IgG1
Immunoglobulin 1
IHC
Immunohistochemistry
ILD
Interstitial lung disease
IMP
Investigational medicinal product
INR
International Normalised Ratio
IR-A
Insulin receptor A
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
Ki-67
Antigen KI67
KM
Kaplan-Meier
LDL
Low-density lipoprotein
LSLT
Last Subject Last Treatment
LSLVPE
Last Subject Last Visit Primary Endpoint


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LSLVSE
Last Subject Last Visit Secondary Endpoint 
LVEF
Left Ventricular Ejection Fraction
mAb
Monoclonal antibody
mBC
Metastatic breast cancer
MAPK
Mitogen-activated protein kinase
MedDRA
Medical Dictionary for Drug Regulatory Activities 
MRI
Magnetic resonance imaging
mTOR
Mechanistic target of rapamycin
mTORC1
mTOR complex 1
MUGA
MUltiGated Acquisition scan
nAb
Neutralising antibody
NCI
National Cancer Institute
NE
Not evaluable
NFBSI-16
Network Functional Assessment of Cancer Therapy-Breast 
Cancer Symptom Index
NIMP
Non-investigational medicinal product
NSAID
Nonsteroidal anti-inflammatory drugs
NTX
N-terminal cross-linked telopeptide of type I collagen
NYHA
New York Heart Association
OME
Oral morphine equivalent
OPU
Operative Unit
OR
Objective response
ORR
Objective response rate
OS
Overall survival
p
Probability
P1NP
N-terminal propeptide of procollagen type 1
PFS
Progression-free survival
PgR
Progesterone receptor
PI3K
Phosphatidylinositol 3-kinase
PIK3CA
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
PD
Pharmacodynamics
PD
Progressive disease
PI
Prescribing information
PK
Pharmacokinetics
p.o.
Per os (oral)
PR
Partial response
PRO
Patient Reported Outcome
PTEN
Phosphatase and tensin homolog
Ras
Rat sarcome
RBC
Red blood cell
RECIST
Response Evaluation Criteria In Solid Tumors
REP
Residual Effect Period
RNA
Ribonucleic acid
RS
Randomised set
SAE
Serious Adverse Event
sAg
Surface antigen
SC
Steering Committee
SD
Stable disease


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SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SS
Skeletal scintigraphy
SUSAR
Suspected Unexpected Serious Adverse Reactions
SV
Screening visit
TNM
Tumour-lymph nodes-metastases; classification of malignant tumours 
Tmax
Time from dosing to the maximum plasma concentration
TMF
Trial Master File
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper limit of institutional normal
V
Visit
VAS
Visual analogue scale
VEGF-C
Vascular endothelial growth factor C
vs.
Versus
WBC
White blood cell
WHO
World Health Organization
XR
Radiography


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Breast cancer is one of the most common cancers in women. More than 180,000 
estimated deaths due to breast cancer are expected annually in the United States and 
Europe combined (http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx). The traditional 
separation of breast cancers into HR-positive and -negative cases helps to guide patient 
management. The only markers with an associated targeted therapy are currently the 
estrogen receptor (ER) and the human epidermal growth factor receptor 2 (HER2).
Approximately 15% of patients with breast cancer have HER2 overexpressing and/or 
amplified tumours; these patients are treated with a combination of trastuzumab+/-
pertuzumab, monoclonal antibodies targeting HER2, and chemotherapy. For the two-thirds 
of breast cancers which are positive for ER and/or progesterone receptor (PgR), endocrine 
therapy with tamoxifen or aromatase inhibitors is generally indicated. However, a 
subgroup of ER+ patients relapses irrespective of standard hormonal therapy. While early 
stage disease is curable, patients with metastatic breast cancer (mBC) have a median 
overall survival (OS) of only 2 to 3 years (R16-3983). De novo or acquired resistance to 
endocrine therapy remains an important clinical problem. HR+ advanced or metastatic 
breast cancer still has a dismal prognosis. Until recently, progression-free survival (PFS) 
was less than one year for HR+/HER2- mBC patients when diagnosed with metastatic 
disease. Only after combinations of the mechanistic target of rapamycin (mTOR) inhibitor 
everolimus and exemestane median PFS increased from 3.2 to 7.8 months (R16-4906) and 
cyclin-dependent kinases (CDK) 4/6 inhibitors further improved median PFS to 20-25 
months in 1st line setting and 9.5-16 months in 2nd line setting (R16-4899, R17-2796, R17-
2798, R17-2979, R17-2980). None of the latter trials to date showed overall survival 
benefit (R17-2892). Eventually patients relapse and /or develop resistance to endocrine or 
other follow-up treatment and succumb to their disease.
Combination of mTOR inhibition and hormone treatment:
BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) examined the safety and efficacy 
of everolimus (10 mg/day orally) in combination with exemestane (25 mg/day p.o.) versus 
exemestane alone in post-menopausal women with ER+/HER2- advanced breast cancer 
who recurred or progressed while on or following previous treatment with hormonal 
therapies letrozole or anastrozole (R12-5635). At a pre-planned analysis, the trial met its 
primary endpoint of PFS by local investigator assessment and treatment with everolimus 
and exemestane improved median PFS to 7.8 months from 3.2 months for exemestane 
alone (hazard ratio 0.45 [95% confidence interval (CI): 0.38, 0.54]; p<0.0001). PFS results 
by independent central review were consistent with investigator assessment. PFS results 
were consistent across subgroups of age, race, presence and extent of visceral metastases, 
and sensitivity to prior hormonal therapy in the primary analysis (R12-5635), while a later 
subgroup analysis revealed a longer median PFS of 9.9 months for patients without visceral 
metastases (R16-0802). Objective response rate was 12.6% (95% CI: 9.8, 15.9) in the 
everolimus plus exemestane arm vs. 1.7% (95% CI: 0.5, 4.2) in the placebo plus 
exemestane arm. There were 3 complete responses (0.6%) and 58 partial responses (12.0%) 
in the everolimus plus exemestane arm. There were no complete responses and 4 partial 
responses (1.7%) in the placebo plus exemestane arm. In BOLERO-2, adding everolimus 


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to exemestane did not confer a statistically significant improvement in the secondary 
endpoint OS despite producing a clinically meaningful and statistically significant 
improvement in the primary endpoint, PFS (4.6 months prolongation in median PFS; P 
<0.0001): Median OS in patients receiving everolimus and exemestane was 31.0 months 
[95% CI 28.0-34.6 months] compared with 26.6 months (95% CI 22.6-33.1 months) in 
patients receiving placebo and exemestane (hazard ratio = 0.89; 95% CI 0.73-1.10; log-
rank P = 0.14) (R16-4900).
Most common grade 3/4 adverse events (AEs) were stomatitis (8% vs 1%), anemia (5% vs
<1%), dyspnea (4% vs 1%), hyperglycemia (4% vs <1%), fatigue (3% vs 1%), 
and pneumonitis (3% vs 0%) for the everolimus and exemestane and exemestane 
groups, respectively.
Data from a correlative exploratory analysis of genetic alterations (next generation 
sequencing) and everolimus benefit suggest that the efficacy of everolimus was largely 
independent of the most commonly altered genes or pathways of which they are 
components (PIK3CA, FGFR1, and CCND1) in HR+/HER2- breast cancer (R16-4905).
Cyclin-dependent kinase (CDK) 4/6 inhibitors:
Cell cycle and gene transcription are under the control of CDKs, whose activity depends 
on binding to cyclins. Deregulated CDK activities have been reported in a variety of 
human cancers, representing potential for therapeutic targets (R16-2249; R16-3979) 
especially, but not exclusively, HR+ breast cancer. Several selective CDK4/6 inhibitors 
were developed in HR+ mBC and based on significant PFS benefit palbociclib received 
FDA (Food and Drug Administration) accelerated approval in 2015 in combination with 
letrozole (R17-2798, R17-2980) and, in 2016 in combination with fulvestrant (R17-
2979). As of July 2019, three CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) are 
approved for treatment of HR+ breast cancer when added to endocrine therapies in both 
first- and subsequent treatment lines (R16-4899, R17-2796). Approvals were based on 
significant PFS benefit. OS data are still immature, with the exception of the Paloma-3 
study where an increased median survival was observed with the addition of palbociclib 
to fulvestrant.
Current treatment standards:
For post-menopausal women, aromatase inhibitors (AIs, e.g. letrozole or anastrozole) and 
fulvestrant are the preferred first-line endocrine therapy. CDK4/6 inhibitors palbociclib, 
ribociclib may be added to first-line therapy. As second-line therapy fulvestrant may be 
administered alone or in combination with palbociclib or abemaciclib, alternatively 
exemestane plus mTOR inhibitor everolimus may be given to post-menopausal women 
with HR+ mBC whose disease progresses while receiving nonsteroidal AIs alone or in 
combination with CDK4/6 inhibitors. Single- agent endocrine therapy or abemaciclib can 
also be considered. It is not uncommon for patients to alternate between endocrine 
therapy and chemotherapy over the course of their disease based of the extent of cancer 
burden, adverse profile of treatment regimens and disease-related symptoms. A variety of 
sequences for endocrine therapy alone or in combination can be appropriate. 
Premenopausal women with hormone-receptor positive metastatic breast cancer should 
be offered ovarian suppression or ablation. Thereafter, endocrine treatment of 
premenopausal women parallels that of postmenopausal women. (R17-2894) Guidelines 


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recommend a combination of a different endocrine therapy than used previously with a 
CDK 4/6 inhibitor or everolimus for premenopausal women on ovarian suppression.
Chemotherapy is usually given to patients with immediately life-threatening disease, 
endocrine refractory disease, or to patients with symptomatic visceral disease.
Despite evidence that patients with non- visceral involvement in general have less 
aggressive disease, treatment algorithms are used for all HR+/HER2- mBC patients alike 
without accounting for presence of visceral or non-visceral disease (P17-09321; R17-
2894; R17-2948).
Combination of mTOR inhibitor and exemestane with insulin-like growth factor 
(IGF) pathway inhibition:
At ASCO 2010, Di Cosimo et al. presented initial data that the combination of the oral 
mTOR inhibitor ridaforolimus with the IGF-1 receptor (IGF-1R) antibody dalotozumab 
was tolerable and had promising antitumor activity in heavily pre-treated advanced cancer, 
particularly in ER+/high proliferation breast cancer. Of 23 breast cancer patients enrolled 
at the time of analysis, 5 ER+ (4 of these with high Ki67) breast tumours had efficacy 
signals (2 partial responses [PRs], 1 stable disease [SD] for 9 months, and 2 partial 
metabolic responses on FDG-PET scan) (R13-2056; R17-3094).
Preclinical data on xentuzumab, which is an IGF-ligand blocking monoclonal antibody 
(mAb) support a combination of xentuzumab, with rapalogs (P16-16103) particularly in 
patients with non-visceral HR+/HER2- mBC who frequently have (i) bone metastases 
and/or (ii) lymph node metastases.
(i)
There is a clear rationale for a biological role of bone-derived IGF-1 in osteolytic 
bone metastases, which are predominant in HR+/HER2- mBC patients. IGF-1 
which is stored in large amounts in the bone matrix is released by excessive bone 
destruction in metastatic lesions and promotes proliferation of tumour cells, thereby 
contributing to the vicious cycle that increases both bone destruction and tumour 
burden. Published experimental evidence suggests that bone-derived IGF-1 may 
also promote homing of cancer cells to the bone (‘seed-and-soil’ hypothesis). 
Suppression of IGF signaling was shown to inhibit bone metastases in breast cancer 
models (P04-04292; R17-2113; R17-2114; R17-2115; R17-2116; R17-2118; R17-
2119) and may be facilitated by xentuzumab, an IGF-ligand blocking monoclonal
antibody.
(ii)
Published clinical data also suggest a significant correlation between high 
circulating levels of IGF-1, IGF-binding protein 3 (IGFBP3), and VEGF-C and 
lymph node metastasis in ER+ mBC patients. Preclinical studies indicate that IGF-
1 may promote lymph node metastasis by increasing VEGF-C expression in 
tumour cells, thereby inducing lymphangiogenesis. Further, IGF-1 secreted by 
lymph node stromal cells was found to promote breast cancer cell proliferation 
and anchorage-independent growth (R17-2300; R17-2303; R17-2306). As such 
inhibition of IGF via a ligand blocking monoclonal antibody like xentuzumab may 
provide a rationale treatment option.


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1.2
DRUG PROFILE
For a more detailed description of the xentuzumab profile please refer to the current 
Investigator’s Brochure (IB; c01690707) and for everolimus and exemestane to the 
current Summary of Product Characteristics (SmPC) or the US Prescribing Information 
(PI).
1.2.1
Xentuzumab
Xentuzumab is a humanised IgG1 monoclonal antibody that binds with high affinity to 
IGF-1 and IGF-2, and potently neutralises the proliferative and pro-survival cellular 
signaling triggered by both proteins.
Mode of action differentiation to IGF-1R targeted antibodies was demonstrated, in 
particular through inhibition of IGF-2 stimulated insulin receptor-A (IR-A) activation, an 
additional proliferative and pro-survival pathway not inhibited by IGF-1R targeted mAbs.
As of January 2018, xentuzumab is in Phase II of clinical development and has been 
investigated in a total of 7 clinical studies. Overall, 146 patients with cancer have received 
xentuzumab in monotherapy studies, 333 patients have been treated in combination 
therapy studies.
The recommended xentuzumab dose for Phase II clinical development is 1000 mg weekly. 
In the absence of a maximum tolerated dose in the dose escalation trials (up to 1800 mg 
weekly or 3600 mg every 3 weeks), this dose was selected based on the integration of 
preclinical and clinical (safety, anti-tumour activity) data as well as pharmacokinetic 
(PK)/pharmcodynamic (PD) relationship (IGF-1 saturation, inhibition of IGF bioactivity).
Maximum plasma concentrations of xentuzumab were observed at or shortly after the end 
of the intravenous infusion. Thereafter, plasma concentrations declined, at least biphasic, 
with a terminal half-life in the order of 6 days. No deviation from dose-proportional 
pharmacokinetics has been observed. Repeated weekly dosing resulted in about 1.5fold 
accumulation of xentuzumab plasma concentrations at steady state.
The AEs observed during xentuzumab treatment to date have generally been of mild to 
moderate intensity (National Cancer Institute [NCI]) Common Terminology Criteria for 
Adverse Events [CTCAE] grades 1 or 2) or consistent with the safety profile of 
combination backbone treatment or the underlying neoplastic conditions of patients 
enrolled into the studies. The most frequently reported AEs for xentuzumab monotherapy 
were fatigue, decreased appetite, nausea, diarrhoea, and vomiting. Abnormal liver enzyme 
elevation tests were observed at low frequencies and were generally of low grade 
(CTCAE grades 1 and 2) in all monotherapy studies. No cases of drug-induced liver 
injury were reported. There were no signs of cardiac toxicity, and no laboratory findings 
that would indicate kidney damage in patients treated with xentuzumab. No clinically 
relevant hyperglycaemia has been observed so far.
The most frequently reported serious adverse events (SAE) for xentuzumab monotherapy 
were dyspnoea and pneumonia. AEs leading to death were reported for 3 patients (acute 
respiratory failure, dyspnoea, and malignant neoplasm progression); none of these events 
was considered by the investigator to be related to xentuzumab.
To date the only expected serious adverse reactions identified for xentuzumab are 


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infusion- related reactions observed in patients who received xentuzumab treatment 
(c01690707).
Anti-tumour activity has been observed in the Phase I monotherapy study 1280.1, with 2 
partial responses according to Response Evaluation Criteria In Solid Tumors (RECIST, 
R09-0262) criteria in a patient with nasopharyngeal cancer and a patient with a peripheral 
primitive neuroectodermal tumor/Ewing sarcoma and 2 patients with partial response in 
the Phase I monotherapy study 1280.15. In addition, considerable proportions (12% to 
45%) of heavily pre-treated patients in the Phase I monotherapy studies were reported 
with stable disease when treated with xentuzumab.
Lately a marked improvement in PFS was observed in a pre-specified subgroup of 
HR+/HER- mBC patients with non-visceral disease (also a stratification factor) who 
received xentuzumab in addition to everolimus and exemestane (n=33 out of 140 patients, 
17 in the xentuzumab and 16 in the control arm, HR=0.21, 95% CI: 0.05-0.98, interaction 
p- value=0.014). In this subgroup, two PFS events occurred in the xentuzumab treatment 
arm compared to nine PFS events in the control arm. Similar improvement in PFS was 
observed in the nested “bone-only” metastasis subgroup (n=16, HR=<0.01 (no events 
observed in the xentuzumab arm compared to 4 in the control arm), interaction p-
value=0.0159).
1.2.2
Everolimus
Everolimus (RAD001, Afinitor®, 
) is the 40-O-(2-hydroxyethyl) derivative of 
sirolimus; it inhibits mTOR by binding with high affinity to its intracellular receptor 
KBP12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) 
and thus inhibits mTOR kinase activity.
Everolimus has been developed as both an immunosuppressant for the treatment of 
transplant organ rejection and as an anticancer agent (R13-2184). A Phase I study 
conducted in solid tumour patients identified mucositis and fatigue as dose-limiting 
toxicities when everolimus was administered as a single agent using a weekly schedule. 
Everolimus was rapidly absorbed with a Tmax of 0.5-2.5 h, exposure was dose proportional 
over the therapeutic dose range (2.5-25 mg), with steady-state concentrations achieved 
within 7 days or less following once-daily dosing (R08-5716, R13-0654, R13-0655). Its 
terminal half-life is 30 h (range, 26- 38 h). Metabolism of everolimus occurred primarily 
in the gut and liver by cytochrome
P450 3A4, 3A5 and 2C8, with the majority of drug (approximately 98%) excreted in the 
bile in the form of metabolites (R08-5716).
Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the 
multidrug efflux pump P-glycoprotein (PgP). In vitro, everolimus is a competitive inhibitor 
of cytochrome P450 (CYP) 3A4 and a mixed inhibitor of CYP 2D6 (R12-5281).
Everolimus is approved for various conditions: advanced hormone receptor-positive, 
HER2- negative breast cancer (in the European Union (EU): with the restriction “for 
patients without symptomatic visceral disease”), advanced neuroendocrine tumours of 
pancreatic origin, advanced renal cell carcinoma, renal angiomyolipoma with tuberous 
sclerosis complex and subependymal giant cell astrocytoma with tuberous sclerosis 
complex. Additionally, biologic activity has been seen in a variety of tumours, including 
gastric cancer, hepatocellular carcinoma and lymphoma and Phase III trials are under way. 


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The approved treatment dose of everolimus in advanced HR+ breast cancer is 10 mg daily 
(please refer to the most current drug prescribing information for update).
1.2.3
Exemestane
Exemestane is an irreversible, steroidal aromatase inactivator. Exemestane structure is 
related to androstenedione, a natural substrate of the aromatase enzyme. Exemestane binds 
irreversibly to the active site of the enzyme and causes its inactivation.
Exemestane inhibition of aromatase results in deep suppression of circulating estrogen 
concentrations in post-menopausal women, which is frequently below the detection limits 
of standard assays, but has no detectable effect on adrenal biosynthesis of corticosteroids 
or aldosterone. Unlike tamoxifen, exemestane has no partial estrogen agonist activity 
(R13-0738).
Following oral administration to healthy post-menopausal women, exemestane is rapidly 
absorbed with a mean Tmax of 1.2 hours. After maximum plasma concentration is 
reached, levels decline polyexponentially with a mean terminal half-life of about 24 
hours. The pharmacokinetics of exemestane is dose proportional after single (10 to 200 
mg) or repeated oral doses (0.5 to 50 mg). Steady-state was achieved within 7 days 
following once-daily dosing (R13-0766). Exemestane is extensively distributed and is 
cleared from the systemic circulation primarily by metabolism. Studies using human liver 
preparations indicate that CYP 3A4 is the principal isoenzyme involved in the oxidation 
of exemestane. It does not inhibit any of the major CYP isoenzymes, including CYP 1A2, 
2C9, 2D6, 2E1, and 3A4.
Exemestane plasma levels increased after a high-fat breakfast. Exemestane is mainly 
excreted from urine and feces (R13-0738).
Exemestane use is associated with myalgias and arthralgias, as well as reduced bone 
mineral density and increased risk of fracture, which do not appear to persist at follow-up, 
with subsequent return to pre-treatment values. Compared with tamoxifen, there is a 
reduced incidence of endometrial changes, thromboembolic events, and hot flashes. 
Limited evidence shows non-adherence in 23-32% of patients. Evidence is growing in 
support of exemestane in all clinical settings. It is generally more efficacious and has a 
better safety profile than tamoxifen (R13-0738). How it compares with the non-steroidal 
aromatase inhibitors remains to be established (R13-1990).
Exemestane is indicated for the treatment of advanced breast cancer in post-menopausal 
women whose disease has progressed following tamoxifen or anti-oestrogen therapy. The 
approved treatment dose of exemestane is 25 mg taken once daily after a meal (please refer 
to the most current drug prescribing information for update).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Despite the introduction of everolimus and lately CDK4/6 inhibitors to overcome 
endocrine resistance, there is still an unmet need in women with advanced or metastatic 
HR+/HER2- breast cancer and eventually patients succumb to their disease. Dysregulation 
of both insulin-like growth factor signaling and the phosphatidylinositol 3-kinase (PI3K) -
protein kinase B-alpha (AKT) - mTOR signaling pathways are linked to the acquired 


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resistance to hormonal therapy in breast cancer (R13-1977, R13-1980). Targeting the IGF 
pathway using xentuzumab, a ligand blocking antibody, in combination with everolimus 
and exemestane showed promising results in a subgroup of 33/140 HR+/HER2- mBC 
patients with non-visceral disease in the Phase Ib/II trial 1280.4. Of the 17 non-visceral 
patients on the xentuzumab arm 2 had a PFS event compared to 9 of the 16 patients on the 
control arm, leading to a hazard ratio (HR) of 0.21 with a corresponding 95% confidence 
interval (CI) of 0.05, 0.98 (p-value of 0.029, c22665932-01).
The effect was even more pronounced in 16 patients with bone metastases only, with no 
PFS events observed in any of the 7 patients on the xentuzumab arm compared to 4 of the 
9 patients on the control arm. Based on these results, demonstrating increased efficacy in 
HR-positive, HER2-negative mBC patients without visceral disease who were treated with 
a combination of xentuzumab with standard of care everolimus/exemestane, trial 1280-
0022, a double blind, randomized, Phase II trial will be initiated in female patients with 
HR+/HER2- advanced or metastatic breast cancer with non-visceral disease.
1.4
BENEFIT - RISK ASSESSMENT
Trial 1280.4, a Phase Ib/II open-label, randomised study of xentuzumab in combination 
with exemestane and everolimus versus exemestane and everolimus alone in women with 
locally advanced or metastatic breast cancer (HR+/HER2- mBC) was terminated early in 
October 2016 due to a Data Monitoring Committee (DMC) recommendation and an 
observed preliminary HR for PFS of 1.38 (95% CI: 0.687-2.778). Although this indicated 
low probability to achieve the desired HR at the time of primary analysis, a subgroup 
analysis of PFS in the pre-specified subgroup of patients with non-visceral disease 
derived clear benefit as described in section 1.3.
The safety profile of xentuzumab monotherapy is tolerable. In combination with 
everolimus and exemestane the safety profile of the combination is largely dominated by 
side effects observed for the backbone therapy. To date the only expected serious adverse 
reaction identified for xentuzumab are infusion-related reactions mostly CTCAE grade 1 
and 2 (c01690707).
Addition of xentuzumab 1000 mg to established backbone treatment in Phase Ib/II trial 
1280.4 did not add any safety concerns, however provided increased efficacy to a 
subgroup of female HR+/HER2- metastatic breast cancer patients with non-visceral 
disease. These patients frequently suffer from bone and lymph node metastases and there 
is a sound scientific rationale supporting the antitumour activity of xentuzumab in this 
patient population (see Section 1.1). Therefore further assessment of the observed 
preliminary treatment effect in patients with HR+/HER2- mBC without visceral disease is 
warranted in a large confirmatory trial. To safeguard patients in this proposed Phase II, a 
DMC will continuously monitor patients’ safety as outlined in Section 8.7. The benefit 
risk is considered positive.
Although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations in selected liver laboratory parameters 
to ensure patients´ safety, see also Section 5.2.6, adverse events of special interest.


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The 1280-0022 phase II trial recently completed primary endpoint analysis and showed no 
added benefit of xentuzumab compared to placebo, in patients with everolimus and exemestane 
backbone therapy, when treating trial participants with metastatic breast cancer, HR+, HER2-
and non-visceral disease. No new safety signals were observed with the addition of xentuzumab 
to the everolimus and exemestane combination.
In consideration of these top line results and in accordance with clinical trial protocol, as of 29 
September 2021, Boehringer Ingelheim recommended to immediately discontinue xentuzumab 
and placebo administrations. Sites were also recommended to discontinue associated 
assessments related to primary endpoint assessments, including central imaging, central 
laboratory sampling and shipments and PRO questionnaires. Lastly, sites were advised that 
patients no longer needed to be followed for overall survival after they had completed the 
required safety follow up visits. 
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
This double-blind, placebo-controlled, randomised Phase II trial will be performed in 
female patients with HR+/HER2- advanced or metastatic breast cancer and non- visceral 
disease. The main objective of the trial is to assess the efficacy of xentuzumab in 
combination with everolimus and exemestane over everolimus and exemestane in this 
patient population. Efficacy will be assessed by determining whether or not the criterion 
for expanding the trial seamlessly into a Phase III trial is met. If the seamless option is met 
the trial will be expanded into a confirmatory Phase III trial with formal superiority 
hypothesis testing. If the seamless option is not met, the observed results will be evaluated 
in an explorative manner to see if they are sufficient for further development of this 
compound in this indication.
All imaging-related endpoints will be both independently assessed (in a blinded fashion) 
and investigator assessed according to RECIST 1.1 (see Appendix 10.4). The data from 
the independent assessments will be considered primary, with investigator assessment 
data as supportive.
2.1.2
Primary endpoint
The primary endpoint to determine efficacy of xentuzumab is progression-free survival 
(PFS) which is defined as time from randomisation until disease progression according to 
Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) or death from any 
cause, whichever occurs earlier.
2.1.3
Secondary endpoints

Overall survival (OS) is defined as the time from randomisation until death from 


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any cause.

Disease control (DC) is defined as a best overall response of complete response (CR), 
partial response (PR), stable disease (SD) or Non-CR/Non-Progressive Disease (Non-
CR/Non-PD). SD and Non-CR/Non-PD must have a minimum duration of 24 weeks 
from randomisation. Best overall response is defined according to RECIST version 1.1 
and will consider all tumour assessments from randomisation until the earliest of 
disease progression, death or last evaluable tumour assessment before start of 
subsequent anti- cancer therapy, loss to follow-up or withdrawal of consent.

Duration of DC is defined as the time from randomisation until the earliest of
disease progression or death, among patients with DC.

Objective response (OR) is defined as a best overall response of CR or PR. Best 
overall response is defined according to RECIST version 1.1 and will consider all 
tumour assessments from randomisation until the earliest of disease progression, 
death or last evaluable tumour assessment before start of subsequent anti-cancer 
therapy, loss to follow-up or withdrawal of consent.

Time to pain progression or intensification of pain palliation defined as the time from 
randomisation until the earliest of a clinically significant increase in pain (≥2-point 
increase from baseline in the Brief Pain Inventory– Short Form [BPI-SF] Item 3) 
without a decrease in analgesics use, or intensification in pain palliation (≥2-point 
increase in the 8-point Analgesic Quantification Algorithm [AQA]), or death.
* Note if the trial is expanded the secondary endpoint of OS is included in the 
statistical testing strategy in a hierarchical manner subsequent to significance being 
observed in the primary endpoint, for further details refer to Section 7.2.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This double-blind, placebo-controlled, randomised Phase II trial is designed to assess 
the efficacy of xentuzumab in combination with everolimus and exemestane compared 
to everolimus and exemestane alone in female patients with HR+/HER2- locally 
advanced or metastatic breast cancer and non-visceral disease.
If the criterion for the seamless option (to be defined in the DMC charter, prior to trial 
initiation) is met then the trial will be expanded into a confirmatory Phase III trial and 
remain double-blind. If the seamless option is not met, the observed results will be 
evaluated in an explorative manner to see if they are sufficient for further development of 
this compound in this indication (e.g. via a separate Phase III trial).
The trial will be performed by investigators specialised in the treatment of breast cancer. 
Patient inclusion will be based on locally confirmed HR+ and HER2-status. Archival
tissue biopsies (most recent biopsy from initial diagnosis or metastatic setting) will be 
provided to retrospectively confirm HR+ and HER2-status by central assessment if 
possible. Provision of biopsy samples from the bone is not acceptable. Receptor status 
should be assessed by ASCO/CAP guidelines (R15-6055, R17-4255). Patients must not 
have visceral metastases, i.e. metastases to lung, liver, pleura or peritoneum, malignant 
pleural or peritoneal effusions. Patients must not have evidence of brain metastases. 
Patients meeting all eligibility criteria will be randomised 1:1 to the experimental treatment 
arm containing xentuzumab or to the placebo control arm of the trial (Figure 3.1: 1). 
Patients will be treated in 28-day cycles until the end of cycle 20 (week 80) and in 56-day 
cycles from Cycle 21 (week 80) until they have PD, occurrence of intolerable AEs or 
withdraw consent. Patients will be randomised in blocks, treatment will be double blinded 
and randomisation will be stratified by the presence of bone-only metastases (Yes/No), and 
prior CDK4/6 inhibitor treatment (i.e. palbociclib, ribociclib, abemaciclib) (Yes/No). Use 
of xentuzumab or placebo beyond radiological progression will be allowed if deemed 
beneficial by the investigator and agreed with the patient. PFS as assessed by an 
independent blinded review according to RECIST 1.1 will be the primary endpoint. Safety 
and tolerability will be assessed by incidence and severity of adverse events according to 
CTCAE version 5.0 (R18- 1357). PK sampling and monitoring of anti-drug antibodies 
(ADAs) and neutralising antibodies (nAb) will be conducted throughout the trial in both 
treatment arms. Patients’ safety, pattern of their disease progression and post progression 
information will be monitored throughout the trial by an independent DMC (see Section
8.7).
The end of treatment (EOT) information has to be obtained when the trial treatment is 
permanently discontinued. EOT is defined as permanent discontinuation of all trial drugs. 
All patients who end the trial treatment for any reason other than progression of disease or 
start of further anti-cancer therapy will be followed for tumour assessment. All patients 
will be followed for drug-related serious adverse events/adverse events of special interest
as described in the Flow Chart and Section 6.2.3.


