Clinical trial NCT03099174
Conditions: Neoplasms Breast Neoplasms
Sponsor: Boehringer Ingelheim
Start date: 2017-05-04; Completion date: 2024-05-16
Enrollment: 133 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study in adult patients with different types of cancer. The purpose of this study is to find a safe dose of:

* Xentuzumab in combination with abemaciclib
* Xentuzumab in combination with abemaciclib and hormonal therapies The study also tests whether these medicines make tumours shrink in participants with lung and breast cancer.

Participants can stay in the study as long as they benefit from and can tolerate treatment. All participants get xentuzumab infusions and abemaciclib tablets. Participants who have breast cancer get different types of hormonal therapies in addition to xentuzumab and abemaciclib.

For all participants, the size of the tumour is measured regularly. Doctors also regularly check the general health of the participants."

Detailed description:

Arms: arm 1: Patients with solid tumours received 1000 milligram (mg) Xentuzumab (weekly 10 mg/milliliter intravenous infusion) and 150 mg Abemaciclib (every 12 hours three 50 mg film coated tablets) in a 28-day cycle until disease progression, intolerability of the study medication, or consent withdrawal. arm 2: Patients with Hormone receptor+ (HR+) Human epidermal growth factor receptor 2 (HER2-) breast cancer received 1000 milligram (mg) Xentuzumab (weekly 10 mg/milliliter intravenous infusion) and 150 mg Abemaciclib (every 12 hours three 50 mg film coated tablets) in a 28-day cycle until disease progression, intolerability of the study medication, or consent withdrawal. Combined with a background therapy of 2.5 mg Letrozole (once daily film-coated tablet). arm 3: Patients with Hormone receptor+ (HR+) Human epidermal growth factor receptor 2 (HER2-) breast cancer received 1000 milligram (mg) Xentuzumab (weekly 10 mg/milliliter intravenous infusion) and 150 mg Abemaciclib (every 12 hours three 50 mg film coated tablets) in a 28-day cycle until disease progression, intolerability of the study medication, or consent withdrawal. Combined with a background therapy of 1 mg Anastrozole (once daily film-coated tablet). arm 4: Patients with Hormone receptor+ (HR+) Human epidermal growth factor receptor 2 (HER2-) breast cancer received 1000 milligram (mg) Xentuzumab (weekly 10 mg/milliliter intravenous infusion) and 150 mg Abemaciclib (every 12 hours three 50 mg film coated tablets) in a 28-day cycle until disease progression, intolerability of the study medication, or consent withdrawal. Combined with a background therapy of 500 mg Fulvestrant (Faslodex®) (once a month intramuscular injection, with an additional 500 mg dose given two weeks after the first dose). arm 5: Patients with non-small cell lung cancer (NSCLC) received 1000 milligram (mg) Xentuzumab (weekly 10 mg/milliliter intravenous infusion) and 150 mg Abemaciclib (every 12 hours three 50 mg film coated tablets) in a 28-day cycle until disease progression, intolerability of the study medication, or consent withdrawal. arm 6: Patients with HR+ HER2- breast cancer \& non-visceral disease received 1000 milligram (mg) Xentuzumab (weekly 10 mg/milliliter intravenous infusion) and 150 mg Abemaciclib (every 12 hours three 50 mg film coated tablets) in a 28-day cycle until disease progression, intolerability of the study medication, or consent withdrawal. Combined with a background therapy of 500 mg Fulvestrant (Faslodex®) (once a month intramuscular injection, with an additional 500 mg dose given two weeks after the first dose). arm 7: Patients with HR+ HER2- breast cancer \& with visceral disease received 1000 milligram (mg) Xentuzumab (weekly 10 mg/milliliter intravenous infusion) and 150 mg Abemaciclib (every 12 hours three 50 mg film coated tablets) in a 28-day cycle until disease progression, intolerability of the study medication, or consent withdrawal. Combined with a background therapy of 500 mg Fulvestrant (Faslodex®) (once a month intramuscular injection, with an additional 500 mg dose given two weeks after the first dose). arm 8: Patients with HR+ HER2- breast cancer \& with non-visceral disease received 1000 milligram (mg) Xentuzumab (weekly 10 mg/milliliter intravenous infusion) and 150 mg Abemaciclib (every 12 hours three 50 mg film coated tablets) in a 28-day cycle until disease progression, intolerability of the study medication, or consent withdrawal. Combined with a background therapy of 500 mg Fulvestrant (Faslodex®) (once a month intramuscular injection, with an additional 500 mg dose given two weeks after the first dose).
Interventions: intervention 1: Xentuzumab intervention 2: Abemaciclib intervention 3: Letrozole intervention 4: Anastrozole intervention 5: Fulvestrant intervention 6: Abemaciclib
Intervention descriptions: intervention 1: Once weekly administrated through one hour intravenous infusion intervention 2: Treatment/28-day cycle p.o. Q12H on Days 1-28 (dose determined in Cohort A) Abbreviations: PO = orally; Q12H = every 12 (± 2) hours intervention 3: Once a day intervention 4: Once a day intervention 5: Once a month, with an additional dose given two weeks after the first dose. Each dose is given as two slow injections lasting one to two minutes, with one injection being given into the muscle of each buttock intervention 6: Treatment/28-day cycle p.o. Q12H on Days 1-28 (dose determined in Cohort D) Abbreviations: PO = orally; Q12H = every 12 (± 2) hours

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c09049566-10
EudraCT No.:
EU Trial No:
2016-003142-85
BI Trial No.:
1280.18
BI Investigational 
Product(s):
Xentuzumab (BI 836845)
Title:
An open label, phase Ib, dose-escalation study evaluating the safety 
and tolerability of xentuzumab and abemaciclib in patients with 
locally advanced or metastatic solid tumours and in combination 
with endocrine therapy in patients with locally advanced or 
metastatic hormone receptor-positive, HER2-, breast cancer, 
followed by expansion cohorts.
Lay Title:
This study in patients with different types of cancer (solid 
tumours) aims to find a safe dose of xentuzumab in combination 
with abemaciclib with or without hormonal therapies. The study 
also tests how effective these medicines are in patients with lung 
and breast cancer.
Clinical Phase:
Phase Ib
Trial Clinical 
Monitor:
 
Phone:
Coordinating 
Investigator:
Phone: 
Status:
Final Protocol (Revised Protocol based on global amendment 8)
Version and Date:
Version: 9.0
Date: 04 Mar 2022
Page 1 of 177
Proprietary confidential information.
2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022
Title of trial:
An open label, phase Ib, dose-escalation study evaluating the safety 
and tolerability of xentuzumab and abemaciclib in patients with 
locally advanced or metastatic solid tumours and in combination with 
endocrine therapy in patients with locally advanced or metastatic 
hormone receptor-positive, HER2-, breast cancer, followed by 
expansion cohorts.
Coordinating 
Investigator:
Trial site(s):
Multi-centre trial, international in about 40 sites in US, Europe and
Asia including Japan
Clinical phase:
Ib
Trial Design


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001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022
Objective(s):
Dose finding cohorts A, B, C and D:
To determine the maximum tolerated dose (MTD) / recommended 
phase II dose (RP2D) of xentuzumab in combination with 
abemaciclib with or without hormonal therapy (letrozole, anastrozole, 
fulvestrant).
Expansion cohorts E, F, D1 and D2:
To assess the anti-tumour activity of xentuzumab in combination with 
abemaciclib in patients with non-small cell lung cancer (cohort E), to 
assess the anti-tumour activity of the triplet combination xentuzumab, 
abemaciclib and fulvestrant in patients with locally advanced/
metastatic, HR+ breast cancer who have progressed following prior 
aromatase inhibitor therapy and prior CDK4/6 inhibitor treatment 
(cohort F), and to assess anti-tumor activity of the triplet combination 
xentuzumab, abemaciclib and fulvestrant in patients with locally 
advanced/metastatic HR+ breast cancer visceral disease (Cohort D1) 
or non-visceral disease (Cohort D2) who have progressed following 
endocrine therapy.
Exploratory Objective:
To expand the understanding of the study drug and the disease 
explorative biomarkers will be measured and analysed. These 
analyses are hypothesis generating.
Methodology:
Prospective, open-label, non-randomised, multiple dose finding, 
phase Ib study, followed by expansion cohorts


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022
Dose finding cohorts:
Cohort A: will identify the MTD/RP2D1 of the 
xentuzumab/abemaciclib combination in patients with solid 
tumours. 
Cohorts B, C & D (dose finding): will identify the MTD/RP2D2-4 of 
the xentuzumab/ abemaciclib combination on a background therapy 
of letrozole OR anastrozole OR fulvestrant (referred to as “triplets”) 
in postmenopausal women with locally advanced/metastatic 
hormone receptor positive (HR+) breast cancer. 
Expansion cohorts:
Cohort E: will further characterize safety, tolerability, PK, and 
preliminary efficacy of the xentuzumab/abemaciclib combination in 
a single-arm dose expansion group of non-small cell lung cancer 
patients.
Cohort F: will investigate the efficacy and PK of the triplet 
combination xentuzumab/abemaciclib and fulvestrant in a single-
arm expansion group of patients with locally advanced/metastatic 
hormone receptor positive (HR+) breast cancer and only non-
visceral disease who have progressed following endocrine therapy
(aromatase inhibitor) and prior CDK inhibitor treatment.
Cohorts D1 and D2: will explore anti-tumor activity of the triplet 
combination xentuzumab, abemaciclib and fulvestrant in patients 
with locally advanced/metastatic HR+ breast cancer visceral disease 
(Cohort D1) or non-visceral disease (Cohort D2) who have 
progressed following endocrine therapy (aromatase inhibitor or 
Selective Estrogen Receptor Modulator).
No. of patients: 
N= approximately 148
Dose finding cohorts:
Cohort A: approx. 12 evaluable patients 
Cohort B: approx. 12 evaluable patients


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022
Cohort C: approx. 12 evaluable patients
Cohort D (dose finding): approx. 12 evaluable patients
Expansion cohorts :
Cohort E: 20 evaluable patients
Cohort F: 20 evaluable patients with non-visceral disease
Cohort D1: 30 evaluable patients with visceral disease
Cohort D2: 30 evaluable patients with non-visceral disease
total entered:
Approximately 148 evaluable patients 
each treatment:
*
Dose finding cohorts:
o
Cohort A (xentuzumab + abemaciclib):  ̴ 12 evaluable 
patients
o
Cohorts B, C, D (dose finding) (xentuzumab + 
abemaciclib + hormonal therapy): ̴  12 evaluable patients 
per cohort
*
Expansion cohorts:
o
Cohort E  (xentuzumab + abemaciclib):  ̴ 20 evaluable 
patients 
o
Cohort F (xentuzumab + abemaciclib + fulvestrant):  ̴ 20 
evaluable patients with non-visceral disease
o
Cohort D1: (xentuzumab + abemaciclib + fulvestrant):  ̴
30 evaluable patients with visceral disease
o
Cohort D2: (xentuzumab + abemaciclib + fulvestrant):  ̴
30 evaluable patients with non-visceral disease
Diagnosis :
Patients with advanced/metastatic solid tumours in Cohort A; non-
small cell lung cancer in Cohort E; pre-/peri-/post- menopausal 
women with locally advanced/metastatic hormone receptor-positive 
HER2-negative breast cancer in Cohorts B, C, D (dose finding), and 
expansion cohorts F (with non-visceral disease), D1(with visceral 
disease) and D2 (with non-visceral disease).
Main criteria
for inclusion:
(see section 3.3 for details)


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022
Cohort A (Solid Tumours)

Patient must be able to swallow oral capsules or tablets

Male or female patients ≥ 18 years (≥20 years for Japan 
only) at screening willing and able to use highly effective 
methods of birth control per ICH M3 

Patients with histologically or cytologically confirmed 
diagnosis of advanced and/or metastatic, measurable or 
evaluable, non-resectable solid tumours 

Patients must have received and failed, or have been 
intolerant to, all treatment known to confer clinical benefit, 
or have no therapeutic options available as deemed 
appropriate by their treating physician

Life expectancy ≥ 3 months in the opinion of the investigator
Cohort B, C, D (dose finding), F, D1 and D2 (Breast Cancer):

Patient must be able to swallow oral capsules or tablets.

Women ≥ 18 years (≥20 years for Japan only) at screening
who have postmenopausal status.

Histologically or cytologically proven diagnosis of breast 
cancer with evidence of locally advanced not amenable to 
curative resection or metastatic disease

HR+ (local lab results at screening or at the time of 
diagnosis)

HER2 negative (local lab results at screening or at the time 
of diagnosis)

Previous adjuvant and neoadjuvant chemotherapy is 
permitted. 0-2 prior lines of chemotherapy for the metastatic 
setting are allowed (except Cohorts D1, D2, and F).

At least 1 evaluable lesion (measurable or non-measurable) 
that can be accurately assessed at baseline with CT or MRI 


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001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022
or PET-CT (CT portion of diagnostic quality) and which is 
suitable for accurate repeated measurement. 

Cohort B, C, D (dose finding): Must be eligible for the 
corresponding hormonal therapy. For Cohorts B and C 
previous treatment with fulvestrant or exemestane is 
allowed. For Cohort D (dose finding) prior therapy with non-
steroidal aromatase inhibitors (anastrozole, letrozole) or 
exemestane are permitted.
For Cohorts D1, D2 and F only:

Have either measurable disease or non-measurable bone only
disease.

No more than one prior line of endocrine therapy for 
metastatic disease is allowed.

Progression on or after endocrine therapy is required (see 
section 3.3.2)

For cohort F: Patients with resistance to prior therapy with 
an aromatase inhibitor (AI) and CDK4/6 inhibitor (excluding 
abemaciclib) for locally advanced or metastatic breast 
cancer. 

For cohort D1 (visceral disease) patient must have at least 
one documented visceral metastasis (i.e.: lung, liver, pleural, 
peritoneal, malignant pleural effusion and malignant 
peritoneal effusion involvement) (see section 3.1.); for 
cohort D2 and F (non-visceral disease), patient must not 
have any visceral metastasis (e.g. breast, lymph node, soft 
tissue, bone allowed).
Cohort E (NSCLC):

Patient must be able to swallow oral capsules or tablets.

Male or female patients ≥ 18 years (≥20 years for Japan 
only) at screening willing and able to use highly effective 
methods of birth control per ICH M3 


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001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022

Histologically or cytologically confirmed diagnosis of stage 
IV NSCLC.

The participant must have progressed after platinum-based 
chemotherapy AND immunotherapy (unless deemed 
inappropriate candidates for immunotherapy by their treating 
physician) AND have received 1 or a maximum of 2 other 
prior chemotherapy for advanced and/or metastatic disease 
OR must be judged by the physician as ineligible for further 
standard second-line chemotherapy. Prior treatment with 
epidermal growth factor receptor-tyrosine kinase inhibitor 
(EGFR-TKI) and anaplastic lymphoma kinase (ALK) 
inhibitors is mandatory in participants whose tumours have
either EGFR-activating mutations or ALK translocations. 
Prior targeting agents and neoadjuvant/adjuvant therapies are 
permitted.

Have measureable disease per RECIST 1.1.
Exclusion Criteria:
All cohorts:

Any documented active or suspected malignancy or history 
of malignancy, other than the disease under study, within 3 
years prior to screening, except appropriately treated basal 
cell carcinoma of the skin or in situ carcinoma of uterine 
cervix or ductal carcinoma in situ (DCIS) if properly treated 
in opinion of the investigator.

Prior anti-cancer chemotherapy, biological or radiation 
therapy, androgens, thalidomide, other anticancer agents, or 
any investigational drug within 21 days (14 days for non-
myelosuppressive agents); and/or 4 weeks for 
immunotherapy, before starting any of the trial drugs.

Prior anti CDK agents (except in cohort F where only prior 
therapy with abemaciclib is excluded) 


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001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022

Prior radiotherapy to ≥25% of bone marrow regardless of 
when it was received 

Unresolved treatment related toxicity from prior therapy of > 
CTCAE grade 1at study entry (except for stable sensory 
neuropathy ≤CTCAE grade 2 and alopecia).   

Previous treatment with IGF-1R targeting compounds. 

Known active uncontrolled or symptomatic CNS metastases, 
carcinomatous meningitis, or leptomeningeal disease, as 
indicated by clinical symptoms, cerebral oedema, and/or 
progressive growth. History of CNS metastases or cord 
compression are eligible if they have been definitively 
treated (e.g. radiotherapy, stereotactic surgery) and are 
clinically stable, off anticonvulsants and steroids for at least 
4 weeks. Patients with brain metastases are eligible if they 
are asymptomatic, completed radiotherapy for at least 4 
weeks, or are on a stable dose of steroids for at least 4 weeks. 
Patients are not eligible if they have spinal cord compression
(except Cohorts D1, D2 and F).

Inadequate bone marrow reserve or organ function 

Pre-existing renal disease including glomerulonephritis, 
nephritic syndrome, Fanconi Syndrome or renal tubular 
acidosis 

Refractory nausea and vomiting, chronic GI diseases, 
inability to swallow the product, or previous significant 
bowel resection that would preclude adequate absorption of 
abemaciclib or resulting in baseline Grade 2 or higher 
diarrhoea.   

Patients with Diabetes Type I or uncontrolled Type II 
(defined by HgBA1C > 8%)

Patients with advanced/metastatic, symptomatic, visceral 
spread, that are at risk of life-threatening complications in 
the short term including patients with massive uncontrolled 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022
effusions (pleural, pericardial, peritoneal), pulmonary 
lymphangitis, and over 50% of liver involvement in 
metastases. 

Prior hematopoietic stem cell or bone marrow transplant

Have had major surgery (excluding biopsy) < 28 days of the 
initial dose of any of the study drugs or planned major 
surgery during study participation.

Have a personal history of any of the following conditions:
syncope of cardiovascular etiology, ventricular arrhythmia
(including but not limited to ventricular tachycardia and
ventricular fibrillation), or sudden cardiac arrest. Subjects
with controlled atrial fibrillation for >30 days prior to study
treatment are eligible.

Have active bacterial or fungal (that is, requiring intravenous 
[IV] antibiotics or therapy at time of initiating study 
treatment), and/or known viral infection 

Patients with baseline Grade ≥ 2 hyperglycaemia or patients 
with baseline Grade ≥ 2 diarrhoea

Patients needing treatment with CYP3A4 inhibitors/inducers 
cannot be included in the trial. (See Appendix 10.1)
For Cohorts D1, D2 and F only:

Have received prior treatment with chemotherapy (except for 
neoadjuvant/adjuvant chemotherapy), fulvestrant, 
everolimus, alpelisib or abemaciclib. For cohorts D1 and D2 
only: prior treatment with palbociclib or ribociclib is also 
excluded. 

Patients with evidence or history of central nervous system 
metastasis are excluded. 

Have initiated bisphosphonates or approved RANK ligand
(RANK-L) -targeted agents (for example, denosumab) <7 
days prior to initiation of any study drug.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022
Test product(s):
Xentuzumab (Boehringer Ingelheim): IGF-1/-2 mAb
Abemaciclib (LY2835219; 
): CDK 4/6 inhibitor
dose:
Dose finding cohorts:
*
Cohort A: starting dose is 1000 mg iv once weekly for 
xentuzumab and 150 mg every 12 hours for abemaciclib
*
Cohorts B, C and D (dose finding): MTD1/RP2D1 of 
xentuzumab in combination with abemaciclib as determined in 
cohort A, plus letrozole (cohort B), anastrozole (Cohort C) or 
fulvestrant (cohort D).
Expansion cohorts:
*
Cohort E: MTD1/RP2D1 of xentuzumab in combination with 
abemaciclib as determined in cohort A.
*
Cohorts F, D1 and D2: MTD4/RP2D4 of the triplet combination 
xentuzumab, abemaciclib and fulvestrant as determined in 
cohort D (dose finding).
mode of 
administration:
Xentuzumab: intravenously, weekly dosing
Abemaciclib: oral, continuous dosing every 12 hours 
Background endocrine 
therapy:
Letrozole, anastrozole, fulvestrant 
dose:
Letrozole/anastrozole/fulvestrant at standard doses
mode of 
administration:
Letrozole, anastrozole, fulvestrant standard mode of administration 
Duration of treatment:
Xentuzumab will be given until disease progression, intolerability of 
the study medication or consent withdrawal.
Abemaciclib will be given until disease progression, intolerability of 
the study medication or consent withdrawal.
Endpoints
Primary endpoints:


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022
For each dose finding cohorts A, B, C and D:
*
Maximum tolerated dose (MTD) 
*
Number of patients with DLT during the MTD evaluation period 
(first 28-day cycle)
For expansion cohort E:
*
Objective response (CR, PR per RECIST 1.1)
For cohorts D1 and D2:
*
PFS rate at 18 month
For expansion cohort F:
*
Disease control (CR, PR, SD lasting at least 24 weeks per 
RECIST 1.1)
Secondary endpoints:
For each dose finding cohorts A, B, C and D:
*
No secondary endpoint
For each expansion cohorts E, F, D1 and D2:
*
Disease control (CR, PR, SD lasting at least 24 weeks per 
RECIST 1.1) (only for Cohorts D1, D2 and E)
*
Time to objective response
*
Duration of objective response 
*
Duration of disease control 
*
Progression-free survival (PFS)
*
Objective response (only for Cohorts D1, D2 and F)
Safety criteria:
Incidence and severity of reported AEs. AEs will be assessed using 
the National Cancer Institute [NCI] Common Terminology Criteria 
for Adverse Events [CTCAE] version 4.03 (R10-4848)


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
30 Nov 2016
Trial number:
1280.18
Revision date: 
04 Mar 2022
Statistical methods:
All endpoints for each dose finding cohorts and each expansion 
cohorts will be analysed using descriptive statistics.
For dose finding cohorts, inter-patient dose (de-)escalation is guided 
by a Bayesian Logistic Regression Model (BLRM) with overdose 
control that will be fitted to binary toxicity outcomes. The estimate 
of parameters will be updated as data are accumulated using the 
BLRM. At the end of each dose finding, the toxicity probability at 
each dose level will be calculated to determine an estimate of the 
MTD.


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FLOW CHART – COHORT A (SOLID TUMOURS)
Study period
Screening 
(a)
Treatment Courses 
(b)
EOTV 
(c)
FU
(d)
SCR
Course 1
Course 2 onwards
Visits (V)
Screening
1
2
3
4
1
2
3
4
Days
Within 28d 
before 
C1V1
1
8 ±1
15 
±1
22±1
1 
±2
8 
±2
15 
±2
22 
±2
Within 
7d after 
last 
drug 
intake
42 +7d 
after 
last 
drug 
intake
Informed consent (1)
X
Demographics
X
Medical history
X
Inclusion/exclusion 
criteria (2)
X (2)
X (2)
Physical exam (3)
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
Vital signs (4)
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
12-lead ECG 
(triplicate) (5)
X
X
X
X
X
X
X
Safety lab (6)
X
X
X
X
X
X
X 
(7)
X
X
Archival tumour tissue 
collection (8)  
X
Blood sample for 
biomarkers (9)
X
X
X
X
X
X
Pharmacokinetics (10)
X
X
X
X
X
Pharmacogenomics 
and cfDNA (11)
X
X
(12)
X
PGx Plasma -exosomal 
RNA (13)
X
X
X
X
DNA banking (14)
X
Immunogenicity 
(ADA) (15)
X
X
X
X
X
Tumour assessment 
and bone scan by 
RECIST 1.1 (16)
X
X 
(16)
X
Adverse event
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Abemaciclib 
dispensation (17)
X
X
Xentuzumab i.v. (17)
X
X
X
X
X
X
X
X
Compliance check 
abemaciclib (18)
X
X
Termination of trial 
medication
X
Completion of the 
study participation
X
a
Screening: The screening visit should be performed within 28 days prior to first drug administration (C1V1). Safety 
lab at the screening assessment can serve as the C1V1 assessment if performed within 72 hours before the first 
treatment and does not need to be repeated 
b
Treatment courses: All courses are 4 weeks in duration (28 days). All subsequent visit dates should be calculated 
based on Course 1 Visit 1 date. One or more visits can be skipped in case of treatment interruption. Patients may 
continue on treatment until the criteria for stopping medication are met (see Section 3.3.4). A duration of 
approximately 6 cycles is expected.


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c
EOTV: End of Treatment visit. If the decision to permanently discontinue all study treatments is taken during a
scheduled visit, the End Of Treatment Visit (EOTV) should be performed instead of the scheduled visit (within 7 
calendar days after last drug administration)
d 
FU: All patients should have a follow-up visit 42 days (+7days) after the permanent discontinuation of the study 
drugs
1.
Written informed consent must be obtained before any protocol specific screening assessment is performed 
2.
In/Exclusion criteria must be checked at screening and ensured before study medication has been firstly administered.
3.
Physical exam: includes a thorough cardiopulmonary, abdominal and lymph node exam and an assessment of the mental 
and neurological status
4.
Vital signs: includes respiratory rate, pulse, temperature and blood pressure
5.
12-lead ECG: 12-Lead resting electrocardiograms (ECG) are recorded locally and in triplicate. ECG will be performed 
at Screening, EOTV and FU visit.  ECG will be repeated at Visit 1/Day 1, and Visit 3/Day 15 of Course 1, 2, 3; and at 
Visit 1/Day 1 of Courses 6,9,12, etc. ECG should be performed prior to xentuzumab infusion.
6.
Safety labs: includes haematology (CBC), coagulation, negative serum pregnancy test for women with childbearing 
potential and biochemistry . Urinalysis only at screening and EOTV. Fasting blood test is required for metabolic panels.
See Section 5.3.3 for detail. Safety lab can be performed one day prior to the scheduled test. Unscheduled safety lab 
should be performed if clinically indicated and documented in the eCRF
7.
For course 2 only
8.
Archival tumour tissue collection: the most recent/appropriate archival tumour tissue must be collected prior to the start 
of trial treatment. Refer to Appendix 10.3 for tissue requirements
9.
Blood soluble biomarkers: for detailed sampling time schedule, refer to Section 5.5 and Appendix 10.2.1
10. Pharmacokinetics: Course 1, Course 2-12, 15, 18, EOTV and FU visits. For detailed PK sampling time schedule, refer to 
Section 5.4.1 and Appendix 10.2.1 for cohorts A, B, C and D
11. Pharmacogenomics and cfDNA. See Section 5.5 for more details on collection time points. Briefly, one blood sample to 
isolate genomic DNA will be obtained at C1V1 before treatment. 3 plasma samples will be collected to isolate circulating 
nucleic acids (e.g. cfDNA) from plasma: at C1V1 before treatment, at C3V1 and at the EOTV. 
12. For course 3 only
13. PGx Plasma: blood samples will be collected before treatment on C1V1, C1V3 (Day 15), C2V1, C3V1 and beyond, and 
at the EOTV. Samples will be used to evaluate exosomal RNA.
14. DNA banking: For details please refer to Section 5.5.1.
15. Immunogenicity (ADA): On days when xentuzumab is dosed and EOTV and FU visit at time points specified in Flow 
Chart and Appendix 10.2.1, ADA samples are to be collected prior to xentuzumab infusion. ADA samples must be 
collected at Course 1, Course 2-12, 15, 18, at EOTV and at the FU visit. For detailed sampling schedule, refer to Appendix 
10.2.1
16. Tumour assessments should include CT or MRI scans of the chest, abdomen and pelvis, and, if clinically indicated, any
other known or suspected sites of disease (e.g. breast, neck, brain etc.) accordingly to RECIST 1.1. After study entry, all 
lesions identified as target and non-target lesions during the screening should be followed up at all pre-specified imaging 
time points. The same radiographic procedure must be used throughout the study. Bone scans must be performed at 
screening (see Section 5.2 for more detail). 
Assessment will be performed at the following time points until progression/start of further treatment (tumour assessments 
after start of xentuzumab should be performed no more than 7 days prior to the scheduled tumour assessment date up to 
week 48 AND no more than 14 days prior to the scheduled tumour assessment date after week 48):

At screening (within 28 days prior to starting of treatment)

Every 8 weeks (±7days): during week 8 (49-63 days after start of xentuzumab), during week 16 (105-119 days 
after start of xentuzumab), during week 24 (161-175 days after start of xentuzumab), during week 32 (217-231
days after start of xentuzumab), during week 40 (273-287 days after start of xentuzumab), during week 48 (329-
343 days after start of xentuzumab)

Every 12 weeks after week 48 (±7days) (e.g. during week 60 (406-434 days after start of xentuzumab), during 
week 72 (490-518 days after start of xentuzumab), etc.)
In the event of an interruption/delay to treatment, the tumour assessment schedule should not be changed. 
Except in case of discontinuation from treatment due to progression, tumour assessment at EOTV is not necessary if the 
previous evaluation was done within 4 weeks of EOTV
Unscheduled scan based on the investigator’s judgement is allowed and should also be documented in eCRF 
17. Abemaciclib and xentuzumab should be dispensed through IRT. Patient’s screening, all drug dispensation visits and 
EOTV will be collected in the IRT system
18. Compliance check: on Day 1 of every course starting on course 2 and at EOTV


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c09049566-10
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FLOW CHART – COHORT B (BC TRIPLET WITH LETROZOLE)
Study period
Screening 
(a)
Treatment Courses 
(b)
EOTV 
(c)
FU (d)
SCR
Course 1
Course 2 onwards
Visits (V)
Screening
1
2
3
4
1
2
3
4
Days
Within 
28d before 
C1V1
1
8 
±1
15 
±1
22 
±1
1 
±2
8 
±2
15 
±2
22 
±2
Within 7d 
after last 
drug 
intake
42 +7d 
after last 
drug 
intake
Informed consent (1)
X
Demographics
X
Medical history
X
Inclusion/exclusion 
criteria (2)
X (2)
X (2)
Physical exam (3)
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
Vital signs (4)
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
12-lead ECG (triplicate) 
(5)
X
X
X
X
X
X
X
Safety lab (6)
X
X
X
X
X
X
X 
(7)
X
X
Archival tumour tissue 
collection (8)  
X
Blood sample for 
biomarkers
(9)
X
X
X
X
X
X
Pharmacokinetics (10)
X
X
X
X
X
Pharmacogenomics and 
cfDNA (11)
X
X
(12)
X
PGx Plasma -exosomal 
RNA (13)
X
X
X
X
DNA banking (14)
X
Immunogenicity (ADA) 
(15)
X
X
X
X
X
Tumour assessment and 
bone scan by RECIST 
1.1 (16)
X
X
(16)
X
Adverse event
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Abemaciclib and 
letrozole dispensation 
(17)
X
X
Xentuzumab i.v. (17)
X
X
X
X
X
X
X
X
Compliance check 
abemaciclib and 
letrozole (18)
X
X
Termination of trial 
medication
X
Completion of the study 
participation
X
a
Screening: The screening visit should be performed within 28 days prior to first drug administration (C1V1). Safety 
lab at the screening assessment can serve as the C1V1 assessment if performed within 72 hours before the first 
treatment and does not need to be repeated 


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b
Treatment courses: All courses are 4 weeks in duration (28 days). All subsequent visit dates should be calculated 
based on Course 1 Visit 1 date. One or more visits can be skipped in case of treatment interruption. Patients may 
continue on treatment until the criteria for stopping medication are met (see Section 3.3.4). A duration of 
approximately 12 cycles is expected.
c
EOTV: End of Treatment visit. If the decision to permanently discontinue all study treatments is taken during a 
scheduled visit, the End Of Treatment Visit (EOTV) should be performed instead of the scheduled visit (within 7 
calendar days after last drug administration)
d 
FU: All patients should have a follow-up visit 42 days (+7days) after the permanent discontinuation of the study 
drugs
1.
Written informed consent must be obtained before any protocol specific screening assessment is performed 
2.
In/Exclusion criteria must be checked at screening and ensured before study medication has been firstly administered.
3.
Physical exam: includes a thorough cardiopulmonary, abdominal and lymph node exam and an assessment of the mental 
and neurological status
4.
Vital signs: includes respiratory rate, pulse, temperature and blood pressure
5.
12-lead ECG: 12-Lead resting electrocardiograms (ECG) are recorded locally and in triplicate. ECG will be performed 
at Screening, EOTV and FU visit.  ECG will be repeated at Visit 1/Day 1, and Visit 3/Day 15 of Course 1, 2, 3; and at 
Visit 1/Day 1 of Courses 6,9,12, etc. ECG should be performed prior to xentuzumab infusion.
6.
Safety labs: includes haematology (CBC), coagulation, negative serum pregnancy test for women with childbearing 
potential and biochemistry. Urinalysis only at screening and EOTV. Fasting blood test is required for metabolic panels. 
See Section 5.3.3 for detail. Safety lab can be performed one day prior to the scheduled test. Unscheduled safety lab 
should be performed if clinically indicated and documented in the eCRF
7.
For course 2 only
8.
Archival tumour tissue collection: the most recent/appropriate archival tumour tissue must be collected prior to the start 
of trial treatment. Refer to Appendix 10.3 for tissue requirements
9.
Blood soluble biomarkers: for detailed sampling time schedule, refer to Section 5.5 and Appendix 10.2.1
10. Pharmacokinetics: Course 1, course 2-12, 15, 18, EOTV and FU visits. For detailed PK sampling time schedule, refer to 
Section 5.4.1 and Appendix 10.2.1 for cohorts A, B, C and D
11. Pharmacogenomics and cfDNA See Section 5.5 for more details about collection timepoints. Briefly, one blood sample 
to isolate genomic DNA will be obtained at C1V1 before treatment. 3 plasma samples will be collected to isolate 
circulating nucleic acids (e.g. cfDNA) from plasma: at C1V1 before treatment, at C3V1 and at the EOTV. 
12. For course 3 only
13. PGx Plasma: blood samples will be collected before treatment on C1V1, C1V3 (Day 15), C2V1, C3V1 and beyond and 
at the EOTV. Samples will be used to evaluate exosomal RNA. 
14. DNA banking: For details please refer to Section 5.5.1.
15. Immunogenicity (ADA): On days when xentuzumab is dosed and EOTV and FU visit at time point specified in the Flow 
Chart and Appendix 10.2.1, ADA samples are to be collected prior to xentuzumab infusion. ADA samples must be 
collected at Course 1, course 2-12, 15, 18, at EOTV and at the FU visit. For detailed sampling schedule, refer to Appendix 
10.2.1
16. Tumour assessments should include CT or MRI scans of the chest, abdomen and pelvis, and, if clinically indicated, any 
other known or suspected sites of disease (e.g. breast, neck, brain etc.) accordingly to RECIST 1.1. After study entry, all 
lesions identified as target and non-target lesions during the screening should be followed up at all prespecified imaging 
time points. The same radiographic procedure must be used throughout the study. Bone scans must be performed at 
screening (see Section 5.2 for more detail). 
Assessment will be performed at the following time points until progression/start of further treatment (tumour assessments 
after start of xentuzumab should be performed no more than 7 days prior to the scheduled tumour assessment date up to 
week 48 AND no more than 14 days prior to the scheduled tumour assessment date after week 48):

At screening (within 28 days prior to starting of treatment)

Every 8 weeks (±7days): during week 8 (49-63 days after start of xentuzumab), during week 16 (105-119 days 
after start of xentuzumab), during week 24 (161-175 days after start of xentuzumab), during week 32 (217-231
days after start of xentuzumab), during week 40 (273-287 days after start of xentuzumab), during week 48 (329-
343 days after start of xentuzumab)

Every 12 weeks after week 48 (±7days) (e.g. during week 60 (406-434 days after start of xentuzumab), during 
week 72 (490-518 days after start of xentuzumab), etc.)
In the event of an interruption/delay to treatment, the tumour assessment schedule should not be changed. 
Except in case of discontinuation from treatment due to progression, tumour assessment at EOTV is not necessary if the 
previous evaluation was done within 4 weeks of EOTV
Unscheduled scan based on the investigator’s judgement is allowed and should also be documented in eCRF 
17. Abemaciclib, letrozole (in certain countries) and xentuzumab should be dispensed through IRT. Patient’s screening, all 
drug dispensation visits and EOTV will be collected in the IRT system
18. Compliance check: on Day 1 of every course starting at course 2 and at EOTV


Boehringer Ingelheim
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c09049566-10
Trial Protocol
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FLOW CHART – COHORT C (BC TRIPLET WITH ANASTROZOLE)
Study period
Screening 
(a)
Treatment Courses
(b)
EOTV 
(c)
FU
(d)
SCR
Course 1
Course 2 onwards
Visits (V)
Screening
1
2
3
4
1
2
3
4
Days
Within 
28d before 
C1V1
1
8 
±1
15 
±1
22 
±1
1  
±2
8 
±2
15 
±2
22 
±2
Within 
7d after 
last drug 
intake
42 +7d 
after last 
drug 
intake
Informed consent (1)
X
Demographics
X
Medical history
X
Inclusion/exclusion 
criteria (2)
X (2)
X 
(2)
Physical exam (3)
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
Vital signs (4)
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
12-lead ECG (triplicate) 
(5)
X
X
X
X
X 
X
X 
Safety lab (6)
X
X
X
X
X
X
X 
(7)
X
X
Archival tumour tissue 
collection (8)  
X
Blood sample for 
biomarkers
(9)
X
X
X
X
X
X
Pharmacokinetics (10)
X
X
X
X
X
Pharmacogenomics and 
cfDNA (11)
X
X
(12)
X
PGx Plasma -exosomal 
RNA (13)
X
X
X
X
DNA banking (14)
X
Immunogenicity (ADA) 
(15)
X
X
X
X
X
Tumour assessment and 
bone scan by RECIST 
1.1 (16)
X
X 
(16)
X
Adverse event
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Abemaciclib and 
anastrozole dispensation 
(17)
X
X
Xentuzumab i.v. (17)
X
X
X
X
X
X
X
X
Compliance check 
abemaciclib and 
anastrozole (18)
X
X
Termination of trial 
medication
X
Completion of the study 
participation
X
a
Screening: The screening visit should be performed within 28 days prior to first drug administration (C1V1). Safety 
lab at the screening assessment can serve as the C1V1 assessment if performed within 72 hours before the first 
treatment and does not need to be repeated 


Boehringer Ingelheim
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c09049566-10
Trial Protocol
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b
Treatment courses: All courses are 4 weeks in duration (28 days). All subsequent visit dates should be calculated 
based on Course 1 Visit 1 date. One or more visits can be skipped in case of treatment interruption. Patients may 
continue on treatment until the criteria for stopping medication are met (see Section 3.3.4). A duration of 
approximately 12 cycles is expected.
c
EOTV: End of Treatment visit. If the decision to permanently discontinue all study treatments is taken during a 
scheduled visit, the End Of Treatment Visit (EOTV) should be performed instead of the scheduled visit (within 7 
calendar days after last drug administration)
d 
FU: All patients should have a follow-up visit 42 days (+7days) after the permanent discontinuation of the study 
drugs
1.
Written informed consent must be obtained before any protocol specific screening assessment is performed 
2.
In/Exclusion criteria must be checked at screening and ensured before study medication has been firstly administered.
3.
Physical exam: includes a thorough cardiopulmonary, abdominal and lymph node exam and an assessment of the mental 
and neurological status
4.
Vital signs: includes respiratory rate, pulse, temperature and blood pressure
5.
12-lead ECG: 12-Lead resting electrocardiograms (ECG) are recorded locally and in triplicate. ECG will be performed 
at Screening, EOTV and FU visit.  ECG will be repeated at Visit 1/Day 1, and Visit 3/Day 15 of Course 1, 2, 3; and at 
Visit 1/Day 1 of Courses 6,9,12, etc. ECG should be performed prior to xentuzumab infusion.
6.
Safety labs: includes haematology (CBC), coagulation, and negative serum pregnancy test for women with childbearing 
potential and biochemistry. Urinalysis only at screening and EOTV.Fasting blood test is required for metabolic panels. 
See Section 5.3.3 for detail. Safety lab can be performed one day prior to the scheduled test. Unscheduled safety lab 
should be performed if clinically indicated and documented in the eCRF
7.
For course 2 only
8.
Archival tumour tissue collection: the most recent/appropriate archival tumour tissue must be collected prior to the start 
of trial treatment. Refer to Appendix 10.3 for tissue requirements
9.
Blood soluble biomarkers: for detailed sampling time schedule, refer to Section 5.5 and Appendix 10.2.1
10. Pharmacokinetics: Course 1, Course 2-12, 15 and 18, EOTV and FU visits. For detailed PK sampling time schedule, refer 
to Section 5.4.1 and Appendix 10.2.1 for cohorts A, B, C and D
11. Pharmacogenomics and cfDNA See Section 5.5 for more details about collection timepoints. Briefly, one blood sample 
to isolate genomic DNA will be obtained at C1V1 before treatment. 3 plasma samples will be collected to isolate 
circulating nucleic acids (e.g. cfDNA) from plasma: at C1V1 before treatment, at C3V1 and at the EOTV. 
12. For course 3 only
13. PGx Plasma: blood samples will be collected before treatment on C1V1, C1V3 (Day 15), C2V1, C3V1 and beyond, and 
at the EOTV. Samples will be used to evaluate exosomal RNA.
14. DNA banking: For details please refer to Section 5.5.1.
15. Immunogenicity (ADA): On days when xentuzumab is dosed and EOTV and FU visit at time points specified in Flow 
Chart and Appendix 10.2.1, ADA samples are to be collected prior to xentuzumab infusion. ADA samples must be 
collected at Course 1, Course 2-12, 15 and 18, at EOTV and at the FU visit. For detailed sampling schedule, refer to 
Appendix 10.2.1
16. Tumour assessments should include CT or MRI scans of the chest, abdomen and pelvis, and, if clinically indicated, any 
other known or suspected sites of disease (e.g. breast, neck, brain etc.) accordingly to RECIST 1.1. After study entry, all 
lesions identified as target and non-target lesions during the screening should be followed up at all prespecified imaging 
time points. The same radiographic procedure must be used throughout the study. Bone scans must be performed at 
screening (see Section 5.2 for more detail). 
Assessment will be performed at the following time points until progression/start of further treatment (tumour assessments 
after start of xentuzumab should be performed no more than 7 days prior to the scheduled tumour assessment date up to 
week 48 AND no more than 14 days prior to the scheduled tumour assessment date after week 48):

At screening (within 28 days prior to starting of treatment)

Every 8 weeks (±7days): during week 8 (49-63 days after start of xentuzumab), during week 16 (105-119 days 
after start of xentuzumab), during week 24 (161-175 days after start of xentuzumab), during week 32 (217-231
days after start of xentuzumab), during week 40 (273-287 days after start of xentuzumab), during week 48 (329-
343 days after start of xentuzumab)

Every 12 weeks after week 48 (±7days) (e.g. during week 60 (406-434days after start of xentuzumab), during 
week 72 (490-518 days after start of xentuzumab), etc.)
In the event of an interruption/delay to treatment, the tumour assessment schedule should not be changed. 
Except in case of discontinuation from treatment due to progression, tumour assessment at EOTV is not necessary if the 
previous evaluation was done within 4 weeks of EOTV
Unscheduled scan based on the investigator’s judgement is allowed and should also be documented in eCRF 
17. Abemaciclib, anastrozole (in certain countries) and xentuzumab should be dispensed through IRT. Patient’s screening, 
all drug dispensation visits and EOTV will be collected in the IRT system
18. Compliance check: on Day 1 of every course starting at course 2 and at EOTV


Boehringer Ingelheim
04 Mar 2022
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c09049566-10
Trial Protocol
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FLOW CHART – COHORT D – DOSE FINDING (BC TRIPLET WITH 
FULVESTRANT)
Study period
Screening 
(a)
Treatment Courses 
(b)
EOTV 
(c)
FU
(d)
SCR
Course 1
Course 2 onwards
Visits (V)
Screening
1
2
3
4
1
2
3
4
Days
Within 28d 
before 
C1V1
1
8 ±1
15 
±1
22 
±1
1  ±2
8 
±2
15 
±2
22 
±2
Within 
7d after 
last 
drug 
intake
42 +7d 
after 
last 
drug 
intake
Informed consent (1)
X
Demographics
X
Medical history
X
Inclusion/exclusion 
criteria (2)
X (2)
X (2)
Physical exam (3)
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
Vital signs (4)
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
12-lead ECG (triplicate) 
(5)
X
X
X
X
X
X
X
Safety lab (6)
X
X
X
X
X
X
X 
(7)
X
X
Archival tumour tissue 
collection (8)  
X
Blood sample for 
biomarkers
(9)
X
X
X
X
X
X
Pharmacokinetics (10)
X
X
X
X
X
Pharmacogenomics and 
cfDNA (11)
X
X
(12)
X
PGx Plasma -exosomal 
RNA (13)
X
X
X
X
DNA banking (14)
X
Immunogenicity (ADA) 
(15)
X
X
X
X
X
Tumour assessment and 
bone scan by RECIST 
1.1 (16)
X
X 
(16)
X
Adverse event
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Abemaciclib 
dispensation (17)
X
X
Xentuzumab i.v. (17)
X
X
X
X
X
X
X
X
Fulvestrant i.m. (17)
X
X
X
Compliance check 
abemaciclib (18)
X
X
Termination of trial 
medication
X
Completion of the study 
participation
X
a
Screening: The screening visit should be performed within 28 days prior to first drug administration (C1V1). Safety 
lab at the screening assessment can serve as the C1V1 assessment if performed within 72 hours before the first 
treatment and does not need to be repeated 


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b
Treatment courses: All courses are 4 weeks in duration (28 days). All subsequent visit dates should be calculated 
based on Course 1 Visit 1 date. One or more visits can be skipped in case of treatment interruption. Patients may 
continue on treatment until the criteria for stopping medication are met (see Section 3.3.4). A duration of 
approximately 12 cycles is expected.
c
EOTV: End of Treatment visit. If the decision to permanently discontinue all study treatments is taken during a 
scheduled visit, the End Of Treatment Visit (EOTV) should be performed instead of the scheduled visit (within 7 
calendar days after last drug administration)
d 
FU: All patients should have a follow-up visit 42 days (+7days) after the permanent discontinuation of the study 
drugs
1.
Written informed consent must be obtained before any protocol specific screening assessment is performed 
2.
In/Exclusion criteria must be checked at screening and ensured before study medication has been firstly administered
3.
Physical exam: includes a thorough cardiopulmonary, abdominal and lymph node exam and an assessment of the mental 
and neurological status
4.
Vital signs: includes respiratory rate, pulse, temperature and blood pressure
5.
12-lead ECG: 12-Lead resting electrocardiograms (ECG) are recorded locally and in triplicate. ECG will be performed 
at Screening, EOTV and FU visit.  ECG will be repeated at Visit 1/Day 1, and Visit 3/Day 15 of Course 1, 2, 3; and at 
Visit 1/Day 1 of Courses 6,9,12, etc. ECG should be performed prior to xentuzumab infusion.
6.
Safety labs: includes haematology (CBC), coagulation, negative serum pregnancy test for women with childbearing 
potential and biochemistry. Urinalysis only at screening and EOTV. Fasting blood test is required for metabolic panels. 
Baseline Local FSH and estradiol levels should be within 14 days of initial dose of study treatment. See Section 5.3.3 for 
detail. Safety lab can be performed one day prior to the scheduled test. Unscheduled safety lab should be performed if 
clinically indicated and documented in the eCRF
7.
For course 2 only
8.
Archival tumour tissue collection: the most recent/appropriate archival tumour tissue must be collected prior to the start 
of trial treatment. Refer to Appendix 10.3 for tissue requirements
9.
Blood soluble biomarkers: for detailed sampling time schedule, refer to Section 5.5 and Appendix 10.2.1
10. Pharmacokinetics: Course 1, Course 2-12, 15, 18, EOTV and FU visits. For detailed PK sampling time schedule, refer to 
Section 5.4.1 and Appendix 10.2.1 for cohorts A, B, C and D
11. Pharmacogenomics and cfDNA See Section 5.5 for more details about collection timepoints. Briefly, one blood sample 
to isolate genomic DNA will be obtained at C1V1 before treatment. 3 additional blood samples will be collected to isolate 
circulating nucleic acids (e.g. cfDNA) from plasma: at C1V1 before treatment, at C3V1 and at the EOTV. 
12. For course 3 only
13. PGx Plasma: blood samples will be collected before treatment on C1V1, C1V3 (Day 15), C2V1, C3V1 and beyond, and 
at the EOTV. Samples will be used to evaluate exosomal RNA. 
14. DNA banking: For details please refer to Section 5.5.1.
15. Immunogenicity (ADA): On days when xentuzumab is dosed and EOTV and FU visit at time points specified in the Flow 
Chart and Appendix 10.2.1, ADA samples are to be collected prior to xentuzumab infusion. ADA samples must be 
collected at Course 1, Course 2-12, 15, 18, at EOTV and at the FU visit. For detailed sampling schedule, refer to Appendix 
10.2.1
16. Tumour assessments should include CT or MRI scans of the chest, abdomen and pelvis, and, if clinically indicated, any 
other known or suspected sites of disease (e.g. breast, neck, brain etc.) accordingly to RECIST 1.1. After study entry, all 
lesions identified as target and non-target lesions during the screening should be followed up at all prespecified imaging 
time points. The same radiographic procedure must be used throughout the study. Bone scans must be performed at 
screening (see Section 5.2 for more detail). 
Assessment will be performed at the following time points until progression/start of further treatment (tumour assessments 
after start of xentuzumab should be performed no more than 7 days prior to the scheduled tumour assessment date up to 
week 48 AND no more than 14 days prior to the scheduled tumour assessment date after week 48):

At screening (within 28 days prior to starting of treatment)

Every 8 weeks (±7days): during week 8 (49-63 days after start of xentuzumab), during week 16 (105-119 days 
after start of xentuzumab), during week 24 (161-175 days after start of xentuzumab), during week 32 (217-231
days after start of xentuzumab), during week 40 (273-287 days after start of xentuzumab), during week 48 (329-
343 days after start of xentuzumab)

Every 12 weeks after week 48 (±7days) (e.g. during week 60 (406-434 days after start of xentuzumab), during 
week 72 (490-518 days after start of xentuzumab), etc.)
In the event of an interruption/delay to treatment, the tumour assessment schedule should not be changed. 
Except in case of discontinuation from treatment due to progression, tumour assessment at EOTV is not necessary if the 
previous evaluation was done within 4 weeks of EOTV
Unscheduled scan based on the investigator’s judgement is allowed and should also be documented in eCRF 
17. Abemaciclib, xentuzumab and fulvestrant (in certain countries) should be dispensed through IRT. Patient’s screening, all 
drug dispensation visits and EOTV will be collected in the IRT system
18. Compliance check: on Day 1 of every course starting at course 2 and at EOTV


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FLOW CHART – COHORT E (NSCLC EXPANSION COHORT)
Study period
Screening 
(a)
Run-in 
(b)
Treatment Courses
(c)
EOTV 
(d)
FU
(e)
SCR
R
Course 1
Course 2 onwards
Visits (V)
Screenin
g
1
2
3
1
2
3
4
1
1b
2
3
4
Days
Within 
28d 
before 
Run-in 
V1
-
9
-
2
-
1
1
8 
±
1
15±
1
22±
1
1 
±2
4
±
1 
(f)
8 
±2(g
)
15 
±
2
22±
2
Withi
n 7d 
after 
last 
drug 
intake
42 
+7d 
after 
last 
drug 
intak
e
Informed consent
(1)
X
Demographics
X
Medical history
X
Inclusion/exclusio
n criteria (2)
X (2)
X 
(2)
Physical exam (3)
X
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
X
Vital signs (4)
X
X
X
X
X
X
X
X
X
X
X
Dispense Patient 
Diary (5)
X
X
ECOG 
performance 
status
X
X
X
X
X
X
12-lead ECG 
(triplicate) (6)
X
X
X
X
X
X 
X
X
Safety lab (7)
X
X
X
X
X
X
X
X 
(8
)
X
X
Archival tumour 
tissue collection 
(9)  
X
Blood sample for 
biomarkers (10)
X
X
X
X
X
X
X
Pharmacokinetics 
(11)
X
X
X
X
X
*
X 
(12) X (12)
X
X
Pharmacogenomic
s and cfDNA (13)
X
X
X 
(14)
X
PGx Plasma -
exosomal RNA
(15)
X
X
X
X
X
DNA banking (16)
X
Immunogenicity 
(ADA) (17)
X
X
X
X
X
X
Tumour 
assessment and 
bone scan by 
RECIST 1.1 (18)
X
X 
(18)
X
Adverse event
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
therapy
X
X
X
X
X
X
X
X
X
X
X
X
Abemaciclib 
dispensation (19)
X
X
X
Xentuzumab i.v. 
(19)
X
X
X
X
X
X
X
X
Compliance check 
abemaciclib (20)
X
X
X


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Termination of 
trial medication
X
Completion of the 
study participation
X
* 
A 24 h sample is also required at C2V1D2 (see Appendix 10.2.2)
a
Screening: The screening visit should be performed within 28 days prior to first drug administration (Run-in period). 
Safety lab at the screening assessment can serve as the Run-in Visit 1 assessment if performed within 72 hours before 
the first treatment and does not need to be repeated
b
Run in: Consists of 9 days. During the run-in period, patients should take daily abemaciclib treatment. At days with 
PK sampling, patients have to take their morning dose of abemaciclib in the hospital to allow proper PK sampling.
c
Treatment courses: All courses are 4 weeks in duration (28 days). All subsequent visit dates should be calculated 
based on Course 1 Visit 1 date. One or more visits can be skipped in case of treatment interruption. Patients may 
continue on treatment until the criteria for stopping medication are met (see Section 3.3.4). A duration of 
approximately 6 cycles is expected.
d
EOTV: End of Treatment visit. If the decision to permanently discontinue all study treatments is taken during a
scheduled visit, the End Of Treatment Visit (EOTV) should be performed instead of the scheduled visit (within 7 
calendar days after last drug administration)
e 
FU: All patients should have a follow-up visit 42 days (+7days) after the permanent discontinuation of the study 
drugs
f
On course 2 only for PK purposes
g
No time window is applicable for course 2 when PK determinations are scheduled for the visit
1.
Written informed consent must be obtained before any protocol specific screening assessment is performed 
2.
In/Exclusion criteria must be checked at screening and ensured before study medication has been firstly administered
3.
Physical exam: includes a thorough cardiopulmonary, abdominal and lymph node exam and an assessment of the mental 
and neurological status
4.
Vital signs: includes respiratory rate, pulse, temperature and blood pressure
5.
A patient diary will be handed over to the patient at Run-In Visit 1 and at C1V4. Patients have to fill in this diary up to  
Run-In V3 and C2V1, respectively (see also Section 4.3 for a short description of the diary)
6.
12-lead ECG: 12-Lead resting electrocardiograms (ECG) are recorded locally and in triplicate. ECG will be performed 
at Screening, Run-in visit 2 Day -2, EOTV and FU visit.  ECG will be repeated at Visit 1/Day 1, and Visit 3/Day 15 of 
Course 1, 2, 3; and at Visit 1/Day 1 of Courses 6,9,12, etc. ECG should be performed prior to xentuzumab infusion.
7.
Safety labs: includes haematology (CBC), coagulation, negative serum pregnancy test for women with childbearing 
potential and biochemistry. Urinalysis only at screening and EOTV. Fasting blood test is required for metabolic panels. 
See Section 5.3.3 for detail. Safety lab can be performed one day prior to the scheduled test. Unscheduled safety lab 
should be performed if clinically indicated and documented in the eCRF
8.
For course 2 only
9.
Archival tumour tissue collection: the most recent/appropriate archival tumour tissue must be collected prior to the start 
of trial treatment. Refer to Appendix 10.3 for tissue requirements
10. Blood soluble biomarkers: for detailed sampling time schedule, refer to Section 5.5 and Appendix 10.2.2
11. Pharmacokinetics: to be collected at Run-In period as well as in treatment courses 1-12, 15, 18, EOTV and FU visit. For 
detailed PK sampling time schedule, refer to Section 5.4.1 and Appendix 10.2.2 for cohort E.  
Please note: At days of PK sampling of abemaciclib, patients have to take their morning dose in the hospital in order to 
allow for proper PK sampling
12. PK sampling at this visit only in course 2 
13. Pharmacogenomics and cfDNA See Section 5.5 for more details on collection timepoints. Briefly, one blood sample to 
isolate genomic DNA will be obtained at Run-in V1 before treatment. 4 plasma samples will be collected to isolate 
circulating nucleic acids (e.g. cfDNA) from plasma: at Run-in V1, at C1V1 before treatment, at C3V1 and at the EOTV. 
14. For course 3 only
15. PGx Plasma: Blood samples will be collected before treatment at run-in V1, on C1V1, C1V3 (Day 15), C2V1, C3V1 
onwards and at the EOTV. Samples will be used to evaluate exosomal RNA.
16. DNA banking: For details please refer to Section 5.5.1.
17. Immunogenicity (ADA): On days when xentuzumab is dosed and EOTV and FU visit at time points specified in Flow 
Chart and Appendix 10.2.2, ADA samples are to be collected prior to xentuzumab infusion. ADA samples must be 
collected at Run In, in treatment courses 1-12, 15, 18, EOTV and at the FU visit. For detailed sampling schedule, refer to 
Appendix 10.2.2
18. Tumour assessments should include CT or MRI scans of the chest, abdomen and pelvis, and, if clinically indicated, any 
other known or suspected sites of disease (e.g. breast, neck, brain etc.) accordingly to RECIST 1.1. After study entry, all 
lesions identified as target and non-target lesions during the screening should be followed up at all prespecified imaging 
time points. The same radiographic procedure must be used throughout the study. Bone scans must be performed at 
screening (see Section 5.2 for more detail). 


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Assessment will be performed at the following time points until progression/start of further treatment (tumour assessments 
after start of xentuzumab should be performed no more than 7 days prior to the scheduled tumour assessment date up to 
week 48 AND no more than 14 days prior to the scheduled tumour assessment date after week 48):

At screening (within 28 days prior to starting the run-in period)

Every 8 weeks (±7days): during week 8 (49-63 days after start of xentuzumab), during week 16 (105-119 days 
after start of xentuzumab), during week 24 (161-175 days after start of xentuzumab), during week 32 (217-231
days after start of xentuzumab), during week 40 (273-287 days after start of xentuzumab), during week 48 (329-
343 days after start of xentuzumab)

Every 12 weeks after week 48 (±7days) (e.g. during week 60 (406-434 days after start of xentuzumab), during 
week 72 (490-518 days after start of xentuzumab), etc.)
In the event of an interruption/delay to treatment, the tumour assessment schedule should not be changed. 
Except in case of discontinuation from treatment due to progression, tumour assessment at EOTV is not necessary if the 
previous evaluation was done within 4 weeks of EOTV
Unscheduled scan based on the investigator’s judgement is allowed and should also be documented in eCRF 
19. Abemaciclib and xentuzumab should be dispensed through IRT. Patient’s screening, all drug dispensation visits and 
EOTV will be collected in the IRT system
20. Compliance check: On Day -1, on Day 1 of every treatment course starting on course 2, and at EOTV


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FLOW CHART – COHORT F (BC EXPANSION COHORT)
Study period
Screening(a)
Treatment Courses (b)
EOTV 
(c)
FU (d)
SCR
Course 1
Course 2 onwards
Visits (V)
Screening
1
2
3
4
1
2
3
4
Days
Within 28d 
before 
C1V1
1
8 
±1
15±1
22±1
1 
±2
8*
±2
15*
±2
22*
±2
Within 
7d 
after 
last 
drug 
intake
42 +7d after last drug 
intake
Informed consent (1)
X
Demographics
X
Medical history
X
Inclusion/exclusion 
criteria (2)
X (2)
X 
(2)
Physical exam (3)
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
Vital signs (4)
X
X
X
X
X
X
X
X
ECOG performance 
status
X
X
X
X
X
12-lead ECG 
(triplicate) (5)
X
X
X
X
X 
X
X 
Safety lab (6)
X
X
X
X
X
X
X 
(7)
X
X
Archival tumour tissue 
collection (8)  
X
DNA banking (9)
X
Tumour assessment 
and bone scan by 
RECIST 1.1 (10)
Per institutional practice
Adverse event
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Abemaciclib 
dispensation (11)
X
X
Xentuzumab i.v. (11)
X
X
X
X
X
X
X
X
Fulvestrant i.m. (11)
X
X
X
Compliance check 
abemaciclib (12)
X
X
Termination of trial 
medication
X
Completion of the 
study participation
X
a
Screening: The screening visit should be performed within 28 days prior to first drug administration (C1V1). Safety 
lab at the screening assessment can serve as the C1V1 assessment if performed within 72 hours before the first 
treatment and does not need to be repeated
b
Treatment courses: All courses are 4 weeks in duration (28 days). All subsequent visit dates should be calculated 
based on Course 1 Visit 1 date. One or more visits can be skipped in case of treatment interruption. Patients may 
continue on treatment until the criteria for stopping medication are met (see Section 3.3.4). A duration of 
approximately 24 cycles is expected.
c
EOTV: End of Treatment visit. If the decision to permanently discontinue all study treatments is taken during a 
scheduled visit, the End Of Treatment Visit (EOTV) should be performed instead of the scheduled visit (within 7 
calendar days after last drug administration)
d
FU: All patients should have a follow-up visit 42 days (+7days) after the permanent discontinuation of the study 
drugs. Patients who have not progressed and not started further treatment at FU should have additional limited 
follow-up visits at scheduled tumor assessment until progression, start of further anticancer treatment, consent 
withdrawal, lost to follow-up or death. See Section 5.2 and Section 6.2.3
*
When xentuzumab is discontinued, the visit can be conducted by phone


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1.
Written informed consent must be obtained before any protocol specific screening assessment is performed 
2.
In/Exclusion criteria must be checked at screening and ensured before study medication has been firstly administered
3.
Physical exam: includes a thorough cardiopulmonary, abdominal and lymph node exam and an assessment of the mental 
and neurological status. When xentuzumab is discontinued, physical exam can be done as per institutional practice.
4.
Vital signs: includes respiratory rate, pulse, temperature and blood pressure. When xentuzumab is discontinued, vital 
signs assessments can be done as per institutional practice.
5.
12-lead ECG: 12-Lead resting electrocardiograms (ECG) are recorded locally and in triplicate. ECG will be performed 
at Screening, EOTV and FU visit.  ECG will be repeated at Visit 1/Day 1, and Visit 3/Day 15 of Course 1, 2, 3; and at 
Visit 1/Day 1 of Courses 6,9,12, etc. ECG should be performed prior to xentuzumab infusion. When xentuzumab is 
discontinued, ECGs can be omitted.
6.
Safety labs: includes haematology (CBC), coagulation, and negative serum pregnancy test for women with childbearing 
potential and biochemistry. Urinalysis only at screening and EOTV. Fasting blood test is required for metabolic panels. 
Baseline Local FSH and estradiol levels should be within 14 days of initial dose of study treatment. See Section 5.3.3
for detail. Safety lab can be performed one day prior to the scheduled test. Unscheduled safety lab should be performed 
if clinically indicated and documented in the eCRF. When xentuzumab is discontinued, safety labs can be done as per 
institutional practice.
7.
For course 2 only
8.
Archival tumour tissue collection: the most recent/appropriate archival tumour tissue must be collected prior to the start 
of trial treatment. Refer to Appendix 10.3 for tissue requirements
9.
DNA banking: For details please refer to Section 5.5.1.
10. Tumour assessments will be performed according to institutional practice. Only the overall response will be collected in 
the eCRF.
11. Abemaciclib, xentuzumab and fulvestrant (in certain countries) should be dispensed through IRT. Patient’s screening, all 
drug dispensation visits and EOTV will be collected in the IRT system
12. Compliance check: On Day -1, on Day 1 of every treatment course starting on course 2, and at EOTV


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FLOW CHART – COHORTS D1 AND D2 (BC EXPANSION COHORTS)
Study period
Screening (a)
Treatment Courses (b)
EOTV 
(c)
FU (d)
SCR
Course 1
Course 2 onwards
Visits (V)
Screening
1
2
3
4
1
1b
2
3
4
Days
Within 28d 
before 
C1V1
1
8 
±1
15
±1
22
±1
1 
±2
4 
±1 
(e)
8*
±2
(f)
15*
±2
22*
±2
Within 
7d after 
last 
drug 
intake
42 +7d 
after 
last 
drug 
intake
Informed consent (1)
X
Demographics
X
Medical history
X
Inclusion/exclusion 
criteria (2)
X (2)
Physical exam (3)
X
X
X
X
X
Height
X
Body weight
X
X
X
X
X
Vital signs (4)
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
12-lead ECG (triplicate) 
(5)
X
X
X
X
X 
X
X 
Safety lab (6)
X
X
X
X
X
X
X 
(7)
X
X
Archival tumour tissue 
collection (8)  
X
DNA banking (9)
X
Tumour assessment and 
bone scan by RECIST 1.1 
(10)
Per institutional practice
Adverse event
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Abemaciclib dispensation 
(11)
X
X
Xentuzumab i.v. (11)
X
X
X
X
X
X
X
X
Fulvestrant i.m. (11)
X
X
X
Compliance check 
abemaciclib (12)
X
X
Termination of trial 
medication
X
Completion of the study 
participation
X
* 
A 24 h sample is also required at C2V1D2 (see Appendix 10.2.4)
a
Screening: The screening visit should be performed within 28 days prior to first drug administration (C1V1). Safety 
lab at the screening assessment can serve as the C1V1 assessment if performed within 72 hours before the first 
treatment and does not need to be repeated.
b
Treatment courses: All courses are 4 weeks in duration (28 days). All subsequent visit dates should be calculated 
based on Course 1 Visit 1 date. One or more visits can be skipped in case of treatment interruption. Patients may 
continue on treatment until the criteria for stopping medication are met (see Section 3.3.4). A duration of 
approximately 24 cycles is expected.
c
EOTV: End of Treatment visit. If the decision to permanently discontinue all study treatments is taken during a 
scheduled visit, the End Of Treatment Visit (EOTV) should be performed instead of the scheduled visit (within 7 
calendar days after last drug administration)
d
FU: All patients should have a follow-up visit 42 days (+7days) after the permanent discontinuation of the study 
drugs. Patients who have not progressed and not started further treatment at FU should have additional limited 
follow-up visits at scheduled tumor assessment until progression, start of further anticancer treatment, consent 
withdrawal, lost to follow-up or death. See Sections 5.2 and 6.2.3 
e
On course 2 only for PK purposes
f
No time window is applicable for course 2 when PK determinations are scheduled for the visit


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*
When xentuzumab is discontinued, the visit can be conducted by phone
1.
Written informed consent must be obtained before any protocol specific screening assessment is performed 
2.
In/Exclusion criteria must be checked at screening and ensured before study medication has been firstly administered
3.
Physical exam: includes a thorough cardiopulmonary, abdominal and lymph node exam and an assessment of the mental 
and neurological status. When xentuzumab is discontinued, physical exam can be done as per institutional practice.
4.
Vital signs: includes respiratory rate, pulse, temperature and blood pressure. When xentuzumab is discontinued, vital 
signs assessments can be done as per institutional practice.
5.
12-lead ECG: 12-Lead resting electrocardiograms (ECG) are recorded locally and in triplicate. ECG will be performed 
at Screening, EOTV and FU visit.  ECG will be repeated at Visit 1/Day 1, and Visit 3/Day 15 of Course 1, 2, 3; and at 
Visit 1/Day 1 of Courses 6,9,12, etc. ECG should be performed prior to xentuzumab infusion. . When xentuzumab is 
discontinued, ECGs can be omitted.
6.
Safety labs: includes haematology (CBC), coagulation, and negative serum pregnancy test for women with childbearing 
potential (within 14 days of first study dose) and biochemistry. Urinalysis only at screening and EOTV. Fasting blood 
test is required for metabolic panels. Baseline Local FSH and estradiol levels should be within 14 days of initial dose of 
study treatment. See Section 5.3.3 for detail. Safety lab can be performed one day prior to the scheduled test. Unscheduled 
safety lab should be performed if clinically indicated and documented in the eCRF. . When xentuzumab is discontinued, 
safety labs can be done as per institutional practice.
7.
For course 2 only
8.
Archival tumour tissue collection: the most recent/appropriate archival tumour tissue must be collected prior to the start 
of trial treatment. Refer to Appendix 10.3 for tissue requirements
9.
DNA banking: For details please refer to Section 5.5.1.
10. Tumour assessments will be performed according to institutional practice. Only the overall response will be collected in 
the eCRF.
11. Abemaciclib, xentuzumab and fulvestrant (in certain countries) should be dispensed through IRT. Patient’s screening, all 
drug dispensation visits and EOTV will be collected in the IRT system
12. Compliance check: on Day 1 of every treatment course starting on course 2, and at EOTV


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART – COHORT A (SOLID TUMOURS).......................................................14
FLOW CHART – COHORT B (BC TRIPLET WITH LETROZOLE)..........................16
FLOW CHART – COHORT C (BC TRIPLET WITH ANASTROZOLE) ....................18
FLOW CHART – COHORT D – DOSE FINDING (BC TRIPLET WITH 
FULVESTRANT)................................................................................................20
FLOW CHART – COHORT E (NSCLC EXPANSION COHORT)................................22
FLOW CHART – COHORT F (BC EXPANSION COHORT)........................................25
FLOW CHART – COHORTS D1 AND D2 (BC EXPANSION COHORTS)..................27
TABLE OF CONTENTS ......................................................................................................29
ABBREVIATIONS................................................................................................................34
1.
INTRODUCTION...............................................................................................36
1.1
MEDICAL BACKGROUND.............................................................................36
1.2
DRUG PROFILE................................................................................................38
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....41
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................41
2.2
TRIAL OBJECTIVES........................................................................................42
2.3
BENEFIT - RISK ASSESSMENT.....................................................................43
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................46
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................46
3.1.1
Administrative structure of the trial .................................................................48
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................49
3.3
SELECTION OF TRIAL POPULATION .......................................................51
3.3.1
Main diagnosis for trial entry ............................................................................51
3.3.2
Inclusion criteria .................................................................................................51
3.3.3
Exclusion criteria ................................................................................................55
3.3.4
Removal of patients from therapy or assessments...........................................58
3.3.4.1
Removal of individual patients .............................................................................58
3.3.4.2
Discontinuation of the trial by the sponsor...........................................................59
3.3.5
Replacement of patients......................................................................................60
4.
TREATMENTS...................................................................................................61
4.1
INVESTIGATIONAL TREATMENTS ...........................................................61
4.1.1
Identity of the Investigational Medicinal Products..........................................61
4.1.2
Selection of doses in the trial..............................................................................63
4.1.2.1
Part 1 .....................................................................................................................63


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4.1.2.2
Part 2 .....................................................................................................................65
4.1.2.3
Part 3 .....................................................................................................................66
4.1.3
Method of assigning patients to treatment groups...........................................66
4.1.4
Drug assignment and administration of doses for each patient......................66
4.1.4.1
Initial study drug assignment and administration .................................................66
4.1.4.2
Temporary treatment interruption and dose reduction..........................................67
4.1.5
Blinding and procedures for unblinding...........................................................71
4.1.5.1
Blinding.................................................................................................................71
4.1.5.2
Unblinding and breaking the code ........................................................................72
4.1.6
Packaging, labelling, and re-supply...................................................................72
4.1.7
Storage conditions...............................................................................................72
4.1.8
Drug accountability.............................................................................................72
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................73
4.2.1
Other treatments and emergency procedures..................................................73
4.2.2
Restrictions ..........................................................................................................74
4.2.2.1
Restrictions regarding concomitant treatment ......................................................74
4.2.2.2
Restrictions on diet and life style..........................................................................75
4.2.2.3
Restrictions regarding men and women of childbearing potential .......................75
4.2.2.4
Supportive Care.....................................................................................................75
4.2.2.5
Growth Factor Therapy.........................................................................................76
4.2.2.6
Therapy for Diarrhoea...........................................................................................76
4.2.2.7
Ovarian suppression with gonadotropin-releasing hormone agonists ..................76
4.3
TREATMENT COMPLIANCE........................................................................77
4.4
MANAGEMENT OF EXPECTED ADVERSE EVENTS..............................78
4.4.1
Increased Serum Creatinine ..............................................................................78
4.4.2
Management and grading of infusion reactions...............................................78
4.4.3
Management of Neutropenia..............................................................................79
4.4.4
Management of Hepatotoxicity..........................................................................79
4.4.5
Venous Thromboembolism ................................................................................80
4.4.6
Guidance for Interstitial lung disease/Pneumonitis.........................................80
5.
VARIABLES AND THEIR ASSESSMENT ....................................................81
5.1
TRIAL ENDPOINTS..........................................................................................81
5.1.1
Primary Endpoint(s)...........................................................................................81
5.1.2
Secondary Endpoint(s) .......................................................................................82
5.2
ASSESSMENT OF EFFICACY........................................................................85
5.3
ASSESSMENT OF SAFETY.............................................................................85
5.3.1
Physical examination ..........................................................................................85
5.3.2
Vital Signs............................................................................................................85
5.3.3
Safety laboratory parameters ............................................................................86
5.3.4
Electrocardiogram ..............................................................................................87
5.3.5
Other safety parameters.....................................................................................87
5.3.6
Assessment of adverse events.............................................................................87
5.3.6.1
Definitions of AEs ................................................................................................87
5.3.6.2
Adverse event collection and reporting ................................................................91


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5.3.6.3
Exemption to (S)AE Reporting.............................................................................92
5.3.7
Dose Limiting Toxicities (DLTs)........................................................................93
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................94
5.4.1
Assessment of Pharmacokinetics.......................................................................94
5.4.2
Methods of sample collection .............................................................................95
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................96
5.5
ASSESSMENT OF BIOMARKER(S) ..............................................................96
5.5.1
Biobanking.........................................................................................................100
5.5.1.1
DNA Banking .....................................................................................................100
5.6
OTHER ASSESSMENTS.................................................................................100
5.6.1
Assessment of Immunogenicity........................................................................101
5.7
APPROPRIATENESS OF MEASUREMENTS............................................101
6.
INVESTIGATIONAL PLAN...........................................................................103
6.1
VISIT SCHEDULE...........................................................................................103
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ...............103
6.2.1
Screening and run-in period(s)........................................................................103
6.2.2
Treatment period(s)..........................................................................................104
6.2.2.1
Cohort A, B, C, and D (dose finding).................................................................104
6.2.2.2
Cohort E..............................................................................................................105
6.2.2.3
Cohorts D1, D2 and F .........................................................................................106
6.2.3
Follow Up Period and Trial Completion.........................................................107
6.2.3.1
End of treatment visit..........................................................................................107
6.2.3.2
Follow-up period.................................................................................................107
6.2.3.3
Trial Completion.................................................................................................107
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
.............................................................................................................................108
7.1
STATISTICAL DESIGN - MODEL...............................................................108
7.2
NULL AND ALTERNATIVE HYPOTHESES .............................................112
7.3
PLANNED ANALYSES...................................................................................113
7.3.1
Primary endpoint analyses...............................................................................113
7.3.2
Secondary endpoint analyses ...........................................................................113
7.3.4
Safety analyses...................................................................................................115
7.3.5
Pharmacokinetic and pharmacodynamic analyses........................................116
7.4
INTERIM ANALYSES ....................................................................................117
7.5
HANDLING OF MISSING DATA .................................................................117
7.6
RANDOMISATION .........................................................................................118
7.7
DETERMINATION OF SAMPLE SIZE .......................................................118
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY................................................................................122
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT .........................................................................................................122
8.2
DATA QUALITY ASSURANCE ....................................................................123


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8.3
RECORDS.........................................................................................................123
8.3.1
Source documents .............................................................................................123
8.3.2
Direct access to source data and documents...................................................124
8.3.3
Storage period of records .................................................................................125
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................125
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......125
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.....................................................................................................................125
8.6
TRIAL MILESTONES.....................................................................................126
8.7
PROTOCOL VIOLATIONS ...........................................................................127
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY............................................................................127
9.
REFERENCES..................................................................................................128
9.1
PUBLISHED REFERENCES..........................................................................128
9.2
UNPUBLISHED REFERENCES....................................................................130
10.
APPENDICES...................................................................................................131
10.1
INDUCERS AND STRONG INHIBITORS OF CYP3A4 ............................131
10.2
PHARMACOKINETICS PLAN .....................................................................132
10.2.1
FLOW CHART for PK, immunogenicity, and biomarkers for cohorts A, B, 
C, and D (dose finding).....................................................................................132
10.2.1.1
Flowchart for PK, immunogenicity, and biomarkers for Cohorts A, B, C, and D 
(dose finding) in treatment course 1 ...................................................................132
10.2.1.2
FLOW CHART for PK, immunogenicity, and biomarkers for cohorts A, B, C, 
and D (dose finding) in courses 2-12, 15, and 18, EOTV and FU......................133
10.2.2
FLOW CHART for PK, immunogenicity, and biomarkers for cohort E....134
10.2.2.1
FLOW CHART for PK, immunogenicity, and biomarkers for cohort E in Run-in 
phase and treatment course 1 ..............................................................................134
10.2.2.2
FLOW CHART for PK, immunogenicity, and biomarkers for cohort E in 
treatment course 2...............................................................................................135
10.2.2.3
FLOW CHART for PK, immunogenicity, and biomarkers for cohort E in 
treatment courses 3-12, 15, 18 and EOTV and FU visit.....................................136
10.2.3
FLOW CHART for PK, immunogenicity, and biomarkers for cohort F....137
10.2.3.1
FLOW CHART for PK, immunogenicity, and biomarkers for cohort F in 
screening and treatment course 1........................................................................137
10.2.3.2
FLOW CHART for PK, Immunogenicity, biomarkers for cohort F in treatment 
courses 2-12, 15, 18, EOTV and FU...................................................................138
10.2.4
FLOW CHART for PK, immunogenicity, and biomarkers for cohorts D1 
and D2 ................................................................................................................139
10.2.4.1
FLOW CHART for PK, immunogenicity, and biomarkers for cohorts D1 and D2 
in treatment course 1...........................................................................................139
10.2.4.2
FLOW CHART for PK, immunogenicity, and biomarkers for cohorts D1 and D2 
in treatment course 2...........................................................................................140
10.2.4.3
FLOW CHART for PK, Immunogenicity, biomarkers for cohorts D1 and D2 in 
treatment courses 3, 4, 6, 12, 24, EOTV and FU................................................141
10.3
TUMOUR TISSUE SAMPLE REQUIREMENTS........................................142