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Figure 3.1: 1 Trial design
The primary PFS analysis for this Phase II trial will take place after approximately
40 patients have had an event of disease progression (independent assessment) or death; 
this is defined as the “Last Subject Last Visit Primary Endpoint” (LSLVPE). Patients will 
be followed up for OS (FU-OS) until all patients have completed treatment and attended 
the first follow-up visit (FU1). This time point is defined as the “Last Subject Last Visit 
Secondary Endpoint” (LSLVSE).
Note if at the time of LSLVPE the trial meets a pre-defined criterion (to be defined in 
the DMC charter) the trial will be expanded seamlessly into a confirmatory Phase III 
trial, changes to the LSLVPE and LSLVSE will be provided in a protocol amendment.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The trial is designed with two parallel arms in order to assess the efficacy and safety of 
xentuzumab in combination with everolimus and exemestane when compared to placebo 
in combination with everolimus and exemestane.
The trial will be conducted in a double-blind fashion as information about treatment 
assignment can consciously or unconsciously influence the behaviour and decisions of 
patients, investigators, care-givers and third-party evaluators. By blinding patients and 
investigators to treatment introduction of bias will be limited. This is particularly important 
as not only weekly i.v. infusions of blinded trial treatment, but also regular blood collection
for assessment of PK, ADAs and biomarkers will be performed. If the trial would be 
conducted in an unblinded fashion the latter could lead to non-compliance, bias, affect 
accrual and data integrity and eventually trial outcome.
The backbone therapy for trial 1280-0022, everolimus and exemestane, is standard of care 
therapy for women with advanced HR+/HER2- advanced or metastatic breast cancer who 
failed/had recurrent disease after or on treatment with a non-steroidal aromatase inhibitor
e.g letrozole or anastrazole. It is used according to its approved label or as recommended 
by guidelines (P17-09321, R17-2948).
Patients with non-visceral disease constituted 41.5% of the population included into 
the confirmatory trial for everolimus (BOLERO-2 trial) and with 9.9 months had a 


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better median PFS compared to patients with visceral metastases who showed 6.8 
months median PFS (R16-0802).
Patients should have archival tumour tissue available and a sample of this will be provided 
for analysis of HR/HER2 status by a central lab (biopsy sample from the bone is not 
acceptable). It is well documented in the scientific literature that there are discrepancies in 
biomarker analyses between local and central labs e.g. up to 23% discordance rate for 
HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) (R09-
6008; R09-6009; R09-6011). HR/HER2 tests will be performed by a central laboratory 
based on ASCO/CAP guidelines (R15-6055, R17-4255) but results are not required to 
confirm eligibility.
A Steering Committee (SC) will be established for this trial. The SC will monitor the 
trial on a regular basis (see Section 8.7).
An independent DMC will be appointed to periodically assess the trial data, including the 
aggregated data at the treatment level to ensure overall safety and integrity of the trial. A 
decision as to whether or not the trial is expanded into a Phase III trial will be made by 
the DMC at the time-point of the primary PFS analysis for this Phase II trial. The 
criterion for expansion will be pre-defined in the DMC charter, prior to trial initiation. 
For further details refer to Sections 7.4 and 8.7.
3.3
SELECTION OF TRIAL POPULATION
It is estimated that approximately 180 patients will be screened for the trial in order to 
enrol approximately 80 eligible patients (see section 7.7). The trial will run at 
approximately 80 sites globally in approximately 15 countries. The rate of randomisation 
will vary by trial site, but is expected to be approximately 1 to 2 patients per site. 
Additional countries may be added if necessary.
Enrolment is competitive. Investigators will be notified when the appropriate number of 
patients has been screened and screening is complete, thereafter additional patients will not 
be allowed to be recruited for this trial. Patients who have signed an informed consent and 
are eligible prior to notification of the termination of recruitment will be allowed to 
continue in the trial.
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) at the investigational site irrespective of 
whether they have been treated with investigational drug or not.
3.3.1
Main diagnosis for trial entry
All patients that will be included into the trial must be female patients diagnosed with 
histologically confirmed HR+/HER2- advanced or metastatic breast cancer and non-
visceral disease. Male breast cancer patients will be excluded from participation in this trial 
as breast cancer in male and female patients has different biology and little is known about 
tolerability and efficacy of hormone treatments in male patients (R17-4300; R17-4303).


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3.3.2
Inclusion criteria
1. Histologically confirmed breast cancer with documented ER-positive and/or PgR-
positive and HER2-negative status if there are at least 1% positive tumour nuclei in the 
sample as defined in the relevant American Society of Clinical Oncology 
(ASCO)/College of American Pathologists (CAP) Guidelines (R15-6055, R17-4255)
2. Locally advanced or mBC not deemed amenable to curative surgery or curative 
radiation therapy
3. Archival tumour sample available at the time of informed consent and provided to 
the central laboratory around the time of randomisation. Patients must provide a
formalin-fixed paraffin embedded (FFPE) tissue biopsy sample preferably taken at 
the time of presentation with recurrent or metastatic disease (provision of a biopsy 
sample taken from the bone is not acceptable). If archival tissue is not available, 
provision of detailed information from the original histology report may be agreed 
with the sponsor on a case by case basis.
4. Patients must satisfy the following criteria for prior therapy:

Disease progression during treatment or within 12 months of completion of 
endocrine adjuvant therapy 
OR

Disease progression while on or within 1 month after the end of prior endocrine
therapy for advanced/metastatic breast cancer (Note: the endocrine therapy does 
not have to be the treatment immediately prior to trial entry).
5. Inclusion criteria 5 is not applicable for patients enrolled after protocol version 4 is 
approved.
6. Inclusion criteria 6 is not applicable for patients enrolled after protocol version 4 is 
approved.
7. Female patients ≥18 years old or over the legal age of consent in countries where that 
is greater than 18 years at the time of informed consent. Patients must be either:

Premenopausal on ovarian suppression with a gonadotropin-releasing 
hormone (GnRH) agonist with FSH and estradiol in postmenopausal range
(initiated at least 28 days prior screening ) OR

Post-menopausal, defined as one of the following:
•
Age ≥ 60 years
•
Age < 60 years and amenorrheic for 12 or more months in the absence of 
chemotherapy, tamoxifen, toremifene, or ovarian suppression, and FSH and 
estradiol in the postmenopausal range.
•
If taking tamoxifen or toremifene, and age < 60 years, then FSH and 
estradiol level in post-menopausal range.
•
Surgical menopause with bilateral oophorectomy
8. Patients must have an indication for combination treatment with everolimus 
and exemestane.
9. Patients must have

At least one measurable non-visceral lesion according to RECIST version 1.1 in 
either lymph nodes, soft tissue, skin
AND/OR

At least one measurable non-visceral lesion according to RECIST version 1.1 as 
lytic or mixed (lytic + blastic) in bone
AND/OR


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
At least one non-measurable (lytic, mixed lytic + blastic, or blastic) bone lesion 
according to RECIST version 1.1
10. Eastern Cooperative Oncology Group (ECOG) performance score 0 or1 (R04-1314)
11. Fasting glucose <8.9 mmol/L (<160 mg/dL) and HbA1c <8.0%
12. Adequate organ function, defined as all of the following:
a) Absolute neutrophil count (ANC) ≥1500/mm3
b) Platelet count ≥100,000/mm3
c) International Normalised Ratio (INR)1 ≤2.0
d) Serum creatinine ≤1.5 times upper limit of institutional normal (ULN) or creatinine 
clearance ≥50 mL/min (measured or calculated by Cockcroft and Gault formula).
e.) Total Bilirubin ≤1.5 times ULN (patients with Gilbert syndrome total bilirubin must
be <4 times ULN)
f) Aspartate amino transferase (AST) and alanine amino transferase (ALT) ≤2.5 times the 
ULN
g) Fasting triglycerides ≤300 mg/dL or 3.42 mmol/L h) Haemoglobin (Hgb) ≥9.0 g/dL
13. Recovered from any previous therapy related toxicity to ≤Grade 1 at study entry (except 
for stable sensory neuropathy ≤Grade 2 and alopecia)
3.3.3
Exclusion criteria
1.
Previous treatment with agents targeting the IGF pathway, AKT, or mTOR 
pathways (sirolimus, temsirolimus, etc.)
2.
Prior treatment with exemestane (except adjuvant exemestane stopped >12 
months prior to start of study treatment as long as the patient did not recur 
during or within 12 months after the end of adjuvant exemestane)
3.
Evidence of visceral metastasis/es (i.e. liver, lung, peritoneal, pleural 
metastases, malignant pleural effusions, malignant peritoneal effusions) at 
screening. NOTE: Patients with a past history of visceral metastases are 
eligible if visceral metastases have completely resolved at least 3 months 
prior to screening.
4.
History or evidence of metastatic disease to the brain
5.
Leptomeningeal carcinomatosis
6.
Known hypersensitivity to any of the study drugs or their excipients
7.
Any contraindication to treatment with everolimus or exemestane
8.
More than 1 prior line of chemotherapy for HR+ HER2- metastatic breast cancer
9.
Radiotherapy within 4 weeks prior to the start of study treatment, except in case of 
localised radiotherapy for analgesic purpose or for lytic lesions at risk of fracture 
which can then be completed within two weeks prior to study treatment
10. Major surgery (major according to the investigator’s assessment) performed 
within 4 weeks prior to randomisation or planned after screening
11. Use of concomitant systemic sex hormone therapy (e.g. Megace) within 2 weeks prior 
to start of trial treatment. NOTE: Ovarian suppression with GnRH agonists is 
permitted in premenopausal patients.
12. History or presence of cardiovascular abnormalities such as uncontrolled 
hypertension, congestive heart failure NYHA classification of ≥3, unstable angina or 
poorly controlled arrhythmia which are considered as clinically relevant by the
investigator. Myocardial infarction within 6 months prior to randomisation.
13. Any history of or concomitant condition that, in the opinion of the Investigator, would 


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compromise the patient’s ability to comply with the study or interfere with the 
evaluation of the efficacy and safety of the study medications.
1.
To avoid inclusion of patients with active bleeding, bleeding diathesis
14. Previous or concomitant malignancies at other sites, except effectivelytreated
a) Non-melanoma skin cancers
b) Carcinoma in situ of the cervix
c) Ductal carcinoma in situ
d) Other malignancy that has been in remission for more than 3 years and is 
considered to be cured.
15. Known pre-existing interstitial lung disease (ILD).
16. Known active hepatitis B infection (defined as presence of Hep B sAg and/or Hep 
B DNA), active hepatitis C infection (defined as presence of Hep C RNA) and/or
known Human immunodeficiency virus (HIV) carrier
17. Active infectious disease which puts the patient at increased risk in the opinion of the 
investigator
18. Any history or presence of uncontrolled gastrointestinal disorders that could affect 
the intake and/or absorption of the study drug (e.g. nausea, uncontrolled vomiting, 
Crohn’s disease, ulcerative colitis, chronic diarrhoea, malabsorption) in the opinion 
of the investigator
19. Previous randomisation in this trial
20. Concurrent participation in another clinical trial with an investigational device ordrug.
21. Patients receiving concomitant immunosuppressive agents or chronic corticosteroid 
use except in cases outlined below:
Topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways 
diseases), eye drops, mouth washes or local injections (e.g. intra-articular) are
allowed
Patients on stable low dose of corticosteroids for at least two weeks before study 
entry are allowed
22. Patients who have taken or wish to continue the intake of restricted medications
(see Section 4.2.2.1) or any drug considered likely to interfere with the safe 
conduct of the trial must have stopped them at least 2 weeks before C1V1.
Treatment with denosumab/bisphosphonates is allowed.
23. Growth hormones or growth hormone inhibitors
24. More than 1 prior treatment line with a CDK4/6 inhibitor
25. Pregnant or nursing (lactating) women.
26. Women of child-bearing potential* unless they are using highly effective non-
hormonal methods of contraception that achieve a failure rate of less than 1% per 
year when used consistently and correctly during dosing of study treatment and for 
at least 1 month after the last dose of exemestane, 8 weeks after the last dose of 
everolimus and 6 months after the last dose of xentuzumab/placebo (whichever is 
the longest). Highly effective contraception methods include: 

True abstinence, when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of exposure to IMP and 
withdrawal are not acceptable methods of contraception. 

Total hysterectomy or tubal ligation at least six weeks before taking study treatment. 


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
Sterilisation of male partner (at least 6 months prior to screening). For female subjects 
on the study, the vasectomized male partner should be the sole partner for that subject.

Combination of the following: 
o
Placement of an intrauterine device (IUD)** or intrauterine system (IUS)**
o
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
*A woman is considered of childbearing potential (WOCBP), i.e. fertile, following 
menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy.
** Non-hormone releasing only
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole 
(“withdrawal of consent”) with very different implications, please see Sections 3.3.4.1
and 3.3.4.2 below.
An excessive withdrawal rate can have a severe negative impact on the scientific value of 
the trial. Every effort should be made to keep the randomised patients in the trial: if 
possible on treatment, or at least to collect important trial data. Measures to control the 
withdrawal rate include careful patient selection, appropriate explanation of the trial 
requirements and procedures prior to randomisation, as well as the explanation of the 
consequences of withdrawal. The decision to withdraw from trial treatment or from the 
whole trial as well as the reason must be documented in the patient files and case report 
form (CRF).
3.3.4.1 
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:

The patient wants to withdraw from trial treatment, without the need to justify 
the decision.

The patient requires palliative radiotherapy or needs to take concomitant drugs that 
interfere with the investigational product or other trial medication (see Section 4.2.2).

The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, adverse events, other diseases, secondary malignancy or pregnancy).

Has radiologic documentation of progressive disease per RECIST version 1.1   
(Section 5.1) unless the investigator documents that the patient, after discussion with 
the investigator, will continue treatment beyond progression due to clinical benefit
(Section 6.2.2.1).

The patient is diagnosed with ILD and meets the criteria for discontinuation in section 
4.4.3

The patient has repeatedly shown to be non-compliant with important trial 
procedures and, in the opinion of both, the investigator and sponsor representative, is 
not willing or able to stick to the trial requirements in the future.

The patient violates eligibility criteria which would affect the safety of the patient 
(after discussion between the sponsor and the investigator). 


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
The patient entered the trial as premenopausal on ovarian suppression and estradiol 
increases above postmenopausal levels for more than 4 weeks (exceptions to this 
must be discussed with sponsor and patient may be able to stay treatment if they are 
clinically benefitting from treatment and reestablishment of ovarian suppression, e.g. 
by oophorectomy, is expected).
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation (EOT and end of residual effect [EOR]/FU1 visit) and further follow up 
as outlined in the Flow Chart and Section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must 
be recorded in the CRF. These data will be included in the trial database and reported.
Patients in whom visceral disease is detected by central review of baseline scan will have 
the possibility to continue treatment on trial after discussion of individual benefit/risk 
with their investigator.
After completion of the final analyses (see Section 7.3), the Sponsor may remove patients 
from the trial if the patient has access to the trial medication via an alternative source, e.g. 
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 the trial treatment will be incurred by the Sponsor until disease 
progression occurs.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need 
to justify the decision.
This will however mean that no further information may be collected for the purpose of 
the trial and negative implications for the scientific value may be the consequence. 
Furthermore it may mean that further patient follow up on safety cannot occur. The EOT 
visit should be performed after permanent discontinuation of study medication. Wherever 
possible patients should be encouraged to return for the EOR/FU1 visit to ensure 
patient’s safety and that all AEs are followed.
If a patient wants to withdraw consent, the investigator should explain the difference 
between treatment withdrawal and withdrawal of consent for trial participation and explain 
the options for continued follow up after withdrawal from trial treatment, please see 
Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the Sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular 
trial site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive 
benefit- risk-assessment that could significantly affect the continuation of the trial
3. Violation of Good Clinical Practice (GCP), the trial protocol, or the contract 


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impairing the appropriate conduct of the trial
4. All efficacy analyses (see Section 7.3) are complete and all patients have either ended 
study medication or are eligible to receive trial medication under the conditions 
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
Patients will either receive xentuzumab in combination with everolimus and exemestane or 
placebo in combination with everolimus and exemestane (see Tables 4.1.1: 1, 4.1.1: 2,
4.1.2: 1 and 4.1.2: 2).
As of 29 Sept 2021, based on the primary analysis of top line results, Boehringer 
Ingelheim recommended to immediately discontinue xentuzumab and placebo 
administrations.
4.1.1
Identity of the Investigational Medicinal Product (IMP) and Comparator
Table 4.1.1: 1
Xentuzumab
Substance:
Xentuzumab (BI 836845)
Pharmaceutical formulation:
Concentrate for solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/mL supplied in 20 mL vials (200 mg/vial)
Posology:
Weekly infusions of 1000 mg for one hour
administered on Day 1, 8, 15, and 22 of 28-day
cycles and on Day 1, 8, 15, 22, 29, 36, 43, and 50 of 
56-day cycles (infusion solution is diluted to a total 
of 250 mL of 0.9% isotonic sodium chloride solution 
to a concentration of 4 mg/mL). Infusion duration 
may be extended up to a maximum of three hours in 
cases of grade ≥2 infusion reactions.
Route of administration:
Intravenous infusion


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Table 4.1.1: 2
Placebo
Substance:
Placebo
Pharmaceutical formulation:
Concentrate for solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
N/A
Posology:
Weekly infusions for one hour administered on 
the same days as defined in Table 4.1.1: 1.
Route of administration:
Intravenous infusion
Detailed instructions for preparing and handling the infusions, including information on 
infusion equipment, infusion procedure and disposal of unused medication, will be given 
in the pharmacist manual/ISF.
4.1.2
Background medication
The background medication consists of everolimus and exemestane (Tables 4.1.2: 1
and 4.1.2: 2) which must be taken in combination with xentuzumab or placebo, 
respectively. Everolimus and exemestane are not considered as investigational in this
trial. However if mandated by local requirements can be regarded as investigational
e.g IMP.
Table 4.1.2: 1
Everolimus
Substance:
Everolimus (Afinitor®)
Pharmaceutical formulation:
Tablets
Source:
Unit strength:
2.5 mg and 5 mg
Dose:
10 mg daily in accordance with the current SmPC for 
EU or the PI of the respective country
Posology:
Once per day, at approximately the same time of day,
after a meal
Route of administration:
Oral


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Everolimus is a registered commercially available drug. It will be supplied by the 
Sponsor, either via a local supplier not managed through the IRT system, or via the 
central depot managed through IRT system. 
Table 4.1.2: 2
Exemestane
Substance:
Exemestane (Aromasin®)
Pharmaceutical formulation:
Tablets
Source:
 or other companies with 
therapeutic equivalents
Unit strength:
25 mg
Dose:
25 mg daily in accordance with the current SmPC for 
EU or the PI of the respective country
Posology
Once per day, at approximately the same time of day, 
after a meal
Route of administration:
Oral
Exemestane is a registered commercially available drug and generic versions are 
available. It will be supplied by the Sponsor, either via a local supplier not managed 
through the IRT system, or via the central depot managed through IRT system. 
4.1.3
Selection of doses in the trial
In this trial, the dose of exemestane is 25 mg daily based on the label. The dose of 
everolimus is 10 mg daily, which is the approved dose for the trial population (please refer 
to the latest version of SmPC or PI).
In the Phase Ib part of BI trial 1280.4 of everolimus/exemestane and xentuzumab in 
patients with advanced or metastatic breast cancer, the recommended Phase II dose was 
determined as 10 mg daily everolimus and 25 mg daily exemestane in combination with 
1000mg xentuzumab weekly (c03569433-01).
The approval of 10 mg daily dose of everolimus in breast cancer patients is based on 
BOLERO-2 study in which, 50% patients reported grade 3 or 4 AEs (R12-5281) with 
67% patients requiring dose reduction or treatment interruption (R13-1647). The first 
dose reduction step in BOLERO-2 was 50% or 5 mg daily dose. The mean dose intensity 
of everolimus was 7.1 mg/day and 7.9 mg/day for patients at least 65 years old and those 
below 65 years old, respectively. All of these implied that everolimus can be tolerated at 
different dose levels.
A semi-mechanistic PK/PD model was developed describing the kinetics of the 
interaction between xentuzumab and the different PD biomarkers (i.e. free IGF-1 and 


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free IGF-2). Simulations using this model indicate that a weekly dosing of 1000 mg 
xentuzumab reduces free IGF-1 concentration by more than 90% and in addition free 
IGF-2 by 64% at trough steady-state relative to pre-treatment; this is considered a 
relevant biological effect. Therefore, a weekly dose of 1000 mg xentuzumab is 
considered a suitable dose in HR+/HER2- breast cancer patients.
4.1.4
Method of assigning patients to treatment groups
Eligible patients will be randomised to receive either xentuzumab in combination with 
everolimus and exemestane or placebo in combination with everolimus and exemestane 
in a 1:1 ratio according to a randomisation plan. The assignment will occur in a blinded 
fashion via Interactive Response Technology (IRT).
4.1.5
Drug assignment and administration of doses for each patient
The treatment medication assignment for xentuzumab and placebo will be managed through 
an IRT system.
Everolimus and exemestane will be supplied to all investigator sites by the Sponsor, either 
via a local supplier not managed through the IRT system, or via the central depot along with 
the xentuzumab/placebo and managed through the IRT system.
4.1.5.1 
Drug assignment and administration
Treatment will commence within 7 days of randomisation. Any exceptions to this must be 
discussed and agreed with the Sponsor.
Xentuzumab/Placebo
Patients will be treated with 1000 mg xentuzumab/placebo starting at C1V1. 
Xentuzumab/placebo will be administered at the investigator site intravenously over one 
hour with a constant infusion rate on the treatment day as specified in the Flow Chart. If 
the scheduled infusion of xentuzumab/placebo is not performed within the time window, 
this treatment will be skipped. Subsequent visits will follow the original visit date 
schedule. Mannitol is used in the formulation of xentuzumab/placebo, so infusion duration 
of less than one hour must be avoided. The infusion time may be extended to over one 
hour and up to a maximum of three hours in cases of CTCAE grade ≥2 infusion reactions. 
In case of a delay or an interruption of infusion, the reason and the exact time of deviation 
must be recorded in the CRF. The accuracy of this information is crucial for the proper 
evaluation of PK and other data. 
Detailed information of dispensation, preparation, and handling of xentuzumab/placebo 
will be described in the pharmacy manual/ISF.
Drug holidays for up to 14 calendar days (i.e. one missed xentuzumab infusion) e.g. 
vacation, are allowed, if previously agreed with the investigator. This is not considered 
non-compliance (for further details also refer to Section 4.3). Missed infusions due to 
recovery from AEs are not considered “Drug holidays”. Duration of drug holidays beyond 


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14 calendar days has to be agreed with the sponsor.
Everolimus
The recommended treatment dose for everolimus is 10 mg once daily. Complete guidelines 
for management and administration of everolimus can be found in the EU SmPC or the PI 
of the respective country. Please always refer to the current SmPC/PI for instructions. 
Treatment interruptions and dose adjustments should follow the SmPC/PI.
Everolimus will be prescribed by the investigator. Everolimus is supplied by the Sponsor
and will be dispensed at visits described in the Flow Chart either by the investigator, site 
staff or the affiliated pharmacy through IRT. During the trial, patients may be administered 
a combination of different dose strengths of everolimus. For example, 10 mg everolimus 
can be given as one tablet of 10mg, two tablets of 5 mg or one tablet of 5 mg plus two 
tablets of 2.5 mg.
Per CTP version 6, the revised and reduced flow chart should be referenced. 
Exemestane
The recommended treatment dose for exemestane is one 25 mg tablet once daily after a 
meal. Complete guidelines for management and administration of exemestane can be 
found in the EU SmPC or the PI of the respective country. Please always refer to the 
current SmPC/PI for instructions. Treatment interruptions should follow the SmPC/PI.
Exemestane will be prescribed by the investigator. Exemestane is supplied by the Sponsor
and will be dispensed at visits described in the Flow Chart either by the investigator, site 
staff or the affiliated pharmacy through IRT. 
Per CTP version 6, the revised and reduced flow chart should be referenced. 
4.1.5.2
Temporary treatment pauses and dose reduction
Treatment pauses for each of the combination partners, i.e. xentuzumab/placebo, 
everolimus and exemestane are possible when AEs occur. For everolimus and 
exemestane, please refer to the current SmPC/PI. Dose reductions for treatment-related 
AEs are only recommended for everolimus. For details refer to the current SmPC/PI.
Xentuzumab/Placebo: For xentuzumab/placebo no dose reductions are allowed. In the 
event of an AE ≥CTCAE grade 3 considered to be related to xentuzumab, treatment 
should be paused until the patient has recovered from the drug-related toxicity to grade 
≤1 or baseline. Baseline is defined as the CTCAE grade at the start of treatment. 
If a patient has not recovered to CTCAE grade ≤1 or baseline within 14 days, 
continuation of treatment should be discussed with the sponsor. If the patient is deriving 
obvious clinical benefit according to the investigator’s judgement, continuation of 
treatment with xentuzumab/placebo will be decided by the Sponsor and the investigator.
During temporary treatment pauses of xentuzumab/placebo, the scheduled drug infusion 
will be missed. Upon restart of xentuzumab/placebo treatment, infusions should be 
resumed according to regular visit schedule.


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If grade 2 AEs persist for ≥7 days despite treatment and are poorly tolerated by the patient, 
the investigator may choose to pause but must resume treatment within 14 days. For 
recovery and continuation of treatment refer to previous paragraphs.
Xentuzumab/placebo, everolimus/exemestane: In case all treatment drugs need to be 
paused for recovery from treatment-related AEs, patients must resume treatment within 14 
days. If the patient is not able to restart treatment within 14 days but is deriving obvious 
clinical benefit according to the investigator’s judgement, continuation of treatment will be 
decided following agreement between the Sponsor and the investigator.
In the case of adverse events not considered related to xentuzumab, everolimus or 
exemestane, the study drug(s) may be interrupted for up to 14 days, but no dose reduction 
should occur. If the patient is not able to restart treatment within 14 days but is deriving 
obvious clinical benefit according to the investigator’s judgement, continuation of treatment 
will be decided following agreement between the Sponsor and the investigator
4.1.6
Blinding and procedures for unblinding
4.1.6.1
Blinding
The trial will be performed according to a parallel-group, double-blind, placebo-controlled 
design. How long patients, investigators and everyone involved in trial conduct or analysis 
or with any other interest in this double-blind trial will remain blinded with regard to the 
randomised treatment assignments will be dependent upon whether or not the criterion for
the seamless option is met. If the criterion for the seamless option is met then the trial will 
be expanded into a confirmatory Phase III trial and will remain double-blinded until the 
database lock for the primary PFS analysis time-point of the expanded trial. If the criterion 
is not met then the trial will be fully unblinded at the time of the database lock for the 
primary PFS time-point of the unexpanded Phase II trial. The randomisation code will be 
kept secret by Clinical Trial Support up to database lock for whichever primary analysis 
time point is applicable. 
As no added benefit of xentuzumab compared to placebo was observed at the Phase II 
primary PFS analysis time-point, blinding of the trial in anyway is no longer necessary.
The independent DMC will have access to the unblinded treatment codes in order to 
allow them to periodically assess the trial data to ensure the overall safety and integrity of 
the trial, as well as to conduct the pre-specified Phase II primary PFS analysis detailed in 
Section 7.4. For further details refer to Section 8.7 as well as the DMC charter.
Due to a visible difference in xentuzumab versus placebo the pharmacy/dispensing team 
will be unblinded to treatment arm and an unblinded CRA will be employed to monitor 
compliance within the pharmacy department. Procedures to ensure blinding of the 
investigator and the trial team are documented in a separate blinding plan and filed in the 
TMF.
4.1.6.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used 
in an emergency situation when the identity of the trial drug must be known to the 


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investigator in order to provide appropriate medical treatment or otherwise assure safety 
of trial participants. The reason for unblinding must be documented in the source 
documents and/or appropriate CRF page along with the date and the initials of the person 
who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group 
to access the randomisation code for individual patients during trial conduct. The access 
to the code will only be given to authorised Pharmacovigilance representatives and not 
be shared further.
4.1.7
Packaging, labelling, and re-supply
The investigational product and the AMPs, if applicable, will be provided by BI or a 
designated CRO. They will be packaged and labelled in accordance with the principles 
of Good Manufacturing Practice (GMP). Re-supply to the sites will be managed via an 
IRT system, which will also monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.8
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 unblinded CRA or appropriate back-up (as provided 
in the list of contacts) must be contacted immediately.
4.1.9
Drug accountability
The investigator and/or pharmacist and/or investigational drug storage manager will 
receive the investigational drugs delivered by the sponsor when the following 
requirements are fulfilled:

Approval of the clinical trial protocol by the institutional review board (IRB) / 
ethics committee,

Availability of a signed and dated clinical trial contract between the Sponsor and 
the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. 
They must not be forwarded to other investigators or clinics.
The background treatment will be supplied by the Sponsor.
The investigator and/or pharmacist and/or investigational drug storage manager must 
maintain records of the IMP/AMP’s delivery to the trial site, the inventory at the site, the 


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use by each patient, and the return to the sponsor or warehouse/drug distribution centre or 
alternative disposal of unused products at site. If applicable, the Sponsor or 
warehouse/drug distribution centre 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 IMP/AMP and trial patients. The 
investigator/pharmacist/investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the clinical 
trial protocol (CTP) and reconcile all IMPs/AMPs received from the sponsor and/or 
provided by the investigational site. At the time of return to the sponsor and/or appointed 
contract research organisation (CRO)/destruction at site, the 
investigator/pharmacist/investigational drug storage manager must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
4.2.1.1
Rescue medication
Rescue medications to reverse the effects of xentuzumab/placebo are not available. Side 
effects of these treatments should be treated symptomatically. There is no specific 
antidote to overdosage of xentuzumab/placebo. For details regarding everolimus and 
exemestane refer to the current SmPC/PI.
4.2.1.2
Emergency procedures
There are no special emergency procedures to be followed that are specific for this protocol.
Precaution should be taken to avoid extravasation of xentuzumab/placebo. Patients should 
be asked to report any pain or burning at the site of injection immediately. If extravasation 
is suspected the infusion should be stopped immediately.
To date the only expected serious adverse reactions identified for xentuzumab are 
infusion- related reactions observed in patients who received xentuzumab treatment 
(c01690707).
Xentuzumab/placebo infusion should always be administered under close supervision 
of a medically qualified staff member with immediate availability of appropriate 
resuscitation facilities.
Infusion reactions may occur during xentuzumab/placebo infusions and include pyrexia, 
chills, rigors, dyspnoea, urticaria, bronchospasm, hypotension and hypertension. A one hour 
observation period is recommended following each infusion. If there is no infusion reaction 
during the first treatment cycle, the observation period following xentuzumab/placebo
infusions may be adjusted at the discretion of the investigator. Mild to moderate 
infusion reactions may be managed with a slower infusion rate and prophylactic 
antihistamines for subsequent dosing. Severe reactions require immediate and 


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permanent discontinuation of infusion (see Table 4.2.1.2: 1).
The infusion reactions should be treated symptomatically as judged clinically relevant by 
the investigator. For symptomatic treatment of infusion reactions: hydrocortisone, 
antihistamines such as chlorphenamine accompanied by an antipyretic/analgesic and/or a 
bronchodilator is recommended. The infusion duration may be extended to over one hour 
and up to a maximum of three hours, see Section 4.1.4.
Table 4.2.1.2: 1
Infusion reaction management
Infusion 
reaction 
grade
Description of event
Management
CTCAE 
grade 1 or 2
Grade 1:
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated
Grade 2:
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, i.v. fluids); 
prophylactic medications 
indicated for ≤24 h
In the event of CTCAE grade 1 
infusion reactions, the infusion rate 
should be reduced by 50%.
Grade 2 infusion reactions may require 
symptomatic treatment, as described to the 
left (with infusion interruption).
Once the event has resolved, the 
infusion may be restarted at the 
reduced rate.
CTCAE grade 3
Grade 3:
Prolonged (e.g., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
clinical sequelae
For patients experiencing CTCAE grade 
3 infusion reactions, infusion should be 
interrupted immediately and patients 
should receive aggressive symptomatic 
treatment, as described above. Only after 
all the symptoms have disappeared, the 
infusion may be re-started if it is within 3 
h since the infusion start. The infusion 
rate should be reduced by 50% after re-
start.
CTCAE grade 4
Grade 4:
Life-threatening consequences; 
urgent intervention indicated
Patients experiencing CTCAE grade 4 
infusion reactions, such as anaphylaxis 
during an infusion, should have the 
infusion immediately stopped and receive 
appropriate treatment, as described 
above, including use of resuscitation if 
needed. Such patients
should NOT receive any further 
xentuzumab/placebo treatment.