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10.4
TUMOUR RESPONSE ASSESSMENT ACCORDING TO RECIST 1.1..143
10.5
CLINICAL EVALUATION OF LIVER INJURY ........................................145
10.5.1
Introduction.......................................................................................................145
10.5.2
Procedures .........................................................................................................145
10.6
STATISTICAL APPENDIX............................................................................146
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................151
11.1
GLOBAL AMENDMENT 1 ............................................................................151
11.2
GLOBAL AMENDMENT 2 ............................................................................154
11.3
GLOBAL AMENDMENT 3 ............................................................................157
11.4
GLOBAL AMENDMENT 4 ............................................................................164
11.5
GLOBAL AMENDMENT 5 ............................................................................167
11.6
GLOBAL AMENDMENT 6 ............................................................................168
11.7
GLOBAL AMENDMENT 7 ............................................................................171
11.8
GLOBAL AMENDMENT 8 ............................................................................175


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AUC
BC
Area under the Curve
Breast Cancer
b.i.d.
bis in die (twice daily dosing)
BIRDS
BLRM
Boehringer Ingelheim Regulatory Documents for Submission
Bayesian Logistic Regression Model
CCDS
CDK
Company Core Data Sheet
Cyclin-dependent Kinase
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
DLT
Drug Induced Liver Injury
Dose Limiting Toxicity
EDC
Electronic Data Capture
ePRO
EOTV
EWOC
Electronic Patient Reported Outcome
End of Trial Visit
Escalation With Overdose Control
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
FU
FUV
Flow Chart
Follow Up
Follow Up Visit
GCP
Good Clinical Practice
HR
Hormone Receptor
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
IGF
i.m.
Independent Ethics Committee
Insulin-like Growth Factor
Intramuscular
IRB
Institutional Review Board
IRR
Infusion Related Reaction
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
LA
intravenous
Locally Advanced
LoEE
mAB
List of Essential Element 
Monoclonal Antibody
MedDRA
Medical Dictionary for Drug Regulatory Activities


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MST
MTD
NSCLC
Medical Sub team
Maximum Tolerated Dose
Non-Small Cell Lung Cancer
OPU
OS
Operative Unit
Overall Survival
PD
Pharmacodynamics
PK
Pharmacokinetics
p.o.
per os (oral)
PCC
PFS
pRb
Protocol Challenge Committee
Progression-free survival
Retinoblastoma protein
q.d.
quaque die (once a day)
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
SC
Serious Adverse Event
Steering Committee
s.c.
subcutaneous
SmPC
Summary of Product Characteristics
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TMW
Trial Medical Writer
TSAP
WHO/ECOG
Trial Statistical Analysis Plan
World Health Organization / Eastern Cooperative Oncology Group


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Hormone receptor-positive (HR+) breast cancer (BC)
Breast cancer is one of the most common cancers in women. In 2012, there were approximately 
226,870 new cases of breast cancer and 39,510 deaths from the disease among women in the 
United States (Siegel et al. 2012 R12-2864). 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). The treatment for women diagnosed with hormone receptor positive (HR+) mBC 
includes endocrine therapy (R16-3983). However, de novo or acquired resistance to endocrine 
therapy remains an important clinical problem. Many HR+ breast cancers demonstrate 
overexpression of cyclin D1 (R16-3978), which interacts with cyclin-dependent kinases 4 and 
6 (hereafter CDK4/6) in an active protein complex that promotes cell proliferation. 
Consequently, CDK4/6 represents a potential therapeutic target for HR+ breast cancers, and 
CDK4/6 inhibitors need to be evaluated for their potential to improve clinical outcomes for 
women with HR+ mBC.
Despite recent advances, hormone-positive HR+ advanced or metastatic breast cancer still has 
a dismal prognosis with median progression-free survival (PFS) of less than a year; almost all 
patients will develop resistance to endocrine treatment and succumb to their disease eventually. 
Biochemical and genetic characterization of D-type cyclins, their cyclin D–dependent kinases 
(CDK4 and CDK6), and the polypeptide CDK4/6 inhibitor p16INK4A over two decades ago 
revealed how mammalian cells regulate entry into the DNA synthetic (S) phase of the cell-
division cycle in a retinoblastoma protein (pRb)–dependent manner. These investigations 
provided proof-of-principle that CDK4/6 inhibitors, such as abemaciclib, particularly when 
combined with co-inhibition of allied mitogen-dependent signal transduction pathways, might 
prove valuable in cancer therapy. The recent FDA approval of the CDK4/6 inhibitor palbociclib 
(Ibrance™), used with the aromatase inhibitor letrozole and fulvestrant for breast cancer 
treatment, highlights long-sought success by showing unprecedented efficacy in this setting. 
Moreover, the newest findings herald clinical trials targeting other cancers such as non-small 
cell lung cancer (NSCLC). Rapidly emerging data with selective inhibitors of CDK4/6 have 
validated these cell-cycle kinases as anticancer drug targets, corroborating longstanding 
preclinical predictions (R16-2249; R16-3979).
Non-small cell lung cancer (NSCLC)
Lung cancer is the most common cancer worldwide as well as the leading cause of cancer 
related deaths in both men and women. Non-small cell lung cancer (NSCLC) accounts for up 
to 85% of all lung cancers and of these, adenocarcinoma and squamous cell carcinoma (SCC) 
account for 50% and 30% respectively. Most of these patients present with locally advanced 
inoperable or metastatic disease, which makes their cancer incurable, and unfortunately almost 
all of these patients will die from their illness. Despite multiple advances in the staging, 
diagnostic procedures and therapeutic options, the overall outlook has not greatly changed for 
the majority of patients with the overall 5-year survival having only marginally increased over 
the last decade from 15.7% to 17.4% (P15-10237). Smoking remains the major cause of 
NSCLC, although the identification of driver oncogenes in non-smoking patients represents a 
critical novel finding during the last decades that fundamentally changed the management of 


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this disease. The recognition that NSCLC is not a single disease entity today is a well-known 
reality that has led to divide NSCLC into different sub-types, each one with specific algorithms 
of treatment, based on histological and molecular features (reviewed in P16-09577 and P15-
10237). 
Thus, the landscape of NSCLC therapies has rapidly been evolving beyond chemotherapy over 
the last few years. The discovery of oncogenic driver mutations has led to new ways in 
classifying NSCLC as well as offered novel therapeutic targets for anticancer therapy. Targets 
such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase 
(ALK) gene rearrangements have successfully been targeted with appropriate tyrosine kinase 
inhibitors (TKIs). Other driver mutations such as ROS, MET, RET, BRAF have also been 
investigated with targeted agents with some success in the early phase clinical setting. Novel 
strategies in the field of immune-oncology have also led to the development of inhibitors of 
cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death-1 receptor (PD-1), which 
are important pathways in allowing cancer cells to escape detection by the immune system 
(P15-10237).
Despite this impressive progress, however, there remain many patients that are refractory to 
immune checkpoint inhibitors (e.g. nivolumab and pembrolizumab) or chemotherapy and 
who do not benefit from targeted agents against activating -mutations in the EGFR gene or 
the ALK translocation, such as afatinib or crizotinib, respectively. Clearly, therefore, novel 
agents against additional molecular targets are desperately needed. In this regard, the insulin 
growth factor-1 receptor (IGF-1R) is a heterodimeric transmembrane tyrosine kinase receptor 
that is a mediator of cellular proliferation and frequently overexpressed in NSCLC.
CDK4/6 inhibitors (Abemaciclib)
During the cell cycle, the G1 restriction point controls entry into S phase and is essential for 
maintaining control of cell division (R16-2249, R16-3704). The cyclin-dependent kinases 
(CDKs), CDK4 and CDK6 (hereafter designated CDK4/6), participate in a complex with D-
type cyclins to initiate the transition through the G1 restriction point by phosphorylating and 
inactivating the retinoblastoma (Rb) tumour suppressor protein. 
Alterations in this pathway occur frequently in human cancers, amongst others HR+ BC, 
NSCLC and Pancreatic Cancer, and involve 1) loss of CDK inhibitors by mutation or 
epigenetic silencing, 2) mutation/overexpression of either CDK4/6 or cyclin D, or 3) 
inactivation of Rb. These alterations render cells less dependent on mitogenic signalling for 
proliferation. With the possible exception of those tumours with complete inactivation of Rb, 
which functions downstream of the CDK4/6-cyclinD complex, most cancers are potentially 
sensitive to pharmacologic inhibition of CDK4/6. All of these cancers are potentially sensitive 
to pharmacologic inhibition of CDK4/6. From a therapeutic standpoint, the goal of inhibiting 
CDK4/6 with a small molecule inhibitor is to prevent cell cycle progression through the G1 
restriction point, thus arresting tumour growth in the cancers investigated in the present trial.
Targeting IGF in cancer (xentuzumab)
The insulin-like growth factor (IGF) signalling system consists of ligands (insulin-like growth 
factors 1 and 2 (IGF-1, IGF-2), IGF-binding proteins (IGFBPs), and receptors (IGF-1R, IGF-
2R and insulin receptor IR)). Evidence that targeting IGF may be useful in cancer treatment 
was first recognized decades ago. Research in IGF signalling has shown that it controls key 
cellular activities, including proliferation, growth, and survival and is often deregulated in 


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neoplasia (R12-4524, P15-00363, P15-10395). There is experimental and clinical evidence that 
cancer cells express insulin and IGF-1 receptors. Expression of IGF-1R or its ligand is 
increased in a variety of cancers, including lung, colon, prostate, breast, ovarian, liver cancer 
and sarcoma (R12-4524, P15-00363, P15-10395). Therefore, the IGF system is an attractive 
tempting target for anti-cancer drug development. 
Pharmacologic targeting strategies include inhibition of receptor function with anti-receptor 
antibodies or small molecule receptor tyrosine kinase inhibitors (R12-4524, P15-00363, P15-
10395). Xentuzumab offers an alternative approach by acting as a ligand specific antibody. 
Most cancers express IGF-1 receptors, but there is evidence that autocrine and/or paracrine 
expression of ligands, particularly IGF-2, is deranged in neoplasm (R10-5355). In addition, the 
IGF-2 gene is an imprinted gene; loss of imprinting is one of several mechanisms leading to 
IGF-2 overexpression (R10-5694). Further, IGF-2 activates insulin receptor which was not 
targeted by any of the IGF-1 receptor monoclonal antibodies. Thus, targeting IGF-1 and IGF-
2 by neutralization may lead to a higher probability of response to a therapeutic strategy and
may confer an advantage over previously attempted approaches. Xentuzumab is a humanized 
monoclonal antibody directed against insulin-like growth factors 1 and 2 (IGF-1/-2) with the 
potential of anti-neoplastic activity. Despite encouraging preliminary evidence of clinical 
activity of several anti-IGF-1R agents, the therapeutic value of targeting the IGF/IGF-1R 
signalling system remains incompletely tested, given that the development of certain promising 
agents (e.g., figitumumab, ganitumab, dalotuzumab, R1507) has been discontinued in some 
indications. Efficacy signals generated by these and other agents warrant further exploration of 
the potential therapeutic value of targeting the IGF pathway in patients with various cancers.
1.2
DRUG PROFILE
For a more detailed description of the xentuzumab profile and abemaciclib profile please refer 
to the current Investigator’s Brochure (IB) and for letrozole, anastrozole and fulvestrant to the 
SmPC or US PI.
Xentuzumab
Xentuzumab is a humanized IgG1 monoclonal antibody that binds with high affinity to IGF-1 
and IGF-2, and potently neutralizes the proliferative and pro-survival cellular signalling 
triggered by both proteins. Mode of action differentiation to IGF-1 receptor (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.
At the cut-off date of 18 January 2019, a total of about 494 patients were treated in the 
xentuzumab clinical program: Eighty-one (81) patients were treated in two xentuzumab Phase 
I dose-escalation trials, examining a weekly and a three-weekly dosing schedule. Dose 
escalation to 1800 mg weekly or 3600 mg q3w did not identify a maximum-tolerated dose. A 
relevant biological dose for xentuzumab monotherapy in solid tumours was determined at 1000 
mg weekly, used as the recommended dose for further Phase II trials (RP2D).
Moreover, in a phase Ib / randomized phase II study of xentuzumab in combination with 
everolimus and exemestane in patients with advanced or metastatic hormone-receptor positive


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(HR+) breast cancer (Study 1280.4), 24 patients were treated in the dose escalation part (Ib) of 
this trial.
The MTD of xentuzumab was 1000 mg/week in combination with exemestane 25 mg/day and 
everolimus 10 mg/day, which was also determined as the RP2D.
Lastly, a completed phase Ib trial evaluates the safety and anti-tumour activity of xentuzumab
in combination with afatinib in patients with non-small cell lung cancer with resistant to 
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. At the time of the data 
cut-off (18 January 2019), the safety profile was as expected for monotherapy of afatinib. The
RP2D has been determined at 40 mg/day afatinib and 1000 mg/week xentuzumab. 
No relevant hyperglycaemia has been observed so far. Xentuzumab was well tolerated, with 
no relevant side effects reported. The type and pattern of adverse events (AEs) observed to date 
have generally been of mild to moderate intensity (CTCAE Grades 1 or 2) or consistent with 
the safety profile of combination backbone treatment or consistent with the underlying 
neoplastic conditions of patients enrolled on the study. The most frequently reported AEs for 
xentuzumab monotherapy were fatigue, decreased appetite, nausea, diarrhoea, and vomiting.
Infusion-related reaction (IRR) is a listed side effect of xentuzumab treatment.
Promising early efficacy signals in the dose escalation part of the 2 phase I studies have been 
observed with two confirmed antitumour responses (Partial Responses) according to RECIST 
criteria in a patient with nasopharyngeal cancer and a patient with a peripheral primitive 
neuroectodermal tumour (PPNET) or Ewing sarcoma. Moreover, twelve confirmed disease 
stabilizations (SD) have been observed in heavily pre-treated patients suffering from advanced 
or metastatic solid tumours. In the expansion cohorts at R2PD, no further objective responses 
have been observed.
At a planned interim analysis of the randomized phase II part, based on the recommendation 
of data monitoring committee, recruitment of phase II part was stopped and xentuzumab 
treatment was discontinued. According to latest analysis, in the overall population, PFS did not 
improve with the addition of xentuzumab to everolimus plus exemestane. Nevertheless, a 
favorable signal was observed in the pre-specified subgroup of patients without visceral 
metastasis (report c22665932-01).
In the aforementioned ongoing trial in HR+ metastatic breast cancer, the safety profile of 
xentuzumab in combination with everolimus and exemestane is considered favourable and as 
expected, since the observed safety profile of this triple combination is consistent with 
previously reported data for the combination doublet everolimus and exemestane (Bolero-2 
trial) (Baselga et al. 2011: R12-5635). The same applies for the combination with enzalutamide 
in CRPC, where the safety profile of this doublet is consistent with previously reported data 
for enzalutamide (Affirm and Prevail trials) (R13-1229, R15-1307). 
Abemaciclib
Abemaciclib (LY2835219) is a small-molecule inhibitor of CDK4 and CDK6 that is 
structurally distinct from other dual inhibitors (such as palbociclib and ribociclib) and notably 
exhibits greater selectivity for CDK4 compared with CDK6. Consistent with its activity against 
CDK4 and CDK6, abemaciclib inhibits Rb phosphorylation and leads to G 1 arrest in RB-
proficient cell lines. In a colorectal cancer xenograft model used to develop an integrated 
pharmacokinetic/pharmacodynamic model, abemaciclib can be dosed orally on a continuous 
schedule to achieve sustained target inhibition and demonstrates not only durable cell cycle 


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inhibition but also single-agent antitumour activity. Abemaciclib demonstrates suitable 
physical and pharmacokinetic (PK) properties, an acceptable toxicity profile in nonclinical 
species, and antitumour activity in multiple mouse models of human cancer.
Tumour growth inhibition is observed in multiple other human cancer xenograft models, 
including those derived from non–small cell lung cancer (NSCLC), melanoma, glioblastoma, 
and mantle cell lymphoma. Abemaciclib distributes across the blood–brain barrier and 
prolongs survival in an intracranial glioblastoma xenograft model, suggesting potential 
efficacy against primary and metastatic tumours involving the central nervous system (R16-
3982). Importantly, abemaciclib has demonstrated early evidence of activity against HR+ mBC 
with a confirmed objective response rate (ORR) of 19.7% in the recent Monarch 1 study (R16-
5327). 
Abemaciclib has been approved by US FDA for the treatment of metastatic breast cancer in 
three different settings. The approval include combination with an aromatase inhibitor as initial 
endocrine-based therapy for the treatment of postmenopausal women with HR+, HER2− 
advanced or metastatic breast cancer (Monarch 3), in combination with fulvestrant for the 
treatment of women with HR+, HER2− advanced or metastatic breast cancer with disease 
progression following endocrine therapy. (Monarch 2), and as monotherapy for the treatment 
of HR+, HER2− advanced or metastatic breast cancer with disease progression following 
endocrine therapy and prior chemotherapy in the metastatic setting (Monarch 1).
The approval of abemaciclib plus fulvestrant was based on Monarch 2 study, which is a 
randomized, placebo-controlled study in women with HR-positive and HER2-negative 
metastatic breast cancer. A total of 669 patients who had disease progression following 
endocrine therapy and had not received chemotherapy for metastatic disease were randomized 
2:1 to either oral abemaciclib or placebo plus intramuscular fulvestrant injection. Treatment 
was continued in the absence of disease progression or unmanageable toxicity. The study was 
positive for primary endpoint investigator-assessed PFS. Abemaciclib plus fulvestrant 
significantly improved PFS versus placebo plus fulvestrant (median 16.4 v 9.3 months, hazard 
ratio 0.553) (R17-2796).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
In early-phase clinical studies, abemaciclib has shown encouraging clinical activity in HR-
positive breast cancer and NSCLC as well as other solid tumours with a favourable safety 
profile (Study JPBA and Monarch 1 trial; R16-3982, R16-5327). In September 2017, 
abemaciclib in combination with fulvestrant was approved by US FDA for the treatment of
women with HR-positive, HER2-negative advanced or metastatic breast cancer with disease 
progression following endocrine therapy (R18-2693). Oncogenic activation of the PI3K–
mTOR pathway, which is governed by IGF1/IGF-1R, is also capable of stimulating cyclin D1–
CDK4/6 activity, due in part to the increased translation of the cyclin D1 mRNA transcript, 
and to the stabilization of the cyclin D1 protein (see R16-3979). This scenario prompts the 
implementation of triple combination studies involving the addition of a IGF/IGF-1R 
signalling inhibitor such as xentuzumab, to the established antihormonal plus CDK4/6 inhibitor 
regimens in the present trial. It seems likely that CDK4/6 inhibitors will generally prove most 
effective when used in combination with other agents that either reinforce the cytostatic activity 
of CDK4/6 inhibitors or convert reversible cytostasis into irreversible growth arrest or cell 
death (R16-3979). In this regard, preclinical and clinical data indicate that aberrant regulation 
of the IGF system is attributed to the pathogenesis of breast cancer and also contributes to the 
resistance to endocrine therapy (R16-3981). 
Despite recent progress in the treatment of metastatic NSCLC, these neoplasms basically 
remain intractable in the metastatic setting, with a median overall survival of less than 12 
months in patients with stage IV disease. Hence, new therapeutic approaches are urgently 
warranted in these areas of high unmet medical need. The IGF/IGF-1R signalling network has 
also been implicated in the pathogenesis of NSCLC. Specifically, a large body of literature has 
highlighted the ability of IGF/IGF-1R to mediate resistance to other treatment modalities in 
NSCLC, and conversely has identified proteins capable of compensating for IGF-1R blockade 
(P15-00363).
Early evaluations of ongoing clinical trials of anti-IGF/IGF-1R agents including xentuzumab
as a single agent, as well as in combination with everolimus and exemestane in HR+ BC (P16-
09570), have shown clinical benefit (objective tumour responses or disease stabilizations) in 
patients with advanced and otherwise incurable cancers. 
The insulin-like growth factor receptor (IGF-1R) signalling pathway has been an active area of 
oncology research for the last decade. IGF-1R is present on most cancer cells, and inhibition 
of this receptor slowed tumour growth and increased the antitumour activity of chemotherapy, 
radiation, and biologic agents in xenograft models. In addition, activation of the IGF-1R 
pathway has been postulated as a mechanism of signalling escape from other anticancer 
treatments including hormones and targeted agents, including CDK4/6 inhibitors. 
In this regard, a drug synergy screen and network modelling in dedifferentiated liposarcoma 
recently identified CDK4 and IGF-1R as synergistic drug targets (R16-0845). Further 
experiments confirmed that combined inhibition of CDK4 and IGF-1R cooperatively 
suppresses the activation of proteins within the AKT pathway. These data suggest that dual 


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blockade of CDK4 and IGF1R signalling results in cooperativity such that two prosurvival 
pathways are inhibited.
More recently, Heilman and co-workers found that concurrent targeting of CDK4/6 and IGF-
1R resulted in synergistic effects on proliferation of CDKN2A-mutant PaC cell lines in vitro 
and potent suppression of tumour growth in vivo, suggesting that alterations in these pathways 
converge to promote the growth of CDKN2A-deleted PaC cells (R16-0844). 
This study therefore aims to determine the safety, toxicity and recommended phase II dose 
(RP2D) as well as potential early efficacy signals for the further development of the 
combination therapy of xentuzumab and abemaciclib in a variety of cancers with a high unmet 
medical need, especially NSCLC. In an attempt to further improve outcomes for patients with 
HR+ BC, the combination of abemaciclib, xentuzumab and hormonal therapy (fulvestrant) is 
also investigated in this trial in expansion cohorts to determine the RP2D and efficacy for that
triple combination. After the US FDA’s approval of abemaciclib in combination with 
fulvestrant and based on the above mentioned potential synergy with supports the triple 
combination (xentuzumab, abemaciclib, and endocrine therapy), expansion cohorts in patients 
HR-positive, HER2-negative advanced or metastatic breast cancer will be added to this trial to 
evaluate the efficacy and safety of triple combination of xentuzumab, abemaciclib, and 
fulvestrant. Early efficacy signal of addition of xentuzumab to new standard-of-care could be 
obtained in the expansion cohorts.
2.2
TRIAL OBJECTIVES
For each dose finding cohorts (A, B, C and D):
The primary objective of each dose finding cohort is to determine the maximum tolerated dose 
(MTD) / recommended phase II dose (RP2D) of xentuzumab in combination with abemaciclib 
with or without hormonal therapy (letrozole, anastrozole, fulvestrant). Dose limiting toxicities 
(DLT) will be assessed during the first treatment cycle to assess the MTD/RP2D.
In case that no MTD is reached a RP2D dose will be determined taking into account safety data 
and other available information. This will be agreed with the Steering Committee. 
For each expansion cohorts (E, F, D1 and D2):
The objective of the cohort E is to assess the anti-tumour activity of xentuzumab in combination 
with abemaciclib in patients with non-small cell lung cancer.
Cohort F will assess the anti-tumour activity of the triplet combination xentuzumab / 
abemaciclib and fulvestrant in a single-arm expansion group of patients with locally advanced 
/ metastatic hormone receptor positive (HR+) HER2- breast cancer who have progressed 
following prior therapy with an aromatase inhibitor and a different CDK4/6 inhibitor 
(excluding abemaciclib). 
The primary objective of cohorts D1 and D2 is to assess the anti-tumour activity of the triplet 
combination xentuzumab, abemaciclib and fulvestrant in patients with locally advanced / 
metastatic HR+ breast cancer who have progressed on prior endocrine therapy. Cohort D1 


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will assess the anti-tumos activity for subjects with visceral metastasis and Cohort D2 for 
subjects with non-visceral metastasis.
2.3
BENEFIT - RISK ASSESSMENT
There is a high unmet medical need for patients with advanced or metastatic HR+ BC and
NSCLC, as described in Sections 1.1 and 2.1. Both abemaciclib and xentuzumab have shown 
encouraging preliminary anti-cancer activity in early-phase clinical trials.
Therefore, and because this trial will enrol patients without curative therapeutic options, it is 
believed that patients with solid tumours, NSCLCor HR+ BC treated with xentuzumab plus 
abemaciclib with or without hormonal background therapy at standard doses will have better 
efficacy (clinical benefit) compared to abemaciclib with or without hormonal background 
therapy alone.
Abemaciclib
Hematologic toxicities including neutropenia, leukopenia, anaemia, and thrombocytopenia 
have been observed in patients treated with abemaciclib, and causality has been established. 
Patients will therefore be monitored closely for signs of infection, anaemia, and bleeding. 
Gastrointestinal toxicities including diarrhoea, nausea, and vomiting have been observed in 
patients treated with abemaciclib, and causality has been established. Patients will therefore be 
monitored closely for gastrointestinal side effects. Patients with these symptoms will be 
evaluated promptly, treated supportively, and monitored closely for sequelae such as 
dehydration. Because diarrhoea possibly related to abemaciclib has been manageable with 
standard antidiarrheal agents such as loperamide, early treatment of diarrhoea is recommended 
in this trial.
Xentuzumab
As of 18 January 2019, xentuzumab was well tolerated in clinical trials, with no relevant 
specific side effects reported. The type and pattern of adverse events (AEs) observed to date 
have generally been of mild to moderate intensity (CTCAE Grades 1 or 2) or consistent with 
the safety profile of combination backbone treatment or consistent with the underlying 
neoplastic conditions of patients enrolled on the study. The most frequently reported AEs for 
xentuzumab monotherapy were fatigue, decreased appetite, nausea, diarrhoea, and vomiting.
Infusion-related reaction (IRR) is a listed side effect of xentuzumab treatment. There have been 
3 serious IRRs reported. One event was Grade 3 or higher. All events recovered with 
management per protocol. Only 1 patient discontinued the study due to an infusion-related 
reaction. Infusions of xentuzumab should be administered under close supervision of a 
medically qualified staff member with availability of resuscitation facilities. As mannitol is 


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used in the formulation of xentuzumab, infusion durations of less than one hour should be 
avoided. Following each infusion, a one hour observation period is recommended.
Infusion reactions will be graded and treated following standard of care or local guidance in 
this trial. 
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 5.3.6.1.
More information about the known and expected benefits, risks, and reasonably anticipated 
adverse events (AEs) of abemaciclib and xentuzumab may be found in the Investigators’ 
Brochures (IBs) (see current versions). Information on AEs expected to be related to the 
investigational product may be found in Section 7 of the IBs. Information on serious adverse 
events (SAEs) expected in the study population independent of drug exposure and that will be 
assessed by the sponsor in aggregate, periodically during the course of the study, may be found 
in Sections 6 (Effects in Humans) of the IBs.
The sponsor, monitor, and investigators will perform this study in compliance with the 
protocol, good clinical practice (GCP) and International Conference on Harmonisation (ICH) 
guidelines, and applicable regulatory requirements.
During the trial, investigators are advised to manage treatment-related side-effects proactively. 
Suggested supportive care measures for the management of treatment related AEs and 
instructions for dose reductions for individual patients are provided in Section 4.4
Regular and frequent assessment of clinical benefit throughout the trial will ensure that any 
patient not deriving clinical benefit will be withdrawn from the trial treatment. The safety of 
all patients, dose selection and benefit/risk assessment are under frequent surveillance by a 
Steering Committee (SC) (refer to Section 3.1.1). The SC will carefully assess the observed 
benefits and adverse events and give advice on potential treatment discontinuation.
Based on the good safety profiles of xentuzumab and abemaciclib, as well as standard hormonal 
therapy with letrozole, anastrozole or fulvestrant, as single agents, it is expected that the 
combination treatment can be safely initiated at the doses specified in Section 4.1.2.
As part of the trial, patients are required to provide blood samples and archival tumour tissue 
to analyse candidate predictive biomarkers, pharmacokinetics and immunogenicity. For blood 
samples, in some instances this is already becoming standard clinical practice at specialised 
oncology centres, but for some patients this will be an additional procedure compared to routine 
clinical practice. Apart from that, there are no invasive procedures in addition to standard 
oncology practice.
Based on the disease under study, the inclusion of women of childbearing potential, using 
contraception as described in Section 4.2.2.3, in this study is justified. To minimize the risk of 
unintentional exposure of an embryo or foetus to the investigational drug, men and women of 
childbearing potential must agree to the requirements for pregnancy testing and contraceptive 
methods described in this protocol.


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Based on previous experiences with these drugs, the side effect profile is predictable and 
manageable for each compound. Safe doses will be established for each set of combination 
partners during the dose finding parts of the trial. It is expected that those combinations will 
improve the efficacy of abemaciclib in NSCLC as well as abemaciclib in combination with 
hormonal therapy in HR+ BC (i.e. letrozole, anastrozole, fulvestrant) by delaying or reversing 
the resistance mechanisms to these drugs. Additionally, abemaciclib and xentuzumab have 
exhibited preliminary activity signal in cancers with a high unmet medical need for a new 
treatment armamentarium.
Based on the pharmacological mechanism and existing non-clinical and clinical data, there is 
currently no definitive evidence that xentuzumab, either as monotherapy or in combination 
with abemaciclib/endocrine therapy, will increase the occurrence or worsen the outcomes of a 
COVID-19 infection. In the target population of patients with advanced or metastatic breast 
cancer and progression on at least one prior endocrine based regimen, the benefit-risk 
assessment for xentuzumab remains positive also in the presence of a COVID-19 outbreak. 
The decision on whether to continue study drugs if a patient develops COVID-19 will be left 
to the investigator’s benefit/risk assessment on a case-by-case basis. Based on laboratory data 
and any adverse event that may occur, the clinical trial protocol include guidance for 
continuation, interruption, dose reduction, and discontinuation of study drugs.
In conclusion, given the good tolerability profile, non-overlapping and manageable toxicities 
as well as preliminary activity of abemaciclib and xentuzumab as well as the established 
hormonal therapy (letrozole, anastrozole, fulvestrant) in the aforementioned life-threatening 
cancers with high unmet medical need, the potential benefits expected from xentuzumab in 
combination with abemaciclib with or without hormonal background therapy are anticipated to 
outweigh its risks.
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 of 1280-0022, as of 19 October 2021, Boehringer 
Ingelheim recommended to immediately discontinue xentuzumab treatment. Sites were also 
recommended to discontinue associated assessments, including central laboratory sampling. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial is an open-label, non-randomised, phase Ib international, multicentre study of the 
combination of xentuzumab and abemaciclib (doublet) with or without a background of 
hormonal therapy, such as 2.5 mg letrozole or 1 mg anastrozole or 500 mg fulvestrant (referred 
to as triplets) .
The study consists of
-
4 dose finding cohorts (A, B, C, D (dose finding)) and 
-
4 expansion cohorts (E, F, D1 and D2)
The different dose levels to be used at each cohort are described under Section 4.1.2.
The study will be conducted, chronologically, in 3 parts: 
Part 1
Cohort A is a dose finding cohort in approximately 12 evaluable patients to determine the 
maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D1) of the doublet 
xentuzumab and abemaciclib in solid tumours. Once the RP2D1 has been established Part 2 of 
this trial will commence. 
Part 2 (all cohorts in part 2 can be conducted in parallel)
Cohort B is a dose finding cohort in approximately 12 evaluable patients to determine the 
maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D2) of the triplet 
xentuzumab and abemaciclib and letrozole in breast cancer. 
Cohort C is a dose finding cohort in approximately 12 evaluable patients to determine the 
maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D3) of the triplet 
xentuzumab and abemaciclib and anastrozole in breast cancer. 
Cohort D (dose finding) is a triplet-dose finding investigation in approximately 12 evaluable 
patients to determine the maximum tolerated dose (MTD) or recommended phase 2 dose 
(RP2D4) of the triplet xentuzumab and abemaciclib and fulvestrant in breast cancer. Once the 
RP2D4 has been established Part 3 of this trial will commence.
Cohort E is a single arm expansion in 20 NSCLC patients evaluable for response based on the 
abemaciclib and xentuzumab doublet RP2D1 as defined in Cohort A.
Part 3
Cohort F will investigate the efficacy of the triplet combination with fulvestrant at the RP2D4
of the abemaciclib and xentuzumab and fulvestrant triplet, as defined by cohort D data, in a 
single arm expansion cohort in 20 breast cancer patients evaluable for response. Based on the 
subgroup findings from the previous study 1280.4 (see Section 1.2), cohort F will recruit 
patients without visceral disease.
Cohort D1 and Cohort D2 will be opened once the RP2D4 of Cohort D (dose finding) has been 
determined. At least 30 patients will be treated to evaluate anti-tumour activity, safety, and 
pharmacokinetics of the triplet combination in Cohorts D1 and D2. Cohort D1 will recruit 
patients with visceral metastasis (at least one visceral metastasis) and Cohort D2 will recruit 
patients with non-visceral metastasis (absence of visceral metastasis). Visceral metastasis is 


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defined as lung, liver, pleural, peritoneal, malignant pleural effusion and malignant peritoneal 
effusion involvement (i.e. an internal organ in the great cavity of the trunk proper) at the time 
of study entry.
Figure 3.1:1 Trial Design
For dose finding cohorts A, B, C and D:
There are 4 dose-finding cohorts in this trial (i.e. cohorts A, B, C, and D). Each of them may 
end-up to a different RP2D (i.e. RP2D1, RP2D2, RP2D3 and RP2D4, respectively). For each 
dose finding cohort, dose (de-)escalation is guided by a Bayesian logistic regression model 
(BLRM) with overdose control (R13-4803) that will be fitted to binary toxicity outcomes. For 
further details, please refer to Section 4.1.2 and Section 7.1.


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Figure 3.1:2 Trial plan for patients in Cohorts A, B, C, D (dose finding), D1, D2 and F
Figure 3.1:3 Trial plan for patients in Cohort E 
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multicentre trial. Tasks and responsibilities are defined in a contract. 
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
Screening
Within 28 days 
before C1V1
Treatment courses
28d courses of Abemaciclib + 
xentuzumab with or without hormonal 
therapy until criteria for stopping 
medication are met.
EOTV
Within 7d 
after last 
drug 
administrat
ion
FU
42(+7)d 
after last 
drug 
administr
ation
Determination of MTD/RP2D or 
assessment of anti-tumor activity
On-study period for AE/SAE collection
Run-in
9d of 
Abemacicli
b therapy
Screening
Within 28 days 
before Run in 
V1
Treatment courses
28d courses of Abemaciclib + 
xentuzumab with or without 
hormonal therapy until criteria for
stopping medication are met.
EOTV
Within 7d 
after last 
drug 
administra
tion
FU
42(+7)d 
after last 
drug 
administr
ation
On-study period for AE/SAE 
collection


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direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and internal SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation of 
the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be found 
in the ISF.
A Steering Committee (SC) consisting of independent experts and sponsor representatives will 
be established to support the Coordinating Investigator who will be the chair of the Steering 
Committee. The composition and the frequency of the meetings 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 an SC-charter filed in the 
TMF. The Steering Committee will monitor the trial on a regular basis (all operational aspects, 
recruitment issues, data quality, etc.) and will be responsible for advising on the escalation/de-
escalation in the dose finding cohorts and the different RP2D’s. The SC can also advice to stop 
a cohort or the trial based on the emerging clinical trial data.
BI will appoint CROs and independent service providers for special services such as central 
laboratory services for biomarker testing and part of bioanalytical testing, biosample collection 
and logistics, and Interactive Response Technologies (IRT) for trial medication logistics. The 
analysis of biomarker and PK will be performed by BI or a CRO appointed by BI.
On-site monitoring will be performed by BI or Contract Research Organisations (CRO) 
appointed by BI.
All trial relevant documentation will be stored in the (e-) trial master file (e-TMF) at BI. In 
addition each site will have an Investigator Site File (ISF) containing all trial documents 
relevant for the site.
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This is an open-label, phase Ib study consisting of 4 dose finding cohorts and 4 expansion 
cohorts. An open-label design is standard for a dose finding study. Inclusion of a control group 
is not required for this investigation.


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As no data on the optimal dose for the xentuzumab/abemaciclib combination therapy exist so 
far, the study will first determine the MTD1/RP2D1 of the double drug regimen (in Part 1 cohort 
A) prior to further exploring its anti-tumour activity in Part 2.
The dose escalation/de-escalation steps and the dose-level cohort sizes (in each dose finding 
cohort) will be determined based on the recommendation of the SC, guided by a Bayesian 
model with overdose control. A potential escalation with overdose control design will increase 
the flexibility in terms of intermediate dose levels and number of patients in each dose-level 
cohort. This will increase the chance of treating patients at efficacious doses, while reducing 
the risk of overdosing. This design is not only an efficient method for dose finding studies, but 
also for dose confirmation studies due to its flexibility to react to unforeseen toxicity rates 
(R13-4802). This design is based on practical experience and is an efficient method due to its 
ability to identify the dose with a desired toxicity rate and its allocation of a greater proportion 
of patients to doses at, or close to, that desired dose (R13-4802, R13-4804, R13-4805). The use 
of Bayesian models for Phase I studies has also been advocated by the EMA guideline on small 
populations (R07- 4856) and by the FDA (R16-2270).
In expansion cohorts, a single arm design is justified as the trial is exploratory in its design to 
generate safety and efficacy data. If a positive efficacy signal is observed in this trial, a 
comparative trial may be considered if deemed justified.
The primary endpoint of the expansion cohorts is Objective Response (OR) or PFS rate, which 
is a well-accepted endpoint for such studies. OR rate defined as the proportion of patients with 
tumor size reduction of a predefined amount and for a minimum time period is used as primary 
endpoint for cohort E and F. PFS18 defined as the proportion of patients who were absence of 
disease progression or death at 18th month is use as primary endpoint for cohorts D1 and D2. 
A good response of sufficient duration is reasonably likely surrogate for clinical benefit in 
refractory solid tumour indications or where there is no effective therapy.
PK assessments in the dose escalation cohorts (A, B, C, D (dose finding)) will be limited to the 
assessment of immunogenicity (anti-drug antibodies ADA) together with a concomitant PK 
sample for xentuzumab. The basic PK properties of each of the components have been 
described already.
The potential development of ADAs (immunogenicity against xentuzumab) will be monitored
in all patients throughout the trial duration and beyond this (at EOTV and FUV). Regulatory 
guidelines recommend the monitoring of immunogenicity before, during and beyond treatment. 
A concomitant PK sample is necessary in order to assess whether an ADA sample result is 
conclusive or not and to monitor whether any effects of potential ADAs affect the drug 
concentration.
According to guidelines, combination therapies in oncology should be assessed for their 
potential effects on the exposure of each other. Therefore, PK investigations of the combination 
therapies in the trial will be conducted in the expansion cohort E for abemaciclib with 
xentuzumab and in the expansion cohorts D1 and D2 for fulvestrant with xentuzumab in an 
exploratory fashion. This approach ensures that a certain number of patients, treated at the same 
dose, can be evaluated. An intraindividual assessment of the PK of abemaciclib with and 
without xentuzumab treatment is planned for cohort E. These investigations are performed 
when the drug to be investigated is at steady state. In order to reach steady state levels with the 


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mono-treatment abemaciclib, a Run-in phase of 9 days is necessary. The assessment of the PK 
of the combination is planned to be performed at steady state as well. Xentuzumab reaches 
steady state after around 30d, therefore, the assessment of the combination treatment will be 
conducted in the second treatment cycle (that is >28 days after the first xentuzumab infusion). 
The exposure of xentuzumab will be evaluated descriptively and only a historical comparison 
to mono-treatment with xentuzumab will be done.
In cohorts D1 and D2 no intraindividual comparison of abemaciclib is planned. Exposure to 
abemaciclib, fulvestrant and xentuzumab is to be evaluated descriptively and only compared 
across cohorts or to historical or literature data for fulvestrant.
3.3
SELECTION OF TRIAL POPULATION
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not. 
It is estimated that a total of about 148 evaluable patients will be necessary to determine the 
MTD or the Recommended Phase II Dose, pharmacokinetics and efficacy of xentuzumab and 
abemaciclib with or without background hormone treatment.
Part 1 of the trial will be conducted in about 3-6 sites in US, Europe and Japan. Parts 2 and 3 
of the trial will be conducted in about 40 sites in US, Europe and Japan. If needed, sites from 
other regions may also participate. Each site is expected to enrol about one to five patients. If 
site(s) are unable to recruit patients, additional sites may be opened and underperforming sites 
may be closed.
3.3.1
Main diagnosis for trial entry
Patients to be included in this trial must have diagnosed and histologically, or cytologically, 
confirmed advanced and/or metastatic, measurable or evaluable, non-resectable solid tumours 
(Cohort A), or diagnosed and histologically, or cytologically, confirmed locally advanced 
and/or metastatic HR+ HER2- breast cancer (Cohorts B, C, D (dose finding), F, D1 and D2), 
or diagnosis of stage IV NSCLC (Cohort E).
Patients must not have received prior anti CDK agents (except cohort F) or previous treatment 
with IGF-1R targeting compounds in any setting.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Cohort A (Solid Tumours)
1. Age ≥ 18 years (≥20 years for Japan only) at screening


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2. Signed and dated written informed consent in accordance with GCP and local legislation 
prior to admission to the trial
3. WHO/ECOG performance status 0-1 assessed at screening
4. Patient must be able to swallow oral capsules or tablets.
5. Male or female patients ready and able to use highly effective methods of birth control 
during the study and for 3 weeks following the last dose of abemaciclib per ICH M3 (R2) 
that result in a low failure rate of less than 1% per year when used consistently and 
correctly. A list of contraception methods meeting these criteria is provided in the patient 
information. Women of childbearing potential1 must have a negative serum pregnancy 
test at screening.
6. Patients with histologically or cytologically confirmed diagnosis of advanced and/or 
metastatic, measurable or evaluable, non-resectable solid tumours 
7. Patients must have received and failed, or have been intolerant to, all treatment known to 
confer clinical benefit or have no therapeutic options available as deemed appropriate by 
their treating physician
8. Life expectancy ≥ 3 months in the opinion of the investigator assessed at screening;
Cohorts B, C, D (dose finding) (Breast Cancer):
1. Age ≥ 18 years (≥20 years for Japan only) at screening
2. Signed and dated written informed consent in accordance with GCP and local legislation 
prior to admission to the trial
3. WHO/ECOG performance status 0-1 assessed at screening
4. Patient must be able to swallow oral capsules or tablets.
5. Women who have postmenopausal status due to either  surgical/natural menopause or 
chemical ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with a 
gonadotropin-releasing hormone (GnRH) agonist such as goserelin or radiation-induced 
ovarian suppression.  

postmenopausal status due to surgical/natural menopause requires at least 
one of the following conditions:

prior bilateral oophorectomy

age ≥ 60 years

age < 60 years and amenorrheic (in the absence of tamoxifen, 
toremifene, ovarian suppression, or chemotherapy) for at least 12 
months; and  follicle-stimulating hormone (FSH) and estradiol 
within the postmenopausal range as per institutional reference 
ranges.

Postmenopausal status due to radiation-induced ovarian suppression must be 
confirmed by FSH and estradiol level in the postmenopausal range.
6. Histologically or cytologically proven diagnosis of breast cancer with evidence of locally 
advanced disease not amenable to curative resection or metastatic disease 
7. HR+ (local lab results at screening or, if not available, at the time of diagnosis)
                                                
1 Women of childbearing potential are defined as:
-
having experienced menarche and 
-
not postmenopausal (12 months with no menses without an alternative medical cause) and 
-
not permanently sterilized (e.g. hysterectomy, bilateral oophorectomy or bilateral salpingectomy).


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To fulfil the requirement of HR+ disease, the primary tumour or metastatic lesion of the 
breast cancer must express at least one of the hormone receptors (estrogen receptor [ER] 
or progesterone receptor [PgR]) by immunohistochemistry (IHC).  Estrogen receptor and 
PgR assays are considered positive 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 (Hammond et al. 2010).
8. HER2 negative (local lab results at screening or, if not available, at the time of diagnosis)
as defined by the most recent American Society of Clinical Oncology (ASCO)/College of 
American Pathologists (CAP) Guidelines (Hammond et al. 2010).
9. Previous adjuvant and neoadjuvant chemotherapy is permitted. 0-2 prior lines of 
chemotherapy for the metastatic setting are allowed.
10. At least 1 lesion (measurable or non-measurable) that can be accurately assessed at 
baseline with CT or MRI or PET-CT (CT portion of diagnostic quality) and which is 
suitable for accurate repeated measurement. 
11. Cohort B, C, D: Must be eligible for the corresponding hormonal therapy (letrozole, 
anastrozole or fulvestrant). For Cohorts B and C previous treatment with fulvestrant or 
exemestane is allowed. For Cohort D prior therapy with non steroidal aromatase 
inhibitors (anastrozole, letrozole) or exemestane are permitted. 
Cohort E (NSCLC):
1. Age ≥ 18 years (≥20 years for Japan only) at screening
2. Signed and dated written informed consent in accordance with GCP and local legislation 
prior to admission to the trial 
3. WHO/ECOG performance status 0-1 assessed at screening
4. Patient must be able to swallow oral capsules or tablets.
5. Male or female patients ready and able to use highly effective methods of birth control 
during the study and for 3 weeks following the last dose of abemaciclib per ICH M3 (R2) 
that result in a low failure rate of less than 1% per year when used consistently and 
correctly. A list of contraception methods meeting these criteria is provided in the patient 
information. Women of childbearing potential2 must have a negative serum pregnancy 
test at screening.
6. Histologically or cytologically confirmed diagnosis of stage IV NSCLC.
7. The participant must have progressed after platinum-based chemotherapy AND 
immunotherapy (unless deemed inappropriate candidates for immunotherapy by their 
treating physician) AND have received 1 or a maximum of 2 other prior chemotherapy 
for advanced and/or metastatic disease OR must be judged by the physician as ineligible 
for further standard second-line chemotherapy. Prior treatment with epidermal growth 
factor receptor-tyrosine kinase inhibitor (EGFR-TKI) and anaplastic lymphoma kinase 
(ALK) inhibitors is mandatory in participants whose tumour has EGFR-activating 
mutations or ALK translocations. Prior targeting agents and neoadjuvant/adjuvant 
therapies are permitted.
8. Have adequate organ function including haematology, renal, and liver.
9. Have measureable disease per RECIST 1.1.
                                                
2 Women of childbearing potential are defined as:
-
having experienced menarche and 
-
not postmenopausal (12 months with no menses without an alternative medical cause) and 
-
not permanently sterilized (e.g. hysterectomy, bilateral oophorectomy or bilateral salpingectomy).


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Cohort D1,  Cohort D2 and Cohort F (Breast Cancer):
1. Age ≥ 18 years (≥20 years for Japan only) at screening
2. Signed and dated written informed consent in accordance with GCP and local legislation 
prior to admission to the trial
3. WHO/ECOG performance status 0-1 assessed at screening
4. Patient must be able to swallow oral capsules or tablets.
5. Women who have postmenopausal status due to either  surgical/natural menopause or 
chemical ovarian suppression (initiated at least 28 days prior to Day 1 of Cycle 1) with a 
gonadotropin-releasing hormone (GnRH) agonist such as goserelin or radiation-induced 
ovarian suppression.  

postmenopausal status due to surgical/natural menopause requires at least 
one of the following conditions:

prior bilateral oophorectomy

age ≥ 60 years

age < 60 years and amenorrheic (in the absence of tamoxifen, 
toremifene, ovarian suppression, or chemotherapy) for at least 12 
months; and  follicle-stimulating hormone (FSH) and estradiol 
within the postmenopausal range as per institutional reference 
ranges.

Postmenopausal status due to radiation-induced ovarian suppression must be 
confirmed by FSH and estradiol level in the postmenopausal range.
6. Histologically or cytologically proven diagnosis of breast cancer with evidence of locally 
advanced disease not amenable to curative resection or metastatic disease 
7. HR+ (local lab results at screening or, if not available, at the time of diagnosis)
To fulfil the requirement of HR+ disease, the primary tumour or metastatic lesion of the 
breast cancer must express at least one of the hormone receptors (estrogen receptor [ER] 
or progesterone receptor [PgR]) by immunohistochemistry (IHC).  Estrogen receptor and 
PgR assays are considered positive 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 (Hammond et al. 2010).
8. HER2 negative (local lab results at screening or, if not available, at the time of diagnosis)
as defined by the most recent American Society of Clinical Oncology (ASCO)/College of 
American Pathologists (CAP) Guidelines (Hammond et al. 2010).
9. Have a negative serum pregnancy test at baseline (within 14 days prior to randomization) 
and agree to use medically approved precautions to prevent pregnancy during the study 
and for 3 weeks following the last dose of abemaciclib and for at least 6 months after last 
dose of xentuzumab if postmenopausal status is due to ovarian suppression with a GnRH 
agonist.
10. Have either measurable disease or non-measurable bone only disease. Measurable and 
nonmeasurable diseases are defined according to the Response Evaluation Criteria in 
Solid Tumors (RECIST Version 1.1 [v1.1]. Nonmeasurable bone only disease may
include any of the following: blastic bone lesions, lytic bone lesions without a measurable 
soft tissue component, or mixed lytic-blastic bone lesions without a measurable soft tissue 
component.


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Cohort D1 and D2 only:
11. Patients must fulfil 1 of the following criteria:
a.
Relapsed with radiologic evidence of progression while receiving neoadjuvant 
or adjuvant endocrine therapy, with no subsequent endocrine therapy received 
following progression.
b. Relapsed with radiologic evidence of progression within 1 year from 
completion of adjuvant endocrine therapy, with no subsequent endocrine 
therapy received following progression.
c.
Relapsed with radiologic evidence of progression more than 1 year from 
completion of adjuvant endocrine therapy and then subsequently relapsed with 
radiologic evidence of progression after receiving treatment with either an 
antiestrogen or an aromatase inhibitor as first-line endocrine therapy for 
metastatic disease. Patients may not have received more than 1 line of 
endocrine therapy or any prior chemotherapy for metastatic disease.
d. Presented de novo with metastatic disease and then relapsed with radiologic 
evidence of progression after receiving treatment with either an antiestrogen or 
an aromatase inhibitor as first-line endocrine therapy for metastatic disease. 
Patients may not have received more than 1 line of endocrine therapy or any 
prior chemotherapy for metastatic disease.
12. For cohort D1 (visceral disease) patient must have at least one documented visceral 
metastasis; for cohort D2 (non-visceral disease), patient must not have any visceral 
metastasis.
Cohort F only:
13. Patients with resistance to prior therapy with an aromatase inhibitor (AI) and CDK4/6 
inhibitor (excluding abemaciclib) for locally advanced or metastatic breast cancer, 
defined as radiologic evidence of disease progression while on, or within 30 days after 
last dose of AI and/or CDK4/6 inhibitor (excl. abemaciclib) administered as first-line 
therapy for locally advanced or metastatic disease. Patients may not have received more 
than 1 line of prior endocrine based therapy or any prior chemotherapy for 
advanced/metastatic disease.
14. Patient must not have any visceral metastasis (example of allowed lesions are in breast, 
lymph nodes, soft tissue, bone).
3.3.3
Exclusion criteria 
Cohorts A, B, C, D (dose finding), and E:
1. Any documented active or suspected malignancy or history of malignancy, other than the 
disease under study, within 3 years prior to screening, except appropriately treated basal 
cell carcinoma of the skin or in situ carcinoma of uterine cervix or ductal carcinoma in 
situ (DCIS) if properly treated in opinion of the investigator.
2. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
3. Previous treatment in this trial


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4. Currently enrolled in another investigational device or drug study, or less than 21 days 
since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s).
5. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable study subject or unlikely to complete the trial
6. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
Men who plan to father a child while in the trial.
7. Prior anti-cancer chemotherapy, biological or radiation therapy, androgens, thalidomide, 
other anticancer agents, or any investigational drug within 21 days (14 days for non-
myelosuppressive agents); and/or 4 weeks for immunotherapy, before starting any of the 
trial drugs.
8. Prior anti CDK agents 
9. Prior radiotherapy to ≥ 25% of bone marrow regardless of when it was received
10. Unresolved treatment related toxicity from previous therapy of > CTCAE grade 1 at study 
entry (except for stable sensory neuropathy ≤CTCAE grade 2 and alopecia) 
11. Previous treatment with IGF-1R targeting compounds 
12. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, 
or leptomeningeal disease, as indicated by clinical symptoms, cerebral oedema, and/or 
progressive growth. History of CNS metastases or cord compression are eligible if they 
have been definitively treated (e.g. radiotherapy, stereotactic surgery) and are clinically 
stable, off anticonvulsants and steroids for at least 4 weeks. Patients with brain metastases 
are eligible if they are asymptomatic, completed radiotherapy for at least 4 weeks or are 
on a stable dose of steroids for at least 4 weeks. Patients are not eligible if they have 
spinal cord compression.
13. The patient has serious and/or uncontrolled pre-existing medical condition(s) that, in the 
judgement of the Investigator, would preclude participation in this study, including 
interstitial lung disease, severe dyspnoea at rest or requiring oxygen therapy.
14. Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following: ANC < 1.5 x 109/L, platelets < 100 x 109/L, haemoglobin <90g/L, ALT > 2.5 
x ULN or > 5 x ULN in the presence of liver metastases, total bilirubin >1.5 x ULN or >3 
x ULN in patients with Gilbert's Syndrome, serum creatinine > 1.5 x ULN concurrent 
with creatinine clearance ≤ 50 mL/min.
15. Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi 
Syndrome or renal tubular acidosis
16. Refractory nausea and vomiting, chronic GI diseases, inability to swallow the product, or 
previous significant bowel resection that would preclude adequate absorption of 
abemaciclib or resulting in baseline Grade 2 or higher diarrhoea.
17. History of hypersensitivity to active or inactive excipients of xentuzumab, abemaciclib or 
letrozole/anastrozole/fulvestrant, or loperamide hydrochloride, or drugs with similar 
chemical structures
18. Patients with Diabetes Type I or uncontrolled Type II (defined by HgBA1C > 8%).
19. Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-
threatening complications in the short term including patients with massive uncontrolled 
effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and over 50% of 
liver involvement in metastases.
20. Prior hematopoietic stem cell or bone marrow transplant


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21. Have a personal history of any of the following conditions: syncope of cardiovascular
etiology, ventricular arrhythmia (including but not limited to ventricular tachycardia and
ventricular fibrillation), or sudden cardiac arrest. Subjects with controlled atrial fibrillation
for >30 days prior to study treatment are eligible.
22. Erythropoietin, G-CSF, and GM-CSF are not allowed within 2 weeks prior to study. The 
primary prophylactic use of G-CSF is not permitted but it may be used to treat treatment-
emergent neutropenia.
23. Have had major surgery (excluding biopsy) < 28 days of the initial dose of any of the 
study drugs or planned major surgery during study participation.
24. Have active bacterial or fungal infection (that is, requiring IV antibiotics or therapy at 
time of initiating study treatment), and/or known viral infection (for example, human 
immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen, or hepatitis C 
antibodies). Screening is not required for enrolment.
25. Patients with baseline Grade ≥2 hyperglycaemia or patients with baseline Grade ≥ 2 
diarrhoea
26. Patients needing treatment with CYP3A4 inhibitors/inducers cannot be included in the 
trial. (See Appendix 10.1)
Cohort D1, Cohort D2 and Cohort F (Breast Cancer):
1. Any documented active or suspected malignancy or history of malignancy (including 
inflammatory breast cancer), other than the disease under study, within 3 years prior to 
screening, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix or ductal carcinoma in situ (DCIS) if properly treated in 
opinion of the investigator.
2. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
3. Previous treatment in this trial
4. Currently enrolled in another investigational device or drug study, or less than 21 days 
since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s).
5. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
them an unreliable study subject or unlikely to complete the trial
6. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
7. Prior anti-cancer chemotherapy, biological or radiation therapy, androgens, thalidomide, 
other anticancer agents, or any investigational drug within 21 days (14 days for non-
myelosuppressive agents); and/or 4 weeks for immunotherapy, before starting any of the 
trial drugs.For cohort F only: prior palbociclib or ribociclib treatment within 14 days 
before starting any of the trial drugs.
8. Have received prior treatment with chemotherapy (except for neoadjuvant/adjuvant 
chemotherapy), fulvestrant, everolimus, alpelisib or abemaciclib. For cohorts D1 and D2 
only: prior treatment with palbociclib or ribociclib is also excluded
9. Prior radiotherapy to ≥ 25% of bone marrow regardless of when it was received
10. Unresolved treatment related toxicity from previous therapy of > CTCAE grade 1 at study 
entry (except for stable sensory neuropathy ≤CTCAE grade 2 and alopecia) 
11. Previous treatment with IGF-1R targeting compounds
12. Have clinical evidence or history of central nervous system metastasis. Screening is not 
required for enrolment.


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13. The patient has serious and/or uncontrolled pre-existing medical condition(s) that, in the 
judgement of the Investigator, would preclude participation in this study, including 
interstitial lung disease, severe dyspnoea at rest or requiring oxygen therapy.
14. Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following: ANC < 1.5 x 109/L, platelets < 100 x 109/L, haemoglobin <90g/L, ALT > 2.5 
x ULN or > 5 x ULN in the presence of liver metastases, total bilirubin >1.5 x ULN or >3 
x ULN in patients with Gilbert's Syndrome, serum creatinine > 1.5 x ULN concurrent 
with creatinine clearance ≤ 50 mL/min.
15. Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi 
Syndrome or renal tubular acidosis
16. Refractory nausea and vomiting, chronic GI diseases, inability to swallow the product, or 
previous significant bowel resection that would preclude adequate absorption of 
abemaciclib or resulting in baseline Grade 2 or higher diarrhoea.
17. History of hypersensitivity to active or inactive excipients of xentuzumab, abemaciclib or 
fulvestrant, or loperamide hydrochloride, or drugs with similar chemical structures
18. Patients with Diabetes Type I or uncontrolled Type II (defined by HgBA1C > 8%).
19. Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-
threatening complications in the short term including patients with massive uncontrolled 
effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and over 50% of 
liver involvement in metastases.
20. Prior hematopoietic stem cell or bone marrow transplant
21. Have a personal history of any of the following conditions: syncope of cardiovascular
etiology, ventricular arrhythmia (including but not limited to ventricular tachycardia and
ventricular fibrillation), or sudden cardiac arrest. Subjects with controlled atrial fibrillation
for >30 days prior to study treatment are eligible.
22. Erythropoietin, G-CSF, and GM-CSF are not allowed within 2 weeks prior to study. The 
primary prophylactic use of G-CSF is not permitted but it may be used to treat treatment-
emergent neutropenia.
23. Have had major surgery (excluding biopsy) < 28 days of the initial dose of any of the 
study drugs or planned major surgery during study participation.
24. Have active bacterial or fungal infection (that is, requiring IV antibiotics or therapy at 
time of initiating study treatment), and/or known viral infection (for example, human 
immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen, or hepatitis C 
antibodies). Screening is not required for enrolment.
25. Patients with baseline Grade ≥2 hyperglycaemia or patients with baseline Grade ≥ 2 
diarrhoea
26. Patients needing treatment with CYP3A4 inhibitors/inducers cannot be included in the 
trial. (See Appendix 10.1)
27. Have initiated bisphosphonates or approved RANK ligand (RANK-L) targeted agents (for 
example, denosumab) <7 days prior to initiation of any study drug.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep patients in the trial as scheduled. This includes 


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careful patient selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment as well as an explanation of the consequences of premature withdrawal. 
An individual patient is to be withdrawn from trial treatment if:
*
The patient withdraws consent for trial treatment or trial participation, without the need to 
justify the decision.
*
The patient develops unequivocal disease progression, supported by radiological evidence 
where possible.
*
The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication in the opinion of both the investigator and sponsor 
representative.
*
The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy)
*
The patient 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. (See Section 4.3)
*
The trial is terminated for any of the reasons listed in Section 3.3.4.2 ” Discontinuation of 
the trial by the sponsor”.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart (FC) and Section 6.2.3.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the eCRF. 
These data will be included in the trial database and reported.
3.3.4.2
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
As described in Section 2.3 Benefit-risk assessment, topline results of 1280-0022 showed no 
added benefit of xentuzumab compared to placebo when treating participants with metastatic 
breast cancer. Although xentuzumab treatment was recommended to be discontinued in 
1280.18, continuation of treatment of patients with xentuzumab was based on an individual 
assessment by the investigator.  Due to the worsening in benefit-risk, the trial will proceed 
towards termination based on the following 3 steps:
a. For xentuzumab-treated patients, the xentuzumab treatment will not extend past the 
drug expiration date (May 2023) of the last planned GMP manufacturing batch of IMP 
xentuzumab (provided that all patients are on xentuzumab for at least 2 years when
they are tolerating the drug without tumor progression). Patients that will discontinue 
xentuzumab can still be eligible for continued treatment with abemaciclib and 


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fulvestrant (standard of care in this setting) provided they are tolerating the drugs
without tumor progression.
b. When all patients have discontinued xentuzumab treatment, if any patient on 
abemaciclib and fulvestrant is able to continue taking these approved medications off 
study, then, at the request of the Sponsor, the patient may end such treatment as part of 
the trial and discontinue study participation (if both the Investigator and patient agree).
c.
After all patients end treatment with all study drugs, the trial will be terminated.
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of patients 
Patients may be replaced for determination of the primary endpoint (MTD) in cases of:

Patient’s withdrawal during the first cycle of treatment for reasons other than DLT, e.g. 
patient no longer wishes to participate, or lost to follow up during first cycle.

Patients who do not experience DLT, but miss more than one dose of xentuzumab during 
the first cycle of treatment, except for dose interruption caused by AE

Patients who do not experience DLT, but miss 3 or more consecutive doses of 
abemaciclib during the first cycle of treatment, except for dose interruption caused by 
AE.

Patients who miss one complete cycle at any time beyond the first cycle of treatment may 
be replaced after discussion between the sponsor and the investigator.

Patients who are non-evaluable with respect to DLT.

Patients with CTCAE grade ≥3 allergic reaction/hypersensitivity to the study drug(s) 
within the first cycle may be replaced.

For cohorts E and F, where objective response or DC is the primary endpoint: if patient 
doesn't have post-treatment radiological tumor assessment for reason other than 
worsening of underlying disease
Patients that have been replaced might continue treatment in the trial should criteria in Section 
4.1.4.2 apply; however these patients will not be considered for analysis of the primary 
endpoint. 


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS 
Patients will receive xentuzumab plus abemaciclib.
Additionally in cohorts B, C, D (dose finding), F, D1 and D2, patients will receive in addition 
background hormonal therapy with letrozole, anastrozole or fulvestrant.
The sources for each of the products are listed in Section 4.1.1. 
As of 19 Oct 2021, based on the primary analysis of top line results of 1280-0022, 
Boehringer Ingelheim recommended to immediately discontinue xentuzumab in 
1280.18 trial. (see Section 2.3) 
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Xentuzumab (Investigational product, IMP)
Substance:
Xentuzumab humanized monoclonal antibody
Pharmaceutical formulation:
Concentrate for solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/ml of xentuzumab supplied in 20 ml vials (200 
mg/vial)
Posology
Once weekly administrated through one hour intravenous 
infusion.
Infusion duration may be extended to over one hour and up 
to a maximum of three hours in cases of grade ≥ 2 infusion 
reactions
Route of administration:
Intravenous infusion. Appropriate dose of xentuzumab will 
be diluted in isotonic sodium chloride solution (0.9%)
Duration of use:
Continuous weekly dosing (days 1, 8, 15 and 22 in a 28-day 
course) in the absence of disease progression, intolerable 
AEs or other reason necessitating withdrawal
Detailed preparation and handling of xentuzumab, including information on infusion 
equipment and infusion procedure, will be described in ISF.


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Table 4.1.1: 2
Abemaciclib (Investigational product, IMP)
Substance:
Abemaciclib. Small molecule CDK4 and CDK6 
inhibitor 
Pharmaceutical formulation:
Capsules
Source:
Unit strength:
A white hypromellose capsule containing 50 mg of 
abemaciclib and the inactive ingredients 
pregelatinized starch, dimethicone, and colloidal 
silicon dioxide.
Posology
Treatment/28-day cycle 150 mg p.o. Q12H on Days 
1-28 (Starting dose Cohort A)
Abbreviations: PO = orally; Q12H = every 12 (± 2) 
hours
Route of administration:
p.o.
Pharmaceutical formulation:
Tablets
Source:
Unit strength:
Film-coated 50 mg tablets
Posology
Treatment/28-day cycle 150 mg p.o. Q12H on Days 
1-28 (Starting dose Cohort A)
Abbreviations: PO = orally; Q12H = every 12 (± 2) 
hours
Route of administration:
p.o.
Table 4.1.1: 3
Fulvestrant. Background endocrine therapy. (Auxiliary Medicinal 
Product, AMP)
Substance:
Fulvestrant (Faslodex®)
Pharmaceutical formulation:
Solution for injection 
Source:
Unit strength:
Prefilled syringes (250 mg fulvestrant in 5mL 
solution).
Route of administration:
Intramuscular injection


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Table 4.1.1: 3 (cont.)
Fulvestrant. Background endocrine therapy. (Auxiliary Medicinal 
Product, AMP):
Substance:
Fulvestrant (Faslodex®)
Posology
500 mg given once a month, with an additional 500-
mg dose given two weeks after the first dose. Each 
dose is given as two slow 250 mg injections lasting 
one to two minutes, with one injection being given 
into the muscle of each buttock
Route of administration:
Intramuscular injection
Table 4.1.1: 4
Anastrozole. Background endocrine therapy. (Auxiliary Medicinal 
Product, AMP)
Substance:
Anastrozole 
Pharmaceutical formulation:
Film Coated Tablet
Source:
EU, US or Japan commercial product as applicable
Unit strength:
1 mg
Posology
1 mg tablet once a day
Route of administration:
p.o.
Table 4.1.1: 5
Letrozole. Background endocrine therapy. (Auxiliary Medicinal 
Product, AMP)
Substance:
Letrozole 
Pharmaceutical formulation:
Film coated tablet.
Source:
EU, US or Japan commercial product as applicable
Unit strength:
2.5 mg
Posology
2.5 mg once daily
Route of administration:
p.o.
4.1.2
Selection of doses in the trial
4.1.2.1
Part 1 
A semi-mechanistic PK/PD model was developed describing the kinetics of the interaction 
between xentuzumab and the different PD biomarkers (i.e. IGF-1, IGF-2, and IGFBP3). 
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.


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In dose finding cohort A, the starting dose of abemaciclib is 150 mg every 12 (±2) hours. 
Based on the recommended phase II dose in one dose finding study using combination of a 
targeted therapy agent with xentuzumab (please refer to the current version of the 
Investigator's Brochure, c01690707-08), a dose level of 1000 mg with weekly dose schedule 
is selected as the starting dose for this study. This dose combination has a prior probability of 
overdosing below 25% (see Section 7.1). Planned dose levels for patients in cohort A are 
displayed in Table 4.1.2.1: 1 below.
Table 4.1.2.1: 1 Concomitant dosing schedule schemes of Cohort A
Dose level
Xentuzumab (mg weekly)
Abemaciclib (mg/12h)
DL0 (starting dose)
1000
150
DL-1a
750
150
DL-1b
1000
100
Dose escalation beyond the highest dose levels planned as shown above will not be considered. 
Above dose levels may be modified and/or additional dose levels/administration regimens may 
be added based on safety profile and other emerging data upon discussion and agreement 
between the sponsor and the SC.
Intra-patient dose escalation is not permitted. Successive dose-level cohorts of patients will 
receive doses of xentuzumab in combination with abemaciclib until the MTD1/RP2D1 is 
established or until the trial is terminated for other reasons (see Section 3.3.4.2). The trial may 
be terminated at any time based on emerging safety concerns without establishing the 
MTD1/RP2D1.
For any dose-level cohort, at least 3 evaluable patients will be required. However, in the case 
that only 2 patients are evaluable and neither has experienced a DLT within the MTD 
evaluation period, then dose-escalation can occur based on these 2 patients.
If DLTs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that dose-level cohort will be stopped. The BLRM will then be re-run 
to confirm that the dose level still fulfils the EWOC principle. Based on this information, the 
SC will evaluate whether the next patients will be enrolled at the same dose level, or if they 
will be enrolled at a lower dose level.
After all patients in the initial dose-level cohort have either experienced a DLT or have been 
observed for at least one course (28 days) without experiencing a DLT, the Bayesian model 
will be updated with the newly accumulated data. The SC will then determine the dose regimen 
for the next dose-level cohort, based on the available toxicity information (including DLTs, 
AEs that are not DLTs, and AE information post-cycle 1), recommendations from the BLRM, 
and other data (e.g. anti-tumour activity, pharmacokinetics) if applicable. Details on the
Bayesian design are provided in Sections 7.1 and Appendix 10.6.


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The overdose risk will be calculated for each further dose combination, and patient enrolment 
into dose levels will be permitted to all dose combinations which fulfil the escalation with 
overdose control (EWOC) criterion. Based on the Bayesian model and the additional 
information as defined above, the SC will decide on the next dose level to be investigated. In 
the SC meeting, data for each patient in the current dose-level cohort will be described in detail, 
updated safety data on other ongoing patients, including data in later courses, will be discussed 
as well.
The SC must reach a consensus on whether to de-escalate, re-escalate and/or expand 
recruitment into particular cohorts, or to declare the MTD1/RP2D1. BI will prepare minutes 
from the SC meetings and circulate them to each Investigator.
To further assess the safety (e.g. specific suspected treatment-related adverse events) of 
xentuzumab in combination with abemaciclib, one or several doses that are considered 
acceptably safe, i.e. shown to be lower than or equal to any potential MTD, may be explored 
to determine the RP2D1. Nevertheless, a minimum of 6 evaluable patients need to be treated at 
the MTD1/RP2D1 in the dose finding cohort A prior to starting part 2 (cohorts B, C, D and E) 
and any dose declared as MTD1/RP2D1 by the SC needs to fulfil the escalation with overdose 
control (EWOC) criteria.
The SC may recommend stopping the dose finding cohort A after the criterion for MTD 
(Section 7.1) is fulfilled. Further patients may be included to confirm the MTD1/RP2D1
estimate, i.e. to confirm that the EWOC criterion is still fulfilled prior to the start of part 2 
(cohorts B, C, D and E).
4.1.2.2
Part 2
The decision on dose escalation/de-escalation, MTD (or Biological Relevant Dose) and RP2D 
will be determined in discussion with at least BI Trial Clinical Monitor, BI project physician 
(TMM) and Coordinating Investigator and taking into account patients’ safety. This decision 
will be documented.
Dose finding cohorts B, C and D (dose finding):
For each cohort, starting dose of xentuzumab and abemaciclib will be the RP2D1 determined 
in cohort A, even if RP2D1 equals the highest dose levels planned (see Table 4.1.2.1: 1). This 
is because the maximum dose of abemaciclib to be explored in triple combination cohorts is 
150mg b.i.d. In that case, the starting dose would then be 1000 mg weekly xentuzumab plus 
150 mg / 12h abemaciclib.
In the three cohorts, patients will receive the dose of background hormonal therapy as defined 
in Tables 4.1.1: 3 to 4.1.1: 5 (i.e. letrozole in cohort B, anastrozole in Cohort C and fulvestrant 
in cohort D).
Dose escalation/de-escalation of xentuzumab and abemaciclib will be conducted as described 
in Section 4.1.2.1 for cohort A using a BLRM with a fixed dose of the background hormonal 
therapy.


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Expansion cohort E:
Patients will be treated at the RP2D1 determined in Cohort A. 
4.1.2.3
Part 3
Cohorts F, D1 and D2
For Cohort F and Cohorts D1 and D2 patients will be treated at the RP2D4 of abemaciclib 
and xentuzumab and fulvestrant triplet as determined in Cohort D (dose finding). 
4.1.3
Method of assigning patients to treatment groups
For the dose finding cohorts, the treatment slots are assigned by the BI Clinical Monitor (CM) 
in close communication (email/phone/fax) with the recruiting sites and IRT system and will be 
assigned on a competitive basis. After the BI Clinical Monitor has been notified by a site about 
a potential patient, the slot will be reserved to this site for a period of time (approximately a 
week) until patient signs ICF, otherwise the slot will be opened up again for all recruiting sites. 
If more than one site notifies potential patients and there are no slots for all proposed 
candidates, BI Clinical Monitor will allocate the slot prioritizing by planned visits calendar, 
balanced number of patients per site and other parameters as applicable. 
Patients that meet the eligibility criteria and who have given their written informed consent 
may not be entered into the study depending on the cohort which is being explored at that 
particular time (for example, but not restricted to, the dose finding cohort A). This needs to be 
discussed and agreed with BI Trial Team.
Prior to inclusion of a new patient, once the slot has been confirmed, the investigator should 
also confirm the respective dose with the BI clinical monitor.
4.1.4
Drug assignment and administration of doses for each patient
The treatment medication assignment for xentuzumab and abemaciclib will be managed 
through IRT system. The treatment medication assignment for anastrozole, letrozole and 
fulvestrant will be managed through IRT system in certain countries only. 
In addition, patient’s screening, run-in, all drug dispensation visits and EOTV will be collected 
in the IRT system.
4.1.4.1
Initial study drug assignment and administration
General information that applies in this study regardless of IRT is described in below sections 
of individual study drug. The medication kit as well as the treatment will be assigned with the 
support from IRT. 
Before entering patients at the next dose level of the dose finding cohorts, it will be ensured 
that all patients at the current ongoing dose level have completed at least one course of 
treatment.


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Xentuzumab
Patients will start treatment with their assigned dose tier (see Section 4.1.2) or RP2D of 
xentuzumab from course 1 day 1. Xentuzumab 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 scheduled infusion of xentuzumab is not performed within the time window, 
this treatment will be skipped and will not be made up. Subsequent visits should follow the 
original visit date schedule. Mannitol is used in the formulation of xentuzumab, 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 specific eCRF. The accuracy of this information is crucial for the proper 
evaluation and appraisal of the pharmacokinetics – in the relevant cohorts – and other data.
Detailed information of dispensation, preparation, and handling of xentuzumab will be 
described in ISF.
Abemaciclib
Abemaciclib will be taken orally every 12 (± 2) hours on days 1 through 28 of a 28-day cycle 
for a total of 56 doses per cycle. During all cycles, abemaciclib should be taken at 
approximately the same times each day. If a patient misses or vomits a dose, that dose should 
be omitted.
No more than 56 doses of abemaciclib should be dispensed for each 28-day cycle.
Abemaciclib dose omissions will be evaluated on a case by case basis and patients may be 
replaced if dose omissions occur within MTD period of a dose finding cohort or if the number 
of dose omissions makes the patient non evaluable regardless of the cohort. 
4.1.4.2
Temporary treatment interruption and dose reduction
DLT, or those AEs requiring dose adjustment as indicated on the label, should be managed by 
treatment interruptions and subsequent dose reductions of the presumed causal study drug(s) 
according to the schedule described in Table 4.1.4.2: 1. Please also refer to Section 4.4 for 
additional recommendations. 
In case of an intolerable adverse event which is suspected to be related to either xentuzumab 
or abemaciclib in the opinion of investigator, the treatment can be interrupted with subsequent 
dose reduction for the suspected agent(s) according to Tables 4.1.4.2: 1 (xentuzumab) and 
4.1.4.2: 2 (abemaciclib). 
In the case of DLT with suspected overlapping toxicities where assigning relatedness to one 
study drug or the other is difficult, or considered related to both xentuzumab and abemaciclib 
the dosing with both study drugs should be held until the adequate resolution of AE (CTCAE 
grade ≤1). Treatment should then be resumed and/or dose reduced as shown in Table 4.1.4.2: 
1 for xentuzumab and in Table 4.1.4.2: 2 for abemaciclib.
Recurrent in the context of dose interruptions and delays refers to the same event and severity 
occurring within 8 weeks (as measured from the stop date of the first event). This does not 


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include events in the same class (for example, neutropenia followed by anemia 1 month 
later).
Further to these recommendations, in Part 1, Cohort A, both xentuzumab and abemaciclib must 
be paused when a DLT occurs during the first treatment course.
The treatment should be paused until patient has recovered from the DLT to grade ≤ 1 or 
baseline. Baseline is defined as the CTCAE grade at the start of treatment. For patients who 
develop DLT, treatment may be resumed at reduced dose according to dose reduction scheme 
of the patient’s starting dosage. If a patient has not recovered to Grade ≤ 1 or baseline within 
28 days, study treatment must be permanently discontinued. In the event that the patient is 
deriving obvious clinical benefit according to the investigator’s judgement, further treatment 
with study drug(s) will be decided in agreement between the sponsor and the investigator.
If one or more of the study drugs is permanently discontinued, the patient can remain on either 
abemaciclib or xentuzumab or endocrine therapy only.
Dose reductions will apply to individual patients only. Doses of xentuzumab and/or 
abemaciclib can be reduced independent of each other. Once the treatment dose of xentuzumab 
is reduced for a particular patient, it should not be increased back to the previous dose.
Abemaciclib dose adjustments are allowed within a cycle and between cycles. Abemaciclib 
must be reduced sequentially by one dose level. For further instructions as regards dose 
adjustments of abemaciclib, please refer to Section 4.2.2.
For patients requiring dose reduction(s) of abemaciclib, any re-escalation to a prior dose level 
is permitted only after discussion and agreement with the sponsor. After re-escalation, 
subsequent dose adjustments should be based on the dose of abemaciclib that the patient is 
currently receiving.
Table 4.1.4.2: 1 Individual dose reductions schedule
Xentuzumab mg/weekly
Abemaciclib mg/12 h
Current dose is 1000
Dose reduce to 750
Current dose is 150
Dose reduce to 100
Current dose is 750
Dose reduce to 500
Current dose is 100
Dose reduce to 50
Current dose is 500
No further dose 
reductions allowed.
Current dose is 50
No further dose 
reductions allowed.
No dose reduction is allowed below 500 mg/weekly for xentuzumab or 50 mg b.i.d. for 
abemaciclib.
Alternative dose modification scheme can only be considered after discussion and agreement 
between the investigator and the BI clinical monitor.


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In the event of any unrelated AEs, the study drug(s) may be interrupted for up to 28 days, but 
no dose reduction should occur. Otherwise, the decision to continue with the study treatment 
will be made by the BI Clinical Monitor in agreement with the investigator.