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4.2.1.3
Concomitant treatments
Symptomatic treatments of tumour-associated symptoms are allowed. Concomitant 
medications or therapy to provide adequate supportive care may be given as 
clinically necessary.
After study enrolment, palliative radiotherapy is not allowed (see also Section 3.3.4.1).
See Section 4.4.1.1 for recommendations on supportive treatments whilst on trial 
treatment.
Premenopausal women must be treated with concomitant ovarian suppression with GnRH 
agonists, e.g. goserelin acetate. Estradiol and FSH need to be in the postmenopausal range 
on ovarian suppression at the time of screening, and monitoring of estradiol to document 
that it remains in the postmenopausal range during trial treatment is mandatory. If the 
estradiol level increases above the postmenopausal range during treatment a repeat test 
should be performed within 4 weeks. If still outside of desired range see Section 3.3.4.1.
Use of denosumab for symptomatic treatment of skeletal-related events in adults with 
bone metastases (see Section 4.2.2.1) and/or bisphosphonate therapy for the treatment of 
osteoporosis are permitted during the study according to guidelines and as per SmPC/PI. If 
bisphosphonate/denosumab therapy is initiated after enrolment, the reason for its use must 
be clearly documented in the CRF and progression of disease must be excluded.
All medications (other than study drugs), including anaesthetic agents, vitamins, 
homeopathic/herbal remedies, nutritional supplements starting from the date of signature 
of informed consent and ending at the EOR/FU1 visit must be listed on the concomitant 
medication page of CRF including trade name, start and end dates, indication for use etc. 
as specified in the Flow Chart. Indicating “parenteral nutrition” or “anesthesia” without 
specifying details will be sufficient.
Hematopoietic growth factors should be reserved to cases of severe neutropenia and 
anemia as per the labelling of these agents following ASCO guidelines (R16-1540).
In case of major surgery no modifications for xentuzumab/placebo treatment are needed.
For everolimus and exemestane please refer to current SmPC/PI
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
No experimental anti-cancer treatment and/or standard chemotherapy, 
immunotherapy, endocrine therapy (except for ovarian suppression in 
premenopausal women as described in section 4.2.1.3), or radiotherapy (other than 
described in Section 4.2.1.3) is allowed concomitantly with the administration of 
study treatments.
No hormone replacement therapy, topical oestrogens (including any intra-vaginal 
preparations), megestrol acetate and selective estrogen-receptor modulators (e.g. 


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raloxifene) is allowed concomitant with the administration of study treatments.
The use of megestrol acetate to improve appetite and to increase weight in cancer-
associated anorexia is not allowed.
Restrictions regarding concomitant medications during everolimus and exemestane 
treatment should follow the current SmPC/PI.
4.2.2.2
Restrictions on diet and life style
Patients need to be fasted for blood draws for safety labs (fasting in this protocol is defined as 
no food or fluid intake with the exception of water for at least 8 hours).
4.3
TREATMENT COMPLIANCE
The study medications will be given in accordance with the protocol and the instructions 
of a site investigator. The investigator should instruct the patient to take the trial drugs 
exactly as described.
The patient will be provided with a Patient Diary to record administration of both 
everolimus and exemestane as well as any observations during their treatment period, for 
example any occurrence of a missed or delayed dose and/or vomiting. 
4.3.1
Xentuzumab/Placebo
Xentuzumab/placebo will be administered as a single infusion under supervision of the 
investigator or dedicated study personnel. In the event that the full dose of 
xentuzumab/placebo is not administered to the patient, it must be documented and 
explained.
Drug holidays, if previously agreed with the investigator and Sponsor, e.g. vacation, will 
not be considered as non-compliance. For details see Section 4.1.5. A minimum number 
of 10 doses of xentuzumab/placebo should be applied per 12 weeks (>80%) but not more 
than 4 doses per year are allowed to be missed. Treatment pauses due to AEs are not 
considered non-compliances either.
4.3.2
Everolimus and exemestane
Patients should be given an appropriate number of everolimus and exemestane tablets to 
be self-administered.
Patients will be asked to bring any remaining trial medication and empty packaging to the
investigator site for a compliance check at the end of each treatment cycle. The remaining 
tablets will be counted by the investigator/site staff and documented. Discrepancies 
between the number of tablets remaining and the calculated number of tablets the patients 
should have taken must be documented and explained. Any remaining medication will be 
collected. If the patient is eligible for further treatment, new trial medication must be 
provided.
The investigator and/or the Sponsor can terminate a patient’s further trial treatment in 


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the event of serious and persistent non-compliance which jeopardizes the patient’s 
safety or renders trial results for this patient unacceptable.
Drug holidays, if previously agreed with the investigator, e.g. vacation, will not be 
considered as non-compliance. For details see Section 4.1.5. Treatment pauses due to AEs 
are not considered non-compliances either.
4.4
MANAGEMENT OF EXPECTED ADVERSE EVENTS
To date the only expected adverse events for xentuzumab are infusion related 
reactions, which will be graded according to CTCAE version 5.0 (R18-1357) and 
treated following standard of care or local guidance. Guidance is also provided in 
Table 4.2.1.2: 1. Immune responses to the xentuzumab mAb will be assessed 
measuring anti-drug antibody levels during the trial.
However, in trial 1280.4 which was utilizing combination treatment with 
xentuzumab/everolimus and exemestane, the following AEs were reported in >20% 
of the patients: Diarrhoea, stomatitis, mucosal inflammation, rash, asthenia, nausea,
cough, decreased appetite, fatigue, hyperglycemia, anaemia, neutropenia, vomiting, 
thrombocytopenia and increased ALT.
Proactive side effect management is crucial to maintain patients on long-term therapy and 
supportive measures for management of adverse events should be started as early as possible 
after onset of symptoms. Patients should be advised to report AEs promptly so that 
appropriate treatment can be initiated.
The following recommendations (as well as those in Appendix 10.2) should be followed 
unless institutional guidelines are available and are implemented based on the investigator’s 
judgement. Side effects observed with everolimus and /or exemestane treatment should be 
managed in accordance with their current SmPC/PI. 
4.4.1
Management of stomatitis/mucosal inflammation
Routine and systematic oral hygiene is extremely important to reduce the incidence 
and severity of the side effects of cancer treatment so it is recommended that all 
patients initiate prophylactic hygiene measures.
Stomatitis most often occurs within the first eight weeks of treatment. Initiating a 
dexamethasone alcohol-free oral solution as a swish and spit mouthwash has been shown to 
reduce the incidence and severity of stomatitis (R17-1688).
4.4.1.1
Treatment recommendations for the prophylaxis of stomatitis

Mouthwashes should be used from C1V1. Mouthwashes eliminate food particles that 
can accumulate and favour bacterial growth. The preferred solutions are dexamethasone 
oral solution (SWISH guidelines – see R17-1688), normal saline, sodium bicarbonate, or 
a mixture of normal saline and sodium bicarbonate. These should be used after each meal 
and before going to bed. Solutions containing alcohol should be avoided as they 


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dehydrate the mucosa. If the mucosa is ulcerated, hydrogen peroxide solution should not 
be used as this will interfere with the formation of granulation tissue and healing of the 
ulcer. 

For sites with access to dexamethasone containing mouthwashes: Patients 
should use dexamethasone containing mouth washes from C1V1 (R17-1688) as
prescribed/provided by investigator/trial site personnel (10 mL of alcohol-free 
dexamethasone 0.5 mg per 5 mL oral solution). The mouthwash should be 
swished for 2 min (a timer should be set) and spit four times daily for 8 weeks. 
Following each mouth wash, patients should not to take anything by mouth for 1 
h for a total of 4 h per day. After the initial 8 week period, the dexamethasone 
mouthwash can be continued for up to 8 additional weeks at the discretion of the 
investigator and patient.
Products containing glycerine or lemon, or toothpastes with an abrasive action should be 
avoided.
Correct oral hygiene should be maintained with daily brushing of the teeth, tongue and 
gums, being performed after meals and before going to bed, using a non-irritant 
toothpaste, a soft toothbrush and dental floss to clean between the teeth. This should be 
followed by rinsing the mouth with a mouthwash.
Dental prostheses should be cleaned and brushed, and at night should be left in 1% 
sodium hypochlorite solution (if they contain no metal) or in a solution of povidone
iodine.
Lips should be kept hydrated using lip balms (cocoa butter), methylcellulose 
solutions, moisturising cream or olive oil. Petroleum jelly or glycerine should be 
avoided because of their dehydrating effects on the lip tissue.

Chlorhexidine can be used in the form of 15 mL of 0.12% chlorhexidine mouthwash 
2-3 times a day. It is an antiseptic with a broad antimicrobial spectrum and has a 
bacteriostatic action and is particularly active against gram-positive microorganisms; 
it is sporostatic and fungistatic (activity against candida). It has a rapid effect and, in 
addition, presents considerable persistence and residual adherence. Due to its cationic 
nature, it has the property of binding to the oral mucosa. 

Foods that trigger pain e.g. acids, spicy and hot foods should be avoided. Patients should 
attempt to eat a soft diet and increase their intake of cold and nutritious fluids.
4.4.1.2
Treatment recommendations for established stomatitis/mucositis
General and grade specific recommendations are described in Table 4.4.1.2: 1.
Treatment is supportive and aims at symptom control. Treatment may include:
Atraumatic cleansing and rinsing with non-alcoholic solutions such as normal saline, 
diluted salt and baking soda solution (e.g. one-half teaspoonful of salt and one teaspoon 
of baking soda in one quart of water every four hours);
Avoidance of agents containing iodine, thyme derivatives and prolonged use of 
hydrogen peroxide;
Dietary manoeuvres such as promotion of soft, non-irritating foods like ice-
creams, mashed/cooked vegetables, potatoes and
Avoidance of spicy, acidic or irritating foods such as peppers, curries, chillies, nuts 


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and alcohol.
If the patient is unable to swallow foods or liquids, parenteral fluid and/or 
nutritional support may be needed. Examples of some of the agents suggested in
Table 4.4.1.2: 1 include: topical analgesics - viscous lidocaine 2%; mucosal 
coating agents - topical kaolin/pectin; oral antacids, maltodextrin, sucralfate; 
topical antifungals - nystatin suspension (adapted from P11-09424).
Lidocaine is an amide-type local anaesthetic that is widely used both topically and 
parenterally. In the management of mucositis, it can be useful for the treatment of 
pain. It is administered locally in the form of a gel or solution. Apply 1% lidocaine 
viscous to ulcers before each meal.
Nystatin is an antifungal (fungistatic) agent with a broad spectrum. Nystatin 
suspension has been studied as prophylaxis against candida in patients on treatment 
with antineoplastic and/or immunosuppressant drugs. Apply after the main meals if 
there are signs of candidal superinfection of mucositis.
Corticosteroids, in the case of mucositis, reduce the inflammatory reaction that occurs in 
this condition, probably by inhibiting the production of leukotrienes and prostaglandins.
Triamcinolone acetonide 0.1% in orabase qsp 30 g or
Hydrocortisone 1% in orobase qsp 50 g
Applications are performed 2-3 times a day with the recommendation not to eat or drink 
for 30 minutes after the application to facilitate its adherence to the mucosa. In case of 
no improvement of mucositis/stomatitis, additional therapy may be added:
Fluconazol oral 100 mg daily in case of no improvement with topical antifungal 
treatment with nystatin. Please note that fluconazole is a moderate inhibitor of CYP 
3A4, which may potentially have an impact on metabolism of everolimus and
exemestane.
Systemic antiherpetic therapy (i.e. Famvir 750 mg/d for 7 days otherwise Aciclovir 
oral or i.v.) at investigator’s discretion.
For dose reduction, interruption or discontinuation of everolimus in the management of 
stomatitis, refer to the current EU SmPC of everolimus or the PI of the respective 
country.
Table 4.4.1.2: 1
Grade-specific treatment recommendations of mucositis/stomatitis
Severity 
(CTCAE 
grading)
Description
Treatment recommendations*
Mild (Grade 1)
Asymptomatic or mild 
symptoms; intervention 
not indic
ated
For sites with access to dexamethasone 
containing mouthwashes:
Swish 10 mL of a 0·9% saltwater solution and 
spit, followed by the same regimen of 
dexamethasone mouthwash as in section 
4.4.1.1 10–15 min later. 
For sites without access to dexamethasone 
containing mouthwashes:
Refer to 4.4.1.1


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Severity 
(CTCAE
grading)
Description
Treatment recommendations*
Moderate (Grade 2)
Moderate pain or ulcer 
that does not interfere 
with oral intake; 
modified diet indicated
Addition of topical analgesic mouth treatments, 
topical corticosteroids, antiviral therapy if 
herpetic infection confirmed, antifungal therapy 
preferably topical on a case by case basis.
Severe (Grade 3)
Severe pain; interfering 
with oral intake
Same as for grade 2; institute additional 
symptomatic therapy (topical or systemic) as 
clinically indicated.
Life 
threatening 
(Grade 4)
Life-threatening 
consequences; urgent 
intervention indicated
Same as for grade 2; institute additional 
symptomatic therapy (topical or systemic) as 
clinically indicated.
4.4.2
Management of hyperglycaemia
In case of hyperglycaemia treatment should follow the institutional standard or guidelines 
(R13-1975). Monitoring of fasting glucose is recommended prior to start of therapy and 
periodically thereafter. Optimal glycaemic control should be achieved before starting trial 
treatment. After commencing the study medications, monitoring of blood glucose should 
be individualized according to baseline glycemic function (normal, prediabetic, risks for 
diabetes mellitus or diabetes mellitus (may refer to R13-1975 and SmPC f/PI for 
everolimus)). If fasting glucose values above 200 mg/dL occur, the investigator should 
evaluate the need to intensify antihyperglycaemic therapy potentially in collaboration with 
the treating physician responsible for the treatment of the diabetic condition or a specialist. 
If hyperglycaemia occurs in patients without history of diabetes or hyperglycaemia and 
without contraindication, oral anti-diabetics, such as metformin 1 g to 2.5 g/d with less 
hypoglycaemic risk, may be started if necessary.
In case of grade 3 or higher hyperglycaemic events, the patient should have immediate 
access to consultation with an endocrinologist or specialist. When the study drugs are 
discontinued, the need for further antidiabetic treatment has to be evaluated depending on 
the blood glucose levels of the patient.
4.4.3
Management of non-infectious pneumonitis/ILD
Non-infectious pneumonitis is a class effect of rapamycin derivatives and has been 
observed in trial 1280.4. Fatal cases of non-infectious pneumonitis (including interstitial 
lung disease) have occurred. Careful assessment of all patients with an acute onset 
and/or unexplained worsening of pulmonary symptoms (dyspnoea, cough, fever) should 
be performed to exclude pneumonitis/ILD. Interruption of study medication may be 
considered pending investigation of these symptoms and appropriate treatment instituted 
as necessary. If pneumonitis/ILD is suspected the investigator should monitor patients 
for clinical symptoms and radiological changes. For dose reduction, interruption or 
discontinuation of the trial drugs, the following guidance should be used:


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
Xentuzumab/Placebo: see section 4.1.5.2

Everolimus/Exemestane: refer to the current EU SmPC of everolimus or the 
PI of the respective country and section 4.1.5.2
4.4.4
Management of neutropenia
Adverse events of neutropenia have been observed in trials with xentuzumab and 
causality has been established with everolimus. Patients should be monitored closely for 
signs of infection. No dose adjustment for xentuzumab is indicated. Dose adjustment 
for severe neutropenia (≥grade 3) should follow the everolimus SmPC/PI. Fever or 
infection in the presence of severe neutropenia should be managed promptly as 
clinically indicated. For management of xentuzumab during an infection, please refer to 
section 4.1.5.2, for management of everolimus, please follow everolimus SmPC/PI.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Response and progression will be evaluated in this trial using RECIST guideline 
(version 1.1) in combination with MD Anderson criteria for patients with target and/or 
non target bone lesions, at the time points specified in the Flow Chart. Adaptions to the 
MD Anderson criteria include clarifications and modifications to the published criteria 
and aim to provide more objective and reproducible assessments for the disease under 
study. A modification to the RECIST 1.1 criteria in regards to target lesion location 
selection will also be also implemented to properly address the patient population being 
studied (R17-4024). See Appendix 10.4 for details on lesion measurements and 
response assessment.
Tumour response will be assessed by the investigator and central independent review 
throughout the trial. Clinical decisions will be based on investigator assessment of tumour 
response. The results of the independent assessment will not be communicated to the 
investigator. Instruction for obtaining images and the shipment/transfer of image data will 
be provided by the central image review provider.
As of 29 September 2021, tumor assessments will be assessed per local practice. Only the 
overall response will be collected in the eCRF.
5.2
ASSESSMENT OF SAFETY
Safety will be assessed as indicated by incidence and severity of AEs, graded according 
to NCI CTCAE version 5.0 (R18-1357).
Effective upon approval of CTPv6.0, Physical examination, Vital signs/ECOG 
Performance Status, and Safety laboratory parameters will be assessed per local 
institutional practice.
5.2.1
Physical examination
A physical examination will be performed at screening and at the timepoints specified in 
the Flow Chart. Of note: Skin lesions have to be properly documented and followed as 
tumour lesions. For details refer to Appendix 10.4.
A full physical examination serves as a clinical tumour assessment and should 
include a cardiopulmonary examination, examination of the regional lymph nodes, the 
abdomen and an assessment of the mental and neurological status. Additional 
symptoms which have not been reported during a previous examination should be 
clarified. Wherever possible the same investigator should perform this examination. 
Includes height (only at SV) and weight.
A limited physical examination should include a cardiopulmonary 
examination, a clinical tumour assessment, an examination of the regional lymph 
nodes and an examination of the abdomen. Includes weight. The results must be 
included in the source documents available at the site.


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5.2.2
Vital signs and ECOG Performance Status
Vital sign measurements (blood pressure [systolic blood pressure, diastolic blood 
pressure], pulse rate, respiratory rate, temperature) and the evaluation of the ECOG 
performance status (see Appendix 10.3) will be performed at the times specified in the 
Flow Chart. Blood pressure and pulse will be measured after the patient has been 
recumbent or seated for about 5 minutes.
2 Baseline images will be assessed for evidence of visceral disease. If visceral disease present refer to Section 3.3.4.1.
5.2.3 
Safety laboratory parameters
Safety laboratory samples will be analysed at a local laboratory. Safety laboratory 
examinations will include tests as presented in Table 5.2.3: 1, and should be obtained at the
time points specified in the Flow Chart. Note: the safety lab blood draw may be taken on the 
day before the xentuzumab infusion so long as it is within the window allowed for the visit. 
Safety laboratory examinations should be taken with the patient in a fasted state (fasting in 
this protocol is defined as no food or fluid intake with the exception of water for at least 8 
hours).
Table 5.2.3:1
Safety laboratory tests
Category
Parameters
Haematology
Red blood cell count (RBC), haemoglobin, haematocrit, platelet count, 
reticulocytes, white blood cell count (WBC) with differential 
(neutrophils, bands, lymphocytes, monocytes, eosinophils, basophils)
Coagulation
International Normalized Ratio (INR), activated Partial 
Thromboplastin Time (aPTT)
Electrolytes
Sodium, potassium, calcium, magnesium, chloride, 
bicarbonate (HCO3)
Biochemistry incl. 
liver and renal 
function tests
Albumin, creatine phosphokinase (CPK); in case of pathological CPK 
further evaluation (e.g. by determination of isoenzymes, troponin 
assays, ECG exam) should be performed as clinically indicated.
Alkaline phosphatase, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT),
γ-glutamyltransferase (GGT), total bilirubin
Blood urea (preferred) or blood urea nitrogen (BUN), creatinine; 
creatinine clearance (for details refer to Section 3.3.2 and
Appendix 10.6)
Pancreatic function 
parameters
Amylase, Lipase


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Lipid profile (fasting)
Total cholesterol, triglycerides, LDL, High-density lipoprotein (HDL)
Hormones
(premenopausal 
women) and 
postmenopausal 
women less than 60 
years of age only)
Premenopausal women:
Estradiol, FSH and Pregnancy testing (serum/urine), see Flowchart
*Postmenopausal women less than 60 years of age (in the absence of 
bilateral oophorectomy):
Estradiol and FSH, see Flowchart
*Effective 29 Sept 2021, hormone testing for post-menopausal
woman is no longer applicable
Table 5.2.3:1 Safety laboratory tests (contd.)
Category
Parameters
Other
Phosphorus, lactate dehydrogenase (LDH), total protein, uric acid
Other (fasting)
Glucose (preferably from plasma) and HbA1c
Urinalysis
pH, protein, glucose, blood, leucocytes, nitrite will be analysed by 
dipstick (semi-quantitative measurements:
-, +,++, +++); in case of pathological finding further evaluation 
should be performed and results documented
The investigator should complete additional evaluations of laboratory tests as clinically 
indicated. Any abnormal and clinically relevant findings from these investigations need to 
be reported as an AE.
5.2.4
Electrocardiogram
A 12-lead resting ECG will be performed at the time points specified in the Flow Chart. 
The investigator or a designee will evaluate whether the ECG is normal or abnormal and 
whether it is clinically relevant, if abnormal. ECGs may be repeated for quality reasons 
and the repeated recording used for analysis.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed 
and/or treated as medically appropriate.
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of 
ECG with findings should be documented in patient’s medical record.
Effective after approval of CTPv6.0 ECG no longer required for ongoing patients.


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5.2.5
Left Ventricular Ejection Fraction
Effective after approval of CTPv6.0 MUGA is assessment is no longer applicable for 
ongoing patients.
Left Ventricular Ejection Fraction (LVEF) as measured by echocardiography or Multiple 
Gated Acquisition (MUGA) scan will be assessed as specified in the Flow Chart. The 
same method of measurement must be used throughout the trial. LVEF assessment does 
not need to be repeated during screening if there is valid result available from an 
assessment which was performed as part of routine clinical practice within 28 days prior to 
start of trial treatment.
Echocardiography will be performed to assess the LVEF according to the 
standard guidelines of the American Society of Echocardiography (R06-1414).
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.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed 
and/or treated as medically appropriate.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a medicinal product and which does not 
necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of 
the following criteria:
-
Results in death,
-
Is life-threatening, which refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
Requires inpatient hospitalisation or
-
Requires prolongation of existing hospitalisation,


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-
Results in persistent or significant disability or incapacity, or
-
Is a congenital anomaly/birth defect,
or
-
Is deemed serious for any other reason if it is an important medical event when 
based on appropriate medical judgement which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse.
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the duration between discontinuation of the trial medication and must be 
reported as described in Section 5.2.6.2, subsections “AE Collection” and AE 
reporting to sponsor and timelines”.
In accordance with the European Medicines Agency initiative on Important Medical 
Events, Boehringer Ingelheim has set up a list of further AEs, which by their nature, can 
always be considered to be “serious” even though they may not have met the criteria of 
an SAE as defined above.
The latest list of “Always Serious AEs” can be found in the Electronic Data Capturing 
(eDC) system. These events should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as 
being of particular concern for prospective safety monitoring and safety assessment within 
this trial,e.g. the potential for AEs based on knowledge from other compounds in the same 
class. AESIs need to be reported to the Sponsor’s Pharmacovigilance Department within 
the same timeframe that applies to SAEs, please see above.
The following are considered as AESIs:
Hepatic injury is defined by the following alterations of hepatic laboratory parameters:
An elevation of AST and/or ALT >3 fold ULN combined with an elevation of 
total bilirubin >2 fold ULN measured in the same blood draw sample, and/or
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the 
eDC system. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, etc.) 
without lab results (ALT, AST, total bilirubin) available, the investigator should make 
sure these parameters are analysed, if necessary in an unscheduled blood test. Should the 
results meet the criteria of hepatic injury alert, the procedures described in the DILI 
checklist should be followed.
Pneumonitis including interstitial lung disease, non-infectious pneumonitis and 
other analogous terms.


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Intensity (severity) of AEs
The intensity (severity) of adverse events should be classified and recorded in the 
CRF according to the CTCAE version 5.0 (R18-1357).
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or 
re-challenge, confounding factors such as concomitant medication, concomitant 
diseases and relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal 
relationship could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drugclass.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. 
pre- existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population 
not exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal 
relationship could be:

No plausible time to onset of the event relative to the time of drug exposure is 
evident (e.g. pre-treatment cases, diagnosis of cancer or chronic disease within 
days / weeks of drug administration; an allergic reaction weeks after 
discontinuation of the drug concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5half-lives).
Of note, this criterion may not be applicable to events whose time cycle is 
prolonged despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation 
(e.g. situations where other drugs or underlying diseases appear to provide a more 
likely explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or 
remains unchanged.
5.2.6.2
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 end of treatment (including 
the Residual Effect Period, REP):


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All AEs (non-serious and serious) and all AESIs.
•
After the end of treatment until the individual patient’s end of trial:
-
All drug-related SAEs and all drug-related AESIs.
•
After the individual patient’s end of the trial:
The investigator does not need to actively monitor the patient for AEs but should report 
drug-related SAEs and drug-related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should however, not be 
reported in the CRF.
The rules for Adverse Event Reporting exemptions still apply.
Figure 5.2.6.2: 1
AE collection periods
The REP is defined as 42 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment. Events which occurred after the REP will be considered as post-treatment 
events.
5.2.6.2.2 
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for 
the reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the 
Sponsor’s unique entry point (country-specific reporting process will be provided in the 
ISF). The same timeline applies if follow-up information becomes available. In specific 
occasions the investigator could inform the sponsor upfront via telephone. This does not 
replace the requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to 
be provided. For follow-up information the same rules and timeline apply as for 
initial information.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form, if applicable. The investigator should determine the 
causal relationship to the trial medication and any possible interactions between the trial 
medication and a NIMP/AMP.
The following should also be recorded as an (S)AE in the CRF and BI SAE form 


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(if applicable):

Worsening of pre-existing conditions other than the underlying disease 
(see exemption below)

Changes in vital signs, ECG, physical examination and laboratory test results, if 
they are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the CRF only. 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.
5.2.6.2.3
Pregnancy
Postmenopausal patients are women of non-childbearing potential. Therefore 
pregnancy is not expected to occur in this patient group.
In rare cases, pregnancy might occur in a premenopausal patient even though she is taking 
ovarian suppression treatment. Once a premenopausal patient has been enrolled in the clinical 
trial and has taken trial medication, the investigator must report any drug exposure during 
pregnancy in a trial participant immediately (within 24 hours) by means of Part A of the 
Pregnancy Monitoring Form to the sponsor’s unique entry point. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Studies (Part B).The ISF will contain the Pregnancy Monitoring Form for 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 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.
5.2.6.2.4
Exemptions to SAE reporting
Exempted outcome events are: Disease progression, Malignant neoplasm progression,
Neoplasm progression.
Disease Progression is a trial endpoint for analysis of efficacy and as such is exempted 
from reporting as an (S)AE. Progression of the subject's underlying malignancy will be 
recorded on the appropriate pages of the CRF as part of efficacy data collection only and 
will not be reported on the SAE Form. It will therefore not be entered in the safety 
database (ARISg) and hence not get expeditiously reported. Death due to disease 
progression is also to be recorded on the appropriate CRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the trial drugs 
and the progression of the underlying malignancy, the event must be reported as an SAE 
on the SAE Form and in the CRF.


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Examples of exempted events of PD may be:

Progression of underlying malignancy (PD): if PD is clearly consistent with 
the suspected progression of the underlying malignancy as defined by the respective 
response criteria.

Hospitalisation/Procedures solely due to the progression of underlying 
malignancy (PD)

Clinical symptoms and/or signs of progression (without confirmation by objective 
criteria e.g. imaging, clinical measurement): if the symptom can exclusively be 
determined to be due to the progression of the underlying malignancy and does meet the 
expected pattern of progression for the disease under study.
Exempted events will be monitored at appropriate intervals by the DMC.
5.2.6.3
Assessment of healthcare resource use
In case patients would be hospitalised due to AEs, the duration of hospital stay as well as 
the need to stay and the duration in the intensive care unit will be documented in the 
CRF. The data collected will be used for a later health economic (cost effectiveness) 
analysis.
Further HCRU data for use in later health economic (cost effectiveness) analysis will 
be captured in the CRF, too (see section 5.6.3).
As of 29 September 2021, healthcare resource questionnaire is no longer applicable for 
ongoing patients.
5.2.7
Safety assessment as of 29 Sept 2021
As of 29 September 2021, all the safety assessments will be done according to local practice. 
    No follow-up information will be collected after patients discontinue study
treatment except all AESIs, SAEs, related AEs still ongoing at the end of treatment, which 
will be followed until resolution/stabilization.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Blood for pharmacokinetic analysis of xentuzumab will be collected at visits specified in 
the Flow Chart at time points as specified in Appendix 10.1. 
The following PK parameters will be calculated by means of non-compartmental analysis 
and evaluated as further endpoints, if calculation is feasible:
-
Pre-dose concentration of xentuzumab shortly before the next infusion (Cpre)
-
Concentration of xentuzumab shortly after end of infusion (C1.25)


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PK sampling scheduled on Day 1 of a cycle should only be performed after the decision 
has been made to prescribe a new cycle of treatment. However, if the decision to 
withdraw a patient from treatment is made after the PK sample was already obtained, 
this PK sample should be registered on the scheduled visit. The sample will be analysed 
as planned.
As of 29 Sept 2021, PK samples will no longer be collected for ongoing patients.
5.3.2
Methods of sample collection
Blood samples should not be obtained from the arm used for infusion. A central venous 
access/central port must not be used due to interference of Li- and Na-Heparin with PK 
assays. The central venous access/central port can only be used when it can be assured that 
no heparin is contained in the blood sample. Otherwise PK sample collection must occur 
by i.v. puncture from the forearm. Details will be provided in the ISF. The actual sampling 
date and time (24 hour time clock) for each sample has to be recorded accurately.
For quantification of xentuzumab plasma concentrations, blood samples will be taken at 
the time points listed in the Flow Chart under PK sampling. A detailed sampling 
schedule is shown in Appendix 10.1. For details on blood volumes to be collected, 
sample handling and logistics refer to the ISF (Laboratory Manual).
After completion of the study, plasma/serum samples may be used for further 
methodological investigations, e.g., stability testing. However, only data related to the 
analyte will be generated by these additional investigations. The study samples will be 
discarded after completion of the additional investigations but not later than 5 years after 
the final study report has been signed.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
Exposure-response relationships will be explored. Formal exposure-response analyses may 
be omitted in case of a negative trial outcome.
5.4
ASSESSMENT OF BIOMARKER(S)
This section refers to both exploratory and probable valid biomarkers. The exploratory 
analyses are hypothesis generating and will be used to expand our understanding of the 
trial drug and the disease. Participation in the biomarker analyses is mandatory for all 
patients. If an individual biomarker is assessed as no longer relevant, testing may be 
discontinued at any time.
Remaining materials from biomarker analyses such as tumour tissue, blood or plasma 


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samples (and isolated DNA and RNA) will be destroyed no later than 3 years after the end 
of the trial if no optional consent for sample biobanking is obtained from the patient (see 
Section 5.4.4).
Detailed instructions for sampling, handling and shipment of samples will be provided in 
the laboratory manual/ISF.
The biomarker analyses will be performed by the Sponsor or a central laboratory 
authorised by the Sponsor.
As of 29 Sept 2021, biomarker samples will no longer be collected for ongoing patients.
5.4.1
Evaluation of molecular and biochemical biomarkers in tumour tissue: 
Tumour tissue at Screening
Patients will be eligible for enrollment into the trial if their documented tumour status is 
HR+/HER2-. Archival tumour tissue (preferably from the most recent biopsy prior to 
entering the study) will be analyzed retrospectively for HR and HER2 status following
ASCO/CAP guidelines (R15-6055, R17-4255). (Note: biopsy samples from the bone must 
not be provided due to not being suitable for HER2 testing). This analysis will be 
performed by a central laboratory nominated and qualified by the Sponsor. Results will 
not be required prior to randomisation.
In addition to the mandatory analysis of HR/HER2 status, archival tumour tissue 
samples may be analysed for:

Gene expression of e.g., but not limited to, IGF, PI3K/mTOR, Ras/MAPK and 
breast cancer signalling relevant genes.