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Table 4.1.4.2: 2 Dose Adjustments and Delays for Toxicity Possibly Related to Abemaciclib*
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Hematologic Toxicity 
Grade 3
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 2.
Dose MAY be 
reduced by 1 dose 
level -
investigator’s 
discretion.
Hematologic Toxicity 
Recurrent Grade 31
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 2.
Dose MUST be 
reduced by 1 dose 
level. 
Hematologic Toxicity 
Grade 4
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 2.
Dose MUST be 
reduced by 1 dose 
level.
Hematologic toxicity:  If 
patient requires 
administration of blood 
cell growth factors.
Regardless of severity. 
(Use of growth factors 
according to ASCO 
Guidelines)
Dose MUST be 
suspended for at least 
48 hours after the last 
dose of blood cell 
growth factors was 
administered and until 
toxicity resolves to at 
least Grade 2. 
Dose MUST be 
reduced by 1 dose 
level unless 
already performed 
for incidence of 
toxicity that led to 
the use of growth 
factor. 
Nonhematologic Toxicity2
(except diarrhoea, ALT 
increase and 
ILD/pneumonitis)
Persistent or recurrent3 Grade
2 that does not resolve with 
maximal supportive measures 
within 7 days to baseline or 
Grade 1
Dose MUST be 
suspended until toxicity 
resolves to either 
baseline or Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
ILD/pneumonitis5
Grade 2 that persists or recurs 
despite maximal supportive 
measures and does not return 
to baseline or Grade 1 within 
7 days
Suspend dose until 
toxicity resolves to 
baseline or ≤Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
ILD/pneumonitis
Grade 3 and 4
Dose MUST be 
discontinued
NA
Nonhematologic Toxicity 
Grade 3 or 4
Dose MUST be 
suspended until toxicity 
resolves to either 
baseline or Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
Diarrhoea
Grade 2 that does not resolve 
within 24 hours to at least 
Grade 1
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 1.
Dose MAY be 
reduced by 1 dose 
level -
investigator’s 
discretion.


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Table 4.1.4.2: 2 (cont.) Dose Adjustments and Delays for Toxicity Possibly Related to 
Abemaciclib*
Toxicity Type
Toxicity Profile and Severity
Dose Suspension
Dose Reduction
Diarrhoea
  
Requires hospitalization or 
Grade 3 or 4
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
Diarrhoea
Grade 2 that persists or recurs 
after resuming the same dose 
despite maximal supportive 
measures 
Dose MUST be 
suspended until toxicity 
resolves to at least 
Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
Increased ALT
Persistent or Recurrent3 Grade 
2 (>3.0-5.0xULN), or Grade 3 
(>5.0-20.0xULN)4
Dose MUST be 
suspended until toxicity 
resolves to either 
baseline or Grade 1.
Dose MUST be 
reduced by 1 dose 
level.
Increased ALT with 
increased total bilirubin, 
in the absence of 
cholestasis
Grade 3 (>5.0xULN) with 
total bilirubin>2xULN
Abemaciclib MUST be 
discontinued
NA
Increased ALT
Grade 4 (>20.0xULN)
Abemaciclib MUST be 
discontinued
NA
*In case that the Toxicity Profile and Severity qualifies for DLT according to Section 5.3.7, dose suspension and 
dose reduction will be followed according to the DLT management instructions
1   Recurrent toxicity refers to the same event occurring within the next 8 weeks (as measured from the stop date 
of the preceding event). As a general guidance, based on the risk/benefit balance assessment per the investigator, 
for a patient who experiences a new episode of Grade 3 hematological toxicity after more than 8 weeks following 
the last episode of same Grade 3 hematological toxicity, the investigator may consider resuming the patient on 
the same drug dose should the patient satisfy the following conditions:
-
shows stable hematological counts (Grade ≤2) during that timeframe
-
has absence of any signs or risk of infection
-
is benefiting from study treatment
2 Additional guidance for renal monitoring is in Section 4.4.1
3 Determination of persistent events will be at the discretion of the investigator. Recurrent toxicity refers to the
same event occurring within the next 8 weeks (as measured from the stop date of the preceding event).
4 Grade 3 ALT increased is a trigger for additional assessments and possibly hepatic monitoring. See
Section 4.4.4 for additional guidance for hepatic monitoring
5 For Japan only: refer to local amendment in Japan for ILD guidance 
Abbreviation:  ASCO = American Society of Clinical Oncology.
Note:  MAY = per the investigator’s clinical judgment; MUST = mandatory.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
In this open-label trial, treatment allocation will not be concealed throughout the trial.
The trial will be handled in an open fashion by the Sponsor during the conduct, data cleaning 
and preparation for analysis. 


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4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated CRO. They will be 
packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
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 for anastrozole, 
letrozole and fulvestrant. For recommended storage conditions regarding abemaciclib and 
xentuzumab, please refer to the medication label. A temperature log must be maintained for 
documentation.
Abemaciclib will be supplied as capsules or tablets for oral administration. The capsules and 
tablets should be stored at room temperature according to the range provided on the product 
label and not opened, crushed, or dissolved. Investigators should instruct patients to store the 
capsules and tablets in the original package and in a location inaccessible to children. Clinical 
study materials will be labelled according to country regulatory requirements.
Xentuzumab is supplied as a liquid formulation at a concentration of 10 mg/mL in 20 mL 
single use vials, which contain 200 mg of xentuzumab per vial. All vials containing 
xentuzumab must be kept refrigerated according to the temperature range provided on the 
product label prior to dosage preparation. 
The vials should not be frozen or shaken and should be kept in the outer carton in order to 
protect from light. They should not be used beyond the expiration date.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately and product quarantined.
4.1.8
Drug accountability
The Investigator and/or Pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:
*
Approval of the trial protocol by the IRB / ethics committee and HA approval,
*
Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site,


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*
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 Form 1572 (USA specific requirement)
The Investigator and/or Pharmacist and/or investigational drug storage manager must maintain 
records of the product’s delivery to the trial site, the inventory at the site, the use by each 
patient, and the return to the sponsor or warehouse / drug distribution centre or alternative 
disposal of unused products. 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 investigational product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the Investigator / Pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
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 may be given for analgesic purposes, lytic 
lesions at risk of fracture or for other reasons (e.g. bronchial obstruction, skin lesions), provided 
that the total dose delivered is in a palliative range to non-target lesion according to institutional 
standards. Information on palliative radiotherapy will be captured in eCRF. It is at the 
investigator’s discretion to withhold the study treatment during palliative radiotherapy. The 
investigators should assess the signs/symptoms carefully to exclude the progressive disease 
prior to the administration of the palliative radiotherapy.
The acute use of bisphosphonates and denosumab for symptomatic treatment of bone 
metastases is permitted during the study, but chronic use for the prevention of bone metastases 
is prohibited. Bisphosphonate therapy for the treatment of osteoporosis, at the doses indicated 
under prescribing information, is permitted during the study. If bisphosphonate therapy is 
initiated after enrolment, the reason for its use must be clearly documented in the eCRF.


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All medications (other than study drug), including anaesthetic agents, vitamins, 
homeopathic/herbal remedies, nutritional supplements, and significant non-drug therapies 
(including physical therapy and blood transfusions) starting or changing after the patient signed 
informed consent must be listed on the concomitant medication page of eCRF including trade 
name, start and end dates, indication for use etc. as specified in the Flow Chart.
If patients receive parenteral nutrition during the trial, the components need not be specified in 
detail. It should just be indicated as “parenteral nutrition”. If a patient requires anaesthesia, it 
will be sufficient to indicate “anaesthesia” without specifying details.
In case of major surgery (as judged by the investigator), it is recommended to stop treatment 
with xentuzumab and/or abemaciclib around one week prior to the surgery, and to restart 
treatment after complete wound healing. If the patient can’t recover within 28 days since 
stopping study medication, patient should be removed from the study. Exception to this in 
patients who derive obvious clinical benefit according to the investigator’s judgement could be 
agreed upon discussion with the Sponsor’s Clinical Monitor.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
With the exceptions listed in the sections below, no other chemotherapy, experimental 
medications, other anticancer therapy, including but not limited to immunotherapy, hormonal 
cancer therapy, radiation, experimental medications, or surgery for cancer will be permitted 
while patients are on study treatment. Use of megestrol acetate as an appetite stimulant is not 
permitted.
Abemaciclib is extensively metabolized through oxidation by CYP3A.  In clinical drug 
interaction studies, coadministration of clarithromycin, a strong CYP3A inhibitor, increased 
exposure (AUC) to abemaciclib by 3.4 fold (Study JPBE) and coadministration of rifampin, a 
strong CYP3A inducer, decreased exposure to abemaciclib by 95% (Study JPBF). Therefore, 
grapefruit juice should be avoided and inducers and strong inhibitors of CYP3A should be 
substituted or avoided whenever possible (See Appendix 10.1). 
During PK assessments of abemaciclib, the concomitant use of inhibitors or inducers of 
CYP3A4 should be avoided whenever possible, i.e. during Run-In, course 1 and course 2 of 
cohort E and during course 1 and 2 of expansion cohorts D1, D2 and F.
Apart from those assessments, patients are recommended to avoid concomitant use of strong 
CYP3A inhibitors and use caution with coadministered moderate or weak CYP3A inhibitors.  
Patients who continue to take strong CYP3A inhibitors should reduce the abemaciclib dose.  In 
patients who are taking the starting dose of 150 mg twice daily, reduce the abemaciclib dose to 
100 mg twice daily or, specifically in the case of ketoconazole, the abemaciclib dose should 
be reduced to 50 mg twice daily. In patients who have had a dose reduction to 100 mg twice 
daily due to adverse reactions, further reduce the abemaciclib dose to 50 mg twice daily. If a 
patient taking abemaciclib discontinues a strong CYP3A inhibitor, increase the abemaciclib 


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dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the strong 
inhibitor. Please refer to current SmPC of Verzenio (abemaciclib).
In case it is unavoidable to treat a patient with a comedication that is a moderate to potent 
inducer or inhibitor of CYP3A4 dose adaptation of abemaciclib should be done as described 
above and according to the SmPC of Verzenio (abemaciclib). Furthermore, the patient should 
be closely monitored and precautions should be taken as described in the SmPC of Verzenio 
(abemaciclib).
Abemaciclib can be coadministered with drugs which are substrates of CYP enzymes.
Abemaciclib and/or its major metabolites inhibit the efflux transporters P-glycoprotein and 
breast cancer resistance protein and renal transporters organic cation transporter 2, multidrug 
and toxin extrusion protein 1 (MATE1), and MATE2-K at clinically relevant concentrations. 
Therefore, substrates of these transporters such as metformin and those with a narrow 
therapeutic index such as digoxin, dofetilide, or dabigatran should be substituted or avoided if 
possible.
Restrictions regarding concomitant treatment with fulvestrant, letrozole or anastrozole:  please 
refer to the most up to date labelling information of each product, as appropriate (i.e. depending 
on the treatment cohort). 
4.2.2.2
Restrictions on diet and life style
Patients have to show up in fasting condition at the site when blood draw for safety lab is 
required.
Grapefruit and/or Seville orange juices must be avoided during treatment with abemaciclib.
4.2.2.3
Restrictions regarding men and women of childbearing potential 
Women of childbearing potential must use the contraception methods described in the patient 
information per ICH M3 (R2) that result in a low failure rate of less than 1% per year when 
used consistently and correctly. A list of contraception methods meeting these criteria is 
provided in the patient information, and must be used from the screening period until 3 weeks 
following the last dose of abemaciclib and at least 6 months after the last dose of xentuzumab.
Men should not father a child during treatment with xentuzumab and for at least 70 days after 
the last dose of xentuzumab.
4.2.2.4
Supportive Care
Patients should receive full supportive care to maximize quality of life. Patients will receive 
supportive care based on the judgment of the treating physician. If it is unclear whether a 
therapy should be regarded as supportive care, the investigator should consult the BI clinical 
monitor. 


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Use of any supportive care therapy should be reported on the electronic case report form 
(eCRF).
4.2.2.5
Growth Factor Therapy
Growth factors may be administered in accordance with American Society of Clinical 
Oncology guidelines (Smith et al. 2006; Rizzo et al. 2008).
4.2.2.6
Therapy for Diarrhoea
At enrolment, patients should receive instructions on the management of diarrhoea.  In the 
event of diarrhoea, supportive measures should be initiated as early as possible.  These 
include the following:
*
At the first sign of loose stools, the patient should initiate anti-diarrheal therapy, if not 
already receiving such therapy (for example, loperamide), and notify the 
investigator/site for further instructions and appropriate follow-up.
*
Patients should also be encouraged to drink fluids (for example, 8 to 10 glasses of 
clear liquids per day).
*
Site personnel should assess response within 24 hours. 
*
If diarrhoea does not resolve with anti-diarrheal therapy within 24 hours to either 
baseline or Grade 1, study drug should be suspended until diarrhoea is resolved to 
baseline or Grade 1.
*
When study drug recommences, dosing should be adjusted, refer to the dose 
adjustment guidelines in Section 4.1.4.2.
In cases of significant diarrhoea, Grade 2 through 4 which has not responded to interventions 
as outlined above, if the investigators are considering the addition of steroids to treat potential 
colitis, the sponsor strongly recommends an endoscopic procedure to document colitis prior 
to initiating steroids.
In severe cases of diarrhoea, the measuring of neutrophil counts and body temperature and 
proactive management of diarrhoea with antidiarrheal agents should be considered.
If diarrhoea is severe (requiring IV rehydration) and/or associated with fever or severe 
neutropenia, broad-spectrum antibiotics such as fluoroquinolones must be prescribed.
Patients with severe diarrhoea or any grade of diarrhoea associated with severe nausea or 
vomiting should be carefully monitored and given intravenous fluid (IV hydration) and 
electrolyte replacement.
4.2.2.7
Ovarian suppression with gonadotropin-releasing hormone agonists 
Patients who are postmenopausal due to ovarian suppression should continue GnRH agonist 
therapy during study treatment.


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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 study drugs exactly as 
prescribed to promote compliance. 
A patient will be considered noncompliant if he or she is judged by the investigator to have 
intentionally or repeatedly taken more than 125% the prescribed amount of abemaciclib or less 
than 75%. Abemaciclib dose suspensions or delays related to toxicity may occur and will not 
result in a patient being considered as noncompliant. Same rules apply to background hormonal 
therapy.
Patients are requested to bring all remaining trial medication including empty package material 
with them when attending visits.
Based on counts, treatment compliance will be calculated as the number of doses taken, divided 
by the number of doses which should have been taken according to the scheduled period, 
multiplied by 100. Compliance will be verified by the on-site monitor authorised by the 
sponsor.
Treatment compliance (%) =
Number of doses actually taken 100
Number of doses which should have been taken
If the number of doses taken is not between 75-125%, site staff will explain the patient the 
importance of treatment compliance.
The investigator and/or the sponsor can withdraw a patient from the study in the event of 
serious and persistent non-compliance which jeopardizes the patient’s safety or render study 
results. 
Xentuzumab 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 is not administered to 
the patient, it must be documented and explained.
A maximum of three consecutive xentuzumab infusions may be skipped for the recovery from 
AEs. Missing xentuzumab treatment for any other reasons is considered non-compliant.  
Patient diary for cohort E
For the purpose of PK characterisation of abemaciclib, patients of cohort E will be dispensed 
a patient diary two times during the conduct of the study: at run-in visit 1 and again at Cycle 1 
visit 4. These patient diaries will collect information about daily intake of abemaciclib and 
potential vomiting events. The first patient diary will collect information during the 3 days 
prior to Run-In Visit 3. The second patient diary will collect information of the 3 days before 
Cycle 2 Visit 1. Site staff will be required to transfer the data from the patient diary into the 
corresponding eCRF fields.


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4.4
MANAGEMENT OF EXPECTED ADVERSE EVENTS.
4.4.1
Increased Serum Creatinine
Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular 
secretion of creatinine without affecting glomerular filtration rate (GFR [as measured by 
ioxhexol clearance]).  In clinical studies, increases in serum creatinine occurred within the first 
month of abemaciclib dosing (remainder elevated but stable through the treatment period), 
were reversible upon treatment discontinuation, and were not accompanied by changes in 
markers of renal function such as blood urea nitrogen, cystatin C, or calculated GFR based on 
cystatin C. 
Dose adjustment (omission, reduction, or discontinuation) should not solely be based on 
interpretation of serum creatinine values because these may not reflect renal function.  If 
deterioration of renal function is suspected per the investigator’s clinical assessment, dose 
alteration should follow the protocol guidance for non-hematological toxicities (Section 
4.1.4.2).
4.4.2
Management and grading of infusion reactions
The xentuzumab 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 infusion with xentuzumab 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 course, the observation period following xentuzumab infusion may 
be adjusted at the discretion of the investigators. Mild to moderate infusion reactions may be 
managed with a slower infusion rate and prophylactic antihistamines for subsequent dosing. 
Severe reactions require immediate and permanent discontinuation of infusion. The 
hypersensitivity reactions will be graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (R10-4848). 
The infusion duration may be extended to over one hour and up to a maximum of three hours.
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.
Infusion reactions will not be reported on the standard AE page but will be reported on a 
separate page specifically for infusion reactions in the CRF.


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Table 4.4.2: 1
Infusion reaction management
Infusion Reaction Grade
Management
CTCAE Grade 1 or 2
In the event of a CTCAE grade 1 infusion reaction, the infusion 
rate should be reduced by 50%. 
A Grade 2 infusion reaction may require symptomatic 
treatment, as described above (with infusion interruption). 
Once the event has resolved, the infusion may be restarted at 
the reduced rate.
CTCAE Grade 3
For patients experiencing a CTCAE grade 3 infusion reaction, 
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 hours since the infusion start. The 
infusion rate should be reduced by half after re-start
CTCAE Grade 4
Patients experiencing CTCAE grade 4 such as anaphylaxis 
during an infusion should have infusion immediately stopped 
and receive appropriate treatment, as described above, 
including use of resuscitation medications If needed. Such 
patients should NOT receive any further xentuzumab treatment.
4.4.3
Management of Neutropenia
Adverse events of neutropenia have been observed in studies with xentuzumab and causality 
has been established with abemaciclib. Patients should be monitored closely for signs of 
infection. Dose adjustment for severe neutropenia (≥ Grade 3) should follow as per Table 
4.1.4.2: 1 (xentuzumab) and Table 4.1.4.2: 2 (abemaciclib) in the protocol. Fever or infection 
in the presence of severe neutropenia should be managed promptly with broad-spectrum 
antibacterial therapy. 
4.4.4
Management of Hepatotoxicity 
Grade ≥3 increased ALT was reported in patients receiving abemaciclib in breast cancer 
studies. Monitor ALT, prior to the start of abemaciclib therapy, every 2 weeks for the first 2 
months, monthly for the next 2 months, and as clinically indicated. Please refer to Flow Chart
for time points. Based on the level of ALT elevations, abemaciclib may require dose 
modification. (see Table 4.1.4.2:2).
In addition, for hepatic toxicity, additional monitoring should be considered.  Details for 
hepatic monitoring depend upon the severity and persistence of observed laboratory test 
abnormalities. If the abnormality persists or worsens, clinical and laboratory monitoring should 
be initiated by the investigator, based on the hepatic monitoring tests (see Section 10.5) and in 
consultation with the Sponsor. Monitoring of ALT, AST, and total bilirubin should continue 
until levels normalize or return to approximate baseline levels. Additional diagnostic testing 
should be considered to rule out cause of increased liver enzymes per the investigator’s 
discretion. 


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4.4.5
Venous Thromboembolism
Venous thromboembolic events were reported in patients receiving abemaciclib plus 
fulvestrant or aromatase inhibitors in breast cancer studies. The majority of the events were 
non-serious and were treated with low-molecular-weight heparin. Generally, these events did 
not result in discontinuation of the study treatment. At this time, the mechanism underlying the 
association between abemaciclib and the occurrence of VTEs is not known. Monitor patients 
for signs and symptoms of deep vein thrombosis and pulmonary embolism and treat as 
medically appropriate.
4.4.6
Guidance for Interstitial lung disease/Pneumonitis
ILD/pneumonitis has been identified as an adverse drug reaction for abemaciclib. Additional 
information is available in the IB of abemaciclib.
Ask your patients to report any new or worsening respiratory symptoms such as cough, 
dyspnea, fever, and investigate and treat as per your local clinical practice (including 
corticosteroids as appropriate). If ILD/pneumonitis is suspected, investigations may include 
imaging such as high resolution computed tomography (HRCT), broncheoalveolar lavage, and 
biopsy as clinically indicated. Refer to Table 4.1.4.2:2 for guidance on dose adjustments of 
abemaciclib for patients with ILD/pneumonitis. Discontinue abemaciclib in cases of severe 
ILD/pneumonitis.


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5. VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint(s)
For dose finding cohorts A, B, C, and D (dose finding):
The primary endpoints for each dose finding cohort are the MTD and the number of patients 
with dose limiting toxicities (DLT) in the MTD evaluation period. 
The MTD evaluation period is defined as the first treatment cycle (28 days). The MTD is 
defined as the highest dose with less than 25% risk of the true DLT rate being above 33%. For 
definition of DLTs, refer to Section 5.3.7
A Bayesian Logistic Regression Model (BLRM) employing the escalation with overdose 
control (EWOC) principle will be used during each dose finding cohort for a selection of doses 
to investigate and for estimation of the MTD. Cohorts of patients will receive xentuzumab and 
abemaciclib (with or without endocrine therapy) until the MTD is reached or until the Steering 
Committee (SC) decides on stopping the dose finding. Each dose-level cohort will consist of 
newly enrolled patients. Estimation of the MTD during each dose finding cohort of the study 
will be based upon the estimation of the probability of a DLT in the MTD evaluation period in 
the set of evaluable patients for MTD. The corresponding methodology is described in Section 
7.
The MTD estimate established during the dose finding cohort will be re-investigated after the 
corresponding expansion cohort by re-running the BLRM including all data from dose finding 
cohort and expansion cohort, in particular also considering the DLT information from all 
treatment cycles.
For expansion cohort E
The primary endpoint for expansion part is objective response (OR) defined as best overall 
response of complete response (CR) or partial response (PR), where best overall response is 
determined according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 
from date of first treatment administration (including run-in for cohort E) until the earliest of 
disease progression, death or last evaluable tumour assessment before start of subsequent anti-
cancer therapy.
For expansion cohorts D1 and D2:
The primary endpoint for expansion part is PFS rate at 18 month defined as the rate of absence 
of disease progression or death at 18th month, where progression is determined according to 
Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1.
For expansion cohort F
The primary endpoint for expansion part is disease control (DC) defined as best overall 
response of complete response (CR) or partial response (PR) or confirmed stable disease (SD) 
(lasting for at least 24 weeks) or Non-CR/ Non-PD (lasting for at least 24 weeks) where best 


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overall response is defined according to RECIST version 1.1 from first treatment 
administration until the earliest of disease progression, death or last evaluable tumour 
assessment before start of subsequent anti-cancer therapy.
5.1.2
Secondary Endpoint(s)
For dose finding cohorts A, B, C, and D (dose finding)
There are no secondary endpoints.
For expansion cohorts E, F, D1 and D2:
The secondary endpoints are:
*
Cohorts D1, D2 and E only: Disease control (DC) defined as best overall response of 
complete response (CR) or partial response (PR) or confirmed stable disease (SD) (. 
lasting for at least 24 weeks) where best overall response is defined according to 
RECIST version 1.1 from first treatment administration until the earliest of disease 
progression, death or last evaluable tumour assessment before start of subsequent anti-
cancer therapy.
*
Time to objective response defined as the time from first treatment administration 
until first documented complete response (CR) or partial response (PR).
*
Duration of objective response defined as the time from first documented complete 
response (CR) or partial response (PR) until the earliest of disease progression or 
death among patients with objective response.
*
Duration of disease control defined as the time from first treatment administration 
until the earliest of disease progression or death, among patients with disease control.
*
Progression-free survival (PFS) defined as the time from first treatment administration 
until tumour progression according to RECIST 1.1 or death from any cause, 
whichever occurs earlier.
*
Cohorts D1, D2 and F only: Objective response (OR) defined as best overall response 
of complete response (CR) or partial response (PR), where best overall response is 
determined according to Response Evaluation Criteria In Solid Tumours (RECIST) 
version 1.1 from date of first treatment administration until the earliest of disease 
progression, death or last evaluable tumour assessment before start of subsequent anti-
cancer therapy.


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5.2
ASSESSMENT OF EFFICACY
Response Evaluation Criteria in Solid Tumours (RECIST) guideline (version 1.1) (R09-0262) 
will be applied as the primary measure for assessment of tumour response, date of disease 
progression, and as a basis for all protocol guidelines related to disease status (e.g. 
discontinuation of study therapy). See Appendix 10.4 for details on lesion measurements and 
response assessment according to RECIST 1.1.
Tumour response will be assessed by Investigator review throughout the study and clinical 
decisions will be based on Investigator assessment.
Imaging will be performed as indicated in the Flow Chart and in Appendix 10.4.
Tumour assessment will be assessed per institutional practice. Only the overall response 
will be collected in the eCRF.
5.3
ASSESSMENT OF SAFETY
5.3.1
Physical examination
A physical examination will be performed at the time points specified in the Flow Chart. A full 
physical exam must include cardiopulmonary examination, examination of the regional lymph 
nodes, and examination of the abdomen and an assessment of the mental and neurological 
status. Additional symptoms which have not been reported during a previous examination must 
be clarified. Wherever possible the same investigator should perform this examination.
When xentuzumab is discontinued, physical examination assessments can be done as per 
institutional practice.
5.3.2
Vital Signs
Vital sign measurements (blood pressure [systolic blood pressure, diastolic blood pressure], 
pulse rate, respiratory rate, temperature and measurement of height (at screening) and body 
weight and the evaluation of the ECOG performance status will be performed at the times 
specified in the Flow Chart and Schedule of Procedures/Assessments (Section 6.2). Blood 
pressure and pulse will be measured after the patient has been recumbent or seated for 5 
minutes.
When xentuzumab is discontinued, vital signs assessments can be done as per 
institutional practice.


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5.3.3
Safety laboratory parameters
Blood samples, including fasting serum samples (fasting state for at least 8 hours) and the 
fasting lipid profile, can be collected up to one day prior to the scheduled time points as 
specified in the Flow Chart and analysed in a laboratory facility at (or close to) the 
investigational site. Safety laboratory examinations include haematology, coagulation, 
biochemistry and urine examination. See Table 5.3.3: 1 for details. In case of abnormal findings 
such as neutropenia or thrombocytopenia, further test may be done if clinically indicated at the 
discretion of the investigator. All analyses are to be performed by the local clinical laboratory.  
Unscheduled safety laboratory examinations will be documented in the eCRF along with the 
results. 
Safety laboratory assessment may be performed according to local practice but must include at 
least all of the following parameters:
Table 5.3.3: 1 Clinical laboratory tests
Category
Parameters
Haematology
Red 
blood 
cell 
count 
(RBC), 
haemoglobin,
haematocrit, platelet count, white blood cell count 
(WBC) with differential (neutrophils1, lymphocytes, 
monocytes, eosinophils, basophils)
Coagulation 
International Normalized Ratio (INR), activated Partial 
Thromboplastin Time (aPTT)
Chemistry
Blood urea or blood urea nitrogen (BUN), creatinine, 
cystatin-C (day 1 of every cycle), alkaline phosphatase 
(AP), aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), γ-glutamyltransferase 
(GGT), bilirubin (total and direct), total protein, 
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
Pregnancy TEST
Electrolytes
Serum (for women of childbearing potential only)
Sodium, potassium, calcium, magnesium
Lipid profile (fasting)
Total cholesterol, triglycerides, LDL, HDL
Other (fasting)
Glucose,  HbA1C and C-peptide
Urinalysis (only at screening and EOTV)
pH, protein, glucose, erythrocytes, leucocytes, ketones 
and nitrite will be analysed by dipstick (semi-
quantitative measurements: -, +, ++, +++); in case of 
pathological finding further evaluation should be 
performed and results documented


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Table 5.3.3: 1 Clinical laboratory tests (cont.)
Category
Parameters
Post-menopausal status (at screening 
only for women <60 years old without 
prior bilateral oophorectomy)
   FSH, estradiol
1 Neutrophils reported by automated differential hematology instruments include both segmented and 
band forms. When a manual differential is needed to report the neutrophils, the segmented and band 
forms should be reported together
When xentuzumab is discontinued, safety labs can be done as per institutional practice.
5.3.4
Electrocardiogram
As per ICH E 14 large targeted proteins and monoclonal antibodies have a low likelihood of 
direct ion channel interactions and a thorough QT/QTc study is not necessary, unless the 
potential for proarrhythmic risk is suggested by mechanistic considerations or data from 
clinical or non-clinical studies, which is not the case for xentuzumab.
Therefore, only local reading of ECG will be conducted in this trial. 12-Lead resting 
electrocardiograms (ECG) are recorded locally and in triplicate. ECG will be performed at 
Screening, at Run in visit 2 Day -2 (in cohorts E and F), at EOTV and FUV.  ECG will be 
repeated at Visit 1/Day 1, and Visit 3/Day 15 of Courses 1, 2, 3; and at Visit 1/Day 1 of Courses 
6, 9, 12, etc. ECG should be performed prior to xentuzumab infusion. 
When xentuzumab is discontinued, ECGs can be omitted.
5.3.5
Other safety parameters
Not applicable.
5.3.6
Assessment of adverse events
Safety assessments will consist of monitoring and recording all adverse events (AEs) and 
serious adverse events (SAEs) and includes periodic physical examinations, measurement of 
vital signs, assessment of performance status, monitoring of laboratory tests (i.e. haematology, 
chemistry, coagulation, urine, etc.)
5.3.6.1
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.


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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.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-label 
use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this 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 

prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
The following hospitalizations are not considered to be serious adverse events (SAEs) 
because there is no “adverse event” (i.e., there is no untoward medical occurrence) associated 
with the hospitalization:

Hospitalizations for respite care 

Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post study drug administration)

Hospitalization for administration of study drug or PK assessment
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
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. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.


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For Japan only: the following events will be handled as “deemed serious for any other reason”. 
An AE which possibly leads to disability will be reported as an SAE.
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be reported as a serious event regardless 
of the duration between discontinuation of the drug and the occurrence of the cancer.
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 given 
above.
The latest list of “Always Serious AEs” can be found in the EDC system. 
These events should always be reported as SAEs as described above.
Adverse events of special interest (AESI)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs: 
Hepatic injury is defined by the following alterations of hepatic laboratory parameters:
For patients with normal liver function (ALT, AST, and bilirubin within normal limits) at 
baseline, an elevation of AST and/or ALT ≥ 3 fold ULN combined with an elevation of total 
bilirubin ≥ 2 fold ULN measured in the same blood draw sample, and/or marked peak 
aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN.
For patients with abnormal liver function tests at baseline (AST and/or ALT > ULN), an 
elevation of transaminase ≥ (baseline + 4x ULN) combined with an elevation of total 
bilirubin ≥ 2 fold ULN measured in the same blood draw sample, with the exclusion of the 
causes due to underlying diseases.  Patients with abnormal liver function tests must have 
their abnormalities and the etiology documented in detail as baseline conditions. Every 
effort should be made to explain possible deteriorations of baseline conditions.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the "DILI checklist" provided in the ISF.
In case of clinical symptoms of 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.
DLT occurs in the dose finding cohorts. Please refer to Section 5.3.7 for definition of DLTs.


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Cases of pneumonitis (including interstitial lung disease, non-infectious pneumonitis and 
other analogous terms) occurring at any cycle in both phases.
Intensity of AEs
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 in the eCRF.
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship could 
be:
•
The event is consistent with the known pharmacology of the drug. 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced.
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
•
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).
•
Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
•
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•
Disappearance of the event even though the study drug treatment continues or remains 
unchanged.


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5.3.6.2
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
Investigator:
•
From signing the informed consent onwards until the end of treatment (including the 
Residual Effect Period, REP): 
- All AEs (non-serious and serious) and all AESIs.
•
After the end of treatment (including the REP) until the individual patient’s end of trial: 
- All related SAEs and all related AESIs.
•
After the individual patient’s end of the trial: 
The Investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the Investigator may become aware of. 
The rules for Adverse Event Reporting exemptions still apply. 
Figure 5.3.6.2: 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 (which includes the run-in period) and throughout the 
REP will be considered as on treatment; please see Section 7.3.4. Events which occurred after 
the REP will be considered as post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
For Japan only: all SAEs must be reported immediately to the head of the trial site.


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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. The Investigator should determine the causal relationship to the 
trial medication and any possible interactions between the investigational drug(s) and a Non-
Investigational Medicinal Product (NIMP) / Auxiliary Medicinal Product (AMP)
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions (see Section 
5.3.6.3 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 trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information can 
be obtained.
Pregnancy
In rare cases pregnancy or pregnancy in a female partner of a male participant may occur in a 
clinical trial. Once a patient has been enrolled into this clinical trial and has taken trial 
medication, the Investigator must report immediately (within 24 hours) a potential drug 
exposure during pregnancy (DEDP) including drug exposure to female partners of male 
participants to the sponsor’s unique entry point (country-specific contact details will be 
provided in the ISF). The Pregnancy Monitoring Form for Clinical Trials (Part A) should be 
used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is 
to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE form 
must be completed in addition.
5.3.6.3
Exemption to (S)AE Reporting
Exempted outcome events are:
Disease progression
Malignant neoplasm progression
Neoplasm progression


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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 (e)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 (e)CRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the study drug(s) 
and the progression of the underlying malignancy, the event must be reported as an SAE on 
the SAE Form and on the (e)CRF.
Examples of exempted events of PD may be:
• Progression of underlying malignancy (Progressive disease [PD]): if PD is clearly consistent 
with the suspected progression of the underlying malignancy as defined by the respective 
response criteria. 
• Hospitalization/Procedures due solely to the progression of underlying malignancy (PD)
• Clinical symptoms and/or signs of progression (without confirmation by objective criteria 
e.g. imaging, clinical measurement): if the symptom can exclusively be determined to be due 
to the progression of the underlying malignancy and does meet the expected pattern of 
progression for the disease under study. 
Exempted events are collected and tracked following a protocol-specified monitoring plan. 
Exempted events will be monitored at appropriate intervals by the Steering Committee.
5.3.7
Dose Limiting Toxicities (DLTs)
A dose limiting toxicity (DLT) in this study is defined as an adverse event or laboratory 
abnormality which 1) is considered related, probably related or possibly related to study drug 
and 2) meets any of the following criteria, unless that toxicity can be clearly attributed to cancer 
progression or to another clearly identified etiology:

CTCAE Grade 3 hyperglycaemia lasting > 48 hours

CTCAE Grade 4 hyperglycaemia

CTCAE Grade ≥ 3 pneumonitis

CTCAE Grade ≥ 3 febrile neutropenia 

CTCAE Grade 4 hematologic toxicity lasting longer than 5 days

CTCAE Grade 4 thrombocytopenia of any duration and Grade 3 thrombocytopenia 
associated with bleeding

AST or ALT > 5x ULN (for baseline AST/ALT ≤ ULN) or > (baseline value + 4x ULN) 
(for baseline AST/ALT > ULN)

CTCAE Grade ≥ 3 diarrhoea, nausea, or vomiting lasting more than 2 days despite maximal
supportive care

CTCAE Grade ≥ 3 skin rash despite adequate supportive care measures 

CTCAE Grade ≥ 3 fatigue/asthenia lasting for more than seven days

Grades 3 to 4 hyperlipidaemia (total cholesterol > 400 mg/dL or triglycerides > 500 mg/dL) 
not improving despite appropriate treatment for 2 weeks


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
Any AE necessitating a 2-week treatment interruption (except for hematologic AEs)

All other non-hematologic toxicities of CTCAE Grade ≥ 3 (except alopecia, infusion-
related reaction and those mentioned above)

Any other study drug related toxicity considered significant enough to be qualified as DLT 
in the opinion of the investigators, and confirmed by the safety review with the BI clinical 
monitor and BI project physician (TMM), will be reported as a DLT
For the purposes of dose finding, only DLT events that occur during the first treatment period 
of 28 days will be considered. Decisions regarding dose escalation/de-escalation steps will be 
made only after discussion between the sponsor and the investigators, and in consideration of 
all the available safety information. Available data of DLTs occurring after first treatment 
course and all unusual/unexpected AE at any time during treatment will be considered for the 
purpose of recommending the dose for cohorts B, C, D (dose finding), E, F, D1 and D2. 
All DLT events that meet AESI criteria need to be reported immediately to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.3.6.2, and documented in the eCRF. 
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
As of 22 Oct 2021, samples for PK are no longer collected for ongoing patients.
PK samples will be collected from all patients in this trial at the time points specified in the 
Flow Chart and in Appendix 10.2
(minimal deviations in the time scheduled will not be 
considered as protocol violation). The actual sampling date and time for blood samples will be 
reported in the eCRF and will be used for determination of PK parameters. To allow a valid 
PK analysis, it is of utmost importance to document the exact clock time of trial medication 
administration and blood sample collection. Any occurrence of vomiting should be 
documented as well. The duration of the xentuzumab infusion will be reported with a start and 
end time in the eCRF. Every attempt should be made to adhere to an infusion time of 
approximately 1 h for xentuzumab with a constant infusion rate.
At days of PK sampling of abemaciclib (cohorts E, F, D1 and D2) patients should be instructed 
to take their morning dose of abemaciclib in the hospital (and not at home as usual). This is 
necessary in order to allow for a valid PK sampling schedule. For details of the PK sampling 
schedule, please refer to Appendix 10.2.
PK parameters will be evaluated according to Section 5.1.3. Non-compartmental PK analysis 
will be done in order to calculate PK parameters (Section 5.1.3) using Phoenix WinNonlin (or 
other validated software) according to BI SOP 001-MCS-36-472 (current version).


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5.4.2
Methods of sample collection
As of 22 Oct 2021, samples for PK and ADA are no longer collected for ongoing 
patients.
Blood samples should be obtained from the arm opposite to the arm used for infusion. In case 
a central venous access is used for infusion, the blood sample can be collected from either 
forearm. The actual sampling date and time (24-hour clock time) 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 in the 
respective cohorts and courses is shown in Appendix 10.2. For details on blood volumes to be 
collected, sample handling and logistics refer to the ISF (Laboratory Manual).  
For quantification of plasma concentrations of abemaciclib and relevant metabolites, blood 
samples will be taken at the time points listed in the Flow Chart under PK sampling. A detailed 
sampling schedule in the respective cohorts and courses is shown in Appendix 10.2. For details 
on blood volumes, sample handling and logistics refer to the ISF (Laboratory Manual).
For quantification of fulvestrant plasma concentrations, blood samples will be taken at the time 
points listed in the Flow Chart under PK sampling. A detailed sampling schedule in the 
respective cohorts and courses is shown in Appendix 10.2. For details on blood volumes, 
sample handling and logistics refer to the ISF (Laboratory Manual).
For ADA assessment, blood will be taken at the time points listed in the Flow Chart under 
ADA sampling. The exact timing of ADA sampling before, during and beyond the treatment 
phase is also shown in Appendix 10.2. For details on blood volumes, sample handling and 
logistics refer to the ISF (Laboratory Manual).  
Plasma samples from the study may be used for further methodological investigations, e.g., 
stability testing.  However, only data related to the analyte and/or bioanalytical assay will be 
generated by these additional investigations. Both PK and ADA 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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5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
No formal analysis of a pharmacokinetic/pharmacodynamic relationship is planned.
Correlation between drug concentration and any type of response may be made if appropriate.
Data may also be used to develop pharmacokinetic/pharmacodynamic models using nonlinear 
mixed effect modelling techniques, if feasible. For this purpose data may also be combined 
with those from other trials. Modelling activities will be planned and documented separately.
5.5
ASSESSMENT OF BIOMARKER(S) 
As of 22 Oct 2021, samples for biomarkers are no longer collected for ongoing 
patients.
In this clinical study explorative biomarkers will be measured and analysed. These analyses 
are hypothesis generating and will be used to expand our understanding of the study drug and 
the disease. Participation in the biomarker analyses is mandatory for patients from all cohorts. 
Evaluation of molecular and biochemical biomarkers in tumour tissue:
Tumour tissue samples will be collected from all patients (except when there is no tumour 
tissue sample available) to explore the potential influence of molecular and biochemical 
alterations within the tumour on treatment response and outcome. No biopsies should be done 
for the only purpose of obtaining tumour tissue for this trial. Tumour tissue samples will be 
analysed for:

Mutations and copy number alterations in genes related to the study drugs and involved 
in tumourigenesis, such as genes of the IGF, PI3K/mTOR, Ras/MAPK, Rb and related 
signalling pathways (e.g. IGF1R, PIK3CA, PTEN, KRAS, MYC, CCND1, CDK4, 
CDK6, RB1 and CDKN2A)

RNA expression of IGF, PI3K/mTOR, Ras/MAPK and cell cycle-related signalling 
pathways (e.g. IGF1, IGF2, IGFBP-family genes, MYC, CCND1, CDK4, CDK6)

Expression of Rb and p16 proteins via biochemical methods (e.g. IHC). According to 
additional knowledge gained from other studies with xentuzumab and/or abemaciclib
broader 
analysis 
of 
the 
samples 
(including 
immunohistochemistry/in-situ 
hybridization/sequencing of e.g. IGF-1/2, PTEN, pAKT, pS6, Ki67) might be 
conducted to e.g. address predictive biomarkers, exceptional response or resistance 
mechanisms.
Individual analyses from tumour tissue will be prioritized based on availability of sufficient 
tissue material.
Molecular evaluation in blood:
Three kinds of blood samples will be collected for genomic analyses from blood and plasma.
One blood sample will be used to isolate genomic DNA, which will be used as a reference 
(normal tissue) to distinguish tumour acquired somatic mutations and will be analysed for the 
indicated panel of genes as in the tumour tissue and/or in the cfDNA (see above).


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Secondly, blood samples will be collected and used to isolate circulating nucleic acids such as 
e.g. cfDNA from plasma. Subsequent analyses of plasma cfDNA may be used for example to 
detect somatic mutations in cancer genes, e.g. IGF pathway-related and known cancer driver 
genes. Additionally, changes in nucleic acid concentration over course of treatment may be 
explored. Analysis of cfDNA 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).
Thirdly, blood samples will be collected and used to evaluate exosomal RNA from plasma. 
Subsequent analyses of plasma exosomal RNA using standard molecular technology will 
include, but not be limited to, cell cycle and proliferation related genes, e.g. CCND1, Ki67, 
RB1, CDK4, CDK6 and CDKN2A.
Methods of sample collection
Formalin fixed paraffin embedded (FFPE) tumour tissue, preferably FFPE blocks, from the 
most recent time point before entering the study will be collected during screening or at a later 
timepoint (see Flow Chart, Table 5.5: 1 and Table 5.5: 2 and Appendix 10.3). The FFPE blocks 
will be used to prepare 25 slides at 5µm thickness. Alternatively, 25 freshly prepared slides at 
5µm thickness from FFPE block can be provided but need to be prepared under RNase-free 
conditions. Isolated nucleic acids (e.g. DNA and RNA) from the tumour tissue will be analysed 
for genomic alterations such as somatic mutations and copy number alterations as well as RNA 
expression levels as described above.
In addition, patients will be asked for three kinds of blood samples:
One blood sample will be collected at C1V1 before treatment (see Flow Chart and Table 5.5: 
1 and Table 5.5: 2). The isolated DNA will be analysed for genomic alterations in a panel of 
cancer -related genes as mentioned for the tissue and/or the cfDNA above serving as a reference 
to allow distinction of tumour-acquired somatic mutations from normal tissue.
For analysis of circulating nucleic acids, blood samples will be collected in plasma preparation 
tubes at each indicated time point before treatment (Run-in and/or C1V1), at C3V1 and at 
EOTV (see Flow Chart and Table 5.5: 1 and Table 5.5: 2). The samples will be used to isolate 
and analyse circulating nucleic acids as described above.
For exosomal RNA analyses, blood samples will be collected in EDTA tubes at each indicated 
time point before treatment is administered to patient (where applicable): At Run-in and/or 
C1V1, at C1V3 (Day 15), at C2V1, at C3V1, at C4V1 onwards and at the EOTV, (see Flow 
Chart and Table 5.5: 1 and Table 5.5: 2). Separation of the plasma from the remaining blood 
should be performed. The samples will be used to isolate circulating exosomes and analyse 
exosomal components such as e.g. RNA.


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Table 5.5: 1 Overview PGx sample collection timepoints for cohorts A-D (dose finding) and 
expansion cohorts D1, D2 and F.
Sample
Timepoints
Screening
C1V1
C1V3
C2V1
C3V1
C4V1 
onwards1
EOT
Archival 
tumour tissue
X
PGx 
blood 
(gDNA)
X
PGx Plasma 
(cfDNA)
X
X
X
PGx Plasma 
(Exosomes)
X
X
X
X
X
X
DNA 
banking
X
1 Refer to the central laboratory manual instructions.
Table 5.5: 2 Overview PGx sample collection timepoints for cohort E 
Sample
Timepoints
Screening
Run-
in V1
C1V1
C1V3
C2V1
C3V1
C4V1 
onwards1
EOT
Archival 
tumour tissue
X
PGx 
blood 
(gDNA)
X
PGx Plasma 
(cfDNA)
X
X
X
X
PGx Plasma 
(Exosomes)
X
X
X
X
X
X
X
DNA 
banking
X
1 Refer to the central laboratory manual instructions.
Remaining samples from pharmacogenomic analyses such as tumour tissue, blood or plasma 
samples (and isolated DNA and RNA) will be destroyed no later than 1 year after the end of 
the trial if no optional consent for sample biobanking is obtained from the patient (see Section 
5.5.1).


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Detailed instructions for pharmacogenomic sampling, handling and shipment of samples will 
be provided in the lab manual.
The biomarker analyses will be performed by Boehringer Ingelheim or a central laboratory 
authorized by Boehringer Ingelheim.
Protein biomarkers from blood:
The following protein biomarkers are planned to be examined in this trial:

Free and total IGF-1 in serum (and optionally free and total IGF-2, dissociable IGF-1 
and IGF-2, and total IGFBP-3)

Phosphorylated and total IGF-1R protein in platelet-rich plasma 
Serial collection of blood samples for the assessment of these markers is mandatory. As 
medical knowledge in this field is constantly evolving, other tissue/blood biomarkers that come 
to be known as potentially relevant prognostic/predictive markers of treatment response may 
also be explored via available tissues/blood or acquisition of additional tumour tissues/blood. 
Biomarkers that come to be known or emerge as not relevant during the study may be 
discontinued.
All samples must be adequately labelled by the study site personnel. Details about blood sample 
collection, plasma/serum preparation, required tubes, labelling of tubes, storage and shipment 
(frequency and addresses)
will be provided in the ISF (laboratory manual).
Biomarker assessments in blood samples
Levels of free and total IGF-1 (optionally IGF-2 and the amount of IGFBP-3) 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 defined as the fraction of total IGF-1 (and total 
IGF-2) that can be bound by xentuzumab under modified, i.e. more highly diluted in vitro 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. Optionally, total 
IGFBP-3 will be relatively quantified in serum using a validated immunoassay.
For quantification of free and total IGF-1 (and optionally free and total IGF-2 and IGFBP-3), 
blood will be taken from a forearm vein at those time points specified in the Flow Chart and 
Appendix 10.2.
Quantification of IGF-2 and IGFBP-3 will be performed if scientifically justified based on 
results of ongoing clinical studies with xentuzumab (e.g. 1280.4).
Biomarkers in platelet-rich plasma
In platelet rich plasma, the level of phosphorylated and total IGF-1R will be analysed via 
immunoassay as an exploratory target engagement biomarker. Based on insights from earlier 
clinical trials with xentuzumab or abemaciclib, the analysis of other proteins involved in IGF, 
insulin and/or cyclin-dependent kinase mediated signalling might be added.


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For this purpose, blood samples will be taken from a forearm vein at screening and at those 
time points specified in the Flow Chart and in Appendix 10.2.
All analyses will be performed at Boehringer Ingelheim or a CRO with given authorization by 
BI.
Remaining samples from protein biomarker analyses such as tumour tissue and blood samples 
will be destroyed no later than 5 years after the end of the trial if no optional consent for sample 
biobanking is obtained from the patient (see Section 5.5.1).
5.5.1
Biobanking
If permission for biobanking is obtained from the patient via an optional informed consent, any 
leftover samples from the study might be stored at Boehringer Ingelheim or contract research 
organization for up to 30 years unless specified otherwise in the protocol.
These samples may be used to further address scientific questions as new information in regard 
to the disease or the study drug becomes available.
5.5.1.1
DNA Banking
One blood sample will be used for DNA Banking if participation and the separate informed 
consent is agreed upon by the patient as noted below. The DNA Banking sample, derived from 
the original blood sample, will be stored at the sponsor. The stored DNA may retrospectively 
be analysed, e.g. to identify whether there are other genetic factors that could contribute to a 
better therapeutic outcome or a higher risk of developing treatment-related adverse drug 
reactions.
Note: Participation in the DNA Banking sampling is voluntary and not a prerequisite for 
participation in the trial. The DNA Banking sample will be stored for up to 30 years after 
separate informed consent is given in accordance with local ethical and regulatory 
requirements.
A blood sample for DNA banking will be collected in a PAXgene Blood DNA tube preferably 
at C1V1 or at Run-in Visit 1 for cohorts with Run-in period (or at a later time) (see Flow Chart
and Table 5.5: 1 and Table 5.5: 2) for those patients who signed a separate PGx informed 
consent for DNA Banking.
5.6
OTHER ASSESSMENTS
The following patient demographic, baseline characteristics and medical history will be
collected on the eCRF:
1. General demography including sex, birth date and race as allowed by local law, 
information on smoking and alcohol history. Collection of race and/or ethnic information 
is necessary in this study because this is a multi-national trial and race and/or ethnicity are 
known to be associated with biology and outcome of breast cancer and NSCLC. Foreign 
regulatory agencies may request data or analysis based on race/ethnic information.
2. Medical history/current medical conditions (including history of menopause, prior and 
concomitant medications and concomitant diagnosis)


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3. History and current disease status including date of first histological diagnosis (month and 
year may be sufficient), type of tumour histology, tumour grade, other diagnosis 
information such as mutations or receptors overexpression, known tumour genetic 
alterations, TNM staging, number and locations of metastatic sites (bone, liver, lung, 
peritoneum, brain, other) at the study entry
4. Previous anticancer treatments: previous surgery, hormonotherapy, chemo-, targeted, or 
radiation therapy will be reported including setting (neoadjuvant vs. adjuvant vs. 
therapeutic), start and end dates (month and year may be sufficient), the therapy protocol 
with the number of courses (chemotherapy), total radiation dose and radiation field 
(radiotherapy), the best response obtained (complete response, partial response, stable 
disease/non-CR/non-PD, progressive disease, unknown) and reason for treatment 
discontinuation
5.6.1
Assessment of Immunogenicity
As of 22 Oct 2021, samples for immunogenicity are no longer collected for ongoing 
patients.
For the determination of anti-drug antibodies (ADA) against xentuzumab, blood samples will 
be taken from a forearm vein in an EDTA anticoagulant blood drawing tube at time points 
specified in the Flow Chart and in Appendix 10.2. Details about blood sample collection, 
EDTA plasma preparation, storage and shipment will be provided in a laboratory manual.
A qualitative screening for anti-drug antibodies against xentuzumab in the plasma samples will 
be performed using a validated immunoassay with xentuzumab as capture reagent. The assay 
enables the sensitive detection of various types of anti-xentuzumab immunoglobulins. ADA 
samples will be analysed in a multi-tiered approach (Screening, confirmatory and Titration) 
where screening positive samples will be confirmed and the confirmed positive samples will 
be tested in titration.
To further characterize the immune response of the ADA, additional analysis may be conducted 
after the completion of this study. The results will be reported separately. For this purpose 
samples will be stored beyond end of study for a maximum period of 5 years or until 
termination of the development project, whichever occurs first.
A detailed description of the assay will be available prior to the start of sample analysis.
5.7
APPROPRIATENESS OF MEASUREMENTS
The RECIST criteria version 1.1 (Appendix 10.4) to be used for evaluation of tumour response 
are well established and scientifically accepted. The Common Terminology Criteria, CTCAE 
version 4.03, 14 June 2010 are used in the assessment of adverse events in cancer patients. 
All measurements performed during this trial will be to monitor safety and tolerability of 
xentuzumab in combination with abemaciclib, with or without hormonal therapy, to determine 
the MTD and /or recommended phase II doses of these combinations.


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The scheduled assessments are to monitor drug induced changes in respect to vital signs, 
standard laboratory values and ECG. Tumour evaluations are necessary for determination of 
tumour response to treatment and possible PD effects. Pharmacokinetic analysis and biomarker 
analysis are necessary for correlation with therapeutic outcome. Immunogenicity testing will 
ensure the detection of any anti-drug antibody reactions as a result of the infusion of 
xentuzumab.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients must provide written informed consent (ICF) before any study related screening 
procedures can be performed.  Allowable time windows for visits are included in the Flow 
Chart.
Investigational drugs xentuzumab and abemaciclib will be dispensed at each visit according to 
the Flow Chart. This also applies to letrozole, anastrozole and fulvestrant in the corresponding 
cohorts (B, C, D (dose finding), F, D1 and D2) 
Patients will receive a new medication kit number through the IRT system on each occasion 
for medications supplied by the sponsor.
All screening assessment including tumour assessments must be completed within 28 days of 
start of run-in/C1V1. However, upon clinical assessment, if a patient presents with clinical 
symptoms of progressive disease, the investigator may use clinical judgement to determine 
whether to have the patient undergo another scan prior to starting treatment. Tumour 
assessments required for study participation which are completed as part of Standard of Care 
before the patient sign the ICF can be used for the screening assessments if they are completed 
within the allowed timeframe.
All patients are to adhere to the visit schedule as specified in the Flow Chart. In the event of 
any study drug interruption or delay of treatment, the tumour assessment schedule should not 
be changed.
Blood samples for pharmacokinetics, biomarkers and immunogenicity will be collected from 
all patients in all cohorts as per Appendix 10.2. Actual clock time for study drug administration 
and for each blood draw needs to be documented in the eCRF.
On visit days when safety lab is scheduled, patients should show up in fasting condition, the 
blood draw can be done up to one day prior to the scheduled date.
In situations where a patient is unable to attend a clinic visit, the investigator must assess the 
risk-benefit for the individual patient and may decide to perform a visit remotely if this is in 
the best interests of the patient and if agreed with the sponsor.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
Screening Period
Refer to the Flow Chart for procedure details. Please review Section 3.3.2 and 3.3.3 for 
eligibility criteria. 
Patients who failed screening may repeat the screening after discussion between investigator 
and sponsor providing that reasons for screening failure were reversible and have resolved.
All screening assessments including tumour imaging scan and ECG must be completed within 
28 days of start of run-in/C1V1. 


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The provision of tumour tissue is mandatory when available. Please refer to Appendix 10.3 and 
Table 5.5: 1 and Table 5.5: 2 for details. 
Demographics (sex, birth date and race as per each country regulation) and baseline conditions 
will be collected during the screening visit (See Section 5.6). 
Cancer history will also be obtained.
Run-in Period (only applicable to cohort E)
Refer to the Flow Chart, Table 5.5: 2 and Appendix 10.2 for details. 
Prior to starting therapy with xentuzumab, patients will receive continuous daily abemaciclib 
for a 9-days run-in period. Abemaciclib and patient’s diary should be dispensed on Day -9 of 
run-in. 
Both, on day -9 and on day -1 of the run-in period, patients must come fasted to the study site 
and must not take abemaciclib until they have been instructed to do so at the clinic visit.
On Day -9 of run-in, prior to the administration of abemaciclib, blood samples for biomarkers, 
pharmacokinetics, ADA, etc. will be collected as well as a safety lab blood draw. Please see 
Appendix 10.2.2.1 and Table 5.5: 2.
On Day -1 of the run-in period, PK samples must be collected before and after the 
administration of abemaciclib. Please see Appendix 10.2.2.1.
6.2.2
Treatment period(s)
Every treatment course is 28 days. All subsequent visit dates should be calculated based on 
Course 1 Visit 1 date. If a visit is missed there will be no re-scheduling; if a patient should 
attend the study site between the “missed” and the next scheduled visit, then the missed visit 
assessments should be performed except for xentuzumab infusion. The current date and the
reason for the delay must be noted in the medical records. 
One or more visits can be skipped in case of treatment interruption. However, in the event of 
any study drug interruption or delay of treatment, the tumour assessment schedule will not be 
changed. 
In this trial, patients may be hospitalized for the day of xentuzumab treatment and PK sampling 
at the discretion of the investigator; patients may be discharged if tolerated the treatment well 
and no safety concerns are present as judged by the investigator. Hospitalizations for this 
purpose should not be recorded as SAEs.
6.2.2.1
Cohort A, B, C, and D (dose finding)
Refer to the Flow Chart and Appendix 10.2.1 for details. 
Course 1, Visit 1 (Day 1 of 1st treatment course)
All procedures must be completed on day 1 of Course 1 except for safety labs, which can be 
performed 1 day prior to the scheduled visit. Patients should come fasted to the study site for 
safety labs.
Sufficient abemaciclib should be made available for the patient. 


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ECG will be collected prior to xentuzumab infusion.
Pharmacogenomics blood sample to evaluate exosomal RNA, blood sample to isolate genomic 
DNA, and a blood sample to analyse circulating nucleic acids will be collected before 
treatment. Also, blood samples for PK, biomarkers and immunogenicity will be collected 
during the visit. Please see Appendix 10.2.1.1 and Table 5.5: 1 for details on sampling time 
points during this visit.
Cohort B: Letrozole will be also dispensed at this visit.
Cohort C: Anastrozole will be also dispensed at this visit.
Cohort D: Fulvestrant will be also administered at this visit.
Course 1, Visit 2 (Day 8±1 of 1st treatment course)
Patients should come fasted to the study site for safety labs.
On Course 1 day 8, prior to the administration of xentuzumab infusion, trough PK as well as 
biomarker and immunogenicity blood samples must be collected. Please see Appendix 10.2.1.1
for details on the sampling schedule for this visit.
Course 1, Visit 3 (15 ±1 days after start of xentuzumab)
Patients should come fasted to the study site for safety labs.
ECG will be collected prior to xentuzumab infusion.
Pharmacogenomics blood sample to evaluate exosomal RNA will be collected before 
treatment. This sample will be used to evaluate exosomal RNA. Please refer to Table 5.5: 1.
Cohort D: Fulvestrant will be also administered at this visit.
Course 1, Visit 4 (22 ±1 days after start of xentuzumab)
Patients should come fasted to the study site for safety labs.
Course 2 (Day 1, 8, 15, 22 ±2 days) and all subsequent visits
Refer to Flow Chart, Table 5.5: 1and Appendix 10.2.1 for details.
Pharmacogenomics blood sample to evaluate exosomal RNA will be collected before treatment 
at Course ≥2 day 1. 
PK, biomarkers, pharmacogenomics and ADA samples are also applicable to these visits. 
Please see Table 5.5: 1 and Appendix 10.2.1.2 for details on the samples to be obtained.
Safety labs on day 15±2 are only applicable to course 2.
6.2.2.2
Cohort E 
Refer to the Flow Chart, Table 5.5: 2 and Appendix 10.2.2 for details. 
Course 1, Visit 1 (Day 1 of 1st treatment course)
All procedures must be completed on day 1 of Course 1 except for safety labs, which can be 
performed 1 day prior to the scheduled visit. For safety labs and PK purposes patients should 


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come fasted to the study site and must not take abemaciclib until they have been instructed to 
do so at the clinic visit.
Sufficient abemaciclib should be made available for the patient at this visit. 
ECG will be collected prior to xentuzumab infusion.
Pharmacogenomics blood sample to evaluate exosomal RNA will be collected before treatment 
(Flow Chart and Table 5.5: 2).
Blood samples for PK, biomarkers, pharmacogenomics and immunogenicity will also be 
collected during this visit. Please see Table 5.5: 2 and Appendix 10.2.2.1 for sampling schedule 
details.   
Course 1, Visit 2 (Day 8±1 of 1st treatment course)
Patients should come fasted to the study site for safety labs.
On Course 1 day 8, prior to the administration of xentuzumab infusion, one trough PK as well 
as biomarker and immunogenicity blood samples must be collected. Please see Appendix 
10.2.2.1 for details on sampling schedule for this visit.
Course 1, Visit 3 (15 ±1 days after start of xentuzumab)
Patients should come fasted to the study site for safety labs.
ECG will be collected prior to xentuzumab infusion.
Pharmacogenomics plasma sample will be collected before treatment. This sample will be used 
to evaluate exosomal RNA (Flow Chart and Table 5.5: 2). Please see Appendix 10.2.2.1 for 
details on sampling schedule.
Course 1, Visit 4 (22 ±1 days after start of xentuzumab)
Patients should come fasted to the study site for safety labs. Patient’s diary will be dispensed 
to the patient at this visit.
Course 2 (Day 1, 8, 15, 22 ±2 days) and all subsequent courses/visits
Refer to the Flow Chart, Table 5.5: 2 and Appendix 10.2.2.2 for details.
Pharmacogenomics blood sample to evaluate exosomal RNA will be collected before treatment 
at Course ≥2 day 1 (Flow Chart and Table 5.5: 2).
PK, biomarkers, pharmacogenomics and ADA samples will also be drawn at these visits. 
Please see Table 5.5: 2 and Appendix 10.2.2.2 for details on the sampling schedule. 
At course 2 visit 1, and for PK purposes, patients should come fasted to the study site and must 
not take abemaciclib until they have been instructed to do so at the clinic visit.
Safety labs on day 15±2 are only applicable to course 2
6.2.2.3
Cohorts D1, D2 and F
Refer to the revised and reduced Flow Chart, for details. 


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6.2.3
Follow Up Period and Trial Completion
6.2.3.1
End of treatment visit
End of Treatment Visit (0-7 days after permanent discontinuation of study drugs)
Refer to the Flow Chart for details. The patient must return all study drugs, and the site must 
document the reason for permanent discontinuation of study medication. If permanent 
discontinuation of study drug occurs during a scheduled visit, examinations as defined for 
EOTV should be performed instead of the examinations for the scheduled visit. 
6.2.3.2
Follow-up period
All patients must have a follow-up visit 42 days (+7days) after the permanent discontinuation 
of study drugs.
This follow-up period is aimed for collection of additional AE and PD information. Refer to 
the Flow Chart for details.
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
Blood samples for soluble biomarkers, PK and ADA must be obtained at this visit. Please refer 
to Appendix 10.2 for sampling schedule details.
6.2.3.3
Trial Completion
Trial completion for an individual patient:
A patient is considered to have completed the trial in case any of the following applies:

Completion of planned follow-up period (follow-up visit)

Lost to follow-up

Refusal to be followed-up

Death
The end of the trial is defined in Section 8.6


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This trial will be performed as an open-label study. The primary objective of the dose finding 
cohorts of this trial is to determine the MTD and the RP2D of:
*
Cohort A: xentuzumab in combination with abemaciclib (without endocrine background 
therapy)
*
Cohort B: xentuzumab in combination with abemaciclib on a background therapy of 
letrozole
*
Cohort C: xentuzumab in combination with abemaciclib on a background therapy of 
anastrozole
*
Cohort D (dose finding): xentuzumab in combination with abemaciclib on a background 
therapy of fulvestrant
To determine the MTD, patients are entered sequentially into escalating or de-escalating dose-
level cohorts. For each treatment combination, the dose finding will be guided by a Bayesian 
5-parameter logistic regression model with overdose control (R15-4233, Chapter 6).
This logistic regression model is defined as follows. Let π1,d1 be the probability of having a 
DLT when giving dose d1 of xentuzumab as monotherapy, and π2,d2 the probability of having a 
DLT when giving dose d2 of the combination partner abemaciclib as monotherapy, 
respectively. A logistic regression is used to model the dose-toxicity relationship for each of 
these drugs individually:
Xentuzumab: logit(π1,d1) =log(α1) + β1log(d1/d1*)
Abemaciclib: logit(π2,d2) =log(α2) + β2log(d2/d2*)
Here, the doses d1* = 1000 mg i.v. once weekly and d2* = 150 mg every 12 hours represent 
the reference doses for xentuzumab and abemaciclib, respectively. 
Assuming no toxicity interaction between the two compounds, the probability of a DLT when 
giving the combination dose d1, d2 is obtained as 
π012,d1,d2 = π1,d1 + π2,d2 - π1,d1π2,d2
with corresponding odds 
odds(π012,d1,d2)= π012,d1,d2 /(1- π012,d1,d2).
In order to account for a potential positive (higher toxicity than expected under independence) 
or negative (lower toxicity than expected under independence) interaction between 
xentuzumab and abemaciclib, a dose-dependent interaction term -∞<η<∞ is introduced in the 
model by the following definition:
odds(π12,d1,d2) = odds(π012,d1,d2) exp(η d1/d1* d2/d2*)
and π12,d1,d2 is used in the likelihood
rd1,d2 ~ Binomial(nd1,d2,π12,d1,d2)
where rd1,d2 denotes the random variable describing the observed number of DLTs in nd1,d2
patients at the dose combination d1, d2.


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Since a Bayesian approach is applied, prior distributions f for each of the parameter vectors 
θ1=(log(α1),log(β1)), θ2=(log(α2),log(β2)) and for the interaction term η need to be specified.
The prior distributions for θk will be specified as a mixture of two bivariate normal 
distributions, 
f(θk) = a1,k f1(θk) + a2,k f2(θk)
with 
a1,k, a2,k the prior mixture weights (a1,k + a2,k = 1), k = 1,2 and
fi(θk) = MVN(µik, ∑ik) a bivariate normal distribution with mean vector µik and covariance 
matrix ∑ik where
Σ = 
	
,
	 ,	 ,


	 ,	 ,


	
,


Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust. 
A weakly informative normal prior distribution will be used for η.
The estimated probability of DLT π12,d1,d2 at each dose combination d1, d2 from the model 
will be summarized using the following intervals:
*
Under dosing: [0.00, 0.16)
*
Targeted toxicity: [0.16, 0.33)
*
Over dosing: [0.33, 1.00]
The BLRM recommended dose combination for the next cohort is the combination with the 
highest posterior probability of the DLT rate falling in the target interval [0.16, 0.33) among 
the dose combinations fulfilling the EWOC principle. Per EWOC it should be unlikely (<25% 
posterior probability) that the DLT rate at the dose combination will exceed 0.33. However, 
the maximum allowable dose increment for the subsequent cohort will be no more than 100 % 
for each drug.
The MTD may be considered reached if one of the following criteria is fulfilled:
1. The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of the 
MTD is above 0.50, or
2. At least 6 patients have been treated at the MTD.
Prior derivation
To determine the prior distributions for θ1 and θ2, a meta-analytic predictive (MAP) approach 
will be used. Toxicity information on xentuzumab and abemaciclib from earlier dose finding 
studies will be incorporated. Exact details on the evaluation of the model using hypothetical 
data scenarios and operating characteristics are provided in the statistical appendix; a brief 
description is given here. 
The historical data for xentuzumab and abemaciclib can be found in Table 7.1:1 and 
Table 7.1:2, respectively.


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Table 7.1: 1
Historical data for xentuzumab
Study
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of patients
1280.1 (weekly infusion)
10 mg
0/3
20 mg
0/3
40 mg
0/3
60 mg
0/3
90 mg
0/3
135 mg
0/3
200 mg
0/3
300 mg
0/3
450 mg
1/6
600 mg
0/3
800 mg
0/3
1000 mg
0/13
1050 mg
0/3
1400 mg
0/3
1800 mg
0/3
1280.15: Japan (weekly 
infusion)
750 mg
0/3
1000 mg
0/9
1400 mg
0/6
Table 7.1: 2 Historical data for abemaciclib  
Study
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of patients
Study I3Y-MC-JPBA
75 mg twice-daily
100 mg twice-daily
150 mg twice-daily
200 mg twice-daily (=MTD)
275 mg twice-daily
0/3
0/4
0/3
1/7
2/3


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Table 7.1: 2 Historical data for abemaciclib (cont.)
Study
Dose
N of patients with DLTs 
during MTD evaluation 
period / N of patients
Study I3Y-JE-JPBC
100 mg twice-daily
150 mg twice-daily
200 mg twice-daily
0/3
0/3
1/6
Study I3Y-MC-JPBA: Phase 1 Study of a CDK4/6 Dual Inhibitor in Patients with Advanced Cancer.
Study I3Y-JE-JPBC: Phase 1 Study of LY2835219 in Japanese patients with Advanced Cancer.
The following steps were used to derive the prior distributions for all parameters:
1. θ1: 
1.
The meta-analytic-predictive prior was derived using the information in 
Table 7.1:1, allowing for substantial between-trial heterogeneity. This mixture 
component was assigned 90% mixture weight.
2.
A second, weakly-informative component was added with 10% mixture 
weight.
2. θ2: 
1.
The meta-analytic-predictive prior was derived using the information in 
Table 7.1:2, allowing for moderate between-trial heterogeneity. This mixture 
component was assigned 90% mixture weight.
2.
A second, weakly-informative component was added with 10% mixture 
weight.
3. η: based on the a priori assumption of no interaction between the two compounds, a 
normal distribution with mean 0 and standard deviation 0.707 was chosen. At the 
starting dose combination, the corresponding 95% prior interval covers an up to 4 fold 
increase (or decrease) in the odds of a DLT over no interaction.
The prior distribution is given in Table 7.1: 3. The corresponding prior probability of a DLT 
at different dose combinations and the corresponding probabilities of under-dosing, targeted 
dosing and overdosing are shown in Table 7.1: 4.
As seen in Table 7.1: 4, the dose combination 1000 mg xentuzumab and 150 mg abemaciclib 
has prior probabilities of overdosing below 25%. Hence, this dose combination fulfils the 
overdose criterion and is therefore suitable starting dose combination.
Table 7.1: 3
Prior distributions for the combination of xentuzumab and abemaciclib 
for Cohort A 
Parameter
Means, standard deviations, 
correlation
Mixture 
weight
Component 1: log(α1), log(β1)
(-3.697, -0.517), (1.031, 0.816), 0.034
0.9
Component 2: log(α1), log(β1)
(-4, -0.5), (2, 1), 0
0.1


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Table 7.1: 3
Prior distributions for the combination of xentuzumab and abemaciclib for 
Cohort A (cont.)
Parameter
Means, standard deviations, 
correlation
Mixture 
weight
Component 1: log(α2), log(β2)
(-2.515, 0.898), (0.829, 0.808), -0.510
0.9
Component 2: log(α2), log(β2)
(-3, 0.9), (2, 1), 0
0.1
η
0, 0.707, NA
NA
Table 7.1: 4
Prior probabilities of DLTs for the combination of xentuzumab and 
abemaciclib for Cohort A
Dose 
xentuzumab
Dose 
abemaciclib
Probability of true DLT rate in
Quantiles
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
750
100
0.873
0.106
0.021
0.083
0.087
0.006
0.056
0.316
750
150
0.706
0.226
0.067
0.137
0.117
0.017
0.102
0.454
1000
100
0.841
0.128
0.032
0.092
0.096
0.007
0.062
0.356
1000
150
0.664
0.238
0.098
0.150
0.134
0.015
0.109
0.517
The prior for cohort A may be updated once the trial has started in case new data that can be 
used will be available. The priors for cohorts B, C, and D(dose finding) will be additionally 
based on available data from this trial. The priors that are used for each BLRM analysis for the 
SC meetings will be documented in the SC minutes. The prior that is used for the final analysis 
will be documented in the TSAP. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory. No formal statistical test will be 
performed.


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7.3
PLANNED ANALYSES
No per protocol set will be used in the analysis. However, important protocol violations will 
be summarised. The TSAP will specify the important protocol violations in detail.
For the determination of the MTD, only MTD evaluable patients will be considered. For the 
analysis of primary and secondary endpoints of the expansion parts and further endpoints of 
dose finding and expansion parts, all patients in the treated set (i.e. patients treated with at least 
one dose of any trial medication, including hormonal therapy) will be included in the analysis. 
Any other analysis sets will be defined in the TSAP. 
The analysis of the primary endpoint of the dose finding cohorts (cohorts A, B, C and D (dose 
finding) respectively) will be conducted when “last-patient-last-visit-primary-endpoint-dose-
finding” has been reached (see Section 8.6).
Primary analysis of expansion cohorts (cohort E, F, D1 and D2) might be done before the end 
of the study. The further details will be described in TSAP.
The results of each dose finding cohorts (A, B, C, and D (dose finding)) and each expansion 
cohorts (E, F, D1 and D2) will be analysed separately.
7.3.1
Primary endpoint analyses
For dose finding cohorts A, B, C, and D (dose finding):
In order to identify the MTD, the number of patients with DLTs during the MTD evaluation 
period at each dose level will be presented. Patients who discontinue during the first treatment 
course for reasons other than DLT will be excluded from the determination of MTD.
For expansion cohort E:
Objective response will be analysed in terms of objective response rate, defined as the 
proportion of patients with best overall response of CR or PR (note that no confirmation is 
required for best overall response).
For cohorts D1 and D2:
PFS rate at 18th month will be derived using Kaplan Meier method. Cohort D1 for visceral vs.
cohort D2 for non-visceral will be displayed separately. The details will be described in the 
TSAP.
For expansion cohort F
DC will be analysed in terms of DC rate, defined as the proportion of patients with best overall 
response of CR, PR, SD lasting for at least 24 weeks or non-CR/non-PD lasting for at least 24 
weeks.
7.3.2
Secondary endpoint analyses
For dose finding cohorts A, B, C, and D (dose finding):
There are no secondary endpoints.


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For expansion cohorts E, F, D1 and D2:
The secondary endpoints will be analysed descriptively.
Disease control for Cohorts D1, D2 and E will be analysed in the same way as the primary 
analysis for Cohort F.
Time to objective response can only be calculated for patients with an objective response:
Time to objective response [days] = date of first documented CR or PR – date of first 
treatment administration +1.
Duration of objective response can only be calculated for patients with an objective response:
*
For patients with disease progression or death:
Duration of objective response [days] = date of outcome – date of first assessment 
indicating objective response +1
*
For patients without disease progression or death:
Duration of objective response (censored) [days] = date of outcome – date of first 
assessment indicating objective response +1
The censoring rules for duration of objective response (i.e. outcome and date of outcome) 
will be described in the TSAP. Only radiological assessments after first assessment indicating 
objective response should be taken into account.
Duration of disease control will be derived as follows:
*
For patients with disease progression or death:
Duration of disease control [days] = date of outcome – date of first treatment 
administration+1
*
For patients without disease progression or death:
Duration of disease control (censored) [days] = date of outcome – date of first treatment 
administration +1
The censoring rules for duration of disease control (i.e. outcome and date of outcome) will be 
described in the TSAP. 
Progression-free survival will be derived as follows:
*
For patients with “event” as an outcome for PFS:
PFS [days] = date of outcome – date of first treatment administration + 1
*
For patients with “censored” as an outcome for PFS:
PFS (censored) [days] = date of outcome – date of first treatment administration + 1
Censoring rules for PFS will be described in the TSAP. 
Objective response for Cohorts D1, D2 and F will be analysed in the same way as the primary
analysis for Cohort E. 


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 42 days after the last dose of trial medication, will be assigned to the 
treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end of 
the residual effect period will be considered ‘treatment-emergent’. The residual effect period 
is defined as a period of 42 days after the last dose of trial medication. Adverse events that start 
before first drug intake and deteriorate under treatment will also be considered as ‘treatment-
emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
DLTs will be tabulated for each dose level in the dose escalation cohorts. The tabulation will 
be done in two ways:

DLTs with onset in the first treatment course, and

All DLTs regardless of treatment course at onset
The definition of DLT and determination of MTD are defined in Section 5.3.7 and Appendix 
10.6 respectively.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will be 
done via comparison of laboratory data to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Treatment groups will be compared descriptively with regard to distribution parameters as well 


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as with regard to frequency and percentage of patients with abnormal values or clinically 
relevant abnormal values.
The following analyses will be presented for the laboratory tests:

Descriptive statistics at each planned assessment, 

Frequency of patients with transitions in CTCAE grade from baseline to worst and last 
values during treatment, and 

Frequency of patients with possible clinically significant abnormalities.
Additional more in-depth analyses of AEs and laboratory data will be performed as needed and 
detailed in the TSAP.
Vital signs, physical examinations, ECG, 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.
7.3.5
Pharmacokinetic and pharmacodynamic analyses


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7.4
INTERIM ANALYSES
No formal interim analysis is planned for efficacy.
In the dose finding cohorts A, B, C, and D, the SC and BI study team will continuously monitor 
and assess safety data to ensure patients’ safety, as well as to determine the MTD and/or the 
RP2D of each dose finding cohorts. If considered necessary, as soon as the MTD and/or the 
RP2D of a particular dose finding cohort is determined, an evaluation of the safety (and 
potentially efficacy) aspects will be performed via a snapshot of the database. Results of this 
evaluation will be documented and stored.
Continuous monitoring of safety data for expansion cohorts E, F, D1 and D2 will be done by 
the SC and BI study team.
Earlier efficacy analyses than those currently planned may be performed to support future 
decision making and trial planning. 
7.5
HANDLING OF MISSING DATA
In general, missing data will not be imputed and all reasonable efforts will be taken during the 
study to obtain such data. 
Missing baseline laboratory values will be imputed by the respective values from the screening 
visit. 
For partial or missing AE onset and/or end dates, BI internal rules will be applied for 
imputation. 
No other imputations will be performed on missing data although every effort will be made to 
obtain complete information on all adverse events, with particular emphasis on potential DLTs.