Expression of Ki-67 protein via biochemical methods (e.g. IHC) to measure the 
proliferative index. This will allow the assessment of luminal A vs. B status. As medical 
knowledge in this field is constantly evolving, broader analysis of the samples (including 
immunohistochemistry/in-situ hybridization/sequencing of e.g. IGF-1/2, IGF-1R, pIGF-
1R, PTEN, pAKT, pS6, E-Cadherin) might be conducted to e.g. address predictive 
biomarkers, exceptional response or resistance mechanisms.

Somatic alterations in genes related to the MoA of the trial drugs and/or involved 
in breast cancer tumourigenesis, e.g. IGF pathway-related and cancer driver
genes.
Individual analyses from tumour tissue will be prioritised based on the 
availability of sufficient tissue material.
Methods of sample collection
Formalin fixed paraffin embedded (FFPE) tumour tissue, preferably FFPE blocks, from 
the most recent time point before consent will be collected during Screening (see 
Flowchart). (Note: biopsy samples from the bone must not be provided). The FFPE blocks 
will be used to prepare 20 slides at ~5µm thickness. Alternatively, 20 freshly prepared 
slides at ~5µm thickness from FFPE blocks can be provided but need to be prepared under 
RNase-free conditions.


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5.4.2
Molecular evaluation in blood:
Two kinds of blood samples will be collected for genomic analyses from blood and plasma.
One blood sample will be used to isolate genomic DNA. The isolated genomic DNA will 
be used as a reference to distinguish somatic alterations in the tumour and will be 
analysed for the same cancer-related genes as the tumour tissue-derived DNA (if 
applicable) and the plasma isolated cfDNA.
From the second blood sample plasma needs to be separated within approximately 4 
hours. The plasma will be used to isolate cfDNA. Subsequent analyses of the plasma may 
involve somatic alteration analysis in the IGF pathway and cancer driver genes of plasma 
isolated cfDNA, potential epigenetic analysis or analysis of plasma derived exosomes. 
Additionally, changes in nucleic acid concentration over the course of treatment may be 
explored. Analysis of cfDNA (that includes ctDNA (circulating tumor DNA)) provides a 
non-invasive technique that might help to find potential biomarkers to predict treatment 
response or resistance mechanisms to the study drug (R14-1645).
Methods of sample collection
For analysis of cfDNA, blood samples will be collected in plasma preparation tubes 
before drug administration at each indicated time point (see Flow Chart). If a patient has 
not progressed at EOT then a blood sample should be collected at the FU-PD visit where 
progression is documented.
5.4.3
Protein biomarkers from blood and urine
IGF and other proteins involved in IGF signalling
Levels of free and total IGF-1 and total IGF-2 (optionally the amount of IGF-BP3, 
dissociable IGF-1 or other factors related to IGF signalling) will be relatively 
quantified in serum using validated immunoassays. Free IGF-1 (and IGF-2) is defined 
as the fraction of total IGF-1 (and total IGF-2) that can be bound by xentuzumab under 
in vitro assay conditions. Dissociable IGF-1 (and IGF-2) is a different representation of 
free IGF-1 (and IGF-2) under more diluted assay conditions. Total IGF-1 (and total 
IGF-2) is quantified in serum samples after splitting the IGF-IGF-binding protein 
complexes and the IGF- xentuzumab immune complexes.
Bone remodelling markers
Biomarkers for bone resorption and formation (including, but not limited to serum N-
terminal propeptide of procollagen type 1(P1NP) and urine N-terminal cross-linked 
telopeptide of type I collagen (NTX)) will be assessed in blood and urine samples (second 
morning void – see Flow Chart) at C1V1 prior to the start of therapy, C2V3 and C4V1 and 
EoT.
Samples for bone biomarkers will be taken prior to administration of trial medication 
and subsequent specimens for comparison should be collected at the same time of day 
as the baseline specimen.
Serial collection of blood samples for the assessment of these markers is mandatory. As 
medical knowledge in this field is constantly evolving, other blood biomarkers that 
come to be known as potentially relevant prognostic/predictive markers of treatment 
response may also be explored via available blood. Biomarkers that come to be known 


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or emerge as not relevant during the trial may be discontinued.
Testing for Cytokine Release
Cytokines are measured to evaluate the influence of xentuzumab on circulating 
cytokines to judge on the likelihood of cytochrome P450 enzyme regulation and 
potential drug drug interaction with small molecule drugs.
A panel of cytokines (including, but not limited to IL-1beta, IL6, TNFα, IL2, IFNγ) will 
be measured in peripheral blood in order to monitor release of cytokines after 
xentuzumab (or placebo) administration. Cytokine measurements will be performed at 
the time points specified in the Flow Chart and Appendix 10.1 will be measured in a 
central lab authorised by Boehringer Ingelheim using immunoassay techniques, such 
MSD assay.
Methods of sample collection
Blood will be taken from a forearm vein or central line at those time points specified in 
the Flow Chart or Appendix 10.1. All samples must be adequately labelled by the site 
personnel.
Urine samples must be provided from the second morning void. When this occurs prior to 
visiting the clinic, the sample should be collected at the patient’s home and brought to the 
respective visit at those time points specified in the Flow Chart or Appendix 10.1.
5.4.4
Biobanking (Optional)
The therapeutic benefit or specific adverse events in patients cannot always be anticipated 
during the trial setup. Later on there may be new scientific knowledge about biomarkers 
and other factors contributing to diseases or the action of a drug. In order to be able to 
address future scientific questions, patients will be asked to voluntarily donate 
biospecimens for banking. If the patient agrees, banked samples may be used for future 
drug development projects, e.g. to identify patients that are more likely to benefit from a 
treatment or experience an adverse event, and thereby better match patients with therapies 
or to gain mechanistic understanding of drug effects and/or to identify genetic or other 
factors associated with response to therapy or the risk of adverse drug reactions.
Participation in biobanking is voluntary and not a prerequisite for participation in the 
trial. Biobanking samples will only be banked after a separate biobanking informed 
consent has been given in accordance with local ethical and regulatory requirements.
The leftovers of the following biomarker samples might be banked:
•
Leftover tumour tissue or derivatives (e.g., RNA, DNA) obtained at screening
•
Plasma, or the derived nucleic acids (e.g. cfDNA), collected at multiple time points 
as defined in the Flow Chart
•
Serum collected at C1V1 as defined in the Flow Chart
5.4.5
Radiomics
Radiomics investigates the potential for enhanced and improved baseline and on-
treatment markers of early efficacy based on comprehensive quantitative CT metrics. 
Analysis of standard-of-care medical imaging may identify gross or fine imaging features 


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linked to characteristics of lesions such as tumour neo-vasculature, necrosis, as well as the 
heterogeneity of the metastatic burden, which may be associated with ongoing intra-
tumoural Darwinian dynamics, regional variations in environmental properties, and 
cellular adaptive strategies. Radiomics thus can be used to build diagnostic, prognostic 
and predictive models and its features can be trained to identify patterns associated with 
favourable outcome and thus generate non-invasive clinical decision tools using standard 
of care CT-scan.
Imaging data used for independent radiological review will be further evaluated using 
integrated assessment of changes based on e.g. tumour volume(s), shape(s), texture(s). 
This exploratory analysis will be performed by a CRO nominated by the Sponsor.
5.5
ASSESSMENT OF IMMUNOGENICITY
5.5.1
Assessment of immunogenicity
Anti-drug antibodies will be determined in a tiered approach for all patients before the 
start of xentuzumab treatment, (baseline immunogenicity assessment), during treatment 
and at end of treatment and follow up visits. Time points for ADA and neutralising 
antibody sampling are specified in the Flow Chart and Appendix 10.1.
Immunogenicity of xentuzumab will be assessed using a multi-tiered approach. All 
samples will first be analysed in the ADA screening assay. Samples found to be putative 
positive in the ADA screening assay will then be assessed in the confirmatory assay. 
Titer will be determined for samples that confirmed positive. 
 
As of 29 Sept 2021, samples for immunogenicity will no longer be collected for 
ongoing patients.
5.5.2
Methods of sample collection
Blood samples should be obtained as described for PK samples.
For ADA and nAb assessment, blood will be taken at the time points listed in the
Flow Chart under ADA/nAb sampling. A detailed sampling schedule is shown in 
Appendix 10.1.
For details on blood volumes to be collected, sample handling and logistics refer to the 
ISF (Laboratory Manual).
After completion of the study, plasma/serum samples may be used for further 
methodological investigations, e.g., improving drug tolerance. However, only data related 
to the analyte will be generated by these additional investigations. The study samples will 
be discarded after completion of the additional investigations but not later than 5 years 
after the final study report has been signed.


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5.6
OTHER ASSESSMENTS
5.6.1
Patient-reported outcomes
Patient reported outcomes (PRO) are considered an important contribution to prescribers, 
patients and health care decision makers when evaluating the clinical utility of a medical 
intervention. The information collected using PRO instruments can lend supportive 
arguments to the clinical activity of therapy and refer to the extent of which patients 
physical, emotional and social well-being are affected by treatment. In this trial the patient 
perspective will be captured using both symptom and disease specific instruments; in 
addition information on health related quality of life will be collected using a generic 
preference based instrument.
PRO will be measured with the following multidimensional questionnaires (see 
Appendix 10.5):
Brief Pain Inventory – Short Form (BPI-SF) (R17-2778)
National Comprehensive Cancer Network Functional Assessment of Cancer 
Therapy- Breast Cancer Symptom Index (NFBSI-16) (R17-3000).
EuroQoL 5-dimension health status self-assessment questionnaire (EQ-5D-5L)
(R12- 1920).
Patient reported outcomes version of the Common Terminology Criteria for 
Adverse Events (PRO-CTCAE) (R18-2068)
Questionnaires will be completed at the time points specified in the Flow Chart. Paper 
questionnaires should be completed at the site by patients 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 so that the responses are not influenced 
(biased).
The questionnaires generally take about 10 minutes to complete. Patients will receive 
the questionnaire in their native language in countries where validated translations 
exist. The answered questionnaires will be entered in the CRF by the site personnel.
BPI-SF
The BPI-SF is a 9 item self-administered questionnaire used to evaluate the severity 
of a patient's pain and the impact of this pain on the patient's daily functioning (R17-


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3500).
The patient is asked to rate their worst, least, average, and current pain intensity in the last 
24 h, list current treatments and their perceived effectiveness, and rate the degree that 
pain interferes with general activity, mood, walking ability, normal work, relations with 
other persons, sleep, and enjoyment of life on a 10 point scale.
Measurement of pain severity: The BPI-SF assesses pain at its “worst,” “least,” 
“average,” and “now” (current pain). In clinical trials, the items “worst” and “average” 
have each been used singly to represent pain severity. In addition a composite of the four 
pain items (a mean severity score) is sometimes presented as supplemental information. 
The use of these single items is supported by the IMMPACT recommendations for 
assessing pain in clinical trials (R07-4358, R09-2344) and by the FDA Draft Guidance for 
Industry: Patient Reported Outcome Measures (R12-5607). In addition, the BPI-FS’s 
developers recommend that all four severity items be used, because the models for 
validation of the BPI-FS included all four items.
Measurement of Pain interference: The BPI-FS measures how much pain has interfered 
with seven daily activities, including general activity, walking, work, mood, enjoyment of 
life, relations with others, and sleep. BPI-FS pain interference is typically scored as the 
mean of the seven interference items. This mean can be used if more than 50% or four of 
seven, of the total items have been completed on a given administration.
Other Items: The item, “Throughout our lives, most of us have had pain from time to 
time (such as minor headaches, sprains, and toothaches). Have you had pain other than 
these everyday kinds of pain today?” is a YES/NO preliminary screening question at the 
beginning of the BPI-FS. The BPI-FS also asks the patient to indicate the percentage of 
relief provided by pain treatments or medications.
NFBSI-16
The NFBSI-16 is an updated version of the Functional Assessment of Cancer Therapy –
Breast Cancer Symptom Index (FBSI) (R17-3502) which includes all eight items from 
the original FBSI and eight additional items. It was developed using methods consistent 
with recent regulatory guidance on patient-reported outcomes as endpoints in clinical 
trials with emphasis on patient input during the development process Statements are 
presented and the patients are asked to indicate their response as it applies to the past 7 
days with 5 response options, from “not at all” to “very much”. A total score can be 
obtained, and higher scores indicate better outcomes than lower ones. It can be 
formatted by the subscales: Disease- Related Symptom, Treatment Side-Effect, General 
Function and Well-Being (R17-3000, R17-3497). The primary aim of the NFBSI-16 is 
to provide a PRO metric based on breast cancer–specific symptoms identified as high 
priority by patients and oncology clinicians.
While this can be clinically informative at the level of the overall index, an examination 
of the specific subscales (e.g., disease-related, treatment side effects, and function and 
well- being) can yield more specific information about changes in target symptoms over 
time or in response to intervention.
Minimally clinically important differences have not yet been confirmed for the NFBSI-
16, but for the original FBSI minimally important differences (2–3 points) are described 
(R17-3000).


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EQ-5D-5L
The EQ-5D is a disease generic instrument that has been widely used and has been 
found to capture Health-related quality of life (HRQOL) changes in oncology. The EQ-
5D-5L essentially consists of 2 pages: the EQ-5D descriptive system and the EQ visual 
analogue scale (EQ VAS) (R12-1920).

The descriptive system comprises five dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems and extreme problems. 
The patient is asked to indicate his/her health state by ticking the box next to the most 
appropriate statement in each of the five dimensions. The scores on these five 
dimensions can be converted to a single summary index number (utility).

The EQ VAS records the patient’s self-rated health on a vertical visual analogue 
scale, where the endpoints are labelled ‘The best health you can imagine’ and ‘The 
worst health you can imagine’. The VAS can be used as a quantitative measure of 
health outcome that reflect the patient’s own judgement.
PRO-CTCAE
PRO-CTCAE is a patient-reported outcome measure developed to evaluate symptomatic 
toxicity in patients on cancer clinical trials. It was designed to be used as a companion to 
the CTCAE criteria, the standard lexicon for adverse event reporting in cancer trials 
(R18-2068). The PRO-CTCAE Instrument & Form Builder was used to select eight items 
(difficulty swallowing, skin cracking at corners of the mouth, decreased appetite, 
vomiting, heartburn, diarrhoea, pain in the abdomen, rash) based on clinical experience 
and overlap with already included items in the NFBSI-16.
As of 29 Sept 2021, patients reported outcomes will no longer be collected for ongoing 
patients.
5.6.2
Analgesics use
Pain palliation resulting from antitumor therapy provides direct evidence of treatment 
benefit when combined with evidence of antitumor activity (R17-3501). Intensification of 
pain palliation will be defined as a ≥2-point increase in the 8-point Analgesic 
Quantification Algorithm (AQA, see Table 5.6.2: 1). AQA is a modification of the World 
Health Organization Analgesic Treatment Ladder that includes additional specificity for 
patients receiving strong opioids. This algorithm facilitates differentiation between the 
full ranges of doses of strong opioids used by patients and thus, more accurately enables 
researchers to determine and control for changes in levels of analgesic medication use 
over time in clinical trials (R17-2771). It will be completed by the investigator at the 
same visits as the PROs.


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Table 5.6.2: 1
AQA
AQA score
Description
0
No analgesic
1
Non-opioid analgesics
2
Weak opioids
3
Strong opioids ≤75 mg OME per day
4
Strong opioids >75–150 mg OME per day
5
Strong opioids >150–300 mg OME per day
6
Strong opioids >300–600 mg OME per day
7
Strong opioids >600 mg OME per day
5.6.3
Health care resource utilisation
Health care resource utilisation (HCRU) data will allow calculation of direct and 
indirect costs and will be used for health economic analysis (i.e. cost-effectiveness 
analysis).
Resource use will be captured at the time points specified in the Flow Chart. Information 
on caregiver support (home care), general practitioner, outpatient and hospital visits 
(other than scheduled visits) will be collected in the CRF and as part of AE reporting to 
inform on healthcare resource use required to treat the trial indication and adverse events 
observed during the trial.
5.7
APPROPRIATENESS OF MEASUREMENTS
All clinical assessments are standard measurements commonly used in studies of 
advanced solid tumours. RECIST version 1.1 is used for assessment of the change in 
tumour burden. These criteria are well established and well received by the regulatory 
authorities and scientific community.
The NCI CTCAE criteria are used in the assessment of AEs in cancer patients. In the 
present trial CTCAE version 5.0 (R18-1357) will be used.
The questionnaires used in the present trial have been validated and address the outcome 
to be evaluated (i.e. symptoms or HRQOL). The BPI-SF has been accepted by multiple 
national authorities including FDA and EMA, and the NFSBI-16 and the PRO-CTCAE 
have been developed in accordance with FDA guidance for patient-reported outcome 
measures.


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6
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The visit schedule is in detail described in the Flow Chart for all patients randomised to 
either the treatment with xentuzumab in combination with everolimus and exemestane or 
to placebo in combination with everolimus and exemestane. Unscheduled visits can be 
performed as necessary and assessments will be performed as required at the discretion of 
the investigator.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
See the Flow Chart and Section 5 for details on the procedures performed at each visit.
Per Protocol version 6, reference the revised and reduced flow chart and section 5 as 
appropriate. 
6.2.1
Screening
Screening Period
All patients will need to sign the informed consent form (ICF). Only patients who have tested
positive for HR and negative for HER2 by prior local analysis according to ASCO/CAP 
guidelines (R15-6055, R17-4255) are eligible for the trial. Archival tumour tissue sample 
must be submitted to the central laboratory to retrospectively confirm HR/HER2 status (see 
Section 5.4). If archival tissue is not available, provision of detailed information from the 
original histology report may be agreed with the sponsor on a case by case basis.  In the case 
that prior information regarding the patient’s genomic breast cancer signature is available, an 
anonymised copy of the report will be collected for the trial database and specified parameters
will also be recorded in the CRF.
Demographic information (sex, date or year of birth (in accordance with local laws and 
regulations), race) will be obtained, based on information in the patients’ medical records. 
Examinations and assessments per Flow Chart will be conducted and patients’ medical 
history will be collected. Inclusion and exclusion criteria must be assessed (see Sections 
3.3.2 and 3.3.3). Baseline images must be available as outlined in the Flow Chart.
Concomitant diagnoses and/or therapies present during trial participation (between first 
ICF and the first follow-up visit) will be recorded in the CRF. Medical history of mBC 
will be obtained and reported in the CRF:

The date of first histological diagnosis

The primary tumour site

The number and location of metastatic sites (e.g. bone, lymph nodes, 
skin, subcutaneous, soft-tissue, (contralateral) breast and combinations
thereof)

Tumour stage according to the TNM-classification at diagnosis

Previous treatment for mBC, including any surgery, radiotherapy, and/or 
systemic therapy, including start and end dates and the outcome.
Re-screening will be allowed once. Re-screened patients will receive a new 


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patient number. In case of re-screening any procedures that fall outside the 
required screening window as defined in Flow Chart must be repeated.
6.2.2
Treatment period
Treatment visits are specified in the Flow Chart and must be conducted as scheduled 
and outlined there. Treatment cycles are 4 weeks (28 days) in duration until treatment 
week 80 and then 8 weeks (56 days) in duration.
All planned visit dates are calculated from the start of day 1 (visit 1) of cycle 1. If a visit is 
missed there will be no re-scheduling; if a patient is required to attend the study site between 
the “missed” and next scheduled visit, then the missed visit assessments should be performed. 
The current date and the reason for the delay must be noted in the medical records. All 
subsequent visits must adhere to the scheduled programme of visits for all cycles of 
treatment.
Imaging visits must adhere to the schedule provided in the Flow Chart at all times, 
unless they are scheduled for suspected PD.
6.2.2.1
End of treatment visit and follow-up visit 1
The EOT visit will be performed as soon as possible (within 14 days) after permanent 
discontinuation of all trial medications for any reason or as soon as possible after the 
investigator became aware that the trial medication had been terminated. Investigators 
must ensure that PK, ADA and nAB samples are taken as described in the Flow Chart,
Section 5.3 and Appendix 10.1.
The follow-up Visit 1 (EOR/FU1) will be performed 42 (+7) days after permanent 
discontinuation of all trial medications and is primarily to collect follow-up safety 
information as required by regulatory authorities. For the majority of patients, progression 
will already be documented at this point.
6.2.2.2
Treatment beyond progression
In case of continued clinical benefit judged by the investigator and based on careful 
clinical assessment, patients may be allowed to continue trial medications beyond disease 
progression as defined by RECIST 1.1 criteria. Clinical benefit can include, but will not be 
restricted to, significant symptom control of originally symptomatic tumours. Patients who 
continue as described will continue to follow the trial schedule for treatment visits (see 
Flow Chart) including the imaging and clinical tumour evaluations. Trial medication may 
be continued as long as judged beneficial by the investigator.
6.2.3
Follow up period and trial completion
Not applicable as per CTP version 6. The end of study is defined as EOR/FUP1
6.2.3.1
Extended follow-up period


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For patients without objective disease progression and who have not started a new anti-
cancer therapy prior to FU1, additional follow-up visits for progression will be performed 
every 56 days (8 weeks) ±7 days after the EOT visit for patients who did not yet start
cycle 20 and every 16 weeks (112 days) for patients who started cycle 20. The follow-up 
for progression period will end at the earliest if one of the following events is met:

Lost to follow-up

Disease progression

Start of a new anti-cancer therapy

Death

End of whole trial as specified in Section 8.6
The following will be obtained and/or performed during the follow-up visits for progression.

For each drug-related SAE/AESI, the investigator should provide the information 
with regard to concomitant medication and the medication administered to treat the 
adverse events on the appropriate CRF pages and the SAE form including trade 
name, indication and dates of administration

Record performance status (ECOG)

Quality of life questionnaires

Perform tumour assessment and imaging

Treatment and start date of any subsequent anti-cancer therapy including the 
name and type of the anti-cancer drug and/or best supportive care (if
applicable)

Outcome (in case the patient had PD the actual date of PD shall be recorded, date 
of and reason for death, if applicable)

Results from pregnancy testing (if applicable) see Flowchart
6.2.3.2
Follow-up for Overall Survival
All patients will be followed up for overall survival at 84 day (12 weeks) intervals until

Death

Lost to follow-up or

Completion of the whole trial (as specified in Section 8.6)
These visits may also be performed by e.g. telephone interview or via written 
correspondence in case the patient is unable to visit the investigator. The following 
information will be collected during the follow-up for survival period:

Date and type of contact

Post progression information including further anti-cancer treatment: regimen and 
drug name, start and stop dates, response to further anti-cancer treatment if
available

For each drug-related SAE/AESI, the investigator should provide the information 
with regard to concomitant medication and the medication administered to treat the 


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AEs on the appropriate CRF pages and the SAE form including trade name, 
indication and dates of administration

Outcome event (record date of and reason for death, if applicable)

Results from pregnancy testing (if applicable) see Flowchart
6.2.3.3
Trial completion for an individual patient
A patient is considered to have completed the trial in case any of the following applies:

Completion of planned follow-up periods

Lost to follow-up

Refusal to be followed-up

Death
If a patient cannot be contacted for vital status, information may also be obtained by 
other means, e.g. contact with patients’ health care providers, public sources, e.g. death 
registry, obituary listing, etc. when it is available and verifiable.


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7
STATISTICAL METHODS AND DETERMINATION
OF SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a randomised, double-blind, placebo-controlled multi-centre trial in women with 
HR+/HER2- advanced or metastatic breast cancer with non-visceral disease. The primary 
objective of the trial is to evaluate whether xentuzumab in combination with everolimus 
and exemestane prolongs PFS, independently assessed according to RECIST 1.1, in 
comparison to everolimus and exemestane alone.
Based upon these design considerations, treatment groups will be compared for the 
primary endpoint via a stratified log-rank test, stratified by the presence of baseline 
bone-only metastases (Yes/No), prior CDK4/6 inhibitor treatment (Yes/No) and 
menopause status (pre/post).
If the criterion for the seamless option is met then this Phase II trial will be expanded into 
a confirmatory Phase III trial, similar to the 2-in-1 design outlined in R18-2061. Pertinent 
detail regarding hypothesis testing, alpha-spending/control along with increases in 
sample size in the expansion scenario has been detailed in the following sections. 
However, prior to expanding the trial additional detail will be provided via a formal 
protocol amendment.
7.2
NULL AND ALTERNATIVE HYPOTHESES
If at the time-point of the primary PFS analysis for this Phase II trial the hazard ratio 
(using the model defined in Section 7.3.1) is below a pre-defined criterion (to be defined 
in the DMC charter, prior to trial initiation), in favour of the xentuzumab arm, then the 
trial will be expanded into a confirmatory Phase III trial. No formal hypothesis testing 
will be performed if the trial is not expanded.
However, if the trial is expanded, formally, the null hypothesis for the primary PFS 
endpoint at the end of Phase III is:
HO : SPFS; xentuzumab (t) <= SPFS; control (t), for all t > 0,
versus the alternative hypothesis:
H1 : SPFS; xentuzumab (t) > SPFS; control (t), for any t > 0,
where SPFS (t) is the probability that a patient passes time t without experiencing a 
PFS event.
The expanded study will be considered positive if the null hypothesis for the 
primary endpoint can be rejected.
Also in the expanded trial scenario, for the secondary OS endpoint, the null hypothesis is:
HO : SOS; xentuzumab (t) <= SOS; control (t), for all t > 0,
versus the alternative hypothesis:
H1 : SOS; xentuzumab (t) > SOS; control (t), for any t > 0,


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where SOS (t) is the probability that a patient passes time t without experiencing an OS event.
The hypothesis testing will be performed on all randomised patients. The testing 
strategy includes the endpoints PFS and OS, tested in a hierarchical manner, and will 
control the overall type-1 error rate at a level of 0.025 (one-sided).
If the trial is expanded then the primary PFS analysis at the end of Phase II will be considered 
as an interim analysis. Refer to Section 7.4 for further details on this planned interim analysis 
and the control of the type I error rate in the situation where the trial is expanded.
Superiority, for the endpoint of interest will be declared if the related null hypothesis is 
rejected in favour of the alternative at the defined significance level and the estimated 
hazard ratio of xentuzumab vs. control is <1.
The primary objective of this Phase II trial, that xentuzumab in combination with 
everolimus and exemestane prolongs PFS, will be addressed by assessing whether or not 
the criterion for the seamless option has been met. If the seamless option is not met, the 
observed results will be evaluated in an explorative manner to see if they are sufficient for 
further development of this compound in this indication (e.g. via a separate Phase III trial). 
If the seamless option is met then expansion into a Phase III trial will allow for formal 
hypothesis testing via a one- sided test at an alpha level determined by a number of factors 
(refer to Section 7.4), controlling for the overall type I error rate of 0.025 (one-sided). The 
hypothesis testing will be supported by the hazard ratio and corresponding 95% CI from a 
stratified Cox proportional hazards model to describe the magnitude and precision of 
treatment effects.
7.3
PLANNED ANALYSES
The primary analysis of PFS for this Phase II trial will take place when approximately 40 
patients have had disease progression (assessed by independent review) or died. The time 
point of reaching 40 events will be estimated using investigator assessed events and the 
discrepancy rates observed between independent and investigator data during the trial. 
The estimation of this time point is likely to lead to some deviation, though relatively 
small, from the planned 40 independent assessed events. Based on assumed median PFS 
times (refer to Section 7.7), the analysis is expected to take place 15 months after the last 
patient has been randomised. This analysis will be performed by the DMC.
If the criterion for the seamless option is met then the trial will be expanded into a 
confirmatory Phase III trial and remain double-blind. If the criterion is not met then the
database will be unblinded and a clinical trial report (CTR) written, including the 
evaluations of the primary, secondary and further endpoints. Note that based on these 
results it is still possible that clinical development in this indication will be continued (e.g. 
via a separate Phase III trial), in addition patients randomised into this Phase II trial will 
have further data collected and reported upon, beyond the unblinding time-point. Blinded 
dummy treatment group assignments will be used in the study database whilst the trial 
remains blinded. Section 4.1.6 provides further details on the blinding and procedures for 
unblinding.
An exception to the above plan will occur if the proportion of randomised patients dropping 
out of the trial without evidence of disease progression, becomes so high that reaching 40 PFS 
events is either not possible, or has not been met 20 months after the last patient has been 
randomised. In such an unlikely scenario no DMC analysis will be performed and therefore 


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the criterion for seamless expansion will not have been met. In this situation the database will 
be unblinded and a CTR written, including the evaluations of the primary, secondary and 
further endpoints.
Imaging related endpoints will be both independently assessed and investigator 
assessed according to RECIST 1.1. The data from the independent assessments will be 
considered primary, with investigator assessment data as supportive.
The primary efficacy analyses will be performed on the randomised set (RS), consisting of 
all randomised patients. Patients randomised and not treated will be analysed according to 
the censoring rules defined in Section 7.5. Randomised patients who receive the wrong 
treatment will be analysed according to their planned randomised treatment group. No per-
protocol analysis is planned.
Stratification (where stated) of analyses will be based on the presence of baseline bone-
only metastases (Yes/No), prior CDK4/6 inhibitor treatment (Yes/No) and menopause 
status (pre/post). Refer to Section 7.6 for further details on the randomisation stratification 
factors.
The safety analysis will be based on the treated set (TS), consisting of all patients treated 
with at least one dose of any study treatment. Patients will be analysed according to the 
actual treatment received.
7.3.1
Primary endpoint analyses
The primary endpoint of this study is PFS defined as the time from the date of 
randomisation to the date of disease progression, or to the date of death if a patient died 
earlier. The date of progression will be based on independent assessment according to the 
RECIST 1.1 criteria.
For patients with ‘event’ as an outcome for PFS:

PFS [days] = date of outcome – date of randomisation + 1
For patients with ‘censored’ as an outcome for PFS:

PFS (censored) [days] = date of outcome – date of randomisation + 1
The censoring rules for PFS (i.e. outcome and date of outcome) are described in Table 7.5: 
1. The time frame for the primary assessment of PFS will be from randomisation until the 
earliest of disease progression, death or the time point of the primary PFS analysis (refer 
to Section 7.3).
A stratified log-rank test will be used to test the primary hypotheses, if the trial is 
expanded into a Phase III trial.
A stratified Cox proportional hazards model will be used to estimate the hazard ratio and 
its asymptotic two-sided 95% Wald CI between the two treatment groups. A hazard ratio 
of less than one will favour the xentuzumab in combination with everolimus and 
exemestane treatment group.
Kaplan-Meier (KM) estimates will be used to display the distribution of PFS for each 
treatment group on a KM curve. To support the plot estimated survival probabilities at 
specific time points of interest (scheduled imaging time-points) will be tabulated along 
with 95% confidence intervals, using Greenwood’s variance estimate. In addition the 
survival distribution will be used to provide estimates of the median, 25th and 75th


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percentiles.
7.3.2
Secondary endpoint analyses Overall survival
OS will be analysed using the same statistical methods as for PFS. OS will be included in 
the confirmatory strategy in a hierarchical manner if the trial is expanded into a Phase III 
trial.
OS is defined as the time from randomisation until death from any cause. For patients 
with ‘event’ as an outcome for OS:
OS [days] = date of outcome – date of randomisation + 1.
For patients with ‘censored’ as an outcome for OS:
OS (censored) [days] = date of outcome – date of randomisation + 1
The censoring rules for OS (i.e. outcome and date of outcome) are given in Table 7.5: 2.
The time frame for the primary assessment of OS will be from randomisation until the 
earliest of death or the time point of the primary OS analysis (refer to Section 7.3).
In addition to the main analysis the following analyses may be performed to examine the 
pattern of time to death for consistency with the PFS results, while accounting for the 
extent and influence of post-progression intervention if deemed necessary:

describe the cumulative proportion of deaths at each scheduled tumour assessment 
time point

tabulate the specific anti-cancer treatments after progression

describe the effect of additional anti-cancer treatment, by separating patients into 
the following sub-groups:
o
those not eligible for additional treatment

patients who did not progress


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
patients who died within one month of progression
o
those eligible for additional treatment (i.e. those who have progressed and not 
died in the first month after progression)

did not take additional treatment

did take additional treatment
Disease control
DC will be analysed in terms of DC rate (DCR), defined as the proportion of patients 
with best overall response of CR, PR, SD or Non-CR/Non-PD. The DCR will be 
calculated for each treatment group, overall and within each level of the stratification 
factors. Proportions will be presented with 95% CIs. A logistic regression model 
adjusting for the stratification factors where appropriate will be used to compare the 
DCR between the two treatment groups.
For the primary assessment of DC, tumour imaging will be performed every 8 weeks up 
to week 80 and every 12 weeks thereafter until the earliest of disease progression, death 
or last evaluable tumour assessment before the start of subsequent anti-cancer therapy or 
the time point of the primary PFS analysis (refer to Section 7.3).
A best overall response of SD or Non-CR/Non-PD must have a minimum duration of 
24 weeks from the date of randomisation.
Duration of disease control
For all patients with DC the duration of DC is defined as the time from randomisation 
until the earliest of disease progression or death.
For patients with disease progression or death:

Duration of DC [days] = date of outcome – date of randomisation + 1
For patients without disease progression or death:

Duration of DC (censored) [days] = date of outcome – date of randomisation + 1
The censoring rules for DC (i.e. outcome and date of outcome) are described in Table 7.5: 
1. The time frame for the primary assessment of duration of DC will be from 
randomisation until the earliest of disease progression, death or the time point of the 
primary PFS analysis (refer to Section 7.3).
Kaplan-Meier estimates will be used to calculate median duration of DC for each 
treatment group.
Objective response
OR will be analysed in terms of OR rate (ORR), defined as the proportion of patients with 
best overall response of CR or PR. The ORR will be calculated for each treatment group, 
overall and within each level of the stratification factors. Proportions will be presented with 
95% CIs. A logistic regression model adjusting for the stratification factors where 
appropriate will be used to compare the ORR between the two treatment groups.
For the primary assessment of OR, tumour imaging will be performed every 8 weeks up 
to week 80 and every 12 weeks thereafter until the earliest of disease progression, death 
or last evaluable tumour assessment before the start of subsequent anti-cancer therapy or 
the time point of the primary PFS analysis (refer to Section 7.3).
As per RECIST 1.1 guidance confirmation of OR is not a requirement for randomised trials.


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Time to pain progression or intensification of pain palliation
Xentuzumab may delay the time to pain worsening. To investigate this, each patient’s pain 
severity and usage of pain palliation will be assessed. Time to pain progression or 
intensification of pain palliation is defined as the time from randomisation until the earliest 
of a clinically significant increase in pain (≥2-point increase from baseline in the BPI-SF 
Item 3) without a decrease in analgesic use, intensification in pain palliation (≥2-point 
increase in the 8-point AQA) or death.
For patients with ‘event’ as an outcome for pain progression/intensification of pain palliation:
Progression/intensification [days] = date of outcome – date of randomisation + 1.
For patients with ‘censored’ as an outcome for pain progression/intensification of 
pain palliation:
Progression/intensification (censored) [days]=date of outcome – date of randomisation +1
The censoring rules for time to progression/intensification (i.e. outcome and date of 
outcome) will be described in the TSAP. Time to progression/intensification will be 
analysed using the same statistical methods as for the primary endpoint.
The time frame for the primary assessment will be from randomisation until the earliest of 
pain progression, intensification of pain palliation, death or the time point of the primary 
PFS analysis (refer to Section 7.3).


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 42 days after the 
last dose of trial medication, will be assigned to the on-treatment period for evaluation. As 
the treatment arms are made up of a combination of individual treatments a patient may 
have multiple last doses of treatment; therefore the last dose of study medication is defined 
as the latest of these.
All treated patients will be included in the safety analysis, according to the actual trial 
medication they received. In general, safety analyses will be descriptive in nature and will 
be based on BI standards. No hypothesis testing is planned.


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Statistical analysis and reporting of adverse events will concentrate on treatment-
emergent adverse events, i.e. all adverse events occurring between start of treatment and 
end of the residual effect period. Adverse events that start before first drug intake and 
deteriorate under treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the 
MedDRA at the database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will  
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. 
Treatment groups will be compared descriptively with regard to distribution parameters as 
well as with regard to frequency and percentage of patients with abnormal values or 
clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed 
with regard to possible changes compared to findings before start of treatment.
7.4
INTERIM ANALYSES
As the trial will be conducted as a double-blind trial, an independent external DMC will 
be established to periodically assess the progress of the clinical trial, including un-
blinded safety and efficacy assessments.
A decision as to whether or not the trial is expanded into a Phase III trial will be made by 
the DMC at the time-point of the primary PFS analysis for this Phase II trial. In order to 
limit knowledge of the criterion for expansion potentially having an impact on the future 
conduct of the trial, the criterion for expansion will be pre-defined in the DMC charter 
(prior to trial initiation) and not this protocol. This analysis will be conducted after 
approximately 40 PFS events (predicted to occur after 30 months). Note the exception to 
this as specified in Section 7.3.
If the criterion for the seamless option is met and the trial is expanded into a Phase III trial 
then formal hypothesis testing (refer to Section 7.2) will be performed with suitable control 
of the overall type I error rate. In this situation the primary PFS analysis at the end of 
Phase II will be considered as an interim analysis. Under the null hypothesis the 
probability of meeting the criterion for seamless expansion and subsequently achieving a 
one-sided p-value of <0.0249 (see details below) is 0.0028.  Analysis time-points along 
with alpha-spending and control are presented in Figure 7.4: 1 below.
Figure 7.4: 1 Planned testing strategy


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If expanded, some (technical) alpha-level of 0.0001 one-sided (see Figure 7.4: 1) will be 
spent at the time-point of the Phase II primary PFS analysis to adjust for the unblinded 
interim look by the DMC. If the alpha-boundaries are crossed at this interim analysis time 
point there are no plans to stop the trial early. A group sequential design user defined alpha-
spending function has been used to calculate the final level leading to a nominal level of 
approximately 0.0249 (ADDPLAN v6.1.1). The nominal level available will be recalculated 
based on the actual information fraction at the interim, but keeping the alpha spent at 0.0001 
for the interim look.
In order to integrate the secondary endpoint of OS into the confirmatory testing strategy in 
a hierarchical manner, the same alpha-spending function as used for the primary PFS 
endpoint will be applied. Note that although OS is integrated into the testing strategy it will
not be powered for OS and a significant OS benefit is not necessarily expected. The study is 
considered positive if the primary hypothesis on PFS can be rejected.
Further details will be provided in a protocol amendment if the seamless option is met and 
the trial is expanded.
7.5
HANDLING OF MISSING DATA
In general missing efficacy data will not be imputed and all reasonable efforts will be 
taken during the study to obtain such data. Patients with unknown vital status, missing 
tumour imaging data and missing PRO assessments will be censored for time to event 
analyses as detailed below.
Table 7.5: 1 describes how patients will be classified for the analysis of PFS. 
Sensitivity analyses will examine the effect of using alternative rules.
Table 7.5: 1
Derivation rules for PFS
Situation
Outcome
Date of outcome
No baseline radiological assessment
Death on or before the second planned 
radiological assessment
Event
Date of death
Alive or death after second radiological 
assessment
Censored
Date of randomisation
Without post-baseline radiological assessments
Vital status is unknown or known to be alive
Censored
Date of randomisation
Death prior or on the second planned 
radiological assessment
Event
Date of death
Death beyond the second planned 
radiological assessment
Censored
Date of randomisation
With baseline and post-baseline radiological assessments BUT no other anti-cancer 
therapy


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Table 7.5: 1
Derivation rules for PFS (cont’d)
Alive and not progressed, no more 
than one consecutively missed 
radiological assessments
Censored
Date of last radiological 
assessment
Alive and not progressed, two or more 
consecutively missed radiological 
assessments
Censored
Date of last radiological 
assessment prior to 
missed radiological 
assessments
Progressed, zero or one missed 
radiological assessment prior to 
progression
Event
Date of radiological 
assessment of 
progression
Progressed, but two or more 
consecutively missed radiological 
assessments prior to progression
Censored
Date of last radiological 
assessment prior to 
missed assessment
Death but no progression, zero or one 
missed radiological assessment prior 
to death
Event
Date of death
Death without progression, but two or 
more consecutively missed 
radiological assessments prior to death
Censored
Date of last radiological 
assessment prior to 
missed assessments
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer therapy started 
before progression or death
Censored
Date of last radiological 
assessment before 
subsequent anti-cancer 
therapy
No baseline and/or post-baseline imaging 
and subsequent-anti cancer therapy started 
prior to a death
Censored
Date of randomisation
For endpoints related to OR and DC the rules defined above, where applicable, will 
be followed.
Table 7.5: 2 describes how patients will be classified for the analysis of death. Patients 
will be censored at the date of last contact if the investigator is no longer able to contact a 
patient or caregiver, and vital status cannot be determined otherwise, provided that no 
other information indicates that the patient was near death at that point.


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Table 7.5: 2
Derivation rules for OS
Status at time of analysis
Outcome
Date of outcome
Death and the date of 
death is known
Event
Date of death
Death and date of death is 
unknown
Event
Date of last contact when the patient 
is known to be alive + 1 day
Alive
Censored
Date of last contact when the patient 
is known to be alive
Unknown
Censored
Date of last contact when the patient 
is known to be alive
7.6
RANDOMISATION
Patients will be randomised in blocks to double-blind treatment with a 1:1 ratio 
(xentuzumab in combination with everolimus and exemestane: everolimus and 
exemestane alone).
Randomisation will be stratified by the following factors:

Presence of baseline bone-only metastases (Yes, No)

Prior CDK4/6 inhibitor treatment (Yes/No)
BI will arrange for the packaging and labelling of trial medication. The randomisation 
list will be generated using a validated system, which involves a pseudo-random number 
generator so that the resulting treatment will be both reproducible and non-predictable. 
The block size will be documented in the CTR. Access to the codes will be controlled 
and documented.
7.7
DETERMINATION OF SAMPLE SIZE
For the primary endpoint of PFS, it is assumed that xentuzumab in combination with everolimus 
and exemestane will increase the median from 9.9 months (R16-0802) in the everolimus and 
exemestane alone group to 19.8 months. Assuming an exponential distribution, this is equivalent 
to a reduction in the risk for progression of disease or death of 50%, corresponding to an 
underlying hazard ratio (HR) of 0.50. With 80 eligible patients randomised over a 15 month 
period, 40 PFS events are predicted to be reached on average around 30 months after the first 
patient is randomised. This assumes approximately 20% of patients randomised will either drop 
out of the trial without evidence of disease progression or be assessed as non-PD by independent 
assessment when the investigator assigned disease progression. If this proportion differs 
significantly from the 20% assumed then the number of patients randomised may be increased in 
order to observe 40 PFS events in a timely manner, but the number of patients randomised will 
not exceed 100 patients.


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Table 7.7: 1 shows the probability of observing various HR thresholds for different 
underlying (true) HR values and accrued PFS events.
Table 7.7: 1
Probability (%) of observed HR for a range of underlying HRs and PFS 
event numbers
PFS Events
Underlying 
(True) HR
Probability1 observing HR
≤0.50
≤0.60
≤0.75
>0.75
50
HR=1.00
0.7%
3.5%
15.5%
84.5%
40
1.4%
5.3%
18.1%
81.9%
30
2.9%
8.1%
21.5%
78.5%
50
HR=0.60
26.0%
50.0%
78.5%
21.5%
40
28.2%
50.0%
76.0%
24.0%
30
30.9%
50.0%
72.9%
27.1%
50
HR=0.50
50.0%
74.0%
92.4%
7.6%
40
50.0%
71.8%
90.0%
10.0%
30
50.0%
69.1%
86.7%
13.3%
50
HR=0.40
78.5%
92.4%
98.7%
1.3%
40
76.0%
90.0%
97.7%
2.3%
30
72.9%
86.7%
95.7%
4.3%
1 Calculated using the approximate normal distribution of the estimated log HR
With 40 PFS events, if the underlying HR is 0.50, the chance of observing a treatment 
effect with HR of ≤0.60 is 71.8%, while the chance of observing a treatment effect with 
HR of ≤0.75 is 90.0%. Also, if the underlying HR is 1.0, the chance of observing a 
treatment effect with HR of ≤0.60 is 5.3%, while the chance of observing a treatment 
effect with HR of ≤0.75 is 18.1%. If the PFS events were increased from 40 to 50, the 
probability of observing a treatment effect with HR of ≤0.60 is increased by 2.2% (from 
71.8% to 74.0%) for an underlying HR of 0.50, similarly for a treatment effect with HR 
of ≤0.75 the increase in probability is 2.4%.
Probabilities of 71.8 or 90%, respectively, based on 40 PFS events and an underlying HR of
0.50 is considered high enough to provide evidence that will allow an informed decision to 
be made in terms of the next stages of development.
The trial includes a seamless option for the expansion of the ongoing Phase II trial into 
a Phase III trial provided the predefined criterion (to be defined in the DMC charter) is 
met after 40 PFS events have been observed.


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If the trial meets the criterion for expansion a further 220 patients will be randomised, so 
300 patients in total, 150 per treatment arm. Primary analysis would be planned after 
approximately 176 PFS events, 40 from the primary Phase II analysis time-point plus an 
additional 136 events after this time-point. With 220 additional patients randomised into 
the expansion part at a constant rate over a 14 month period, 176 PFS events are predicted 
to be reached on average around 64 months after the first patient is randomised into the 
Phase II trial. This includes a 4-month gap between the Phase II results and starting the 
expanded trial. It is expected that approximately 20% of patients randomised will either 
drop out of the trial without evidence of disease progression or be assessed as non-PD by 
independent assessment when the investigator assigned disease progression. This has been 
accounted for with the planned total of 300 patients to be randomised. Note as for the 
Phase II part if the drop-out rate differs significantly from 20% the total number of patients 
randomised may need to be increased from 300, but will not exceed 375.
The patient numbers have been chosen to provide a sufficient amount of efficacy and 
safety data for submission. A standalone Phase III trial, with an assumed HR of 0.60 and 
176 events, would achieve an overall power of at least 90% controlling the overall type I 
error at 2.5% (one-sided). Also, when considering solely the expansion part with 136 
events it is ensured that based on an assumed HR for the expansion part of 0.60 the 
respective one-sided (second stage) p-value would be less than 0.05 in 90% of the cases. 
Thereby it is assumed that the event size for the second stage is sufficiently large to allow 
for informed decision making on homogeneity across the two trial parts in the case of the 
seamless option being met.
Note that although OS is included in the confirmatory testing strategy, if the trial is 
expanded, no power calculations have been performed as a significant OS benefit is not 
anticipated, due to unequal post-progression treatment being expected to obscure the effect 
of xentuzumab relative to placebo.


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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 Tripartite 
Guideline for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures 
(SOPs), European Directive 2001/20/EC and/or the EU regulation 536/2014 once coming 
into force, and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 
the responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken 
to protect the trial patients against any immediate hazard, as well as of any serious 
breaches of the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the 
following web page: trials.boehringer-ingelheim.com. The rights of the investigator and of 
the sponsor with regard to publication of the results of this trial are described in the 
investigator contract. As a rule, no trial results should be published prior to finalization of 
the Clinical Trial Report unless defined otherwise in the publication strategy.
The certificate of insurance cover is made available to the investigator and the patients, and 
is stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed 
and approved by the respective IRB/Independent Ethics Committee (IEC) and competent 
authority according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from 
each patient (or the patient’s legally accepted representative) according to ICH/GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient 
information form retained by the investigator as part of the trial records. A signed copy of 
the informed consent and any additional patient information must be given to each patient 
or the patient’s legally accepted representative.”
The 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-


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consenting process should be properly documented in the source documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, 
Sponsor’s designees, or by IRB/IEC or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the Sponsor. 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 good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit 
trail). Data reported on the CRF must be consistent with the source data or the 
discrepancies must be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for 
the trial and the investigator may need to request previous medical histories and evidence 
of any diagnostic tests. In this case the investigator must make three documented attempts 
to retrieve previous medical records. If this fails a verbal history from the patient, 
documented in their medical records, would be acceptable.
Before providing any copy of patients’ source documents to the Sponsor or Sponsor 
appointed CRO, 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 to ensure patient confidentiality.
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)

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)


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
Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of 
premature discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial 
participant meets all inclusion criteria and does not meet any exclusion criteria. The 
absence of records (either medical records, verbal documented feedback of the 
patient or testing conducted specific for a protocol) to support inclusion/exclusion 
criteria does not make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The Sponsor will monitor the conduct of the trial by regular on-site monitoring visits and 
in- house data quality review. The frequency of site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and 
the degree of any deviations of the intervention from normal clinical practice.
The investigator/institution will allow on-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 clinical research associate 
(CRA), auditor and regulatory inspector (e.g. FDA). They may review all CRFs and 
informed consents. The accuracy of the data will be verified by direct comparison with the 
source documents described in Section 8.3.1. The sponsor will also monitor compliance 
with the protocol and GCP.
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 (whatever is longer) valid at the time of the end of the 
trial.
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 regulatory reporting obligation and in accordance to 
the requirements defined in this CTP.
Exemptions from expedited reporting are described in Section 5.2.6.2, if applicable.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 


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disclosure to third parties is prohibited with the exceptions noted below. Patient privacy 
will be ensured by using patient identification code numbers. Data protection and data 
security measures are implemented for the collection, storage and processing of patient 
data in accordance with the principles 6 and 12 of the WHO GCP handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the 
trial need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB/IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and 
corresponding data
Measures are in place to comply with the applicable rules for the collection, biobanking 
and future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking 
informed consent

The BI-internal facilities storing biological samples from clinical trial participants 
as well as the external banking facility are qualified for the storage of biological 
samples collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical 
data and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and 
report) ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending 
on the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries 
as specified in the biobanking ICF
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 when the analysis of the LSLVSE (see below) is 
completed and patients have completed FU1 visit see Section 3.3.4.1.
The “Last Subject Last Visit Primary Endpoint” (LSLVPE) is defined as the date 
when the required number of PFS events has occurred for primary endpoint analysis, 
see Section 7.3.
The “Last Subject Last Visit Secondary Endpoint” (LSLVSE) is defined as the date 
when patients have completed FU1.
The “Last Subject Last Treatment” (LSLT) date is defined as the date on which the last 
patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LSLT 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 


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specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by 
the Sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health 
Authority request.
The IEC / competent authority in each participating EU member state will be notified 
about the trial milestones according to the respective laws.
A final report of the clinical trial data will be written after the LSLVSE, see also Section 
7.3. Any data collected in this trial after this will be covered by a revision to the CTR.
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).
The Coordinating Investigators are responsible to coordinate investigators at the 
different sites participating in this trial. Tasks and responsibilities are defined in a 
contract.
A SC consisting of independent experts and Sponsor representatives will be established to 
support the Coordinating Investigators. 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 also summarised in a SC charter filed in the 
TMF.
A DMC will be established. Members of the DMC are independent of BI, they are 
physicians experienced in the treatment of the disease under investigation and a 
statistician. The DMC will evaluate safety and efficacy data as well as results of Phase II 
primary PFS analysis, patients’ pattern of progression on trial treatment and post-
progression information. The DMC will receive urgent significant safety concerns for 
immediate evaluation. While DMC members may be unblinded, measures are in place to 
ensure the blinding for everyone else involved in the trial. Regular DMC meetings will be 
held at specified intervals. The DMC will recommend on 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 authorities, IRBs/IECs, 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 clinical trial 
portal (Clinergize) to facilitate document exchange and maintain an electronic ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required 
activities, in order to
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,


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ensure appropriate training and information of Clinical Trial Managers, CRAs, 
and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the 
respective local or regional BI organisation (Operating Unit, OPU) in accordance with 
applicable regulations and BI SOPs, or by a CRO with which the responsibilities and tasks 
will have been agreed and a written contract filed before initiation of the clinical trial.
Data Management and Statistical Evaluation may be performed by BI or delegated to a 
CRO. Delegation of responsibility and details of which SOPs are applicable will be 
documented.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are 
defined according to BI SOPs. A list of responsible persons and relevant local 
information can be found in the ISF.
Boehringer Ingelheim may appoint additional CROs for specialist services such as central 
laboratory analyses for retrospective analysis of HR+/HER2- status and logistics of all 
tissue and blood samples, central collection of HRQOL data, central imaging, radiomic 
assessments, provision of IRT, and trial medication logistics. Full documentation will be 
stored in the TMF. In addition each site will have an ISF containing all trial documents 
relevant for the site. Details will be provided in respective manuals. Trial documents 
relevant for the site will be available in ISF.


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9
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regeneration of the bone. J Bone Metab 2014;21(1):41-54.
R17-2118
Mundy GR. Metastasis to bone: Causes, consequences and 
therapeutic opportunities. Nat Rev Cancer 2002;2(8):584-93.
R17-2119
Zhang Y, Ma B, Fan Q. Mechanisms of breast cancer bone metastasis.
Cancer Lett 2010;292(1):1-7.
R17-2300
LeBedis C, Chen K, Fallavollita L, Boutros T, Brodt P. Perpheral 
lymph node stromal cells can promote growth and tumorigenicity of 
breast carcinoma cells through the release of IGF-I and EGF. Int J 
Cancer 2002;100:2-8.
R17-2303
Tang Y, Zhang D, Fallvollita L, Brodt P. Vascular endothelial growth 
factor C expression and lymph node metastasis are regulated by the type I 
insulin- like growth factor receptor. Cancer Res 2003;63:1166-71.
R17-2306
Morgillo F, Vita F de, Antoniol G, Orditura M, Auriemma PP, 
Diadema MR, et al. Serum insulin-like growth factor 1 correlates 
with the risk of nodal metastasis in endocrine-positive breast cancer. 
Curr Oncol 2013;20(4):e283-8.
R17-2771
Chung KC, Barlev A, Braun AH, Qian Y, Zagari M. Assessing 
analgesic use in patients with advanced cancer: development of a new 


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scale – the Analgesic Quantification Algorithm.Pain Med
2014;15(2):225-32.
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Mathias SD, Crosby RD, Qian Y, Jiang Q, Dansey R, Chung K. 
Estimating minimally important differences for the worst pain rating of 
the Brief Pain Inventory-Short Form. J Support Oncol 2011;9(2):72-8.
R17-2796
Sledge GW, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. 
MONARCH 2: Abemaciclib in combination with fulvestrant in women 
with HR+/HER2- advanced breast cancer who had progressed whilw 
receiving endocrine therapy. J Clin Oncol 2017; ePub ahead of print.
R17-2798
Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, et al. 
Palbociclib and letrozole in advanced breast cancer. N Engl J Med 
2016:375(20):1925- 36.
R17-2892
Finn RS, Crown J, Lang I, Boer K, Bondarenk I, Kulyk SO, et al. 
Overall survival results from the randomized phase II study of 
palbociclib (P) in combination with letrozole (L)vs letrozole alone for 
frontline treatment of HR+/HER2- advanced breast cancer (PALOMA-
1; TRIO-18). 53rd ASCO, Chicago, 2-6 Jun 2017. J Clin Oncol 
2017;35(Suppl.): Abstract35.
R17-2894
Rugo HS, Rumble RB, Macrae E, Barton DL, Connolly HK, Dickler 
MN, et al. Endocrine therapy for hormone receptor-positive metastatic 
breast cancer: American Society of Clinical Oncology guideline. J Clin 
Oncol 2016;34(25):3069-103.
R17-2947
Maurer W, Bretz F. Multiple testing in group sequential trials 
using graphical approaches. Stat Biopharm Res 2013; 5(4):311-
20.
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Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr 
A, et al. NCCN guidelines insights: Breast cancer, version 1.2017. J 
Natl Compr Canc Netw 2017;15(4):433-51.
R17-2979
Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, et al.
Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment 
of hormone-receptor-positive, HER2-negative metastatic breast cancer 
that progressed on previous endocrine therapy (PALOMA-3): Final 
analysis of the multicenter, double-blind, phase 3 randomised controlled 
trial. Lancet Oncol 2016;17(4):425-39.
R17-2980
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. 
The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination 
with letrozole versus letrozole alone as first-line treatment of oestrogen 
receptor- positive, HER2-negative, advanced breast cancer (PALOMA-
1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015;16(1):25-
35.
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Garcia SF, Rosenbloom SK, Beaumont JL, Merkel D, Roenn JH von, 
Rao D, et al. Priority symptoms in advanced breast cancer: 
development and initial validation of the National Comprehensive 
Cancer Network- Functional Assessment of Cancer Therapy-Breast 
Cancer Syndrome Index (NFSBSI-16). Value Health 2012;15(1): 183-
90.r96-382
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Rugo HS, Tredan O, Ro J, Morales SM, Campone M, Musolino A, et al. 
A randomized phase II trial of ridaforolimus, dalotuzumab, and 


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exemestane compared with ridaforolimus and exemestane in patients 
with advanced breast cancer. Breast Cancer Res Treat 2017.
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Dimitrienko A, Millen B, Lipkovich I. Multiplicity considerations 
in subgroup analysis. Stat Med 2017.
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Jensen SE, Cella D. Use and interpretation of the National 
Comprehensive Cancer Network-Functional Assessment of Cancer 
Therapy symptom indexes in palliative research and treatment: special 
considerations in overian cancer. J Palliat Care Med 2013;3(3):145.
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Cleeland CS. The Brief Pain Inventory: user guide. 2009. 
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Basch E, Trentacosti AM, Burke LB, Kwitkowski V, Kane RC, Autio 
KA, et al. Pain palliation measurement in cancer clinical trials: the US 
Food and Drug Administration perspective. Cancer 2014;120(5):761-7.
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Yost KJ, Eton DT. Combining distribution- and anchor-based approaches 
to determine minimally important differences: the FACIT experience. 
Eval Health Prof 2005;28(2):172-91.
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Costelloe CM, Chuang HH, Madewell JE, Ueno NT. Cancer response 
criteria and bone metastases: RECIST 1.1, MDA and PERCIST. J 
Cancer 2010;1:80-92.
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Hammond MEH, Hayes DF, Wolff AC, Mangu PB, Temin S. 
American Society of Clinical Oncology/College of American 
Pathologists guideline recommendations for immunohistochemical 
testing of estrogen and progesterone receptors in breast cancer. J 
Oncol Pract 2010;6(4):195-7.
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Giordano SH, Cohen DS, Buzdar DS, Perkins G, Hortobagyi GN. 
Breast carcinoma in men: a population-based study. Cancer
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Giordano SH. A review of the diagnosis and management of male 
breast cancer. Oncologist 2005;10(7):471-9.
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9 April 2017); U.S. Department of Health and Human Services, 
National Institutes of Health, National Cancer Institute (2017)
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Chen C, Anderson K, Mehrotra DV, Rubin EH, Tse A. A 2-in-1 
adaptive phase 2/3 design for expedited oncology drug development. 
Contemp Clin Trials 2018;64:238-42.
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Smith AW, Mitchell SA, De Aguiar CK, Moy C, Riley WT, Wagster 
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9.2
UNPUBLISHED REFERENCES
c01690707
. Investigator’s Brochure: Xentuzumab (BI 
836845); current version
c03569433-01
. 1280.4 Synoptic 
Interim Report; Version 1.0 dated 04 August 2015
c22665932-01
. 1280.4 Subgroup Analysis 
Report, Version 1.0 dated 10 August 2018


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10
APPENDICES
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK), PHARMACODYNAMIC (PD), BIOMARKER (BM) AND ANTI-
DRUG-ANTIBODY (ADA) AND NEUTRALIZING ANTIBODY (NAB) SAMPLING
As of 29 Sept 2021, samples will no longer be collected for ongoing patients.
Table 10.1: 1
Time schedule for PK, ADA, nAb, biomarker and cytokine sampling at screening and during treatment, at EOT, and FU
If a patient misses xentuzumab/placebo infusions due to drug holidays replacement samples for PK, ADAs, nAbs should be drawn at -0:05 before the next infusion.
Treatment Cycle
Visit
Day
Event + 
Comment
Planned Time 
[hh:min]
Event
PK
Xentuzumab
ADA
nAB
Free IGF-1
Total IGF-
1 Total 
IGF-2
Bone 
remodellin
g markers 3
Cytokine 
samples
cfDNA
Genomic 
DNA
C1
V1
1
Up to 1 hour before 
start of infusion
-0:05
Blood
sampling
X
X
X
X
X
X
X
X
X
Start of xentuzumab
infusion
0:00
Drug
administr.
15 (+/- 10) minutes 
after end of infusion
1:15
Blood 
sampling
X
X
3 Bone remodelling markers are blood and urine samples. Blood samples are taken at sites at the time points indicated in Table 10.1:1. Urine samples must be from the second 
morning void. When this occurs prior to visiting the clinic, the sample should be collected at the patient’s home and brought to the respective visit.


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Treatment Cycle
Visit
Day
Event + 
Comment
Planned Time 
[hh:min]
Event
PK
Xentuzumab
ADA
nAB
Free IGF-1
Total IGF-1 
Total IGF-2
Bone 
remodelling 
markers 3
Cytokine 
samples
cfDNA
C1
V3
15
Up to 1 hour 
before start of 
infusion
-0:05
Blood 
sampling
X
X
X
C2
V1
1
Up to 1 hour 
before start of 
infusion
-0:05
Blood 
sampling
X
X
X
X
X
X
Start of 
xentuzumab 
infusion
0:00
Drug 
administr.
15 (+/- 10) 
minutes after 
end of 
infusion
1:15
Blood 
sampling
X
X
X
V3
15
Up to 1 hour 
before start of 
infusion 
-0:05
Blood 
sampling
X
C3
V1
1
Up to 1 hour 
before start of 
infusion
-0:05
Blood 
sampling
X
X
X
X
C4
V1
1
Up to 1 hour 
before start of 
infusion
-0:05
Blood 
sampling
X
X
X
X
C6
V1
1
Up to 1 hour 
before start of 
infusion
-0:05
Blood 
sampling
X
X
X
X


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Treatment Cycle
Visit
Day
Event + 
Comment
Planned Time 
[hh:min]
Event
PK
Xentuzumab
ADA
nAB
Free IGF-1
Total IGF-1 
Total IGF-2
Bone 
remodelling 
markers 3
Cytokine 
samples
cfDNA
C12 
V1
1
  Up to 1 hour 
before start of 
infusion
-0:05
Blood 
sampling
X
X
X
C24
V1
1
Up to 1 hour 
before start of 
infusion
-0:05
Blood
sampling
X
X
X
EOT
EOT
0-14
End of Treatment 
Visit 0-14d after  
permanent 
discontinuation of 
study medication
998:00
Blood 
sampling
X
X
X
X
X
EOR-
FU1
EOR-
FU1
42
End of Residual 
effect period and 
follow-up 1
999:00
Blood 
sampling
X
X
X
FU-PD
FU-
PDx
At the time of PD 
for patients who 
did not progress at 
EOT
X


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10.2
RECOMMENDATIONS FOR ADVERSE EVENT TREATMENT
10.2.1 Management of Diarrhoea
Diarrhoea may occur and although usually mild to moderate, it may lead to dehydration and 
require treatment modification or discontinuation, so early management is essential (Table 
10.2.1: 1). At the time of treatment initiation patients should be given a supply of anti-
diarrhoeal medication such as loperamide to keep with them at all times or access to anti-
diarrhoeal medication should be confirmed, and patients should be counselled on the 
appropriate use.
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost 
through diarrhoea.
Table 10.2.1: 1
Grade-specific treatment recommendations of diarrhoea
Severity 
(CTCAE
grading)
Description
Treatment recommendations
Mild (Grade 1)
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared with baseline
Stop laxatives and advise patient to drink 
at least 8-10 glasses of water of clear fluids 
per day; anti-diarrhoeal medication such as 
loperamide 4 mg (2 tablets) to be taken 
immediately, followed by 2 mg (1 tablet) 
after each loose stool until bowel 
movements cease for 12 h
Moderate 
(Grade 2)
Increase of 4-6 stools per 
day over baseline moderate
increase in ostomy output 
compared to baseline; 
limiting instrumental 
activities of daily living 
(ADL)
Continue anti-diarrhoeal medication; 
assess for dehydration and electrolyte 
imbalance; consider i.v. fluids and 
electrolyte replacement
Severe 
(Grade 3)
Increase of ≥7 stools per 
day over baseline; 
hospitalisation indicated; 
severe increase in ostomy 
output compared with 
baseline; limiting self care 
ADL
See grade 2; plus: An infectious process 
should be ruled out with stool cultures; 
aggressive i.v. fluid replacement ≥24 h; 
hospitalisation to monitor progress; 
consider prophylactic antibiotics if patient 
is also neutropenic
Life threatening 
(Grade 4)
Life-threatening 
consequences; urgent 
intervention indicated
See grade 3
* If despite optimal supportive care and a treatment interruption, diarrhoea does not resolve to CTCAE grade ≤1 
within 14 days, treatment must be permanently discontinued.