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Pharmacokinetics:
Drug concentration-time profiles: Concentration data identified with NOS (no sample), NOR 
(no valid result), NOA (not analysed), BLQ (below the limit of quantification) and NOP (no 
peak detectable) will be ignored and not replaced by zero at any time point (including the lag 
phase). Descriptive statistics of concentrations at specific time points will be calculated only 
when at least 2/3 of the individuals have concentrations within the validated concentration 
range.
Pharmacokinetic parameters: 
In the non-compartmental analysis, concentration data identified with NOS, NOR and NOA 
will not be considered. BLQ and NOP values in the lag phase will be set to zero. The lag phase 
is defined as the period between time 0 and the first time point with a concentration above the 
quantification limit. All other BLQ and NOP values of the profile will be ignored. Descriptive 
statistics of parameters will be calculated only when at least 2/3 of the individual parameter 
estimates of a certain parameter are available. Pharmacokinetic parameters which cannot be 
determined will be identified by "not calculated" (NC).
7.6
RANDOMISATION
No randomisation will be performed. In the dose finding cohorts, patients will be assigned 
sequentially to the dose escalation groups. In the expansion cohorts, patients will be assigned 
to a cohort based upon previous MTD/RP2D. Medication numbers will be allocated by an IRT 
system.
7.7
DETERMINATION OF SAMPLE SIZE
No formal statistical power calculations to determine sample size were performed for this 
study. Approximately 148 patients (including patients at MTD) will be expected for this trial 
based on the number of dose levels/cohorts that are tested. Fewer or more patients might be 
needed based on the recommendation of the SC and BI Trial Team and the criteria specified
(see Section 7.1). 
Dose finding cohorts A, B, C and D:
Approximately 12 patients in cohorts A, B, C and D (dose finding) will be needed to define a 
MTD. In total, approximately 48 patients will be needed for the dose finding cohorts. However, 
the actual number of patients will depend on the number of dose levels tested. 
Based on the simulation study to evaluate operating characteristics of the BLRM (see Appendix 
10.6), approximately 12 patients (in mean) are expected to be treated in the dose finding cohort 
A for the model to have reasonable operating characteristics relating to its MTD 
recommendation (see Appendix 10.6).
Considering the toxicity profile of individual compounds, we can assume the same number of 
patients will be needed in the dose finding cohorts B, C and D (dose finding).


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Expansion cohort E:
In expansion cohort E, 20 patients will be treated at the MTD/RP2D.
Assuming a true objective response (OR) rate of 60%, a sample size of 20 patients leads to a 
probability of 87% of observing at least 10 ORs. If the true OR rate is higher, i.e. 80%, the 
probability of observing at least 10 ORs is higher than 99%. The probability to observe a false 
positive signal, i.e. to observe at least 8 ORs if the underlying true OR rate is 20%, is only 3%. 
Table 7.7: 1 summarizes the probabilities of observing certain OR rates based on different 
assumptions on underlying OR rates.
Table 7.7: 1
Objective response rates for Cohort E
True 
OR 
rate
Patients
Probability to observe at least
7 
events
8 
events
9 
events
10 
events
11 
events
12 
events
13 
events
14 
events
15 
events
60%
20
0.99
0.97
0.94
0.87
0.76
0.60
0.42
0.25
0.13
80%
20
>0.99
>0.99
>0.99
>0.99
>0.99
0.99
0.97
0.91
0.80
20%
20
0.09
0.03
< 0.01
< 0.01
< 0.01
< 0.01
< 0.01
< 0.01
< 0.01
An OR rate of 60% would be considered clinically relevant in NSCLC patients (cohort E).
These assumed OR rates and the expected ORs are according to the current knowledge and 
expectations regarding xentuzumab and its combination partners. The calculations were 
performed using R version 3.2.2.
Expansion cohorts D1 and D2:
For each of cohort, D1 for visceral metastasis and D2 for non-visceral metastasis, 30 patients 
will be recruited respectively and treated at the RP2D4. 
For cohort D1, assuming a true PFS rate of 60% at 18th month, 10 months recruitment period
and 20% patient drop rate, a sample size of 30 patients leads to a probability of 62% of
observing at least 57% PFS rate at 18th month. If the true PFS rate is higher, i.e. 63%, the 
probability of observing at least 57% PFS rate is higher than 73%. The probability to observe 
a false positive signal, i.e. to observe at least 57% PFS rate at 18th month if the underlying true 
PFS rate is 43%, is only 8%. Table 7.7: 2 summarizes the probabilities of observing certain 
PFS rates at 18th month based on different assumptions on underlying PFS rates.


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Table 7.7: 2
PFS rates at 18th month for cohort D1
True PFS rate at 18 
month
Patients
Probability to observe PFS rate at 18th month
>0.47
>0.52
>0.57
>0.6
>0.63
43%
30
0.33
0.18
0.08
0.04
0.02
60%
30
0.90
0.79
0.62
0.51
0.39
63 %
30
0.95
0.87
0.73
0.63
0.51
For Cohort D2, assuming a true PFS rate of 69% at 18th month, 10 months recruitment period
and 20% patient drop rate, a sample size of 30 patients leads to a probability of 68% of
observing at least 65% PFS rate at 18th month. If the true PFS rate is higher, i.e. 75%, the 
probability of observing at least 65% PFS rate is higher than 87%. The probability to observe 
a false positive signal, i.e. to observe at least 65% PFS rate at 18th month if the underlying true 
PFS rate is 52%, is only 10%. Table 7.7: 3 summarizes the probabilities of observing certain 
PFS rates at 18th month based on different assumptions on underlying PFS rates.
Table 7.7: 3
PFS rates at 18th month for cohort D2
True PFS rate at 18 
month
Patients
Probability to observe PFS rate at 18th month
>0.56
>0.60
>0.65
>0.69
>0.73
52%
30
0.35
0.22
0.10
0.04
0.02
69%
30
0.92
0.83
0.68
0.52
0.35
75%
30
0.98
0.95
0.87
0.76
0.61
An PFS rate of 60% would be considered clinically relevant in each cohorts: visceral metastasis 
and non-visceral metastasis.
These assumed PFS rates and the expected PFS rates are based on the current knowledge and 
expectations regarding xentuzumab and its combination partners. The assumed true PFS rate 
for each cohort is considered clinically relevant. All calculations were performed using R 
version 3.2.2.
Cohort F:
In expansion cohort F, 20 patients will be treated at the MTD/RP2D.
Assuming a true DC rate of 60%, a sample size of 20 patients leads to a probability of 87% of 
observing at least 10 events. If the true DC rate is higher, i.e. 80%, the probability of observing 
at least 10 events is higher than 99%. The probability to observe a false positive signal, i.e. to 
observe at least 8 events if the underlying true DC rate is 20%, is only 3%. Table 7.7: 4
summarizes the probabilities of observing certain DC rates based on different assumptions on 
underlying DC rates.


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Table 7.7: 4
Disease Control rates for Cohort F
True 
DC
rate
Patients
Probability to observe at least
7 
events
8 
events
9 
events
10 
events
11 
events
12 
events
13 
events
14 
events
15 
events
60%
20
0.99
0.97
0.94
0.87
0.76
0.60
0.42
0.25
0.13
80%
20
>0.99
>0.99
>0.99
>0.99
>0.99
0.99
0.97
0.91
0.80
20%
20
0.09
0.03
< 0.01
< 0.01
< 0.01
< 0.01
< 0.01
< 0.01
< 0.01
A DC rate of 60% would be considered clinically relevant in HR+, Her2- locally advanced 
and/or metastatic breast cancer patients after prior therapy with a different CDK4/6 inhibitor 
and aromatase inhibitor (cohort F).
These assumed and expected DC rates are according to the current knowledge and expectations 
regarding xentuzumab and its combination partners. The calculations were performed using R 
version 3.2.2.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonised standards for Medical Devices (ISO 14155, current version).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 the Japanese GCP regulations (Ministry of Health and Welfare Ordinance 
No. 28, March 27, 1997) and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of the 
protocol or of ICH GCP.
The 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.
For Japan only: the rights of the Investigator / trial site and of the sponsor with regard to 
publication of the results of this trial are described in the Investigator contract / trial site’s 
contract. As a general rule, no trial results should be published prior to finalisation of the 
Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is 
stored in the ISF (Investigator Site File).
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”


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For Japan only: The Investigator must give a full explanation to trial patients based on the 
patient information form. A language understandable to the patient should be chosen, technical 
terms and expressions avoided, if possible. The patient must be given sufficient time to 
consider participation in the trial. The Investigator obtains written consent of the patient’s own 
free will with the informed consent form after confirming that the patient understands the 
contents. 
For Japan only: The Investigator must sign (or place a seal on) and date the informed consent 
form. If a trial collaborator has given a supplementary explanation, the trial collaborator also 
signs (or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the Investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRF) 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
If defined in the protocol, additional records may need to be requested from the Investigator, 
e.g. information from any referral physicians on patient history relevant for AE reporting or 
data required in connection with outcome event collection in outcome studies.
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 subject. 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 subject 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.


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Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted 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, date or year of birth (in accordance with local laws and 
regulations)
*
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
*
Dates of Patient’s visits, including dispensing of trial medication
*
Medical history (including trial indication and concomitant diseases, if applicable)
*
Medication history
*
Adverse events and outcome events (onset date (mandatory), and end date (if available))
*
Serious adverse events (onset date (mandatory), and end date (if available))
*
Concomitant therapy (start date, changes)
*
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
*
Completion of Patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
*
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The Investigator /institution will allow 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 CRA, auditor and regulatory inspector 
(e.g. FDA). The CRA and auditor 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 ICH GCP.


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8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
the national or 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 with 
the requirements. Any exemptions from expedited reporting are described under Section 
5.3.6.2 and Section 5.3.6.3.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
The rights of the trial patient to privacy and protection of the data / patient notes obtained 
during the trial have to be ensured in accordance with local laws and regulations. Procedures 
for data handling and data protection need to be described in the patient information and 
informed consent form. Individual patient data obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient privacy will be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate medical 
personnel responsible for the patient’s welfare. Data generated as a result of the trial need to 
be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular
*
A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)
*
The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.
*
Samples and data are used only if an appropriate informed consent is available.


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8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment (screening) of the first patient in 
the whole trial.
The end of the trial is defined as the date when the last patient in the whole trial completes the 
trial as per definition of trial completion in Section 6.2.3.3. 
The “last-patient-last-visit-primary-endpoint-dose-finding” is defined as the date when all 
patients in a respective dose finding cohort have completed at least the first treatment course. 
Thus, this milestone is defined for each dose finding cohorts (A, B, C and D (dose finding)).
The “last-patient-last-visit-primary-endpoint-expansion” (Cohorts E and F) is defined as 
the date when all patients in a respective expansion cohort have completed at least two tumour 
assessment time points or have permanently discontinued treatment or have completed the trial 
according to Section 6.2.3. Thus, this milestone is defined for each expansion cohorts (E and
F).
The “last-patient-last-visit-primary-endpoint-expansion” (Cohorts D1 and D2) is defined 
as the date when all patients have completed 18 months PFS observation or have permanently 
discontinued treatment or have completed the trial according to Section 6.2.3. Thus, this 
milestone is defined for Cohorts D1 and D2.
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPDD at their site. Early termination of the trial is defined as 
the premature termination of the trial due to any reason before the end of the trial as specified 
in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed the 
trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one year 
from the end of a clinical trial as a whole, regardless of the country of the last patient (EU or 
non-EU).
For Japan only: when the trial is completed, the Investigator should inform the head of the trial 
site of the completion in writing, and the head of the trial site should promptly inform the IRB 
and sponsor of the completion in writing.


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8.7
PROTOCOL VIOLATIONS
For Japan only: the Investigator should document any deviation from the protocol regardless 
of their reasons. Only when the protocol was not followed in order to avoid an immediate 
hazard to trial subjects or for other medically compelling reason, the principal Investigator 
should prepare and submit the records explaining the reasons thereof to the sponsor, and retain 
a copy of the records.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT 
OF TRIAL RELATED INJURY
For Japan only: in the event of health injury associated with this trial, the sponsor is responsible 
for compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P15-00363 
King H, Aleksic T, Haluska P, Macaulay VM. Can we unlock the potential 
of IGF-1R inhibition in cancer therapy? Cancer Treat Rev 40 (9), 1096 –
1105 (2014) 
P15-10237 
Boolell V, Alamgeer M, Watkins DN, Ganju V. The evolution of therapies 
in non-small cell lung cancer. Cancers 7 (3), 1815 – 1846 (2015) 
P15-10395 
Iams WT, Lovly CM. Molecular pathways: clinical applications and future 
direction of insulin-like growth factor-1 receptor pathway blockade. Clin 
Cancer Res 21 (19), 4270 – 4277 (2015)
P16-09570 
Cortes J, Martinez N, Sablin MP, Perez-Fidalgo JA, Neven P, Hedayati E, 
et al
Phase Ib/II trial of xentuzumab, an insulin-like growth factor ligand-
neutralizing antibody, combined with exemestane and everolimus in 
hormone receptor-positive locally advanced or metastatic breast cancer: 
primary phase Ib results. 52nd Ann Mtg of the American Society of Clinical 
Oncology (ASCO), Chicago, 3 - 7 Jun 2016 (Poster)
P16-09577 
Rocco G, Morabito A, Leone A, Muto P, Fiore F, Budillon A. Management 
of non-small cell lung cancer in the era of personalized medicine. Int J 
Biochem Cell Biol 78, 173 - 179 (2016)
R07-4856 
European Medicines Agency (EMEA). Committee for Medicinal Products 
for Human Use (CHMP): guideline on clinical trials in small populations 
(London, 27 July 2006, doc. ref.  CHMP/EWP/83561/2005). London: 
EMEA (2006)
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D et al., New 
response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer 2009;45:228-247.
R10-4848
Common Terminology Criteria for Adverse Events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf (2010)
R10-5355  
Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in 
cancer growth and metastasis: Overview and recent insights. Endocr Rev 28 
(1), 20 – 47 (2007)
R10-5694 
Souza AT de, Hankins GR, Washington MK, Orton TC, Jirtle RI. 
M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss 
of heterozygosity. Nature Genet 11, 447 – 449 (1995) 
R12-2864 
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA 62 (1), 10 –
29 (2012) 
R12-4524 
Pollak M. The insulin and insulin-like growth factor receptor family in 
neoplasia: an update. Nat Rev Cancer 12, 159 – 169 (2012)
R12-5635 
Baselga J, et al. Everolimus in postmenopausal hormone-receptor-positive 
advanced breast cancer. N Engl J Med 366 (6), 520 - 529 (2012)


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R13-1229 
Scher HI, et al, AFFIRM Investigators. Increased survival with 
enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367 
(13), 1187 - 1197 (2012)
R13-4802 
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a 
comparison of trial designs. Cancer Chemother Pharmacol 71, 1107 - 1114 
(2013)
R13-4803 
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the 
Bayesian approach to phase I cancer trials. Stat Med 27, 2420 - 2439 (2008)
R13-4804 
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. 
Translation of innovative designs into phase I trials. J Clin Oncol 25 (31), 
4982 - 4986 (2007)
R13-4805 
Tourneau C le, Gan HK, Razak ARA, Paoletti X. Efficiency of new dose 
escalation designs in dose-finding phase I trials of molecularly targeted 
agents. Plos One 7 (12), e51039 (2012)
R14-1645 
Murtaza M, Dawson SJ, Tsui DWY, Gale D, Forshew T, Piskorz AM, 
Parkinson C, Chin SF, Kingsbury Z, Wong ASC, Marass F, Humphray S, 
Hadfield J, Bentley D, Chin TM, Brenton JD, Caldas C, Rosenfeld N
Non-invasive analysis of acquired resistance to cancer therapy by 
sequencing of plasma DNA.
Nature 497, 108 - 112 (2013)
R15-1307 
Beer TM, et al, PREVAIL Investigators. Enzalutamide in metastatic 
prostate cancer before chemotherapy. N Engl J Med 371 (5), 424 - 433 
(2014)
R15-4233
Zhao W, Yang H, editors. Statistical methods in drug combination studies.
(CRC Biostatistics Series) Boca Raton: CRC Press (2015)
R16-0844
Heilmann AM, Perera RM, Ecker V, Nicolay BN, Bardeesy N, Benes CH, 
Dyson NJ. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the 
growth of p 16INK4A-deficient pancreatic cancers. Cancer Res 74 (14), 39-
47-3958 (2014).
R16-0845
Miller ML, Molinelli EJ, Nair JS, Sheikh T, Samy R, Jing X, He Q, Korkut 
A, Crago AM, Singer S, Schwartz GK, Sander C. Drug synergy screen and 
network modelling in dedifferentiated liposarcoma identifies CDK4 and 
IGF1R as synergistic drug targets. Sci Signal 6 (294), ra85 (2013)
R16-2249 
Sherr CJ, Beach D, Shapiro GI. Targeting CDK4 and CDK6: from 
discovery to therapy. Cancer Discov 6, 353 - 367 (2016)
R16-2270 
Challenge and opportunity on the critical path to new medical products 
(page last updated: 01/25/2016, this report replaces the version posted on 
March 16, 2004). 
http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPath
Initiative/CriticalPathOpportunitiesReports/ucm113411.pdf (access date: 18 
May 2016) ; U.S. Department of Health and Human Services, Food and 
Drug Administration (2016)
R16-3704 
O'Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 
inhibitors. Nat Rev Clin Oncol 13 (7), 417 - 430 (2016)
R16-3978 
Velasco-Velazquez MA, Li Z, Casimiro M, Loro E, Homsi N, Pestell RG. 
Examining the role of cyclin D1 in breast cancer. Future Oncol 7 (6), 753 -
765 (2011)


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R16-3979 
VanArsdale T, Boshoff C, Arndt KT, Abraham RT. Molecular pathways: 
targeting the cyclin cancer research D-CDK4/6 axis for cancer treatment. 
Clin Cancer Res 21 (13), 2905 - 2910 (2015)
R16-3980 
Kumar M, Ernani V, Owonikoko TK. Biomarkers and targeted systemic 
therapies in advanced non-small cell lung cancer. Mol Aspects Med 45, 55 -
66 (2015)
R16-3981 
Hou X, Huang F, Macedo L, Harrington SC, Reeves KA, Greer A, et al 
Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents 
in treatment of estrogen-dependent breast cancer. Cancer Res 71 (24), 7597 
- 7607 (2011)
R16-3982 
Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, 
et al Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, 
for patients with breast cancer, non-small cell lung cancer, and other solid 
tumors. Cancer Discov 6 (7), 740 - 753 (2016)
R16-3983 
Cardoso F, Costa A, Norton L, Cameron D, Cufer T, Fallowfield L, et al.
1st international consensus guidelines for advanced breast cancer (ABC 1). 
Breast 21, 242 - 252 (2012)
R16-5327
Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, Wildiers 
H, Frenzel M, Koustenis A, Baselga J. Monarch 1: results from a phase 2 
study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in 
patients with HR+/HER2- breast cancer, after chemotherapy for metastatic 
disease. 52nd Ann Mtg of the American Society of Clinical Oncology 
(ASCO), Chicago, 3 - 7 Jun 2016
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 while receiving endocrine
therapy. Journal of Clinical Oncology, Published online: 3 June 2017
R18-2693
FDA approves abemaciclib for HR-positive, HER2-negative breast cancer.
https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm5780
81.htm (access date: 23 August 2018); Silver Spring: U.S. Food and Drug 
Administration (2017)
9.2
UNPUBLISHED REFERENCES
c01690707-08
 Investigator’s Brochure Xentuzumab (BI 836845) oncology, 
1280.P1/P2/P3, 26-Jul-2018, Version 11
c26540383
Investigator’s Brochure Abemaciclib LY2835219 
 
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c22665932-01 
1280.4 Subgroup Analysis Report,
Version 1.0 dated 10 August 2018


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10.
APPENDICES
10.1
INDUCERS AND STRONG INHIBITORS OF CYP3A4
The information in this table is provided for guidance to investigators and does not preclude 
the use of these medications if clinically indicated.
Strong Inducers of CYP3A
Carbamazepine
Dexamethasonea
Phenobarbital/phenobarbitone
Phenytoin
Rifapentine
Rifampin
Rifabutin
St John’s wort
Moderate Inducers of CYP3A
Bosentan
Lenisurad
Modafinil
Primidone
Telotristat ethyl
Strong Inhibitors of CYP3A
Aprepitant
Ciprofloxacin
Clarithromycin
Conivaptan
Diltiazem
Erythromycin
Fluconazole
Itraconazole
Ketoconazole
Nefazodone
Posaconazole
Troleandomycin
Verapamil
a
Important note:  All patients may receive supportive therapy with dexamethasone, preferably 7 days, if 
clinically indicated.


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10.2
PHARMACOKINETICS PLAN
10.2.1
FLOW CHART for PK, immunogenicity, and biomarkers for cohorts A, B, 
C, and D (dose finding)
10.2.1.1
Flowchart for PK, immunogenicity, and biomarkers for Cohorts A, B, C, and D
(dose finding) in treatment course 1
Course
Visit
Day
Planned time
[h:min]
Event and comment
Xentuzumab PK
ADA
Total IGF-1/2, IGFBP-3
Free /dissociable IGF-1/2
pIGF-1R/IGF-1R in PRP
SCR
SCR
Within 28d 
before C1V1
-999:00*
Sampling at screening visit
X
1
1
1
-0:05
Blood sampling prior to 
xentuzumab infusion
X
X
X
X
X
0:00
Start of xentuzumab infusion
1:00**
Immediately at the end of 
xentuzumab infusion
X
2
8
168:00
Blood sampling ~5 minutes prior to 
xentuzumab infusion
X
X
X
*Planned time listed at visit SCR is considered to be a dummy planned time to set-up the database, the description in column 
“Day” defines the timing for these specific samples
** If the infusion duration is different from 1h, please adapt the sampling time accordingly.


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10.2.1.2
FLOW CHART for PK, immunogenicity, and biomarkers for cohorts A, B, C, 
and D (dose finding) in courses 2-12, 15, and 18, EOTV and FU
Course
Visit
Day
Planned time
[h:min]
Event and comment
Xentuzumab PK
ADA
Total IGF-1/2, IGFBP-3
Free /dissociable IGF-1/2
pIGF-1R/IGF-1R in PRP
2-12, 
15, 18
1
1
-0:05
Blood sampling prior to 
xentuzumab infusion
X
X
X
X
X
0:00
Start of xentuzumab infusion
1:00**
Immediately at the end of 
xentuzumab infusion
X
EOT
V
EOTV
Within 7d after last 
drug intake
998:00*
End of treatment visit
X
X
X
X
X
FU
FU
42 +7d after last 
drug intake
999:00*
Follow-up
X
X
X
X
X
*Planned times listed at visit EOTV and FU are considered to be dummy planned times to set-up the database, the 
description in column “Day” defines the timing for these specific samples
** If the infusion duration is different from 1h, please adapt the sampling time accordingly.


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10.2.2
FLOW CHART for PK, immunogenicity, and biomarkers for cohort E  
10.2.2.1
FLOW CHART for PK, immunogenicity, and biomarkers for cohort E in Run-in 
phase and treatment course 1
Course
Visit
Day
Planned time
[h:min]
Event and comment
Xentuzumab PK
ADA
Abemaciclib and 
metabolites PK***
Total IGF-1/2, 
IGFBP-3
Free /dissociable
IGF-1/2
pIGF-1R/IGF-1R in 
PRP
SCR
SCR
Within 28d 
before Run 
in V1
-999:00*
Sampling at screening visit
X
Run 
in
1
-9 
-192:05
5 minutes prior to first 
abemaciclib treatment
X
X
X***
X
X
X
3
-1
-0:05
Blood sampling 5 minutes 
prior to abemaciclib 
administration
X***
0:00
abemaciclib administration 
(morning dose)
1:00
X
2:30
X
4:00
X
6:00
X
8:00
X
12:00 
[± 2:00]
Blood sampling before intake 
of evening dose of 
abemaciclib
X
1
1
1
-0:05 
Blood sampling prior to 
xentuzumab infusion and 
abemaciclib administration
X
X
X***
X
X
X
0:00
Start of xentuzumab infusion
0:01
Abemaciclib administration
1:00**
Immediately at the end of 
xentuzumab infusion
X
2
8
168:00
Blood sampling prior to 
xentuzumab infusion
X
X
X
*Planned time listed at visit SCR is considered to be a dummy planned time to set-up the database, the description in column 
“Day” defines the timing for these specific samples
** If the infusion duration is different from 1h, please adapt the sampling time accordingly.
*** At days of abemaciclib PK sampling, patients have to take their morning dose of abemaciclib in the hospital in order to 
allow exact timing of PK sampling


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10.2.2.2
FLOW CHART for PK, immunogenicity, and biomarkers for cohort E in 
treatment course 2
Course
Visit
Day
Planned time
[h:min]
Event and comment
Xentuzumab PK
ADA
Abemaciclib and 
metabolites PK***
Total IGF-1/2, IGFBP-3
Free dissociable IGF-1/2
pIGF-1R/IGF-1R in PRP
2
1
1
-0:05
Blood sampling prior to abemaciclib 
and xentuzumab administration 
X
X
X***
X
X
X
0:00
Start of xentuzumab infusion
0:01
Abemaciclib administration
1:00**
Immediately at the end of 
xentuzumab infusion
X
X
2:30
X
X
4:00
X
X
6:00
X
X
8:00 
X
X
12:00
[± 2:00]
Blood sampling before intake of 
evening dose of abemaciclib
X
X
1
2
23:55
Blood sampling prior to abemaciclib 
administration
X
24:00
Abemaciclib administration
1b
4±1
72:00
Blood sampling at this visit 
X
2
8±1
168:00
Blood sampling ~ 5 min prior to 
abemaciclib administration and 
xentuzumab infusion
X
** If the infusion duration is different from 1h, please adapt the sampling time accordingly.
*** At days of abemaciclib PK sampling, patients have to take their morning dose of abemaciclib in the hospital in order to 
allow exact timing of PK sampling


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10.2.2.3
FLOW CHART for PK, immunogenicity, and biomarkers for cohort E in 
treatment courses 3-12, 15, 18 and EOTV and FU visit
Course
Visit
Day
Planned Time
[h:min]
Event and comment
Xentuzumab PK
ADA
Abemaciclib and 
metabolites PK
Total IGF-1/2, IGFBP-3
Free /dissociable IGF-1/2
pIGF-1R/IGF-1R in PRP
3-12, 
15, 18
1
1
-0:05
Blood sampling prior to abemaciclib 
administration and xentuzumab
infusion
X
X
X
X
X
0:00
Start of xentuzumab infusion
0:01
Abemaciclib administration
1:00**
Immediately at the end of 
xentuzumab infusion
X
EOTV
EOTV
Within 7d
after last 
drug 
intake
998:00*
End of treatment visit
X
X
X
X
X
FU
FU
42 +7d 
after last 
drug 
intake
999:00*
Follow-up
X
X
X
X
X
*Planned times listed at visit EOTV and FU are considered to be dummy planned times to set-up the database, the 
description in column “Day” defines the timing for these specific samples
** If the infusion duration is different from 1h, please adapt the sampling time accordingly.


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10.2.3
FLOW CHART for PK, immunogenicity, and biomarkers for cohort F
As of 22 Oct 2021, samples for PK, immunogenicity and biomarkers are no longer 
collected for ongoing patients.
10.2.3.1
FLOW CHART for PK, immunogenicity, and biomarkers for cohort F in 
screening and treatment course 1
Course
Visit
Day
Planned time
[h:min]
Event and 
comment
Xentuzumab PK
ADA
Abemaciclib and 
metabolites PK***
Total IGF-1/2, 
IGFBP-3
Free /dissociable
IGF 1/2
pIGF-1R/IGF-1R 
in PRP
SCR
SCR
Within 28d 
before Run 
in V1
-999:00
Sampling at screening visit
X
1
1
1
-0:05
Blood sampling prior to abemaciclib 
administration, xentuzumab infusion and 
fulvestrant injection
X
X X***
X
X
X
0:00
Start of xentuzumab infusion
0:01
Abemaciclib administration
0:00
Fulvestrant injection up to 15min. after 
start of xentuzumab infusion
1:00**
Immediately at the end of xentuzumab
infusion
X
2
8
168:00
Blood sampling prior to xentuzumab
infusion
X
X
X
*Planned time listed at visit SCR is considered to be a dummy planned time to set-up the database, the description in column 
“Day” defines the timing for these specific samples
** If the infusion duration is different from 1h, please adapt the sampling time accordingly.
*** At days of abemaciclib PK sampling, patients have to take their morning dose of abemaciclib in the hospital in order to 
allow exact timing of PK sampling


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10.2.3.2
FLOW CHART for PK, Immunogenicity, biomarkers for cohort F in treatment 
courses 2-12, 15, 18, EOTV and FU
Course
Visit
Day
Planned time
[h:min]
Event and comment
Xentuzumab PK
ADA
Abemaciclib and 
metabolites PK
Fulvestrant PK
Total IGF-1/2, IGFBP-3
Free /dissociable IGF-1/2
pIGF-1R/IGF-1R in PRP
2-12, 
15, 18
1
1
-0:05
Blood sampling prior to abemaciclib 
administration, xentuzumab infusion
and fulvestrant injection
X
X
X1
***
X1
X
X
X
0:00
Start of xentuzumab infusion
0:01
Abemaciclib administration
0:00
Fulvestrant injection up to 15min. 
after start of xentuzumab infusion
1:00**
Immediately at the end of 
xentuzumab infusion
X
EOTV
EOTV
Within 7d 
after last 
drug 
intake
998:00*
End of treatment visit
X
X
X
X
X
FU
FU
42 +7d 
after last 
drug 
intake
999:00*
Follow-up
X
X
X
X
X
*Planned times listed at visit EOTV and FU are considered to be dummy planned times to set-up the database, the 
description in column “Day” defines the timing for these specific samples
** If the infusion duration is different from 1h, please adapt the sampling time accordingly.
*** At days of abemaciclib PK sampling, patients have to take their morning dose of abemaciclib in the hospital in order to 
allow exact timing of PK sampling
1 this sample needs to be collected in course 2 and 3 only


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10.2.4
FLOW CHART for PK, immunogenicity, and biomarkers for cohorts D1
and D2
As of 22 Oct 2021, samples for PK, immunogenicity and biomarkers are no longer 
collected for ongoing patients.
10.2.4.1
FLOW CHART for PK, immunogenicity, and biomarkers for cohorts D1 and 
D2 in treatment course 1
Course
Visit
Day
Planned time
[h:min]
Event and 
comment
Xentuzumab PK
ADA
Abemaciclib and 
metabolites PK
Total IGF-1/2, 
IGFBP-3
Free /dissociable
IGF 1/2
pIGF-1R/IGF-1R 
in PRP
SCR
SCR
Within 28d 
before
C1V1
-999:00* Sampling at screening visit
X
1
1
1
-0:05
Blood sampling prior to abemaciclib 
administration, xentuzumab infusion and 
fulvestrant injection
X
X
X
X
X
0:00
Start of xentuzumab infusion
0:01
Abemaciclib administration
0:00
Fulvestrant injection up to 15min. after 
start of xentuzumab infusion
1:00**
Immediately at the end of xentuzumab
infusion
X
2
8
168:00
Blood sampling prior to xentuzumab
infusion
X
X
X
3
15
336:00
Blood sampling prior to xentuzumab
infusion
X
4
22
504:00
Blood sampling prior to xentuzumab
infusion
X
*Planned time listed at visit SCR is considered to be a dummy planned time to set-up the database, the description in column 
“Day” defines the timing for these specific samples
** If the infusion duration is different from 1h, please adapt the sampling time accordingly.


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10.2.4.2
FLOW CHART for PK, immunogenicity, and biomarkers for cohorts D1 and 
D2 in treatment course 2
Course
Visit
Day
Planned time
[h:min]
Event and comment
Xentuzumab PK
ADA
Abemaciclib and 
metabolites PK***
Fulvestrant PK
Total IGF-1/2, IGFBP-3
Free / dissociable IGF-1/2
pIGF-1R/IGF-1R in PRP
2
1
1
-0:05
Blood sampling prior to 
abemaciclib administration, 
xentuzumab infusion and 
fulvestrant injection
X
X
X***
X
X
X
X
0:00
Start of xentuzumab infusion
0:01
Abemaciclib administration
0:00
Fulvestrant injection up to 
15min. after start of xentuzumab
infusion
1:00**
Immediately at the end of 
xentuzumab infusion
X
X1
X1
2:30
X1
X1
4:00
X1
X1
6:00
X1
X1
8:00 
X1
X1
12:00 
[± 2:00]
Blood sampling ~5 minutes 
before intake of evening dose of 
abemaciclib
X1
X1
X1
1
2
23:55
X1
X1
24:00
Abemaciclib administration
1b
4
72:00
Blood sampling prior to 
abemaciclib administration
X1
X1
2
8
168:00
Blood sampling prior to 
xentuzumab infusion
X1
X1
3
15
336:00
Blood sampling prior to 
xentuzumab infusion
X1
4
22
504:00
Blood sampling prior to 
xentuzumab infusion
X1
** If the infusion duration is different from 1h, please adapt the planned time accordingly.
*** At days of abemaciclib PK sampling, patients have to take their morning dose of abemaciclib in the hospital in order to 
allow exact timing of PK sampling
1 these PK samples will be collected for at least 15 subjects in cohort D1 and at least 15 subjects in cohort D2.


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10.2.4.3
FLOW CHART for PK, Immunogenicity, biomarkers for cohorts D1 and D2 in 
treatment courses 3, 4, 6, 12, 24, EOTV and FU
Course
Visit
Day
Planned time
[h:min]
Event and comment
Xentuzumab PK
ADA
Abemaciclib and 
metabolites PK
Fulvestrant PK
Total IGF-1/2, IGFBP-3
Free /dissociable IGF-1/2
pIGF-1R/IGF-1R in PRP
3, 4, 6, 
12, 24
1
1
-0:05
Blood sampling prior to abemaciclib 
administration, xentuzumab infusion
and fulvestrant injection
X
X
X1
X1
X2 X2
X
0:00
Start of xentuzumab infusion
EOTV
EOTV
Within 7d 
after last 
drug 
intake
998:00*
End of treatment visit
X
X
X
X
X
FU
FU
42 +7d 
after last 
drug 
intake
999:00*
Follow-up
X
X
X
X
X
*Planned times listed at visit EOTV and FU are considered to be dummy planned times to set-up the database, the 
description in column “Day” defines the timing for these specific samples
1 this sample needs to be collected in course 3 and course 4 only
2 this sample needs to be collected in course 3, course 4, and course 6 only


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10.3
TUMOUR TISSUE SAMPLE REQUIREMENTS
Marker 
category
Tissue 
type
Amount of tissue
Time point of 
sample taking
Analysis type
PGx
FFPE 
(RNase-
free)
Preferably FFPE 
tumour tissue block 
for preparation of 
8x 5µm sections
screening
RNA expression
PGx/Protein 
Biomarkers
FFPE
Preferably FFPE 
tumour tissue block 
for preparation of 
17x 5µm sections
screening
DNA isolation + 
mutational/CNA 
analysis and 
biochemical protein 
analysis (e.g. IHC)


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10.4
TUMOUR RESPONSE ASSESSMENT ACCORDING TO RECIST 1.1
Response criteria for target lesions
1.   Complete Response (CR):
Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have a 
reduction in short axis to <10mm)
2.   Partial Response (PR):
At least a 30% decrease in the sum of diameters of 
target lesions taking as reference the baseline sum 
diameters
3.   Progression (PD):
At least a 20% increase in the sum of diameters of 
target lesions, taking as references the smallest sum on 
study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute 
increase of at least 5mm (note: the appearance of one or 
more new lesions is also considered progression).
4.   Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as 
references the smallest sum diameters while on study
Response criteria for non-target lesions
1.   Complete Response (CR):
Disappearance of all non-target lesions and 
normalization of tumour marker level. All lymph nodes 
must be non-pathological in size (<10mm short axis)
2.   Non-CR/ Non-PD:
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumour marker level above the normal 
limits
3.   Progression (PD):
Unequivocal progression of existing non-target lesions 
(Note: the appearance of one or more new lesions is 
also considered progression)


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Time point response for patients with measurable disease at baseline
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 all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Time point response for patients with non-measurable disease at baseline
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/ Non-PD
No
Non-CR/ Non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
RECIST 1.1 is as published in Eur. J. Cancer R09-0262
Best overall response is evaluated from first treatment administration until the earliest of 
disease progression, death or last evaluable tumour assessment before start of subsequent anti-
cancer therapy. When stable disease is believed to be best response, it must also meet a 
minimum time from first treatment administration of 48 days (i.e. according Flow Chart, the 
first post−baseline imaging should be performed within 63 days after start of xentuzumab). 
Note that clinical disease assessment will not be considered for determination of best overall 
response. No confirmation is required for best overall response


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10.5
CLINICAL EVALUATION OF LIVER INJURY
10.5.1
Introduction
Alterations of liver parameters, as described in Section 5.3.6.1 (Protocol-Specified Adverse 
events of special interest), are to be further evaluated using the following procedures:
10.5.2
Procedures
Any elevation of ALT/AST and bilirubin qualifying as laboratory alert should be confirmed 
using the initial sample if possible.
If the alert is confirmed on initial sample, or it is not possible to repeat testing using initial 
sample, the following must be completed:
1)
Evaluate patient within 48 hours and
2)
Perform the following laboratory tests: 
1. Repeat of AST, ALT, bilirubin (with fractionation to total and direct) 
2. Haptoglobin
3. Complete blood count and cell morphology
4. Reticulocyte count
5. Creatine Kinase (CK)
6. Lactate dehydrogenase (LDH)
7. Alkaline Phosphatase
The results of these laboratory tests must be reported to BI as soon as possible.
If the initial alert values (i.e. AST,ALT, and bilirubin) are confirmed on the second sample 
described as above, then an abdominal ultrasound or clinically appropriate alternate imaging  
(to rule out biliary tract, pancreatic or intrahepatic pathology, e.g. bile duct stones or neoplasm) 
must be completed within 48 hours. 
The findings from the hepatic imaging (including comparison to prior imaging if available) 
must be made available as soon as possible as part of the adverse event reporting process. In 
the event the etiology of the abnormal liver tests results is not identified based on the imaging 
(e.g. biliary tract, pancreatic or intrahepatic pathology), then the “DILI checklist” must be 
completed.  Details of the “DILI checklist” are provided in the ISF.  The following assessments 
need to be performed in order to complete the “DILI checklist” and results will be reported via 
the eCRF:
obtain a detailed history of current symptoms and concurrent diagnoses and medical history 
according to the “DILI checklist” provided in the ISF;
obtain history of concomitant drug use (including non-prescription medications, herbal and 
dietary supplement preparations), alcohol use, recreational drug use, and special diets 
according to the “DILI checklist” provided in the ISF;
obtain a history of exposure to environmental chemical agents (consider home and work place 
exposure) according to the “DILI checklist” provided in the ISF;
complete the following laboratory tests as detailed in the DILI checklist provided in the ISF:
Clinical chemistry