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In the event that the patient is deriving obvious clinical benefit according to the investigator’s 
judgement, further treatment will be decided in agreement between the Sponsor and the 
investigator.
10.2.2
Management of nausea/vomiting
Nausea and vomiting may significantly affect patients’ adherence to the treatment and their 
quality of life. In order to reduce the occurrence and the intensity of emesis, it is 
recommended that patients are treated according to the recommendations given in Table 
10.2.2: 1.
Table 10.2.2: 1
Grade-specific treatment recommendations of nausea and vomiting
CTCAE grade
Treatment recommendation
Nausea = Grade 0 
and
Vomiting = Grade 0
PRN recommended by investigator’s discretion1
Nausea = Grade 1 
and
Vomiting = Grade 0
Antiemetic treatment1
e.g. 5-HT3 antagonist, prochlorperazine, metoclopramide
Nausea = Grade 2
Antiemetic treatment1
and
e.g. 5-HT3 antagonist, prochlorperazine, metoclopramide
Vomiting = Grade 0 
OR
Appropriate hydration (1.5 L/m2/day plus hydration deficit) 
must be ensured.
Nausea = Grade 0, 1 or 2
and
Vomiting = Grade 1 or 2
Vomiting ≥ Grade 3
Antiemetic treatment1
or
e.g. 5-HT3 antagonist, prochlorperazine, metoclopramide
Nausea ≥ Grade 3
Appropriate hydration (1.5 L/m2/day plus hydration deficit)
must be ensured
1.
Antiemetic treatment should follow the recommendations given in the National Comprehensive Cancer 
Network (NCCN) guidelines for antiemesis or the Consensus Statement of the Antiemetic Subcommittee of 
the Multinational Association of Supportive Care in cancer (MASCC) (R06-0986).


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10.3
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
* As published in R01-0787


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10.4
TUMOUR RESPONSE ASSESSMENT ACCORDING TO MODIFIED 
RECIST 1.1 CRITERIA
The RECIST response evaluation criteria version 1.1 will be adhered to as described in the 
guidelines published in the European Journal of Cancer (R09-0262) and the accompanying 
articles. Trial personnel involved in tumour assessment for this trial must be trained and 
knowledgeable of RECIST criteria version 1.1.
Tumour assessments should include CT scans of the chest, abdomen, pelvis and a brain CT/ 
MRI as well as a bone scan at screening. If clinically indicated, imaging of any other known 
or suspected site of disease (e.g. breast) using an appropriate method (CT scan, MRI, etc.) 
should be performed. The same radiographic procedure must be used throughout the trial. All 
images acquired and skin lesion photos will be sent to a central imaging CRO. If 
mammography is additionally conducted during clinical routine, it should also be sent for 
central imaging assessment together with any correlative images. Breast-ultrasound and 
biopsy data, if available, will be provided to the central imaging CRO for independent review 
by Sponsor datamanagement. As of 29 Oct 2021 due to the outcome of the study, images no 
longer will need to best sent to CRO for independent review.
The preferred method of assessment is a spiral CT scan with i.v. and oral contrast, unless i.v. 
and/or oral contrast are medically contraindicated. Scans of the abdomen, pelvis and other 
areas of the body, but not chest, may be done with MRI instead of CT.
Skin lesions followed as target lesions must be documented by colour digital photography 
and must include in the image a ruler with millimetre subdivisions and a label that includes 
the patient’s ID and exam date.
Bone scans (using 99m-technetium polyphosphonate scintigraphy) must be done at 
screening. During the trial, bone scans must then be repeated as specified in the Flow Chart
with every other CT scan in patients with bone metastasis at baseline. An additional bone 
scan will be performed at week 8. A bone scan shall always be assessed in correlation with 
anatomical imaging, CT, MRI, using a combination of modified RECIST 1.1 with MDA 
criteria (Table 10.4:4), as outlined in detail below in Tables 10.4:1 and 10.4:2 for target and 
non-target lesions.
For the purposes of this trial, patients should be re-evaluated for response at intervals 
described in the Flow Chart. In the event of a treatment delay, interruption or discontinuation 
of treatment, tumour assessment should continue to follow the original schedule.
Follow-up tumour assessments must utilise the same CT/MRI/photographic method and 
acquisition technique (including use or non-use of i.v. contrast) as were used for screening 
assessments to ensure comparability. A chest X-ray or skeletal X-ray which clearly 
demonstrates a new metastatic lesion may be used to document progression in lieu of 
CT/MRI/bone scan. Documentation of new visceral disease by ultrasound alone is not 
sufficient for means of this clinical trial.


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Only those patients who have measurable disease present at baseline and have had their 
disease re-evaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. Patients with disease 
manifestation in bone only will be evaluated according to RECIST 1.1 with modifications for 
assessment guidance and clarification following modified MDA criteria, as outlined below in 
Table 10.4:4.
Measurability of tumour at baseline
Measurable lesions
Lesions that can be accurately measured in at least one dimension with longest diameter
≥10 mm (by CT scan, MRI, caliper measurement), or if reconstructed slice thickness is
>5 mm use double the slice thickness as minimum target lesion measurement, or ≥20 mm (by 
chest X-ray). Pathological lymph nodes, defined as lymph nodes with a short axis >15 mm 
are also measurable.
Measurable disease
Measurable disease requires the presence of at least one measurable lesion.
Non-measurable disease
Non-measurable lesions are all other lesions, including small lesions (longest diameter
<10 mm with CT scan, MRI or caliper measurement, or if reconstructed slice thickness is
>5 mm use double the slice thickness as minimum target lesion measurement, or <20 mm 
with chest X-ray or pathological lymph nodes with shortest axis ≥10 and <15 mm) as well as 
truly non-measurable lesions. Lesions considered truly unmeasurable include leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/ abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques, soft-tissue and skin 
lesions that are <10 mm or are not documented by imaging and photography, bone lesions 
that are either <10 mm or are not lytic or mixed.
New lesions in irradiated fields
At baseline, previously irradiated lesions should not be used as indicator lesions unless they 
have progressed since irradiation. New lesions occurring in previously irradiated fields can be 
used as target lesions.
Methods of measurement
All measurements must be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations must be performed as close as possible to the treatment start and never more than 
4 weeks before the beginning of the treatment. If a lesion is considered too small to measure, 
at a follow-up exam, a default measurement of 5 mm should be applied. If the lesion is not 
visible on imaging or photos, a default measurement of 0 mm should be applied.


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The same method of assessment and the same technique should be used to characterise each 
identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by colour 
photography including a ruler to document the size of the lesion is obligatory.
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Ultrasound, endoscopy and laparoscopy should not 
be used to measure tumour lesions or evaluate tumour response. However, these techniques 
can be useful to supplement information from other techniques.
Baseline Documentation of Target and Non-target Lesions
Modified RECIST version 1.1: All measurable lesions up to a maximum of five lesions in 
total can be selected. These five lesions shall be representative of all involved non-visceral 
anatomical locations. However if a patient presents with target lesions only in bone or in 
lymph nodes or in soft tissue, five lesions within one anatomical location, bone, nodes, soft 
tissue, can be identified as target lesions. The longest diameter (LD) will be measured for all 
lesions except lymph nodes, for which shortest diameter (SD) perpendicular to the LD is 
used. All target lesions will be recorded and numbered at baseline. Target lesions should be 
selected on the basis of their size and their suitability for accurate repetitive measurements 
(either by imaging techniques or clinically).
A sum of diameter (SOD) for all target lesions will be calculated (using ShD for lymph nodes 
and LD for all other lesions) and reported as the baseline SOD. The baseline SOD will be 
used as reference to further characterise the objective tumour response of the measurable 
dimension of the disease (see Table 10.4: 1).


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Table 10.4: 1
Evaluation of target lesions with rules for bone lesions according to 
RECIST 1.1 and modified MDA criteria
Complete Response 
(CR)
For target bone 
lesions:
Disappearance of all target lesions. Any pathological lymph nodes 
must have
reduction in short axis to <10 mm.
•
Complete sclerotic fill-in of lytic lesions on XR or CT
•
Normalization of bone density on XR or CT
•
Normalization of signal intensity on MRI
•
Normalization of tracer uptake on bone scan
Partial Response 
(PR)
For target bone 
lesions:
At least a 30% decrease in the SOD of all target lesions taking as 
reference the baseline SOD.
•
Development of a sclerotic rim or partial sclerotic fill-in of lytic 
lesions on XR or CT.
•
Osteoblastic flare
•
re - Interval visualization of lesions with sclerotic rims or 
new sclerotic lesions in the setting ofother signs of PR and 
absence of progressive bony disease
•
subjective decrease in tracer uptake on bone scan
Stable Disease (SD)
For target bone 
lesions:
Neither sufficient shrinkage to qualify for PR, less than 30% 
decrease, taking as reference the baseline SOD, nor sufficient 
increase to qualify for PD, less than 20% increase, taking as 
reference nadir, the smallest SOD recorded on study (including 
baseline).
No new bone metastases.
Progression (PD)
For target bone 
lesions:
At least a 20% increase in the SOD of all target lesions taking as 
reference the smallest SOD (nadir) recorded on study (including 
baseline), together with an absolute increase in the SOD of at least 
5 mm.
OR
The appearance of one or more new unequivocal lesions.
•
Subjective increase in tracer uptake on bone scan
•
New bone metastases
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements are not required and these lesions should be 
followed as “present” or “absent” (see Table 10.4: 2).


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Table 10.4: 2
Evaluation of non-target lesions and new lesions with rules for bone 
lesions according to RECIST 1.1 and modified MDA criteria
Complete 
Response (CR)
For non-target 
bone lesions:
Disappearance of all non-target lesions. All lymph nodes must be non-
pathological in size
(<10 mm short axis)
•
Complete sclerotic fill-in of lytic lesions on XR or CT
•
Normalization of bone density on XR or CT
•
Normalization of signal intensity on MRI
•
Normalization of tracer uptake on bone scan
Non-CR/Non-PD
For non-target 
bone lesions:
Persistence of one or more non-target lesions
•
Development of a sclerotic rim or partial sclerotic fill-in of lytic 
lesions on XR or CT
•
Osteoblastic flare –
•
Interval visualization of lesions with sclerotic rims or new 
sclerotic lesions and absence of progressive bony disease
•
subjective increase or decrease in the size of ill-defined lesions on 
XR, CT, or MRI not sufficient for either PD or CR
•
subjective increase or decrease in tracer uptake on bone scan not 
sufficient for PD or CR
Progression (PD)
For non-target 
bone lesions:
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.
•
Subjective substantial increase in the size of ill-defined lesions on 
XR, CT, or MRI
•
Subjective substantial increase in tracer uptake on bone scan
•
New bone metastases
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status if in accordance with standard of care and after 
consent from patient based on institutional guidelines.
Evaluation of best response to study treatment
The best response to study treatment is the best response recorded from the start of treatment 
until disease progression or start of further anti-cancer treatment (taking as reference for 
progressive disease the smallest SOD recorded on study). The tables below are showing the 
time point response for patients with target (Table 10.4: 3) and non-target only disease 
(Table 10.4: 4). The time point responses for each patient are used to determine their best 
response to trial treatment.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.


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Table 10.4: 3
Time point response: patients with target disease
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/ Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not evaluated
No
PR
SD
Non-PD or not evaluated
No
SD
Not evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Table 10.4: 4
Time point response: patients with non-target disease
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR / non-PD
No
Non-CR / non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
A “Non-CR/non-PD is preferred over “stable disease” for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised.
Response evaluation rules for bone lesions aligned with the MDA criteria
Target and non-target assessment are adapted in alignment with the MDA criteria (R17-4024;
see Table 10.4: 5). Bone lesion measurements will not be performed perpendicular 
bidimensional, as described in MDA, but unidimensional following RECIST 1.1. The %-
changes of target lesion measurements follow RECIST 1.1, at least 30% decrease for PR and 
at least 20% increase for PD accordingly. Non target lesions’ assessment will not be based on 
quantitative analysis, but according to RECIST 1.1 on qualitative assessment only.
In this patient population with predominantly osteolytic or mixed skeletal metastases from 
breast cancer, a mere lesion counting on bone scans is not sufficient and would be medical 
incorrect and inacceptable. Thus a combination of the RECIST-defined assessment of bone 
lesions in conjunction with the more detailed description of a joined assessment of bone scan 
and anatomical imaging is scientifically reasonable. 99m-technetium bone scan alone may 
show metabolic activity with tracer uptake, which could be misinterpreted as a false positive
progression for responding and healing lesions, and vice versa non-activity with lack of tracer 


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uptake could be misinterpreted as false negative implying response, PR or CR, for 
metabolically inactive lesions. CT or MRI alone may only detect large bone lesions but may 
not be sensitive enough for small, faint or new lesions. The combined evaluation with both 
methods and both criteria thus allows for a more detailed, more precise assessment of the 
skeletal disease and its response to treatment or lack thereof.
Table 10.4: 5
MD Anderson (MDA) criteria*
Response category
Criteria
Complete Response
Complete sclerotic fill-in of lytic lesions on XR or CT 
Normalization of bone density on XR or CT 
Normalization of signal intensity on MRI 
Normalization of tracer uptake on BS
Partial Response
Development of a sclerotic rim or partial sclerotic fill-
in of lytic lesions on XR or CT.
Osteoblastic flare - Interval visualization of lesions 
with sclerotic rims or new sclerotic lesions in the 
setting of other signs of PR and absence of progressive 
bony disease
≥50% decrease in measurable lesions on XR, CT, or 
MRI
≥50% subjective decrease in the size of ill-defined 
lesions on XR, CT, or MRI
≥50% subjective decrease in tracer uptake on SS
Progressive Disease
≥25% increase in size of measurable lesions on XR, 
CT, or MRI
≥25% subjective increase in the size of ill-defined 
lesions on XR, CT, or MRI
≥25% subjective increase in tracer uptake on SS
Stable Disease
No change
<25% increase or <50% decrease in size of measurable 
lesions
<25% subjective increase or <50% subjective decrease 
in size of ill-defined lesions
No new bone metastases
*Measurements are based on the sum of a perpendicular, bidimensional measurement of the greatest diameters 
of each individual lesion (R17-4024).


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10.5
HEALTH-RELATED QUALITY OF LIFE QUESTIONNAIRES
10.5.1 BPI-SF


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10.5.2 NFBSI-16


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10.5.3 EQ-5D-5L


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10.5.4 PRO-CTCAE


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10.6
COCKCROFT-GAULT FORMULA
The following formula may be used for estimated creatinine clearance rate (eCCR) using 
Cockcroft-Gault formula. The use of on-line calculators or formulas which are institution 
standards for eCCR and differ slightly may also be used. The calculations and results must be 
filed in the patient’s chart.
When serum creatinine is measured in mg/dL;
eCCR 140AgeMassinkilograms0.85if Female
72SerumCreatinineinmg/dL
When serum creatinine is measured in µmol/L;
140AgeMassinkilogramsConstant 
eCCR 
SerumCreatinineinµmol/L
Where Constant is 1.23 for men and 1.04 for women.


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11.DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
28 Jun 2018
EudraCT number
EU number
2017-003131-11
BI Trial number
1280-0022
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
Xenera™ 1: A multi-centre, double-blind, placebo-
controlled, randomised phase II trial to compare 
efficacy of xentuzumab in combination with 
everolimus and exemestane versus everolimus and 
exemestane in post-menopausal women with HR+ / 
HER2- metastatic breast cancer and non-visceral
disease
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
x
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as
changes involve logistical or administrative aspects only
Section to be changed
All sections
Description of change
Typos and minor corrections
Rationale for change
To provide correct protocol language
Section to be changed
All sections
Description of change
Phase III was changed to Phase II
Rationale for change
To reflect the change of trial design
Section to be changed
Synopsis
Description of change
Number of participating countries and sites was
deceased
Rationale for change
Update of number of trial sites and countries
Section to be changed
Synopsis
Description of change
Update of trial objectives
Rationale for change
To reflect the change of trial design
Section to be changed
Synopsis
Description of change
Patient numbers were decreased
Rationale for change
Update of patient numbers for Phase II
Section to be changed
Synopsis
Description of change
Clarification that effusion should be malignant
Rationale for change
More details are provided to exclusion criterion
number 3


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Section to be changed
Synopsis
Description of change
Statistics part was adapted
Rationale for change
Change from Phase III to Phase II statistics
Section to be changed
Flow Chart
Description of change
Biomarker sampling and biobanking was adjusted
Rationale for change
Biomarker sampling and biobanking was changed 
to Phase II requirements
Section to be changed
1. Medical background
Description of change
Minor corrections
Rationale for change
Update of recent changes in therapies
Section to be changed
1.2.1 Xentuzumab
Description of change
Minor corrections
Rationale for change
Update with recent IB data
Section to be changed
1.3 Rationale for performing the trial
Description of change
Most current numbers are provided from the
analysis of trial 1280.4
Rationale for change
To provide most current data on which this trial is 
based on
Section to be changed
2.1.1 Main objectives
Description of change
Main objectives were adapted
Rationale for change
Update of Phase III to Phase II objectives of the 
trial
Section to be changed
3.1 Overall trial design and plan
Description of change
Paragraphs added for the option to expand 
seamlessly into Phase III if a pre-defined criterion 
is met
Figure for trial design adapted
Rationale for change
Update on the plan to expand this Phase II 
seamlessly into a Phase III
Provision of current figure for Phase II trial design
Section to be changed
3.2 Discussion of trial design, including the choice
of control group(s)
Description of change
Wording adapted for the option to expand 
seamlessly into Phase III and the change of interim
analysis
Rationale for change
Update for change from Phase III to Phase II
Section to be changed
3.3 Selection of trial population
Description of change
Update on participating sites and countries
Rationale for change
Update for change from Phase III to Phase II
Section to be changed
3.3.3 Exclusion criteria


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Description of change
Clarification that effusion should be malignant
Rationale for change
More details are provided to exclusion criterion 
number 3
Section to be changed
3.3.4.1 Withdrawal from trial treatment
Description of change
Paragraph added for patients with visceral disease:
Rationale for change
Provision of more detail on how to handle 
mistakenly included patients with visceral disease
Section to be changed
4.1.1 Identity of IMP and comparator
Description of change
Unit strength was updated
Rationale for change
Provision of updated details to IMP because a 
different formulation is used
Section to be changed
4.1.6.1 Blinding
Description of change
Description of how to handle blinding if the trial
seamlessly goes into a Phase III was added
Rationale for change
Update on the plan to expand this Phase II 
seamlessly into a Phase III
Section to be changed
4.4 Management of expected adverse events
Description of change
Section 4.4.4 Management of neutropenia was
added
Rationale for change
Provision of guidance on neutropenia
Section to be changed
5.3.2 Methods of sample collection
Description of change
Wording was added on sampling procedure
Rationale for change
Provision of updated instructions for PK sampling
Section to be changed
5.4 Assessment of biomarkers
Description of change
Update of biomarker sampling for Phase II
Further explanation on radiomics was added
Rationale for change
Update for change from Phase III to Phase II
Section to be changed
5.6.1 Patient-reported outcomes
Description of change
An additional questionnaire (PRO-CTCAE) was
added
Rationale for change
Introduction of this PRO will address patients 
assessment of AEs in more detail
Section to be changed
6.2.1 Screening
Description of change
Update on biomarker sampling
Rationale for change
Update for change from Phase III to Phase II
Section to be changed
7. Statistical methods and determination of sample
size
Description of change
Section 7 was partly re-written
Rationale for change
Update for change from Phase III to Phase II
Section to be changed
8.6 Trial milestones
Description of change
Adaptation of trial milestones


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Rationale for change
Update for change from Phase III to Phase II
Section to be changed
10.1 Time schedule for PK, PD and ADA and nAB
blood sampling
Description of change
Update of biomarker sampling for Phase II
Rationale for change
Update for change from Phase III to Phase II
Section to be changed
10.5 Health-related quality of life questionnaires
Description of change
Section 10.5.4 was added
Rationale for change
Provision of PRO-CTCAE questionnaire


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11.2
GLOBAL AMENDMENT 2
Date of amendment
14 Feb 2019
EudraCT number 
EU number
2017-003131-11
BI Trial number
1280-0022
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
Xenera™ 1: A multi-centre, double-blind, 
placebo- controlled, randomised phase II trial 
to compare efficacy of xentuzumab in 
combination with everolimus and exemestane 
versus everolimus and exemestane in post-
menopausal women with HR+ / HER2-
metastatic breast cancer and non-visceral
disease
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
x
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as
changes involve logistical or administrative aspects only
Section to be changed
Title page
Description of change
Clinical Trial Leader updated; Xenera changed 
to Xenera TM
Rationale for change
Administrative change
Section to be changed
Protocol synopsis – Main Inclusion and 
Exclusion Criteria
Description of change
Inclusion 3 and 6, Exclusion 8 updated
Rationale for change
Inclusion 3: Clarification that biopsies cannot 
be performed after consent for the purpose of 
the trial.
Inclusion 6: Administrative grammar changes
Exclusion 8: Updated to match exclusion 
criteria in section 3.3.3
Section to be changed
Protocol synopsis – Safety Criteria
Description of change
CTCAE version 4.03 updated to version 5.0
Rationale for change
Updated to current CTCAE version


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Section to be changed
Flowchart
Description of change
Screening period increased to 28 days; C2V3 
added as a column in flowchart; wording to 
clarify biopsy not performed after consent for 
purpose of the trial updated; diary card added to 
flow chart; section on when safety labs should 
be taken updated; follow up period timepoints 
updated in table to match footnotes; minor 
wording changes and additions to clarify 
procedures to be performed (text added from 
main body of protocol); number of slides 
required to be sent to central lab added; 
confirmation of HER2 changed to analysis of 
HER2
Rationale for change
To ensure that all protocol assessments are 
covered in the flowchart; to ensure biopsies not 
performed after consent for the purpose of the 
trial; to relax the time window for some of the 
screening procedures from 14 to 28 days  based 
on feedback from investigative sites
Section to be changed
Section 1.1 Medical Background
Description of change
Number of deaths due to breast cancer in USA 
and Europe updated
Rationale for change
Corrected to match reference updated in 
November 2018: 
http://globocan.iarc.fr/Pages/fact_sheets_cancer
.aspx
Section to be changed
1.3 Rationale for performing the trial
Description of change
Additional reference added; grammar changes
Rationale for change
To provide a report on the subgroup analysis in 
trial 1280.4; administrative change
Section to be changed
Section 2.1.1 Main Objectives
Description of change
Grammar change
Rationale for change
Administrative change
Section to be changed
Description of change
Rationale for change


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Section to be changed
Description of change
Rationale for change
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
Removal of language regarding fresh tissue 
biopsy after consent; addition of language 
stating archival bone biopsy samples should not 
be sent. 
Grammar changes; changes to the collection of 
safety data in the follow up period.
Rationale for change
Clarification that biopsies cannot be performed 
after consent for the purpose of the trial. 
Administrative changes to make protocol 
consistent with other sections.
Section to be changed
Section 3.2 Discussion of Trial Design, 
Including the Choice of Control Group(s)
Description of change
Grammar changes; clarification that only 
archival biopsy samples should be sent; interim 
analysis removed
Rationale for change
Clarification that biopsies cannot be performed 
after consent for the purpose of the trial; early 
preparations for expanding into a phase III trial 
will already be put into place so administrative 
interim analysis is no longer required
Section to be changed
Section 3.3.2 Inclusion Criteria
Description of change
Inclusion 3 updated to clarify that archival 
tumour sample is accepted and that bone 
samples should not be sent.
Inclusion 6: Grammar change
Rationale for change
Clarification that biopsies cannot be performed 
after consent for the purpose of the trial.


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Section to be changed
Section 3.3.3 Exclusion Criteria
Description of change
Exclusion 22 updated to include a washout 
period for any restricted medications.
Rationale for change
To include wash out period.
Section to be changed
Section 3.3.4.1 Withdrawal from trial treatment
Description of change
Section updated to add that if patient required 
palliative radiotherapy they would need to stop 
trial; pregnancy removed as withdrawal criteria; 
additional withdrawal criteria added to state that 
if patient violates eligibility criteria a discussion 
would need to take place as to whether patient 
stays on trial 
Other grammar changes.
Rationale for change
Palliative radiotherapy updated to match section 
4.2.1.3; pregnancy removed as not applicable; 
withdrawal due to violation of eligibility criteria 
added to cover the situation where it is 
determined that patient is not eligible after 
starting the trial treatment and would be better 
suited to a different treatment regimen e.g. 
discovered to have visceral disease.
Section to be changed
Section 4.1.1 Identity of the Investigational 
Medicinal Product (IMP) and comparator
Description of change
Duration of infusion for xentuzumab/placebo 
updated from about 1 hour to 1 hour
Rationale for change
Duration of infusion updated to match project 
standard
Section to be changed
Section 4.1.2 Background Medication
Description of change
Language changes regarding the sourcing of 
background medication; 10mg unit strength 
added with confirmation that only 2.5 and 5mg 
are provided centrally; additional language 
added about when to take background 
medication; grammar changes
Rationale for change
10mg unit strength added as some sites sourcing 
own medication will use this strength; language 
about when to take medication added as the 
requirement to take at different time on PK 
sampling days was removed from protocol and 
clarification needed on when to take treatment.


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Section to be changed
Section 4.1.3 Selection of doses in the trial
Description of change
Grammar changes
Rationale for change
Administrative changes
Section to be changed
Section 4.1.5 Drug assignment and 
administration
Description of change
Requirement for background medication to be 
taken after the start of the infusion on the days 
of PK sampling removed; grammar changes; 
addition of language for actions required in case 
of unrelated adverse events.
Rationale for change
PK for everolimus and exemstane is not being 
performed for this trial so no requirement to 
take the background medication a set time, 
language added in case of unrelated adverse 
events.
Section to be changed
4.1.6.1 Blinding
Description of change
Interim analysis removed; language added to 
document that there is a visual difference 
between xentuzumab and placebo vials and the 
requirement for third party blinding.
Rationale for change
Early preparations for expanding into a phase 
III trial will already be put into place so 
administrative interim analysis is no longer 
required; to ensure that investigators, ethics 
committees, institutional review boards and 
health authorities are aware of third party 
blinding concept.
Section to be changed
Section 4.1.8 Storage conditions
Description of change
Clinical trial manager updated to unblinded 
CRA or back up
Rationale for change
To clarify that unblinded pharmacies should 
contact unblinded sponsor team. Clinical trial 
managers will remain blinded to treatment arm.
Section to be changed
Section 4.1.9 Drug accountability
Description of change
Administrative changes
Rationale for change
Administrative changes


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Section to be changed
Section 4.2 Other treatments, emergency 
procedures, restrictions (including sections 
4.2.1.1, 4.2.1.2, table 4.2.1.2:1, 4.2.1.3, 4.2.2.1, 
4.2.2.2)
Description of change
Grammar changes; fasting defined in section 
4.2.2.1; additional restricted medications added 
Rationale for change
Information on fasting added to match lab 
manual; additional restricted medications added 
to match exclusion criteria
Section to be changed
Section 4.3 Treatment compliance
Description of change
Information on requirement for patient diary 
added 
Rationale for change
Administrative
Section to be changed
Section 4.4 Management of expected adverse 
events
Description of change
Text changed to clarify that the sections 
following are recommendations and should be 
followed unless institutional standards are 
available and implemented on investigator 
judgment; CTCAE version updated to version 
5.0
Rationale for change
To ensure that investigator sites are aware that 
sections are recommendations and not 
mandated; to use latest CTCAE version
Section to be changed
Section 4.4.1 Management of 
stomatitis/mucosal inflammation
Description of change
Section updated to provide guidance and 
recommendations for sites both with and 
without access to dexamethasone containing 
mouthwashes.
Rationale for change
Updated to further clarify recommendations as 
well as acknowledge that dexamethasone 
containing mouthwashes are not available in all 
participating countries.
Section to be changed
Section 4.4.1.2 Treatment recommendations for 
established stomatitis/mucositis
Description of change
Table 4.4.1.2:1 updated; CTCAE version 4.03 
updated to version 5.0 
Rationale for change
To make table easier to read in cases where 
dexamethasone mouthwashes are not available; 
enable use of the most recent CTCAE version


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Section to be changed
Section 4.4.2 Management of hyperglycaemia
Description of change
Section updated to clarify recommendation in 
case of hyperglycaemia
Rationale for change
To provide further clarification
Section to be changed
Section 5.1 Assessment of Efficacy
Description of change
Addition of language that MD Anderson criteria 
will also be used in selection of target and or 
non-target lesions in the bone; clarification that 
tumour response will be assessed by 
investigator and independent reviewer
Rationale for change
To define modification from Appendix 10.4 in 
the main part of protocol; clarification that 
investigator will also assess response
Section to be changed
Section 5.2 Assessment of Safety
Description of change
Version 4.03 CTCAE updated to version 5.0
Rationale for change
To use current version.
.2
Section to be changed
Section 5.2.2 Vital signs and ECOG 
performance status
Description of change
Title updated to include ECOG performance
Rationale for change
Administrative change
Section to be changed
Section 5.2.3 Safety laboratory parameters
Description of change
Section updated to include fasting requirements 
and to clarify that safety labs can be taken on 
the day before infusion so long as within 
protocol specified visit windows.
Rationale for change
Updated to match lab manual and to provide 
further guidance for site staff.
Section to be changed
Section 5.2.5 Left Ventricular Ejection Fraction
Description of change
Paragraph added that clinically relevant 
findings should be added into CRF
Rationale for change
Administrative change


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Section to be changed
Section 5.2.6 Assessment of adverse events
Description of change
CTCAE version 4.03 updated to version 5.0 
Rationale for change
Enable use of the most recent CTCAE version
Section to be changed
Section 5.3.1 Assessment of pharmacokinetics
Description of change
Removal of statement regarding sample 
collection in case of treatment being 
discontinued early. 
Rationale for change
In case of early treatment discontinuation 
patients would still follow procedures in flow 
chart as normal
Section to be changed
Section 5.4 (including 5.4.1, 5.4.2 and 5.4.3) 
Assessment of biomarkers
Description of change
Section and subsections updated to simplify the 
section, specify required timelines and remove 
duplication; updated to clarify that only archival 
biopsy samples should be sent; additional test to 
be performed (E-cadherin) on the archival 
tumour tissue collected; clarification that biopsy 
of the bone must not be provided to sponsor
Rationale for change
Section updated so that it is more easily 
understandable for sites as well as to clarify that 
fresh tissue biopsies should not be performed 
for the purpose of the trial; additional test added 
to further enhance the results from the trial. 
Section to be changed
Section 5.7 Appropriateness of Measurements
Description of change
CTCAE version 4.03 updated to version 5.0 
Rationale for change
Enable use of the most recent CTCAE version


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Section to be changed
Section 6.2.1 Screening
Description of change
Section updated to clarify that only archival 
tumour tissue should be sent; that anonymized 
report of patients genomic breast cancer 
signature would be collected and entered into 
CRF where available; option to prolong 
screening period to 6 weeks removed
Rationale for change
Section updated to clarify procedures required 
for the trial; prolongation of rescreening period 
removed as screening up to 28 is allowed 
instead of 14 days. In case patient cannot start 
treatment with 28 days then there is option to 
rescreen patient.
Section to be changed
Section 6.2.2 Treatment period (including 
6.2.2.1 and 6.2.2.2_
Description of change
Additional language added to clarify that 
although visit windows are allowed sites should 
refer back to C1V1 and ensure that treatment 
cycles are 28 days in duration; sentence about 
PK samples etc. at end of treatment simplified.
Rationale for change
Administrative
Section to be changed
Section 6.2.3 Follow up period and trial 
completion
Description of change
Clarification on which follow up visits are 
relevant to patients depending on whether or not 
they have  started further anti-cancer therapy
Rationale for change
Administrative
Section to be changed
Section 7.2 Null and Alternative Hypotheses
Description of change
Clarification that null hypothesis for primary 
analysis PFS is at end of phase III; sentence 
added that if the trial was seamlessly expanded 
to phase III then end of phase II would be 
considered as an interim analysis.
Rationale for change
Updated due to removal of interim analysis
Section to be changed
Section 7.3 Planned Analyses
Description of change
Clarification that it will be just the trial database 
that is unblinded; interim analysis removed 
Rationale for change
Early preparations for expanding into a phase 
III trial will be put into place so this 
administrative interim analysis is no longer 
required


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Section to be changed
Description of change
 
Rationale for change
Section to be changed
Section 7.4 Interim analysis
Description of change
Interim analysis removed, Figure 7.4.1 updated
Rationale for change
Updated due to removal of interim analysis
Section to be changed
8.7 Administrative structure of the trial
Description of change
Interim analysis removed; Clinical Monitor 
Local was changed to Clinical Trial Manager 
and Trial Clinical Monitor was changed to 
Clinical Trial Leader; confirmation of HER2 
was changed to analysis
Rationale for change
Early preparations for expanding into a phase 
III trial will already be put into place so this 
administrative interim analysis is no longer 
required; Update to current role names; HER2 
testing will be done but will not overrule sites 
initial test result
Section to be changed
9.1 Published references
Description of change
Reference for 4.03 CTCAE removed and 
reference for 5.00 CTCAE added
Rationale for change
 References updated
Section to be changed
9.2 Unpublished references
Description of change
Additional reference added
Rationale for change
To provide a report on the subgroup analysis in 
trial 1280.4.
Section to be changed
Appendix 10.1 Time schedule for PK, PD, BM 
and ADA and nAB blood sampling
Description of change
Table updated to include genomic DNA sample 
as well as administrative changes to match up to 
Flow Chart and other sections of protocol; time 
window added in for sampling
Rationale for change
Administrative changes


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Section to be changed
10.2.1 Management of diarrhoea
Description of change
Update of CTCAE version 4.03 to version 5.0 
AE grade definitions
Rationale for change
To enable use of the most recent CTCAE 
version
Section to be changed
Section 10.4 Tumour response assessment 
according to modified RECIST 1.1 criteria
Description of change
Updated to remove language about biopsies; 
addition of language about biopsy after 
treatment being according to standard of care
Rationale for change
Biopsies should not be performed as part of the 
trial


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11.3
GLOBAL AMENDMENT 3
Date of amendment
19 Sep 2019
EudraCT number 
EU number
2017-003131-11
BI Trial number
1280-0022
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
Xenera™ 1: A multi-centre, double-blind, 
placebo- controlled, randomised phase II trial 
to compare efficacy of xentuzumab in 
combination with everolimus and exemestane 
versus everolimus and exemestane in women 
with HR+ / HER2- metastatic breast cancer 
and non-visceral
disease
Global amendment due to urgent safety reasons
Global amendment
X
Section to be changed
Title page
Description of change
Removal of the term post-menopausal from the 
title of the trial
Rationale for change
Premenopausal women on ovarian suppression 
will be included in the trial according to 
adapted inclusion 7. 
Section to be changed
Protocol Synopsis-Title of trial
Description of change
Removal of the term post-menopausal from the 
title of the trial
Rationale for change
Premenopausal women on ovarian suppression 
will be included in the trial according to 
adapted inclusion 7.
Section to be changed
Protocol Synopsis-Objectives
Description of change
Removal of the term post-menopausal from the 
objectives section.
Rationale for change
Premenopausal women on ovarian suppression 
will be included in the trial according to 
adapted inclusion 7.
Section to be changed
Protocol Synopsis-Diagnosis
Description of change
Removal of term post-menopausal term from 
the section.
Rationale for change
Premenopausal women on ovarian suppression 
will be included in the trial according to 
adapted inclusion 7.


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Section to be changed
Protocol synopsis – Main Inclusion Criteria
Description of change
Update of the following inclusion bullets:
Inclusion: 3, 4, 5, 6. Removal of two inclusion 
bullets regarding previous therapies. 
Rationale for change
3: Modified to allow for cases where archival 
tissue is not available.
4: Adapted to account for various endocrine 
options (including more than 1 line of nsAI 
in premenopausal and postmenopausal 
patients, including the use of fulvestrant in 
postmenopausal patients.
5: Updated to include premenopausal patients 
on ovarian suppression, updated to bring 
criteria in line with NCCN definition.
6. Option to enroll patients with blastic 
lesions only has been added; for non-
measurable lesions there is no difference for 
determination of PD and date of PD, 
independent of radiographic morphology. 
Bullets 4 and 5 removed, no longer 
applicable as criteria updated in section 3.3.2. 
Section to be changed
Protocol synopsis – Main Exclusion Criteria
Description of change
Update of the following inclusion/exclusion 
bullets: Exclusion: 1, 3, 6, 8, 11, 12 and 13 
added
Rationale for change
1. Patients may now have received previous 
PI3K therapy. Based on emerging preclinical 
evidence.
3. Updated to clarify visceral metastases at 
screening versus historical evidence of 
visceral metastases.
6. Updated to allow one line of chemotherapy 
as chemotherapy is sometimes used in 
patients where a rapid response is required 
for palliation of symptoms.
8. Updated as premenopausal women 
included in the trial will remain on ovarian 
suppression medications.
11. Added to confirm only 1 prior line of 
CDK4/6 inhibitor can be used. Previously 
covered in inclusion 4, which has been deleted.


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12.To account for rare fetal drug exposure risk 
in pre-menopausal population on ovarian 
suppression.
13.Pre-menopausal women cannot be enrolled in 
trial unless on specified method of birth control, 
due to rare risk of pregnancy
Section to be changed
Protocol Synopsis-Statistical methods
Description of change
Addition of menopause status as a stratification 
factor for analysis.
Rationale for change
Premenopausal women on ovarian suppression 
will be included in the trial according to 
adapted inclusion 7.
Section to be changed
Protocol Flow Chart
Description of change
Additional line added for pregnancy and 
hormone level testing
Bullet 10 updated to clarify that baseline 
imaging assessment must be performed 28 days 
prior to start of trial treatment as opposed to 
randomisation
Bullet 25 added to detail pregnancy and 
hormone testing
Rationale for change
Administrative changes
Section to be changed
1.1 Medical Background 
Description of change 
Updated to provide further background on the 
approvals of CDK4/6 inhibitors and their use in 
this patient population, further information 
about the use of these treatments in 
premenopausal women on ovarian suppression, 
as well as the use of chemotherapy.
Rationale for change
Updates and clarifications to reflect changes in 
current therapies and treatment practice.
Section to be changed
1.3 Rationale for performing the trial
Description of change 
Removal of the term post-menopausal from the 
section.
Rationale for change
Premenopausal women on ovarian suppression 
will be included in the trial according to 
adapted inclusion 7.
Section to be changed
2.1 Main objectives, primary and secondary 
endpoints
Description of change 
Removal of the term post-menopausal from the 
section.
Rationale for change
Premenopausal women on ovarian suppression 
will be included in the trial according to 


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adapted inclusion 7.
Section to be changed
3.1 Overall trial design and plan
Description of change 
Language regarding provision of archival tissue 
updated.
Rationale for change
If retrospective provision of archival tissue is 
not possible, the patient will no longer be 
excluded.
Section to be changed
3.2 Discussion of trial, design, including the 
choice of control groups 
Description of change 
Language regarding provision of archival tissue 
updated. Use of everolimus and exemstane 
according to recommendations by guidelines
Rationale for change
To reflect changes in archival tissues collection 
as per inclusion criteria 3
If retrospective provision of archival tissue is 
not possible, patient will not be excluded
Section to be changed
 3.3.1 Main Diagnosis for Trial Entry
Description of change 
 Removal of the term post-menopausal from the 
section.
Rationale for change
 Premenopausal women on ovarian suppression 
will be included in the trial according to adapted 
inclusion 7.
Section to be changed 
3.3.2 Inclusion Criteria 
Description of change
Modification of Inclusion Criteria as listed 
below.
Rationale for change 
Inclusion 3: Modified to allow for cases where 
archival tissue is not available
Inclusion 4: Adapted to account for various 
endocrine options in premenopausal and 
postmenopausal patients, including use of 
fulvestrant in postmenopausal patients.
Inclusion 5 and 6: Deleted to account for 
changes in standard of care for endocrine 
therapy. The protocol aims at a population with 
at least 1 line of prior endocrine therapy, but 
does not now exclude more than 1 line of 
treatment. Based on a recent trial the median 
PFS of fulvestrant was less than 6 months and 
therefore patients who have used fulvestrant for 
less than 6 months are no longer excluded. 
Inclusion 7: Updated to allow the inclusion of 


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premenopausal patients on ovarian suppression. 
Definition of post-menopausal status updated as 
per NCCN guidelines.
Inclusion 9. Option to enroll patients with 
blastic lesions only added. For non-measurable 
lesions, there is no difference for determination 
of PD and date of PD, independent of 
radiographic morphology.
Section to be changed
3.3.3 Exclusion Criteria 
Description of change
Modification of Exclusion Criteria
Rationale for change
Exclusion 1: Removal of the requirement for 
patients not to have received previous PI3K 
therapy. Based on emerging preclinical 
evidence.
Exclusion 3: Update to define visceral 
metastases at screening versus historical 
evidence
Exclusion 8:  One line of chemotherapy is 
sometimes used in patients where a rapid 
response is required for palliation of symptoms
Exclusion 11: Updated as hormonal treatments 
are required for premenopausal patients as per 
revised inclusion 7
Exclusion 24: Exclusion criteria added. More 
than one line of CDK4/6i is not considered 
standard in current practice (was previously 
included in inclusion criteria 4).
Exclusion 25: To account for rare fetal drug 
exposure risk in pre-menopausal population on 
ovarian suppression.
Exclusion 26: Pre-menopausal women cannot 
be enrolled in trial unless on specified method 
of birth control, due to rare risk of pregnancy
Section to be changed
3.3.4.1 Withdrawal from trial treatment
Description of change
Addition of withdrawal criteria regarding 
women on ovarian suppression remaining in 
post-menopausal state. Addition of pregnancy 
as withdrawal criteria.


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Rationale for change
Pre-menopausal women on ovarian suppression 
have been allowed in the trial under protocol 
version 4 but it is important that they remain in 
post-menopausal state throughout the trial.
Women must not get pregnant whilst on study.
Section to be changed
4.1.2 Background medication
Description of change 
Section updated to clarify that everolimus and 
exemestane are not considered as 
investigational in this trial but that where local 
regulatory requirements mandate it then either 
may be considered as IMP and would be 
provided as labelled product to the sites.
Section update to remove 10mg as a unit 
strength used in trial as no supplies will be 
sourced by sites after approval of amendment.
Rationale for change
The use of everolimus in premenopausal 
women on ovarian suppression may be 
considered as off-label use in some countries 
and therefore considered investigational.
Section to be changed
4.1.5 Drug assignment and administration of 
doses of each patient
Description of change 
 The section on sourcing of background 
therapy by sponsor was updated.
Rationale for change
Background therapy will be provided to all 
sites, either via a local supplier or from the 
central depot and managed through the IRT 
system.
Section to be changed
4.1.7 Packaging, labelling, and re-supply
Description of change 
Term revised to investigational products
Rationale for change
Everolimus may be considered as 
investigational in some countries. 
Section to be changed
4.1.9 Drug accountability
Description of change 
Updated based on new strategy for supplying 
everolimus and exemestane to the sites.
Rationale for change
As everolimus may be considered as 
investigational in some countries.
Section to be changed
4.2.1.3 Concomitant treatments
Description of change 
Further information added about the 
requirement for treatments and monitoring for 
pre-menopausal women included in the trial 


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Rationale for change
Ovarian suppression requirements for the   
inclusion of premenopausal women updated
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change 
Further information added about the 
requirement for treatments and monitoring for 
pre-menopausal women included in the trial 
Administrative clarification regarding 
concomitant treatment
Rationale for change
 Ovarian suppression requirements for the   
  inclusion of premenopausal women updated
 Administrative correction 
Section to be changed
 4. 4. 4 Management of neutropenia
Description of change 
Administrative guidance for infection guidance
Rationale for change
Administrative clarification and reference added 
for management of xentuzumab and everolimus 
during infection
Section to be changed
 5.2.3 Safety laboratory parameters
Description of change 
Inclusion of pregnancy testing, FSH and 
estradiol hormone lab parameters.
Rationale for change
Addition of pregnancy and hormone lab values 
due to addition of premenopausal women on 
ovarian suppression
Section to be changed
 5.2.6.2.2 AE reporting to sponsor and timelines
Description of change 
Removal of fax as required method to send SAE 
forms to BI
Rationale for change
Administrative change to allow flexibility in 
how SAE forms are sent to BI.
Section to be changed
 5.2.6.2.3 AE reporting and collection-
Pregnancy 
Description of change 
Addition of pregnancy statement due to 
inclusion of pre-menopausal 
Rationale for change
To define an established reporting and follow up 
process  in the event of pregnancy
Section to be changed
5.4.1 Evaluation of molecular and biochemical   
 biomarkers in tumor tissue
Description of change 
Language regarding provision of archival tissue 
updated.
Rationale for change
To reflect changes in archival tissues collection 
as per inclusion criteria 3 as no longer 
mandatory


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Section to be changed
6.2.1 Screening
Description of change 
Language regarding provision of archival tissue 
updated.
Rationale for change
To reflect changes in archival tissues collection 
as per inclusion criteria 3 as no longer 
mandatory
Section to be changed
 7.1 Statistical Design
Description of change 
Removal of post-menopausal term from title 
Addition of menopause status (pre/post) as a 
stratification factor for analysis
Rationale for change
Premenopausal women on ovarian suppression 
will be included in the trial according to 
adapted inclusion 7.
Section to be changed
 7.3 Planned Analyses
Description of change 
Change of expected timeframe for PFS analysis 
from 18 to 15 months.
Addition of menopause status (pre/post) as a 
stratification factor for analysis
Rationale for change
Confirmation of adjusted timelines
Inclusion of premenopausal women on ovarian 
suppression
Section to be changed
 7.3.1 Primary endpoint analysis
Description of change 
Addition of menopause status (pre/post) as a 
stratification factor for analysis
Rationale for change
Premenopausal women on ovarian suppression 
will be included in the trial according to 
adapted inclusion 7.
Section to be changed
7.4 Interim Analysis
Description of change 
Updated predicted timelines for PFS events to 
30 months.
Rationale for change
Confirmation of adjusted timelines.
Section to be changed
 7.7 Determination of sample size
Description of change 
  Revised recruitment and event predicted
timelines 
Rationale for change
Confirmation of adjusted timelines.


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11.4
GLOBAL AMENDMENT 4
 Date of amendment
05 Feb 2020
EudraCT number 
EU number
2017-003131-11
BI Trial number
1280-0022
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
Xenera™ 1: A multi-centre, double-blind, 
placebo- controlled, randomised phase II trial 
to compare efficacy of xentuzumab in 
combination with everolimus and exemestane 
versus everolimus and exemestane in women 
with HR+ / HER2- metastatic breast cancer 
and non-visceral
disease
Global amendment due to urgent safety reasons
Global amendment
X
Section to be changed
Protocol Synopsis-Number of patients entered
Description of change
Approximately added
Rationale for change
Recruitment may be increased up to a 
maximum of 100 patients in order to ensure the 
required number of events. Further details are 
provided in section 7.7 of protocol.
Section to be changed
Protocol Synopsis-Number of patients on each 
treatment
Description of change
Approximately added
Rationale for change
Recruitment may be increased up to a 
maximum of 100 patients in order to ensure the 
required number of events. Further details are 
provided in section 7.7 of protocol.
Section to be changed
Protocol synopsis – Main Exclusion Criteria
Description of change
Exclusion 13 updated to specify the required 
follow up period for use of contraception for 
each of the three therapies.
Rationale for change
Update of contraception requirements for 
xentuzumab for women of childbearing 
potential to at least 6 months after the last dose, 
based on the 98th percentile for normalization of 
total IGF levels in PK/PD simulations.
Update of contraception requirements for 
backbone therapy according to SmPC.


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Section to be changed
Protocol Flow Chart
Description of change
Additional X added for pregnancy testing 
during follow up phase. 
Footnote ** updated to include reminder that 
pregnancy testing should be performed every 4 
weeks from Cycle 21 onwards where cycles are 
8 weekly in duration. Also updated to allow 
patients discontinuing xentuzumab/placebo to 
switch to 4 weekly visits as on 
everolimus/exemestane alone
Footnote 9 updated to remove serum so that any 
appropriate material can be tested.
Footnote 10 updated to include imaging (if no 
imaging available within 4 weeks) at end of 
treatment for patients discontinuing trial 
treatment without objective progression if 
starting straight away on subsequent anti-cancer 
therapy and not entering FU-PD
Footnote 21 updated to include mention of 
pregnancy testing during overall survival follow 
up
Footnote 25 updated to clarify when pregnancy 
testing should be performed for pre-menopausal 
women as well as the addition of screening 
hormone testing for post-menopausal women 
under 60 years of age (in the absence of 
bilateral oophorectomy) for eligibility purposes.
Rationale for change
Update of contraception requirements for 
xentuzumab for women of childbearing 
potential to at least 6 months after the last dose, 
based on the 98th percentile for normalization of 
total IGF levels in PK/PD simulations.
Flexibility in study visits for patients who 
discontinue xentuzumab/placebo in order to 
help patient retention.
Imaging for patients without objective 
progression and starting new anticancer therapy 
to ensure that a recent image is available for 
PFS assessment
Check of eligibility for post-menopausal 
women less than 60 years of age.
Serum removed to allow more flexibility as 


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biochemistry may be analyzed in plasma or 
serum depending on laboratory test.
Section to be changed
3.2 Discussion of trial, design, including the 
choice of control groups 
Description of change 
Post-menopausal removed from paragraph.
Rationale for change
Everolimus and exemestane are considered 
standard of care to both pre- and post-
menopausal women
Section to be changed
 3.3. Selection of trial population
Description of change 
 Word approximately added and a reference to 
section 7.7 added.
Rationale for change
 Recruitment may be increased up to a 
maximum of 100 patients in order to ensure the 
required number of events. Further details are 
provided in section 7.7 of protocol.
Section to be changed 
3.3.2 Inclusion Criteria 
Description of change
Modification of Inclusion Criteria 11: Word 
plasma removed
Rationale for change 
Although plasma glucose is preferred, glucose 
may be tested from any appropriate sampling 
material.
Section to be changed
3.3.3 Exclusion Criteria 
Description of change
Modification of Exclusion Criteria 26: addition 
of specific timelines for which contraception 
must continue to be used once patient off each 
treatment type.
Footnote for Exclusion Criteria 27: added 
regarding non hormone releasing intrauterine 
device (lUD) or intrauterine system (IUS).
Rationale for change
Update of contraception requirements for 
xentuzumab for women of childbearing 
potential to at least 6 months after the last dose, 
based on the 98th percentile for normalization of 
total IGF levels in PK/PD simulations.
Additional footnote added to clarify that only 
non hormone releasing intrauterine device 
(lUD) or intrauterine system (IUS) can be used
Section to be changed
3.3.4 Withdrawal of patients from therapy or 
assessments 
Description of change
Update of bullet regarding ILD referring to 
section 4.4.3
Rationale for change
Patients should only be withdrawn from trial 


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treatment for ILD following the guidance in the 
SmPCs and guidance on dose changes for 
xentuzumab/placebo in the protocol
Section to be changed
4.1.5.1 Drug assignment and administration
Description of change
Administrative change to remove comparator 
medications being provided by sites
Rationale for change
Per protocol version 4 all comparator 
medication will be supplied by sponsor
Section to be changed
4. 4. 2 Management of hyperglycaemia
Description of change 
Serum removed
Rationale for change
Although plasma glucose is preferred, glucose 
may be tested from any appropriate sampling 
material.
Section to be changed
4. 4. 3 Management of non-infectious 
pneumonitis/ILD
Description of change 
Title of section updated to include ILD
Section updated to be consistent with section 
4.1.5.2 
Rationale for change
To ensure consistency with SmPC and guidance 
in section 4.1.5.2
Section to be changed
5.2.3 Safety laboratory parameters
Description of change 
Table 5.2.3:1 updated:
Hormone testing section simplified but with 
reference to flowchart for details. Hormone 
testing should be done for premenopausal 
women but also post-menopausal women less 
than 60 years of age (in absence of bilateral 
oophorectomy).
Other (fasting) blood tests updated to detail that 
plasma glucose is preferred but any appropriate 
sampling material is permitted.
Rationale for change
Update of contraception requirements for 
xentuzumab for women of childbearing potential 
to at least 6 months after the last dose, based on 
the 98th percentile for normalization of total IGF 
levels in PK/PD simulations.
Other administrative changes.
Section to be changed
6.2.3.1 Extended follow up period
Description of change 
Additional of collection of pregnancy test results 
in extended follow up
Rationale for change
Due to increased pregnancy test requirements


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Section to be changed
6.2.3.2 Follow up for overall survival
Description of change 
Additional of collection of pregnancy test results 
in overall survival follow up
Rationale for change
Due to increased pregnancy test requirements
Section to be changed
7.3 Planned Analyses
Description of change 
Updated to allow for analysis of the phase II 
trial without 40 PFS events with the condition 
that the trial will not be considered to have met 
criteria for seamless transition to phase III
Rationale for change
Updated in the event that a larger number of 
patients than anticipated withdraw from the trial 
with symptomatic progression or AEs and start  
further therapies before objective progression is 
observed, thereby putting the trial at risk for not 
meeting primary analysis target of 40 events.
Section to be changed
7.4 Interim Analysis
Description of change 
Reference to section 7.3 added with regard to 
not reaching 40 events
Rationale for change
Administrative
Section to be changed
7.6 Randomisation
Description of change 
Paragraph regarding percentage of patients to 
be recruited into bone only vs non bone only 
strata removed from section.
Rationale for change
This section has been determined not relevant 
for phase II trial.
Section to be changed
 7.7 Determination of sample size
Description of change 
Section updated to describe situation where 
recruitment may go more than 80 patients but 
no more than 100 patients for the phase II and 
375 for the phase III if this goes ahead.
Rationale for change
Due to higher than expected number of early 
patients dropping out due to symptomatic 
progression, additional patients may need to be 
recruited.


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11.5 GLOBAL AMENDMENT 5
Date of amendment
25 Nov 2021
EudraCT number 
EU number
2017-003131-11
BI Trial number
1280-0022
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
Xenera™ 1: A multi-centre, double-blind, 
placebo- controlled, randomised phase II trial 
to compare efficacy of xentuzumab in 
combination with everolimus and exemestane 
versus everolimus and exemestane in women 
with HR+ / HER2- metastatic breast cancer 
and non-visceral
disease
Global amendment due to urgent safety reasons
Global amendment
X
Section to be changed
Title page
Description of change
 Revision to clinical trial leader assignment
Rationale for change
New clinical trial leader managing trial
Section to be changed
Protocol Flow Chart 
Description of change
New Protocol Flow Chart added 
Rationale for change
New flow chart to reflect reduced procedures 
and assessment to support ongoing patients as a 
result of top line results 
Section to be changed
Section 1.4 Benefit-Risk assessment
Description of change
Updates to benefit risk assessment
Rationale for change
Benefit risk assessment updated to based on 
database lock endpoint analysis, recommending 
study discontinuation of xentuzumab infusions
Section to be changed
Section 4.1- Investigational treatments 
Description of change
Xentuzumab treatment discontinuation 
Rationale for change
Based on the top line results, recommendation 
to stop xentuzumab infusions
Section to be changed
Section 4.1.5.1- Drug assignment and 
administration
Description of change
 Reference to updated flow chart
Rationale for change
Updated flow chart
Section to be changed
Section 4.1.6.1- Blinding 
Description of change
 Clarification on unblinding
Rationale for change
Decision to unblind as there was no added 
benefit based on primary endpoint analysis 


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Section to be changed
Section 5.1- Assessment of Efficacy
Description of change
 Tumor assessments per local practice 
Rationale for change
 Procedural change as a results of primary 
 endpoint analysis 
Section to be changed
Section 5.2- Assessment of Safety
Description of change
Safety assessments per local practice 
Rationale for change
  Procedural change as a results of primary 
 endpoint analysis 
Section to be changed
Section 5.2.3, Table 5.2.3:1- Safety Laboratory 
tests 
Description of change
 hormone testing updated for Post-menopausal 
 woman
Rationale for change
Hormone testing is no longer necessary for 
women less than 60 years of age and in absence 
of bilateral oophorectomy
Section to be changed
Section 5.2.4 Electrocardiogram
Description of change
 Removal of ECG
Rationale for change
 Procedural change as a results of primary 
 endpoint analysis
Section to be changed
Section 5.2.5 Left Ventricular Ejection 
Fractions
Description of change
 Removal of  MUGA 
Rationale for change
 Procedural change as a result of primary 
 endpoint analysis
Section to be changed
Section 5.2.6.2.1 AE Collection
Description of change
 Updated clarification of safety information after 
  REP 
Rationale for change
 Administrative change 
Section to be changed
Section 5.2.6.3 Assessment of Healthcare 
resource use
Description of change
 Removal of Healthcare resource questionnaire 
  use
Rationale for change
  Procedural change as a result of primary 
  endpoint analysis 
Section to be changed
Section 5.2.7 Safety Assessment as of 29 Sep 
2021
Description of change
 Safety Procedure Updates
Rationale for change
  Procedural change as a results of primary 


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  endpoint analysis, As IMP is discontinued 
 safety assessments can be per local practice.
Section to be changed
Section 5.2.7 Safety Assessment as of 29 Sep 
2021
Description of change
 New text to reflect safety information collection
Rationale for change
 Changes to safety information collection due to 
discontinuation of xentuzumab
Section to be changed
Section 5.3 Drug Concentration Measurement 
and Pharmacokinetics
Description of change
 Removal of PK sampling
Rationale for change
  Procedural change as a result of primary 
  endpoint analysis 
Section to be changed
Section 5.4-Assesment of Biomarkers
Description of change
 Removal of Biomarker  sampling
Rationale for change
  Procedural change as a result of primary 
  endpoint analysis 
Section to be changed
Section 5.5-Assesment of Immunogenicity 
Description of change
 Removal of Assessment of Immunogenicity 
Rationale for change
  Procedural change as a results of primary 
  endpoint analysis
Section to be changed
Section 5.6-Other Assessments
Description of change
 Removal of Patient Questionnaires 
Rationale for change
 Procedural change as a result of primary 
analysis 
Section to be changed
Section 6.2 Detail of Trial Procedures at 
Selected Visits 
Description of change
 Administrative Change 
Rationale for change
  Reference to updated flow chart  
Section to be changed
Section 6.2.3 Follow up period and trial 
completion  
Description of change
 Removal of Follow up for PD and follow up for 
 OS 


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Rationale for change
  Procedural change as a result of primary 
  analysis 
Section to be changed
Section 10.4 Tumor Response Assessment 
according to modified recist 1.1 criteria 
Description of change
 Independent imaging review removed
Rationale for change
 Procedural change as a result of completion of 
  primary analysis


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c18323506
9.0
clinical-trial-protocol-version-06
XeneraTM 1: A multi-centre, double-blind, placebo-controlled, randomised phase II
trial to compare efficacy of xentuzumab in combination with everolimus and
exemestane versus everolimus and exemestane in women with HR+ / HER2-
metastatic breast cancer and non-visceral disease
Author-On behalf of First Author
29 Nov 2021 08:50 CET
Author-Statistician
29 Nov 2021 09:04 CET
Approval-Clinical Program
29 Nov 2021 10:00 CET
Approval
06 Dec 2021 16:20 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c18323506
9.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c33744236-02
BI Trial No.:
1280-0022
Title:
XeneraTM 1: A multi-centre, double-blind, placebo-controlled, 
randomised phase II trial to compare efficacy of xentuzumab in 
combination with everolimus and exemestane versus everolimus 
and exemestane in women with HR+ / HER2- metastatic breast 
cancer and non-visceral disease
Including Protocol Amendment 5 <1280-22>-protocol-version-05 
[c18323506-08]
Investigational
Product:
Xentuzumab (BI 836845)
Responsible trial 
statistician:
Phone: 
Date of statistical 
analysis plan:
23 AUG 2021 SIGNED
Version:
2
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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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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS..........................................................................................................8
5.1
PRIMARY ENDPOINT........................................................................................8
5.2
SECONDARY ENDPOINTS ...............................................................................9
5.2.1
Key secondary endpoints ......................................................................................9
5.2.2
Secondary endpoints ...........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS...........................................................19
6.1
TREATMENTS...................................................................................................19
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................19
6.3
PATIENT SETS ANALYSED ...........................................................................20
6.5
POOLING OF CENTRES..................................................................................22
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................22
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................23
7.
PLANNED ANALYSIS ......................................................................................25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........25
7.2
CONCOMITANT DISEASES AND MEDICATION......................................25
7.3
TREATMENT COMPLIANCE ........................................................................25
7.4
PRIMARY ENDPOINT......................................................................................25
7.4.1
Primary analysis of the primary endpoint........................................................26
7.5
SECONDARY ENDPOINTS .............................................................................27
7.5.1
Key secondary endpoints ....................................................................................27
7.5.2
Secondary endpoints ...........................................................................................27
7.7
EXTENT OF EXPOSURE .................................................................................29
7.8
SAFETY ANALYSIS..........................................................................................30
7.8.1
Adverse Events ....................................................................................................30
7.8.2
Laboratory data...................................................................................................32
7.8.3
Vital signs.............................................................................................................33
7.8.4
Electrocardiogram...............................................................................................33
7.8.5
Others ...................................................................................................................34
8.
REFERENCES ....................................................................................................35


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10.
HISTORY TABLE..............................................................................................37


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LIST OF TABLES
Table 5.1: 1
Derivation rules for PFS.....................................................................................9
Table 5.2.2: 1 Derivation rules for pain progression or intensification of pain palliation.......11
Table 6.2: 1
Handling of iPDs ..............................................................................................20
Table 6.7: 1
Nominal time-points and windows for imaging...............................................24
Table 6.7: 2
Nominal time-points and windows for PROs...................................................24
Table 7.8.1: 1 Overview of Special Search Categories ...........................................................31
Table 10: 1
History table .....................................................................................................37


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADA
Anti-drug antibodies
AE
Adverse Event
ALT
Alanine aminotransferase
AQA
Analgesic Quantification Algorithm
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
BIcMQ
Boehringer Ingelheim customised MedDRA Queries
BOR
Best Overall Response
BPI-SF
Brief Pain Inventory – Short Form
CDK
Cyclin-Dependent Kinase
CI
Confidence Interval
COVID-19
Coronavirus Disease 2019
CR
Complete Response
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
DC
Disease Control
DLM
Database Lock Meeting
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EQ-5D-5L
EuroQoL 5-dimension health status self-assessment questionnaire
HLT
High Level Term
HR
Hazard Ratio
ICH
International Conference on Harmonisation
iPD
Important Protocol Deviation
IRT
Interactive Response Technology
ITT
Intention-to-Treat
KM
Kaplan-Meier
Max
Maximum


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Min
Minimum
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model Repeated Measures
MQRM
Medical Quality Review Meeting
nAb
Neutralising antibody
NFBSI-16
Network Functional Assessment of Cancer Therapy-Breast Cancer 
Symptom Index
OR
Objective response
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-free survival
PPS
Per Protocol Set
PR
Partial Response
PRO
Patient Reported Outcome
PRO-CTCAE
Patient Reported Outcomes-Common Terminology Criteria for Adverse 
Events
PT
Preferred Term
Q1
Lower quartile
Q3
Upper quartile
RECIST
Response Evaluation Criteria in Solid Tumours
RPM
Report Planning Meeting
RS
Randomised Set
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SD
Stable Disease
SMQ
Standardised MedDRA Query
SOC
System Organ Class
SSC
Special Search Categories
TFST
Time to First Subsequent Therapy
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TSST
Time to Second Subsequent Therapy
TTE
Time to Event
ULN
Upper Limit of Normal
WHO-DD
World Health Organisation Drug Dictionary


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 guidance (1), the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the protocol, and to include detailed procedures for executing the 
statistical analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including protocol amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomization.
This TSAP currently covers the Phase II part of the study, for the scenario that the criterion 
for expanding the trial seamlessly into Phase III has not been met. In such an instance, the 
trial will be unblinded and the results evaluated in an explorative manner to see if they are 
sufficient for further development of this compound in this indication.
SAS® Version 9.4 or a later version will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The following changes to the statistical methods described in the CTP and subsequent 
amendments are detailed in this TSAP:

Where considered appropriate, the potential impact of Coronavirus Disease 2019 
(COVID-19) on the study will be assessed by producing additional summaries of 
disposition, protocol deviations, treatment compliance, efficacy, treatment exposure 
and adverse events (AEs). The start date for COVID-19 having an impact on the trial 
will be taken as the earliest date of a COVID-19 related protocol deviation, 
discontinuation due to COVID-19, onset of a severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) related AE or COVID-19 related global BI recruitment 
hold (17 MAR20).
5.
ENDPOINTS
Time to event (TTE) endpoints, unless stated otherwise, will be calculated as follows:
For patients with ‘event’ as an outcome:

TTE [days] = date of outcome – date of randomisation + 1
For patients with ‘censored’ as an outcome:

TTE (censored) [days] = date of outcome – date of randomisation + 1
Derivations will be calculated in days but will be presented as months in the respective 
outputs [Months = (Days x 12) / 365.25].
All references to the Response Evaluation Criteria in Solid Tumours (RECIST) are according 
to Version 1.1 in combination with MD Anderson criteria (refer to Section 5.1 of the CTP for 
further details). Unless stated otherwise, all imaging-related endpoints detailed below will 
primarily be derived from blinded independent assessment data, derivations using investigator 
assessment data will also be performed but will be supportive in nature.
5.1
PRIMARY ENDPOINT
The primary endpoint is progression-free survival (PFS) calculated as the time from 
randomisation until progressive disease (PD) according to RECIST or death from any cause, 
whichever occurs earlier. The date of PD will be based upon blinded independent assessment.
The rules to determine the PFS outcome (event or censored) along with the date of outcome 
are specified in Table 5.1: 1. These rules will be applied to the independent assessment data 
prior to analysis.
In order to identify whether radiological imaging assessments are missing, a nominal time-
point based on the scheduling detailed in the CTP will be assigned to each assessment 
according to Table 6.7: 1. If a patient does not have an assessment for one of the scheduled 
time-points, it will count as a missed assessment. Any assessment with an overall tumour 


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response of Not Evaluable (NE) will be considered as a missed assessment and cannot be used 
as an outcome date.
Table 5.1: 1
Derivation rules for PFS
Status at time of analysis
Outcome
Date of outcome
No baseline radiological assessment and/or no post-baseline radiological assessments
Death on or before the second planned 
radiological assessment
Event*
Date of death
Vital status is unknown or alive or death after 
second radiological assessment 
Censored
Date of randomisation
With baseline and at least one post-baseline radiological assessment
Alive and non-PD, no more than one 
consecutively missed radiological assessment
Censored*
Date of last radiological 
assessment
Alive and non-PD, two or more consecutively 
missed radiological assessments
Censored*
Date of last radiological 
assessment prior to missed 
radiological assessments
PD, no more than one consecutively missed 
radiological assessment prior to PD
Event*
Date of radiological 
assessment of PD
PD, two or more consecutively missed 
radiological assessments prior to PD
Censored*
Date of last radiological 
assessment prior to missed 
radiological assessments
Death and non-PD, no more than one 
consecutively missed prior radiological 
assessment prior to death
Event*
Date of death
Death and non-PD, two or more consecutively 
missed radiological assessments prior to death
Censored*
Date of last radiological 
assessment prior to missed 
radiological assessments
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer therapy started before 
the outcomes flagged with a ‘*’ above
Censored
Date of last radiological 
assessment before 
subsequent anti-cancer 
therapy (or date of 
randomisation if none exist)
* For these outcomes if initiation of subsequent anti-cancer therapy occurred prior to the outcome date then the 
rule for the final row of table will be used instead
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
There are no key secondary endpoints defined for the trial.


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5.2.2
Secondary endpoints
Overall survival
Overall survival (OS) will be calculated as the time from randomisation to death from any 
cause. Patients without evidence of death will be censored at the date of last contact when 
known to be alive.
Disease control
Disease control (DC), defined as a best overall response (BOR) of complete response (CR), 
partial response (PR), stable disease (SD) or Non-CR/Non-PD. SD and Non-CR/Non-PD 
must have been observed up until at least the Week 24 tumour assessment.
BOR is defined according to RECIST based on all evaluable tumour assessments from 
randomisation until the earliest of PD, start of subsequent anti-cancer therapy, loss to follow-
up, withdrawal of consent or death. To be aligned with the primary endpoint derivation, 
tumour assessments after two or more consecutively missed assessments will not be 
considered.
Duration of disease control
Duration of DC will be calculated as the time from randomisation until the earliest of PD 
(according to RECIST) or death from any cause, among patients with DC.
The outcome rules defined in Table 5.1: 1 will be used for the calculation.
Objective response
Objective response (OR), defined as a BOR (as detailed for DC) of CR or PR.
Time to pain progression or intensification of pain palliation
Time to pain progression or intensification of pain palliation, defined as the time from 
randomisation until the earliest of:

≥2 point increase from baseline in the Brief Pain Inventory – Short Form (BPI-SF), 
Item 3 (worst pain), without a decrease (of ≥1 point) from baseline analgesics use (via 
the 8-point Analgesic Quantification Algorithm [AQA]), or

≥2 point increase from baseline in the AQA, or

Death
The rules to determine outcome (event or censored) along with the date of outcome are 
specified in Table 5.2.2: 1. These rules will be applied to the independent assessment data 
prior to analysis.
In order to identify whether questionnaire assessments are missing, a nominal time-point 
based on the scheduling detailed in the CTP will be assigned to each assessment according to 
Table 6.7: 2. If a patient does not have an assessment for both the BPI-SF, Item 3 and the 
AQA score at one of the scheduled time-points, it will count as a missed assessment; 


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otherwise, a response will be derived. If a ≥2 point increase from baseline in the BPI-SF, Item 
3 is observed but the AQA score is missing, it will be assumed that no decrease in analgesics 
use has taken place.
Table 5.2.2: 1 Derivation rules for pain progression or intensification of pain palliation
Status at time of analysis
Outcome
Date of outcome
No baseline assessment and/or no post-baseline assessments
Death on or before the second planned 
assessment
Event*
Date of death
Vital status is unknown or alive or death after 
second planned assessment
Censored
Date of randomisation
With baseline and at least one post-baseline assessment
Alive and event-free, no more than one 
consecutively missed assessment
Censored*
Date of last assessment
Alive and event-free, two or more 
consecutively missed assessments
Censored*
Date of last assessment prior 
to missed assessments
Alive with event, no more than one
consecutively missed assessment prior to event
Event*
Date of assessment of event
Alive with event, two or more consecutively 
missed assessments prior to event
Censored*
Date of last assessment prior 
to missed assessments
Death and event-free, no more than one 
consecutively missed assessment prior to death
Event*
Date of death
Death and event-free, two or more 
consecutively missed assessments prior to 
death
Censored*
Date of last assessment prior 
to missed assessments
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer therapy started before 
outcomes flagged with a ‘*’ above
Censored
Date of last assessment 
before subsequent anti-
cancer therapy (or date of 
randomisation if none exist)
* For these outcomes if initiation of subsequent anti-cancer therapy occurred prior to the outcome date then the 
rule for the final row of table will be used instead


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For reporting purposes, all randomised patients will be classified into either 
‘Xe1000+Ev10+Ex25’ or ‘Plc+Ev10+Ex25’ as randomised. For efficacy analyses, the intent-
to-treat (ITT) approach will be used, i.e. patients will be analysed according to the treatment 
group they were randomised to. All planned analyses will be presented by this randomised
treatment group. Handling of patients where treatment group assignment has not been 
followed will be handled on a case-by-case basis, to be agreed at report planning meetings 
prior to database lock. The following study periods are defined:

Screening: day of informed consent to day prior to first administration of study 
treatment

Treatment: day of first administration of study treatment to day of last administration 
of study treatment

Residual effect period (REP): day after last administration of study treatment, for a 
duration of 42 days

Follow-up: day after the end of the REP to trial completion
For safety analyses, treated patients will be analysed according to the initial treatment taken, 
and for safety summaries, data recorded whilst taking study treatment and up to 42 days after 
last administration of study treatment (i.e. including the REP) will be considered as on-
treatment. As the treatment arms are made up of a combination of individual treatments, a 
patient may have multiple last doses of treatment; therefore, the last dose of study medication
is defined as the latest of these.
6.2
IMPORTANT PROTOCOL DEVIATIONS
No per protocol set (PPS) analysis will be performed, hence, no patient will be excluded from 
the analyses (with the exception of patients not providing informed consent). However, 
patients with potentially important protocol deviations (iPDs) will be documented to give an 
indication of the level of adherence to the protocol, refer to Table 6.2: 1. Note this is a 
working list and may not be finalised until the final Medical Quality Review Meeting 
(MQRM), Database Lock Meeting (DBLM) and Report Planning Meeting (RPM) have taken 
place prior to the database lock of the primary PFS analysis.
A frequency table of the above iPDs will be produced. In addition, a frequency table of all 
COVID-19 related non-important and important PDs will be produced.


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Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief Description
Analysis Set Excluded from
A1
Diagnosis of trial disease questionable
None
A2
Prohibited baseline condition, diagnosis or 
treatment
None
A3
Laboratory result indicating inadequate organ 
function at screening
None
A4
Adequate archival tumour tissue not 
available
None
B1
Informed consent not available/not done
All
B2
Informed consent too late
None
B3
Age limit for patient inclusion not adhered to
None
C1
Time window violation for procedures 
performed at screening
None
C2
Trial medication not given according to 
protocol
None
C3
Infusion time for the investigational 
treatment outside of CTP specific boundaries
None
C4
Randomisation not followed
None
D1
Prohibited treatment during trial conduct 
phase
None
E1
Imaging assessments not done according to 
CTP instructions
None
F1
Other protocol violations affecting patient 
rights or safety
None
6.3
PATIENT SETS ANALYSED
The following patient sets are defined:

Enrolled set: 
This patient set includes all patients who have given informed consent. The enrolled 
set will be used for patient disposition summaries.

Randomised set (RS):
This patient set includes all randomised patients, regardless of whether they have 
received treatment or not. The RS will be used for demographic and baseline 
characteristic summaries and the evaluation of primary, secondary and further 
endpoints.


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
Treated set (TS):
This patient set includes all patients who are documented to have received and taken at 
least one dose of any study medication. The TS will be used for the evaluation of 
safety.

PK parameter analysis set (PKS):
This patient set includes all patients in the TS who have at least one valid drug plasma 
concentration available that was not excluded because of protocol deviations affecting 
PK evaluation.


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6.5
POOLING OF CENTRES
This section is not applicable because centre is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
In general, missing data will not be imputed, unless required for the following analyses and 
definitions. Then the rules as described below apply.
For TTE endpoints, patients who are event-free but have dropped out of the trial prematurely 
or are not evaluable for other reasons will be censored according to the rules given in Sections 
5.1, 5.2 and 5.3.
The BPI-SF pain interference aggregated score will only be calculated if 4 or more of the 7 
individual item scores have been completed.
Missing or incomplete dates that affect the evaluation of endpoints will be imputed utilising a 
worst-case approach, which will be applied on a case-by-case basis (depending on the 
affected endpoint) and documented appropriately prior to database lock and unblinding.
For the purposes of potential PFS censoring incomplete start dates of subsequent anti-cancer 
therapy will be imputed. The earliest possible date will be assumed, if this results in a start 
date prior to the stop date of study treatment this will be defaulted to study treatment stop date 
+ 1 day.
Missing or incomplete adverse event (AE) dates will be imputed according to BI standards 
(2).
For the calculation of time to first diagnosis, if the date of diagnosis is incomplete the 1st will 
be used for a missing day and January for a missing month.


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In general, actual patient data as reported in the eCRF will be used for analyses. If the data 
relating to the assignment of stratification factors are missing in the eCRF then the values 
entered into the Interactive Response Technology (IRT) system will be used instead (note 
these entries are automatically transferred to the eCRF).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The last measurement observed prior to start of trial medication will be assigned to baseline. 
Note that for some trial procedures this may be the value measured on the same day trial 
medication was started. In these cases, where time of measurement is not recorded, it will be 
assumed that the measurements were taken prior to the intake of any study medication. 
For measurements where not only the examination date but also time are recorded, 
examination time will be taken into account when defining baseline. Therefore, a 
measurement recorded on the same date as the first study drug administration will be 
considered as the baseline value, if and only if, the recording time was before or the same as 
the time of first study drug administration. If any of these times are missing and the date of 
the measurement is equal to the date of first study drug administration, then the measurement
will be considered according to what was planned in the protocol, i.e. for safety laboratory 
data prior to first study medication. Note this rule will be relaxed for PRO data, as long as the 
baseline assessment of PROs is performed on or prior to the date of first study drug 
administration it will be considered as a valid baseline.
For tumour assessments, baseline evaluations must be performed no more than 28 days prior 
to start of trial medication.
Study days and visits will be labelled according to the flow chart of the CTP.  In alignment 
with the CTP, study day will be calculated relative to the date of the first administration of 
study drug. The day prior to first administration of study drug will be 'Day -1' and the day of 
first administration of study drug will be 'Day 1'. Hence, 'Day 0' will not exist.
In order to identify whether consecutive imaging time points are missing for a patient a 
nominal time point [8, 16, 24 weeks and every 8 weeks thereafter up to 80 weeks, and every 
12 weeks thereafter] will be assigned to each image. This will be achieved by creating time 
windows for each assessment as detailed in Table 6.7: 1 below. If a patient does not have an 
image in one of the time windows when one is expected they will be considered as having 
'missed an assessment' for that time-point. In case a patient has more than one assessment in 
one window, the assessment with the latest outcome will be used for the analysis unless 
progressive disease (PD) has been recorded earlier then PD will be used.  Additionally, if a 
patient has multiple imaging dates within an assessment (e.g. a different target lesion imaging 
date to the non-target lesion imaging date), if the overall response is PD the earliest imaging 
date will be used, otherwise the latest imaging date will be used. Note for the slotting of 
imaging data and the derivation of time to efficacy events in general, ‘Day 1’ will be 
considered as the day of randomisation.


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Table 6.7: 1
Nominal time-points and windows for imaging
Nominal time-point 
[Weeks]
Nominal time-point 
[Days]
Window [Days]
0
1
<=1
8
57
[2, 85]
16
113
[86, 141]
+8 weeks*
+56 days*
[+56 days, +56 days]*
80
561
[534, 603]
92
645
[604, 687]
+12 weeks*
+ 84 days*
[+84 days, +84 days]*
* For subsequent visits, add value to previous record in respective column
In a similar fashion to imaging time points, missed PRO assessments will be identified as 
detailed in Table 6.7: 2.
Table 6.7: 2
Nominal time-points and windows for PROs
Nominal time-point 
[Weeks]
Nominal time-point 
[Days]
Window [Days]
0
1
<=1#
4
29
[2, 43]
8
57
[44, 71]
+4 weeks*
+28 days*
[+28 days, +28 days]*
80
561
[548, 589]
88
617
[590, 645]
+8 weeks*
+56 days*
[+56 days, +56 days]*
* For subsequent visits, add value to previous record in respective column
# Note any Course 1, Visit 1 data recorded prior to starting study medication will be defaulted to Day 1 even if it 
was after the randomisation date
Note if a patient discontinues study treatment and enters the follow-up for progression then 
PRO assessments will follow the imaging assessment schedule, so will either be 8-weekly or 
12-weekly dependent upon whether reached Week 80 (Cycle 20) or not.


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7.
PLANNED ANALYSIS
In general (unless specified elsewhere), BI standards (3) will be followed for the End-Of-Text 
tables. In summary:

The set of statistics for continuous data is N / Mean / Standard Deviation / minimum 
(Min) / lower quartile (Q1) / Median / upper quartile (Q3) / Maximum (Max). Other 
than the Min and Max, all statistics will be presented to one more decimal place than 
the raw data.

Tabulations of frequencies for categorical data will include all possible categories and 
will display the number of observations in a category as well as the percentage (%) 
relative to the respective treatment group (unless otherwise specified, all patients in 
the respective patient set whether they have non-missing values or not). Percentages 
will be rounded to one decimal place. The category ‘missing’ will only be displayed if 
there are actually missing values.

Time-to-event endpoints will be summarised in months [Months = (Days x 12) / 
365.25] to one decimal place. Hazard ratios (HRs) and corresponding confidence 
intervals (CIs) will be presented to two decimal places. P-values will be presented to 
four decimal places.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, for the RS of patients.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report, for the RS of patients.
Concomitant diseases will be coded using the most current version of Medical Dictionary for 
Regulatory Activities (MedDRA) and will be summarised by primary system organ class 
(SOC) and preferred term (PT). Concomitant medications will be coded using the most 
current version of WHO-DD and will be summarised by ATC3 class and PT. In situations 
where a therapy belongs to more than one ATC3 class all classes will be presented, along with 
explanatory footnotes. Separate summaries of concomitant medications started prior to and 
during the period of taking study medication will be produced.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report, for the TS of patients.
Appropriate summaries of compliance before and from the start of the COVID-19 disruption 
will also be produced.
7.4
PRIMARY ENDPOINT
The primary endpoint of PFS as assessed by blinded independent assessment will be analysed 
using the RS of patients.


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7.4.1
Primary analysis of the primary endpoint
The primary endpoint will be analysed using a stratified (presence of baseline bone-only 
metastases, prior CDK4/6 inhibitor treatment, menopause status) log-rank test to assess the 
effect of treatment.
A stratified Cox proportional hazards model will be used to estimate the HR of the treatment 
effect and the corresponding asymptotic two-sided 95% Wald CI. A HR of less than one will 
favour the xentuzumab arm. Breslow’s method for handling ties will be used.
Kaplan-Meier (KM) estimates will be used to display the distribution of PFS for each
treatment group on a KM curve. To support the plot, estimated survival probabilities at
specific time points of interest (scheduled imaging time-points) will be tabulated along with 
95% CIs, using Greenwood’s variance estimate. In addition, the survival distribution will be 
used to provide estimates of the median, 25th and 75th percentiles.
Suitable methods will be used to check the assumption of proportional hazards.


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable, as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
Overall survival
The analysis of this endpoint will follow that of the primary endpoint, detailed in Section 
7.4.1.
Disease control
A logistic regression model adjusting for the previously defined stratification factors will be 
used for the analysis of this binary endpoint. The treatment groups will be compared via the 
likelihood ratio test and presented along with the corresponding odds ratio and 95% CI. An 
odds ratio greater than one will favour the xentuzumab arm.


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Duration of disease control
KM estimates will be calculated for each treatment group to provide estimates of the median, 
25th and 75th percentiles and their corresponding 95% CIs.
Objective response
OR will be analysed as for DC above.
Time to pain progression or intensification of pain palliation
The analysis of this endpoint will follow that of the primary endpoint, detailed in Section 
7.4.1.


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7.7
EXTENT OF EXPOSURE
A descriptive summary of total duration of study treatment will be produced both for the 
combined treatment and for each of the individual components.  A dose reduction summary of 
everolimus will also be produced along with dose intensity summaries for each of the 
individual components of the study treatment. Refer to Section 5.4.2 for further details.
A Kaplan-Meier plot of the time to permanent discontinuation of all study medication (date of 
last administration of study medication – date of first administration of study medication + 1) 
will also be produced by treatment group.  Patients who have not permanently discontinued 
study medication will be censored at the date of the snapshot for the analysis.


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Appropriate summaries of exposure before and from the start of the COVID-19 disruption 
will also be produced.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. In addition to the summaries 
described below, standard tables required for the clinical trials disclosure process 
(ClinicalTrials.gov and EudraCT) will be produced (4).
7.8.1
Adverse Events
AEs will be coded with the most recent version of the MedDRA. The severity of AEs will be 
scaled according to Common Terminology Criteria (CTC) AE version 5.
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and not on the number of AEs.
For analysis, multiple AE occurrence data on the eCRF will be collapsed into an AE if all of 
the following applies:

All AE attributes are identical (Lowest Level Term [LLT], CTCAE grade, action 
taken with trial medication, therapy required, seriousness, reason for seriousness, 
relationship, outcome, AE of special interest)

The occurrences are time overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).
For further details on the analysis and presentation of AE data refer to BI standards (5).
The analysis of AEs will be based on the concept of treatment emergent adverse events. That 
means that all AEs with an onset between first drug intake and last drug intake + REP (42 
days) will be assigned to the randomised treatment. All AEs with an onset before first drug 
intake will be assigned to ‘screening’ and all AEs with an onset after the residual effect period 
will be assigned to ‘post-treatment’ (for listings only). For details on the treatment definition, 
see Section 6.1.
An overall summary of AEs will be presented; along with the standard categories presented 
additional categories for action taken and drug relationship with each compound, worst 
CTCAE grade and infusion related reaction response. The frequency of patients with AEs will 
be summarised by treatment, highest CTCAE grade, primary SOC and PT.  The SOCs will be 
sorted alphabetically; PTs will be sorted by decreasing frequency (within SOC).  Only AEs 
with a given CTCAE grade will be displayed in tables showing AEs by worst CTCAE grade.  
AEs with a missing CTCAE grade will not be displayed in these tables; a footnote will 
explain that these AEs are not included and a separate listing of them will be produced if 
required. The following tables will be produced for AEs during the on-treatment period:

Patients with AEs

Patients with any related AE


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
Patients with related xentuzumab/placebo AEs

Patients with related everolimus AEs

Patients with related exemestane AEs

Patients with SAEs

Patients with related xentuzumab/placebo SAEs

Patients with related everolimus SAEs

Patients with related exemestane SAEs

Patients with other significant AEs, defined as serious and non-serious AEs that lead 
to dose reduction or permanent discontinuation of any study medication

Patients with AEs leading to death (no CTCAE grade required)

Patients with AEs leading to discontinuation of xentuzumab/placebo

Patients with AEs leading to discontinuation of everolimus

Patients with AEs leading to discontinuation of exemestane

Patients with AEs leading to dose reduction of everolimus

Patients with AEs leading to dose interruption of xentuzumab/placebo

Patients with AEs of Special Interest (refer to Section 5.2.6.1 of the CTP)
In addition some AEs are considered to be of particular importance and special search 
categories (SSC) of groupings of PTs based on Standardised MedDRA Queries (SMQ), BI 
customised MedDRA Queries (BIcMQ) or MedDRA High Level Terms (HLT) are defined at 
the project level, the latest version of which will be used. Details of the current version are 
provided in the Table 7.8.1: 1 below.
SSCs summaries of patients with AEs and related AEs by treatment, highest CTCAE grade, 
grouped term and PT will be produced. Similar summaries will be produced for the BIcMQ
SARS-COV-2-infections.
Table 7.8.1: 1 Overview of Special Search Categories
Grouped term
Groupings
Hepatic impairment
SMQ: Drug related hepatic disorders – comprehensive 
search
Hyperglycaemia narrow
SMQ: Hyperglycaemia / new onset diabetes mellitus 
(narrow terms only)
Infusion related reaction
SMQ: Hypersensitivity 
Non-infectious pneumonitis
SMQ: Interstitial lung disease (narrow terms only)
Renal insufficiency
SMQ: Acute renal failure, SMQ: Proteinuria, HLT: 
Glomerulonephritis and nephrotic syndrome
Weight loss
BIcMQ: Weight loss
Neutropenia
SMQ: Haematopoietic leukopenia (narrow terms only)
Stomatitis
BIcMQ: Gastrointestinal mucositis (subsearch1: 
Stomatitis)


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Table 7.8.1: 1 Overview of Special Search Categories (cont.)
Grouped term
Groupings
Asthenia
MedDRA PTs of Asthenia, Fatigue, Lethargy, Malaise, 
and Decreased activity
Haemorrhage
SMQ: Haemorrhage laboratory terms (narrow terms 
only), SMQ: Haemorrhage terms (excl. laboratory 
terms)
Anemia 
SMQ: Haematopoietic erythropenia
Thrombocytopenia
SMQ: Haematopoietic thrombocytopenia (narrow 
terms only)
Thromboembolism
SMQ: Embolic and thrombotic, vessel type unspecified 
and mixed arterial and venous
Bradycardia
SMQ: Torsade de pointes/QT prolongation, PT of 
Bradycardia
Rash
BIcMQ: Skin eruptions (subsearch2: Skin rash 
potentially related to drug use)
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(6). The same on-treatment periods as considered for the analysis of AEs will be applied for 
laboratory values. Patients having at least one post-baseline laboratory value will be displayed 
in the descriptive analyses.
The focus of the laboratory data analysis will be on the following primary laboratory 
parameters:

Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, 
glucose, creatinine, platelets, cholesterol, triglycerides, neutrophils, lymphocytes, 
haemoglobin and white blood cells.
Descriptive statistics including baseline, last value on-treatment and change from baseline to 
last value on-treatment will be produced. CTCAE grades for applicable laboratory parameters 
will be calculated according to CTCAE version 5.  The following outputs will be presented 
for each of the above parameters:

Transitions of CTCAE grade from baseline to worst on-treatment laboratory value

Transitions of CTCAE grade from baseline to last on-treatment laboratory value
Patients with no CTCAE grade due to missing laboratory values will be displayed as
‘Missing’. Note with version 5 of the CTCAE grading some of laboratory parameters detailed 
above (ALT, AST and total bilirubin) can no longer be assigned a grade at baseline. For these 
parameters, the CTCAE shift tables will be replaced by shift tables of pre-defined categories 


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based on Upper Limit of Normal (ULN) values. A similar approach will also be adopted for 
creatinine due the ambiguity of CTCAE grading for grades 2 and 3. The pre-defined 
categories will follow BI standards (7).
Possible clinically significant abnormal laboratory values are defined as those laboratory 
values that are of CTCAE Grade ≥ 2 and show an increase from baseline value by at least one 
CTCAE grade. For those parameters for which no CTCAE has been defined, BI standard 
definition will be used to determine possible clinical significance. Frequency of patients with 
possible clinically significant abnormal laboratory values will be provided whenever 
applicable. If no baseline value is available (or CTCAE grading at baseline cannot be 
assigned) but the patient has a post-baseline laboratory value of CTCAE Grade ≥ 2 an 
increase from baseline will be assumed, i.e. the laboratory value considered as possible 
clinically significant.
Hepatic enzyme elevations (potential Hy’s law cases):
The assessment of hepatic enzyme elevations will include frequencies of patients falling into 
the following categories:

ALT and/or AST ≥ 3 x ULN with total bilirubin ≥ 1.5 x ULN

ALT and/or AST ≥ 3 x ULN with total bilirubin ≥ 2 x ULN

ALT and/or AST ≥ 3 x ULN with total bilirubin ≥ 2 x ULN and alkaline phosphatase 
≥ 2 x ULN

ALT and/or AST ≥ 3 x ULN with total bilirubin ≥ 2 x ULN and alkaline phosphatase 
< 2 x ULN

Maximum ALT: ≥ 3, ≥ 5, ≥ 10 and ≥ 20 x ULN

Maximum AST: ≥ 3, ≥ 5, ≥ 10 and ≥ 20 x ULN

Maximum ALT and AST: ≥ 3, ≥ 5, ≥ 10 and ≥ 20 x ULN

Maximum total bilirubin: ≥ 1.5 and ≥ 2 x ULN

Maximum alkaline phosphatase: ≥ 1.5 and ≥ 2 x ULN
Where applicable for defining the above, events can occur in any order, but must occur within 
30 days of each other, with an increase of either ALT or AST being the trigger for 
evaluations. Along with summaries of the above supportive eDISH plots will also be 
produced.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
In order to investigate potential bradycardia a shift table of heart rate (<60 bpm, ≥60 bpm) at 
baseline by lowest and last on-treatment heart rate (<60 bpm, ≥60 bpm) will be produced. 
Other suitable summaries may be produced to investigate potential bradycardia.
7.8.4
Electrocardiogram
Electrocardiogram (ECG) results will only be listed; any clinically significant abnormalities 
will be recorded as either a concomitant diagnosis or an AE.


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7.8.5
Others
Not applicable.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
BI-KMED-BDS-HTG-0035: “How to Guide: Handling of Missing and Incomplete AE 
dates”
3.
BI-KMED-BDS-HTG-0045: “How to Guide: Standards for Reporting of Clinical Trials 
and Project Summaries”
4.
BI-KMED-BDS-QRG-0010: “Quick Reference Guide: Preparation of tables for results 
disclosure
5.
BI-KMED-BDS-HTG-0066: “How to Guide: Analysis and Presentation of Adverse 
Event Data from Clinical Trials”
6.
BI-KMED-BDS-HTG-0042: “How to Guide: Handling, Display and Analysis of 
Laboratory Data”
7.
BI-KMED-BDS-HTG-0036: “How to Guide: CTCAE Grading for Laboratory Values”


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1
06-OCT-20
None
This is the final TSAP 
2
23-AUG-21
5.2.2
6.7
7.8.1
Clarified the minimum duration of DC.
Allowing baseline PRO assessments 
measured on the same day of starting 
study treatment.
Additional AE table added for ‘any 
related’ AEs. Update to SSCs.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c33744236
2.0
8-01-tsap
XeneraTM 1: A multi-centre, double-blind, placebo-controlled, randomised phase II
trial to compare efficacy of xentuzumab in combination with everolimus and
exemestane versus everolimus and exemestane in women with HR+ / HER2-
metastatic breast cancer and non-visceral disease
Approval-Project Statistician
23 Aug 2021 11:45 CEST
Approval
23 Aug 2021 17:23 CEST
Approval
23 Aug 2021 23:01 CEST
Approval
24 Aug 2021 16:48 CEST
Author-Trial Statistician
24 Aug 2021 16:52 CEST


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c33744236
2.0