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Alkaline phosphatase, cholinesterase (serum)*, albumin, PT or INR, CK, CK-MB, 
coeruloplasmin*, α-1 antitrypsin*, transferrin*, amylase, lipase, fasting glucose, cholesterol, 
triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-
HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-HEV, 
Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody (titer), Anti-
nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-mitochondrial 
antibody, Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), herpes 
simplex virus (IgG, IgM)*, varicella (IgG, IgM)*, parvovirus (IgG, IgM)*
Hormones, tumour marker
Thyroid-stimulating hormone (TSH)*
Haematology
Thrombocytes, eosinophils
*If clinically indicated (e.g. immunocompromised patients)
Long term follow-up
Initiate close observation of subjects by repeat testing of ALT, AST, and bilirubin (with 
fractionation to total and direct) at least weekly until the laboratory ALT and or AST 
abnormalities stabilize or return to normal, then according to the protocol. Depending on 
further laboratory changes, additional parameters identified e.g. by reflex testing will be 
followed up based on medical judgement and Good Clinical Practices (GCP).
and report these via the eCRF.
10.6
STATISTICAL APPENDIX
A Bayesian logistic regression model with overdose control will be used to guide dose 
escalation/ de-escalation in cohorts A, B, C and D(dose finding). The BLRM is introduced in 
Section 7.1, which also specifies the prior for the model in cohort A. The priors for other dose 
finding cohorts (B, C and D(dose finding)) will be documented in the TSAP. After patients in 
each dose group have completed at least one course of treatment, the prior distributions will be 
updated through Gibbs sampling procedures with the accumulated DLT data from the MTD 
evaluation period. Posterior probabilities for the rate of DLT will be summarised from BLRM. 
Selection of the next dose combinations will be based on these probabilities as well as on other 
safety and laboratory data. 
The purpose of this statistical appendix is to present performance metrics (operating 
characteristics) that illustrate the precision of the design in estimating the MTD under various 
dose-toxicity relationships through computer simulation. These results are summarized in 
Table 10.6: 3. In addition, recommendations of the next dose combination by the BLRM with 
overdose control principle are also provided under various hypothetical outcome scenarios in 


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early dose groups to show how it facilitates on-study dose-escalation decisions (see Table 10.6: 
1). 
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.6: 1. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model. For each scenario, the 
probability of target dose and overdose for the current dose combination, as well as the next 
potential dose combination and related probabilities of under-dosing, target dose, and over-
dosing are shown.
For example, scenario 1 shows the example, that at the starting dose combination 150 mg 
abemaciclib and 1000 mg xentuzumab none of 3 patients experiences a DLT. Then, the BLRM 
allows treating patients at the same dose which is the maximum combination dose allows by 
the protocol. 
Scenario 4 shows the example, that at the starting dose combination 150 mg abemaciclib and 
1000 mg xentuzumab none of 6 patients experiences a DLT. Therefore, the MTD in this case 
would be the combination of 150 mg / 1000 mg. 
Scenario 6 shows the example that at the starting dose combination 150 mg abemaciclib and 
1000 mg xentuzumab 2 out of 3 patients experiences a DLT, then none of 3 patients treated at 
100 mg / 1000 mg experiences a DLT. The overdose control of the BLRM suggests escalating 
to 150 mg / 750 mg.
All these scenarios illustrate the adaptive behaviour of the model even in extreme situations.
Table 10.6: 1
Hypothetical data scenarios for cohort A
Scenario
Dose 
combi-
nation 
(mg/mg)
# patient 
/ # DLT
Current dose 
combination
Next 
recommended 
dose 
combination*
Next dose 
combination
P(TD) P(OD)
P(UD) P(TD) P(OD)
1
150/1000
3 / 0
0.179
0.027
150/1000
0.794
0.179
0.027
2
150/1000
3 / 1
0.376
0.141
150/1000
0.483
0.376
0.141
3
150/1000
3 / 2
0.397
0.430
100/1000
0.473
0.365
0.162
4
150/1000
150/1000
3 / 0
3 / 0
0.116
0.009
150/1000
0.876
0.116
0.009
5
150/1000
150/1000
3 / 1
3 / 0
0.312
0.048
150/1000
0.640
0.312
0.048
6
150/1000
100/1000
3 / 2
3 / 0
0.309
0.053
150/750
0.324
0.491
0.185


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Table 10.6: 1 (cont.)
Hypothetical data scenarios for cohort A
Scenario
Dose 
combi-
nation 
(mg/mg)
# patient 
/ # DLT
Current dose 
combination
Next 
recommended 
dose 
combination*
Next dose 
combination
7
150/1000
100/1000
100/1000
3 / 2
3 / 0
3 / 1
0.428
0.081
100/1000
0.491
0.428
0.081
* Recommended dose combination is the dose combination with the highest target probability. Note that other combinations 
have similar target toxicity probabilities.
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating the 
precision of the design in estimating the MTD. Under an assumed true dose-toxicity curve, 
metrics such as the probability of recommending a dose combination with true DLT rate in the 
target interval can be approximated via simulation. 
Table 10.6: 2 describes 4 assumed true dose-toxicity scenarios which were used to assess the 
operating characteristics of this model. These scenarios reflect a wide range of possible cases 
as follows:
*
Scenario 1: aligned with prior means
*
Scenario 2: high-toxicity scenario
*
Scenario 3: low-toxicity scenario
*
Scenario 4: low-high-toxicity scenario
Table 10.6: 2
Assumed true dose-toxicity scenarios for cohort A
Dose 
combination 
(mg/mg)
Scenario
1: Prior
2: High Tox
3: Low Tox
4: Low-High
100/750
P(DLT)
0.083
0.16
0.03
0.08
150/750
0.137
0.24
0.08
0.16
100/1000
0.092
0.17
0.06
0.10
150/1000
0.150
0.31
0.10
0.20
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the following rule:

Escalate to the dose combination which maximises the probability of the targeted 
toxicity region and satisfies the overdose criterion 


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The MTD was considered reached if at least 6 patients have been evaluated at a dose 
combination which is the model’s recommendation for the next dose-level cohort and for 
which the posterior probability of targeted toxicity was at least 50%. Or if in total 6 patients 
have been evaluated at a dose combination which is the model’s recommendation for the next 
dose-level cohort.
It was then assessed how often a dose combination was declared as MTD with true DLT rate 
in the under-, targeted or over-dose range.
Furthermore, the average, minimum and maximum number of patients per trial and the 
average number of DLTs per trial are reported. Results are shown in Table 10.6: 3 below.
Table 10.6: 3
Simulated operating characteristics for cohort A
Scenario
% of trials declaring a MTD with true DLT rate in
# Patients
# DLTs
underdose
target dose
overdose
Stopped
Mean 
(Min-Max)
Mean
(Min-Max)
1: Prior
43.7
54.3
0
2.0
10.86
(3, 21)
2.19
(0, 8)
2: High 
Tox
0
68.3
23.3
8.4
10.68
(3, 21)
3.10
(1, 9)
3: Low 
Tox
23.9
73.3
0
2.8
11.94
(3, 21)
1.75
(0, 7)
4: Low-
High
3.9
55.1
38.9
2.1
12.10
(3, 21)
2.91
(1, 9)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
almost all of the simulated trials (54%) that have found a MTD declared the MTD with true 
toxicity rate in the target interval. Few simulated trials (2.0%) have been stopped before 
declaring a MTD. None of trials declared a MTD with true DLT rate in the overdose interval. 
In scenario 2 (high-toxicity scenario) 68% of the simulated trials that have found a MTD 
declared the MTD with true toxicity rate in the target interval and 23% declared a MTD with 
true DLT rate in the overdose interval. Few simulated trials (8%) have been stopped before
declaring a MTD.
Scenario 3 (low-toxicity scenario) illustrates a behaviour similar to scenario 1.
Scenario 4, a mixture of the high toxicity and the low toxicity scenario, shows characteristics 
of both of these.
The mean patient numbers range from 10.68 patients (Scenario 2) to 12.10 patients (Scenario 
4) and the maximum number of patients was 21. Therefore, the patient numbers are as 
expected.


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By reviewing the metrics presented, it can be seen that the model is not sensitive to different 
scenarios of truth. In general, this model is conservative due to the overdose control criteria. 
In all scenarios, the probabilities of recommending a dose combination with true P(DLT) ≥ 
33% as MTD are much smaller than probabilities of recommending a dose combination with 
true P(DLT) between 16% and 33% as MTD.
On-study recommendations based on the model are consistent with the clinical decision 
making process, and should be considered in conjunction with other available clinical 
information by the SC in deciding the dose levels to be tested in order to determine the MTD 
estimates.
R version 3.2.2 was used for data scenarios and simulations.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Number of global amendment
1
Date of CTP revision
30 January 2017
EudraCT number
2016-003142-85
BI Trial number
1280.18
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
An open label, phase Ib, dose-escalation study 
evaluating the safety and tolerability of 
xentuzumab and abemaciclib in patients with 
locally advanced or metastatic solid tumours and 
in combination with endocrine therapy in patients 
with locally advanced or metastatic hormone 
receptor-positive, HER2-, breast cancer, followed 
by expansion cohorts
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
Yes
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
No
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
No
Section to be changed
Clinical Trial Protocol Synopsis – Main Criteria 
for inclusion –  Cohort A (Solid Tumours)
Description of change
Clarification of the inclusion criteria referring to 
previous treatment for trial disease
Rationale for change
Revision of the wording as per FDA request
Section to be changed
Clinical Trial Protocol Synopsis – Main Criteria 
for inclusion –  Cohort E
Description of change
Additional request to have NSCLC disease 
confirmed by histology or cytology
Rationale for change
Revision of the criteria as per FDA request
Section to be changed
Clinical Trial Protocol Synopsis – Main Criteria 
for inclusion –  Exclusion criteria


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Description of change
Revision of the starting time of trial treatment 3 
half-lives after previous immunotherapy instead 
of 2.
Rationale for change
As per FDA request and in order to minimize 
overlapping toxicities
Section to be changed
Flow Chart Cohort E and F – Blood sample for 
Biomarkers
Description of change
Correction of sampling timepoint at Run-In V3
Rationale for change
Revision of the whole protocol and in order to 
keep consistency between sections. No Biomarker 
sampling needed at Run-In V3 for Cohorts E and 
F.
Section to be changed
Flow Chart Cohort F – Footnote #11
Description of change
Change details form Cohort G to Cohort F
Rationale for change
Correction of a typographic error, as no Cohort G 
planned in the final protocol
Section to be changed
Section 3.3.2. Inclusion Criteria – Cohort A –
Criteria #7
Description of change
Clarification of the inclusion criteria referring to 
previous treatment for trial disease
Rationale for change
Revision of the wording as per FDA request
Section to be changed
Section 3.3.2. Inclusion Criteria – Cohort B, C, D, 
F (Breast Cancer) – Criteria #8
Description of change
Definition of the HER2 negativity as per 
ASCO/CAP guidelines
Rationale for change
Inclusion of this references as per FDA request
Section to be changed
Section 3.3.2. Inclusion Criteria – Cohort B, C, D, 
F (Breast Cancer) – Criteria #10
Description of change
Change from Cohort G to Cohort F
Rationale for change
Correction of a typographic error, as no Cohort G 
planned in the final protocol
Section to be changed
Section 3.3.2. Inclusion Criteria – Cohort E 
(NSCLC) – Criteria #6
Description of change
Additional request to have NSCLC disease 
confirmed by histology or cytology
Rationale for change
Revision of the criteria as per FDA request
Section to be changed
Section 3.3.3. Exclusion Criteria #7


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Description of change
Revision of the starting time of trial treatment 3 
half-lives after previous immunotherapy instead 
of 2.
Rationale for change
As per FDA request and in order to minimize 
overlapping toxicities
Section to be changed
Section 4.1.2.2 Part 2 – Dose finding cohorts B, 
C, D
Description of change
Clarification of the text referring to starting dose 
of the study drugs
Rationale for change
Wording error corrected, in order to add clarity to 
the text
Section to be changed
Section 4.1.4.2 Temporary treatment interruption 
and dose reduction
Description of change
Clarification of the dose interruption 
recommendations, with special clarification for 
potential overlapping toxicities. 
Rationale for change
As per FDA request and in order to minimize 
overlapping toxicities
Section to be changed
Section 4.4.1 Increased serum creatinine
Description of change
Inclusion of the need to perform serum cystatin-C 
testing to identify true renal function beyond 
monitoring creatinine
Rationale for change
As per FDA request and in order to give more 
detailed guidelines in case of renal dysfunction
Section to be changed
Section 5.3.7. Dose Limiting Toxicities (DLTs)
Description of change
Revision of the DLT definition and protocol 
defined DLTs
Rationale for change
As per FDA request and in order to give more 
details to this section.


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11.2
GLOBAL AMENDMENT 2
Number of global amendment
2
Date of CTP revision
22 September 2017
EudraCT number
2016-003142-85
BI Trial number
1280.18
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
An open label, phase Ib, dose-escalation study 
evaluating the safety and tolerability of 
xentuzumab and abemaciclib in patients with 
locally advanced or metastatic solid tumours and in 
combination with endocrine therapy in patients 
with locally advanced or metastatic hormone 
receptor-positive, HER2-, breast cancer, followed 
by expansion cohorts
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
Yes
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
No
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
No
Section to be changed
Clinical Trial Protocol Synopsis – Main Criteria for 
inclusion –  Cohort E
Description of change
Clarification on number of prior lines that 
participants must have received
Rationale for change
To make text consistent with inclusion criteria in 
section 3.3.2.
Section to be changed
Clinical Trial Protocol Synopsis – Main Criteria for 
exclusion 
Description of change
Clarification on prior therapies and unresolved 
toxicities
Rationale for change
To make text consistent with exclusion criteria in 
section 3.3.3.
Section to be changed
Flow Chart Cohort E – Footnote #6
Description of change
Change detail for Run-in visit 2 


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Rationale for change
Correction according to the Flow Chart
Section to be changed
Flow Chart Cohort F
Description of change
Added footnote reference for Fulvestrant
Rationale for change
Correction of typographic error
Section to be changed
Section 3.3.3. Exclusion Criteria #3
Description of change
Change the word enrolment for  treatment
Rationale for change
To avoid confusing terminology
Section to be changed
Section 3.3.3. Exclusion Criteria #7
Description of change
Exclusion of prior corticosteroids is deleted
Rationale for change
To keep consistency with section 4.2.2.
Section to be changed
Section 3.3.3. Exclusion Criteria #10
Description of change
Clarification of the exclusion criteria referring to 
unresolved toxicities from prior treatment
Rationale for change
To add clarity to the criteria
Section to be changed
Section 3.3.3. Exclusion Criteria #18
Description of change
Threshold added for diabetes
Rationale for change
To keep consistency with the synopsis
Section to be changed
4.1.4.1 Initial study drug assignment and 
administration
Description of change
Change of term referring to dose finding cohorts 
Rationale for change
Correct wording error
Section to be changed
4.1.4.2 Temporary treatment interruption and dose 
reduction
Description of change
Clarification on re-escalation possibilities 
Rationale for change
To improve wording clarity
Section to be changed
4.1.4.2 Temporary treatment interruption and dose 
reduction
Description of change
Clarification on dose reduction requirements
Rationale for change
To keep consistency within the section
Section to be changed
4.1.4.2 Temporary treatment interruption and dose
Description of change
Footnote added referring to toxicity management 
Rationale for change
To clarify instructions for toxicity management
Section to be changed
4.4.2 Management and grading of infusion
reactions
Description of change
Clarification on CRF page reporting
Rationale for change
To be consistent with CRF design


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Section to be changed
5.3.4 Electrocardiogram
Description of change
Correction of cohorts with run-in visits
Rationale for change
To correct the typo error
Section to be changed
5.3.6.1 Definitions of AEs
Description of change
The requirement specific for Japan about the reason 
of the decision about causality is deleted
Rationale for change
The requirement is no longer applicable in Japan,
Section to be changed
5.3.7 Dose Limiting Toxicities
Description of change
The list of DLTs definitions is revised
Rationale for change
To make the text consistent with the study drugs 
toxicity profile
Section to be changed
5.4.1 Assessment of Pharmacokinetics
Description of change
Clarification is added about sample timepoints 
Rationale for change
To add some flexibility in the sample time schedule
Section to be changed
5.5 Assessment of biomarker(s)
Description of change
Biomarker name corrected and dissociable IGF 
added
Rationale for change
To correct a typo error and introduce the 
dissociable IGF definition
Section to be changed
5.6.1 Assessment of Immunogenicity
Description of change
Appendix reference corrected
Rationale for change
To correct a typo error
Section to be changed
8.1 Trial approval, patient information, informed 
consent.
Description of change
A clause is added to identify the text that is only 
applicable to Japan
Rationale for change
To clarify that the text is not applicable to all 
participant countries
Section to be changed
10.1 Inducers and Strong Inhibitors of CYP3A4
Description of change
Topical medication considerations
Rationale for change
For clarification purposes
Section to be changed
10.2 Pharmacokinetics plan
Description of change
Dissociable IGF is mentioned in the flowcharts for 
the different cohorts
Rationale for change
To be consistent with section 5.5


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11.3
GLOBAL AMENDMENT 3
Number of global amendment
3
Date of CTP revision
11 Dec 2018
EudraCT number
2016-003142-85
BI Trial number
1280.18
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
An open label, phase Ib, dose-escalation study 
evaluating the safety and tolerability of 
xentuzumab and abemaciclib in patients with 
locally advanced or metastatic solid tumours and 
in combination with endocrine therapy in patients 
with locally advanced or metastatic hormone 
receptor-positive, HER2-, breast cancer, followed 
by expansion cohorts
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
Yes
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval
No
Can be implemented without IRB 
/ IEC / Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
No
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Different sections updated 
Rationale for change
To match with the updates in the different 
protocol sections. 
Section to be changed
Clinical Trial Protocol Synopsis-Flow Chart for 
Cohorts A, B, C and D (dose finding)
Description of change
Footnote #16 corrected
Rationale for change
To clarify an bone scan requirement and correct 
on day windows for week 60 and week 72 
Section to be changed
Clinical Trial Protocol Synopsis-Flow Chart for 
Cohort D (dose finding)
Description of change
Footnote #6 modified
Rationale for change
To reduce the screening window for local FSH 
and estradiol
Section to be changed
Clinical Trial Protocol Synopsis-Flow Chart 
Cohort E and F


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Description of change
Footnote #18 corrected
Rationale for change
To clarify an bone scan requirement and correct 
on day windows for week 60 and week 72 
Section to be changed
Clinical Trial Protocol Synopsis-Flow Chart 
Cohort F
Description of change
Footnote #7 modified
Rationale for change
To reduce the screening window for local FSH 
and estradiol
Section to be changed
Clinical Trial Protocol Synopsis-Flow Chart 
Expansion cohorts D1 and D2
Description of change
New Flow Chart added
Rationale for change
To describe the schedule of activities for BC  
expansion cohorts D1 and D2
Section to be changed
1.2 Drug Profile
Description of change
Text added in the IMPs profile information
Rationale for change
To update with available information
Section to be changed
2.1 Rationale for performing the trial
Description of change
Text added
Rationale for change
Updated information and added rationale for 
expansion cohorts D1 and D2
Section to be changed
2.2 Trial Objectives
Description of change
Text added
Rationale for change
Primary objective for expansion cohorts D1 and 
D2 is described
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
Part 3 design update
Rationale for change
To include and describe expansion cohorts D1 
and D2
Section to be changed
3.2 Discussion of Trial Design
Description of change
Section updated
Rationale for change
For expansion cohorts D1 and D2 description
Section to be changed
3.3 Selection of Trial Population
Description of change
Change the total number of subjects and sites
Rationale for change
To update the figures needed as per the new 
cohorts addition
Section to be changed
3.3.2 Inclusion criteria-Cohort A and E: #5


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Description of change
Required contraception methods timelines 
updated
Rationale for change
According to the updated abemaciclib risk profile
Section to be changed
3.3.2 Inclusion criteria-B, C, D(dose finding) and 
F Cohorts: #5
Description of change
Postmenopausal status requirements wording 
revision
Rationale for change
To improve specificity and clarity in the criteria
Section to be changed
3.3.2 Inclusion criteria- cohorts D1 and D2 
Description of change
Cohorts D1 and D2 inclusion criteria added
Rationale for change
To describe inclusion criteria for expansion 
cohorts D1 and D2 
Section to be changed
3.3.3 Exclusion criteria(cohorts A, B, C, D(dose 
finding), E and F: #7
Description of change
Text modified
Rationale for change
To relax washout required periods 
Section to be changed
3.3.3 Exclusion criteria (cohorts A, B, C, D(dose 
finding), E and F: #12
Description of change
Clarifications on central nervous system disease
Rationale for change
To further clarify 
Section to be changed
3.3.3 Exclusion criteria (cohorts A, B, C, D(dose 
finding), E and F: #24
Description of change
Clarification added on active infections
Rationale for change
To be more specific on active infection definition
Section to be changed
3.3.3 Exclusion criteria:#27
Description of change
New criteria
Rationale for change
To exclude prior everolimus treatment for cohort 
F 
Section to be changed
3.3.3 Exclusion criteria- cohorts D1 and D2
Description of change
Cohorts D1 and D2 exclusion criteria added
Rationale for change
To describe exclusion criteria for expansion 
cohorts D1 and D2
Section to be changed
3.3.5 Replacement of patients
Description of change
Text added for dose interruption both for 
xentuzumab and abemaciclib. Also replacement 
for cohorts E and F is added.
Rationale for change
For clarification purposes for dose interruption 
and provide new instruction for cohort E and F


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Section to be changed
4.1.2 Selection of doses in the trial
Description of change
Updated information for Part 3 
Rationale for change
To include the information for cohorts D1 and D2
Section to be changed
4.1.4.2 Temporary treatment interruption and 
dose reduction
Description of change
Text revised for overlapping toxicities and DLT 
management
Rationale for change
Clarification on the management of overlapping 
toxicities and DLTs
Section to be changed
4.1.4.2:2 Table
Description of change
Header changed
Rationale for change
To clarify that the table is about abemaciclib 
possibly related toxicity. 
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Paragraph deleted as per restrictions for 
abemaciclib.
Rationale for change
Revise the text about CYP3A4 restrictions 
Section to be changed
4.2.2.3 Restrictions regarding men and women of 
childbearing potential
Description of change
Required contraception methods timelines 
updated
Rationale for change
According to the updated abemaciclib risk profile
Section to be changed
4.2.2.7 Restrictions regarding ovarian suppression
Description of change
New section added
Rationale for change
Requirement added to ensure the postmenopausal 
status is maintained
Section to be changed
4.4.2 Management and grading of infusion 
reactions
Description of change
IRR Management instructions revised
Rationale for change
To be in alignment with other xentuzumab trials
Section to be changed
4.4.3 Management on neutropenia
Description of change
New section added
Rationale for change
To reinforce and ensure the monitoring of 
neutropenia as expected adverse event. 
Section to be changed
4.4.4 Management of hepatotoxicity
Description of change
New section added


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Rationale for change
To provide guidance on the management of 
hepatotoxicity as expected adverse event.
Section to be changed
5.1.1 Primary endpoint(s)
Description of change
Section updated for expansion cohorts D1 and D2 
Rationale for change
To describe primary endpoint for expansion 
cohorts D1 and D 2 
Section to be changed
5.1.2 Secondary endpoint(s)
Description of change
Section updated for expansion cohorts D1 and D2 
Rationale for change
Secondary endpoint added for expansion cohorts 
D1 and D2 
Section to be changed
Description of change
Rationale for change
Section to be changed
5.2 Assessment of efficacy
Description of change
Text added for bone scans requirements
Rationale for change
To clarify on the follow up requirements for bone 
metastasis assessments
Section to be changed
5.3.6.2 Adverse event collection and reporting
Description of change
Instructions added for female partner in the 
pregnancy section
Rationale for change
To extend the requirements of  DEDP reporting to 
the female partner of a male participant
Section to be changed
5.3.7 Dose limiting toxicities (DLTs) 
Description of change
Revision of DLT definitions
Rationale for change
To excluded some hematologic toxicities and IRR
Section to be changed
5.4.2 Methods of sample collection
Description of change
Clarification on plasma samples use
Rationale for change
No needed to wait until completion of the study to 
use them. 
Section to be changed
5.5 Assessment of biomarker(s)
Description of change
Addition of sample retention plan
Rationale for change
To clarify on remaining sample retention 
timelines
Section to be changed
6.2. Details of trial procedures at selected visits


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Description of change
Description added for cohorts D1 and D2 
procedures (6.2.2.3) 
Rationale for change
To describe the procedures required for expansion 
cohorts D1 and D2 
Section to be changed
7.3 Planned analysis
Description of change
Description added for the possibility of primary 
analysis for the expansion cohorts
Rationale for change
To clarify on the primary analyses planned
Section to be changed
7.3.1 Primary endpoints analysis
Description of change
Addition of planned analysis for expansion 
cohorts D1 and D2
Rationale for change
To update for cohorts D1 and D2 addition
Section to be changed
7.3.2 Secondary endpoint analyses
Description of change
Addition of secondary endpoint analyses for 
cohorts D1 and D2
Rationale for change
To update for cohorts D1 and D2 addition
Section to be changed
7.3.5 Pharmacokinetic and pharmacodynamics 
analyses
Description of change
Addition of a clarification on the NCA 
Rationale for change
To clarify that only applies to the expansion 
cohorts
Section to be changed
7.4 Interim analyses
Description of change
Added an statement about earlier efficacy 
analyses
Rationale for change
To clarify that other efficacy analyses may be 
performed
Section to be changed
7.7 Determination of sample size
Description of change
Descriptions added for cohorts D1 and D2 
Rationale for change
To update for cohorts D1 and D2 addition
Section to be changed
8.6 Trial milestones
Description of change
Addition of description of LPLVPE-expansion for 
cohorts D1 and D2 
Rationale for change
To specify different milestone for different 
expansion cohorts 
Section to be changed
10.2.3.2 Flow chart for PK, immunogenicity, and 
biomarkers for Cohort F in treatment course 2
Description of change
Updates on the events


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Rationale for change
Clarifications on the requirements about the 
sampling related to the abemaciclib intake
Section to be changed
10.2.4 Flow chart for PK, immunogenicity, and 
biomarkers for cohorts D1 and D2 
Description of change
New flow charts 
Rationale for change
To describe the required sampling for cohorts D1 
and D2 


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11.4
GLOBAL AMENDMENT 4
Number of global amendment
4
Date of CTP revision
09 Apr 2019
EudraCT number
2016-003142-85
BI Trial number
1280.18
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
An open label, phase Ib, dose-escalation study 
evaluating the safety and tolerability of 
xentuzumab and abemaciclib in patients with 
locally advanced or metastatic solid tumours and 
in combination with endocrine therapy in patients 
with locally advanced or metastatic hormone 
receptor-positive, HER2-, breast cancer, followed 
by expansion cohorts
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
Yes
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval
No
Can be implemented without IRB 
/ IEC / Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
No
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Main criteria for inclusion for diagnosis of breast 
cancer corrected
Rationale for change
To be consistent with section 3.3.2
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Correction of flowchart for cohorts C and D for 
baseline tumour assessment timepoint
Rationale for change
For consistency
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Footnote  #16 in Flowchart for Cohorts D1 and 
D2 corrected
Rationale for change
To be consistent  with 10.2.4.3 flowchart
Section to be changed
1.2 Drug profile
Description of change
Safety profile for xentuzumab updated
Rationale for change
Updated data as per cut off of 2019


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Section to be changed
2.1 Rationales for performing the trial
Description of change
Correction made when describing expansion 
cohorts
Rationale for change
Letrozole and anastrozole are not used 
Section to be changed
2.3 Benefit-Risk Assessment
Description of change
Data for xentuzumab updated
Rationale for change
To keep the information up to date
Section to be changed
3.3.2 Inclusion criteria
Description of change
In #9 for cohorts D1 and D2 corrected
Rationale for change
To be consistent with abemaciclib risk profile
Section to be changed
3.3.3 Exclusion criteria 
Description of change
Ex #17 for Cohorts D1 and D2 corrected
Rationale for change
Letrozole and anastrozole do not apply for those 
cohorts
Section to be changed
4.1.4.2 temporary treatment interruption and dose 
reduction
Description of change
Guidelines for abemaciclib toxicity management 
update 
Rationale for change
To be aligned with the most recent abemaciclib 
safety information
Section to be changed
4.2.2 Restrictions
Description of change
Updated instructions and guidelines as per 
inducers and inhibitors of CYP3A
Rationale for change
To be aligned with the most recent abemaciclib 
safety information
Section to be changed
4.4.4 Management of Hepatotoxicity
Description of change
Updated information and guidelines
Rationale for change
To be aligned with the most recent abemaciclib 
safety information
Section to be changed
4.4.5 Venous Thromboembolism
Description of change
New section added
Rationale for change
To provide information ad instructions to manage 
the adverse event
Section to be changed
10.1 Inducers and strong inhibitors of CYP3A4
Description of change
The lists of the strong inhibitors and substrates are 
updated


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Rationale for change
To be aligned with the most recent abemaciclib 
safety information
Section to be changed
10.2.4.1 Flowchart for PK, AD and biomarkers 
for cohorts D1 and D2 in course 1
Description of change
Footnote deleted
Rationale for change
For consistency
Section to be changed
10.2.4.2 Flowchart for PK, AD and biomarkers 
for cohorts D1 and D2 in course 2
Description of change
Fulvestrant PK sample correction
Rationale for change
For consistency
Section to be changed
10.2.4.3 Flowchart for PK, AD and biomarkers 
for cohorts D1 and D2 in courses 3, 4, 6, 12 and 
24
Description of change
Header and footnotes corrected
Rationale for change
For consistency


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11.5
GLOBAL AMENDMENT 5
Number of global amendment
5
Date of CTP revision
03 Jul 2019
EudraCT number
2016-003142-85
BI Trial number
1280.18
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
An open label, phase Ib, dose-escalation study 
evaluating the safety and tolerability of 
xentuzumab and abemaciclib in patients with 
locally advanced or metastatic solid tumours and 
in combination with endocrine therapy in patients 
with locally advanced or metastatic hormone 
receptor-positive, HER2-, breast cancer, followed 
by expansion cohorts
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
Yes
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval
No
Can be implemented without IRB 
/ IEC / Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
No
Section to be changed
3.3.3 Exclusion criteria
Description of change
Exclusion criteria #13 was updated to exclude 
subjects with ILD and other respiratory disorders
Rationale for change
To be in accordance with updated abemaciclib 
safety information
Section to be changed
4.4.6 Guidance for ILD/Pneumonitis
Description of change
New section added
Rationale for change
To be in accordance with updated abemaciclib 
safety information


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11.6
GLOBAL AMENDMENT 6
Date of amendment
23 Dec 2019
EudraCT number
2016-003142-85
BI Trial number
1280.18
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
An open label, phase Ib, dose-escalation study 
evaluating the safety and tolerability of 
xentuzumab and abemaciclib in patients with 
locally advanced or metastatic solid tumours and 
in combination with endocrine therapy in patients 
with locally advanced or metastatic hormone 
receptor-positive, HER2-, breast cancer, followed 
by expansion cohorts
Global Amendment due to urgent safety reasons: 
  
       
Global Amendment
  
       
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Asia region included for trial sites 
Rationale for change
To extend to other Asian sites participation
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Tablets mentioned in the eligibility criteria
Rationale for change
To be consistent with section 3.3.2
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Alpelisib added as prior treatment in the 
exclusion criteria for cohorts D1 and D2
Rationale for change
For a better definition of trial population in 
reaction to a newly approved treatment
Section to be changed
3.3.2 Inclusion criteria
Description of change
Tablets added to inclusion criteria #4 for all 
cohorts
Rationale for change
To be consistent with the possibility of tablets 
intake
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion criteria #9 for cohorts D1 and D2 
updated as per the contraception period required 
for xentuzumab
Rationale for change
Re-assessment of contraception requirements for 
xentuzumab for WOCBP, including PK 
variability and normalization of PD effects.
Section to be changed
3.3.3 Exclusion criteria


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Description of change
Alpelisib added as prior treatment excluded for 
cohorts D1 and D2
Rationale for change
For a better definition of trial population in 
reaction to a newly approved treatment
Section to be changed
4.1.1 Identity of the Investigational  Medicinal 
Products
Description of change
Information added about abemaciclib tablets 
formulation
Rationale for change
Abemaciclib tablets can be administered to the 
study subjects 
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change
The possibility to reduce the abemaciclib dose to 
50 mg BID was added
Rationale for change
To facilitate abemaciclib AE management
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each patient
Description of change
Guidelines for abemaciclib dose adjustment to 
manage ILD/pneumonitis were added
Rationale for change
To be consistent with the abemaciclib IB 
information
Section to be changed
4.1.7 Storage conditions
Description of change
Abemaciclib tablets added
Rationale for change
To provide instruction on tablets storage 
requirements
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Instructions updated 
Rationale for change
To include the options to reduced abemaciclib 
dose to 50 mg twice daily.   
Section to be changed
4.2.2.3 Restrictions regarding men and women of 
childbearing potential
Description of change
Update on the contraception period required for 
xentuzumab
Rationale for change
Re-assessment of contraception requirements for 
xentuzumab for WOCBP, including PK 
variability and normalization of PD effects.
Section to be changed
4.4.6 Guidance for Interstitial lung 
disease/Pneumonitis


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Description of change
Text updated
Rationale for change
To be consistent with table 4.1.4.2:2


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11.7
GLOBAL AMENDMENT 7
Date of amendment
02 Jul 2020
EudraCT number
2016-003142-85
BI Trial number
1280.18
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
An open label, phase Ib, dose-escalation study 
evaluating the safety and tolerability of 
xentuzumab and abemaciclib in patients with 
locally advanced or metastatic solid tumours and 
in combination with endocrine therapy in patients 
with locally advanced or metastatic hormone 
receptor-positive, HER2-, breast cancer, followed 
by expansion cohorts
Global Amendment due to urgent safety reasons: 
  
       
Global Amendment
       
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Text amended in different sections of the synopsis
Rationale for change
To update the synopsis according to the changes 
made in different sections of the protocol
Section to be changed
Flow Chart-Cohort F
Description of change
Run-in visits and corresponding procedures were
removed
Rationale for change
The run-in data from cohort F is no longer 
required for analysis
Section to be changed
Flow Chart-Cohort F 
Description of change
A number PK samples in cycle 2 were removed
Rationale for change
Those PK samples in cohort F no longer required 
for analysis were removed to simplify the study 
procedures    
Section to be changed
Flow Chart-Cohort F
Description of change
Tumour assessment requirements in follow up 
period were highlighted
Rationale for change
To clarify the instructions to follow up for 
progression of disease
Section to be changed
Flow Chart Cohorts D1 and D2
Description of change
Tumour assessment requirements in follow up 
period were highlighted
Rationale for change
To clarify the instructions to follow up for 
progression of disease


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Section to be changed
2.2 Trial Objectives
Description of change
Trial objectives reworded for cohort F
Rationale for change
To accurately describe primary and secondary 
objectives for cohort F
Section to be changed
2.3 Benefit-Risk Assessment
Description of change
Language was added about Covid-19 infection 
Rationale for change
To provide information and guidance on Covid-
19 considerations for the trial
Section to be changed
3.1 Overall Trial Design Plan
Description of change
Section updated for cohort F information
Rationale for change
To accurately describe the design of cohort F
Section to be changed
3.2 Discussion of Trial Design, including the 
choice of control Group(s)
Description of change
Section updated for cohort F
Rationale for change
To amend the PK plan for cohort F
Section to be changed
3.3.2 Inclusion criteria
Description of change
Modified for cohort F
Rationale for change
To provide a detailed definition of the inclusion 
criteria for cohort F
Section to be changed
3.3.3 Exclusion criteria
Description of change
Modified for cohort F
Rationale for change
To provide a detailed definition of the exclusion 
criteria for cohort F
Section to be changed
3.3.5 Replacement of patients
Description of change
Amended for cohort F
Rationale for change
To be consistent with the endpoints updates for 
cohort F 
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Abemaciclib related information was updated
Rationale for change
Modified according to the most current 
information in the abemaciclib SmPC
Section to be changed
4.3 Treatment compliance
Description of change
Patient diary requirement for cohort F was 
removed
Rationale for change
To be consistent with the run-in visits removed
Section to be changed
4.4.1 Increased Serum Creatinine


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Description of change
Language was updated
Rationale for change
According to the latest abemaciclib information 
available
Section to be changed
5.1 Trial Endpoints
Description of change
Specific endpoints for cohort F were revised
Rationale for change
To accurately describe the primary and secondary 
endpoints for cohort F
Section to be changed
5.5 Assessment of Biomarker(s)
Description of change
Headers and footnotes of tables 5.5: 1 and 5.5:2 
were corrected
Rationale for change
Correction needed to resolve an inconsistency 
with the biomarker sampling plan
Section to be changed
6.1 Visit Schedule
Description of change
Language added about the possibility to visit the 
patient remotely
Rationale for change
That is to mitigate the difficulties to visit the 
patient at the site under extraordinary 
circumstances such as relevant infection 
outbreaks or similar. 
Section to be changed
6.2 Details of Trial Procedures at Selected Visits
Description of change
The procedures description were corrected
Rationale for change
To be consistent with the flow charts
Section to be changed
6.2.3.2 Follow up period
Description of change
Details added for follow up period for progression 
of disease
Rationale for change
To improve the description of the procedures 
required during the follow up period
Section to be changed
7.3. Planned Analyses
Description of change
Information added for cohort F
Rationale for change
To describe the analyses planned for cohort F 
endpoints
Section to be changed
7.7 Determination of sample size
Description of change
Specific description for cohort F was added
Rationale for change
Accurately describe the assumptions for cohort F
Section to be changed
10.1 Inducers and strong inhibitors of CYP3A4
Description of change
The list of drugs was revised
Rationale for change
According to the most updated abemaciclib 
information  


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Section to be changed
10.2.3 Flow chart for PK, immunogenicity, and 
biomarkers for cohort F
Description of change
The PK profile for cohort F was reduced
Rationale for change
To simplify the PK profile removing samples no 
longer required


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11.8
GLOBAL AMENDMENT 8
Date of amendment
04 Mar 2022
EudraCT number
2016-003142-85
BI Trial number
1280.18
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
An open label, phase Ib, dose-escalation study 
evaluating the safety and tolerability of 
xentuzumab and abemaciclib in patients with 
locally advanced or metastatic solid tumours and 
in combination with endocrine therapy in patients 
with locally advanced or metastatic hormone 
receptor-positive, HER2-, breast cancer, followed 
by expansion cohorts
Global Amendment due to urgent safety reasons: 
  
       
Global Amendment
  
       
Section to be changed
Flow Chart-Cohort F
Description of change
Schedule of activities revised. Some procedures 
removed
Rationale for change
To reflect reduced procedures and assessments to 
support ongoing patients because of 1280-0022 
primary endpoint analysis results
Section to be changed
Flow Chart-Cohorts D1 and D2
Description of change
Schedule of activities revised. Some procedures 
removed
Rationale for change
To reflect reduced procedures and assessments to 
support ongoing patients because of 1280-0022 
primary endpoint analysis results
Section to be changed
2.3 Benefit-Risk assessment
Description of change
New text added
Rationale for change
Based on the 1280-0022 study results of primary 
endpoint analysis
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
New text added
Rationale for change
To refer to the trial termination possibilities
Section to be changed
3.3.4.2 Discontinuation of the trial by the sponsor
Description of change
New text added
Rationale for change
To describe trial termination possibilities
Section to be changed
4.1 Investigation treatments


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Description of change
Xentuzumab treatment discontinuation 
recommendation added
Rationale for change
Based on benefit-risk change after 1280-022 
primary endpoint analysis results
Section to be changed
5.2 Assessment of efficacy
Description of change
Requirements for response assessments reduced
Rationale for change
Based on benefit-risk change after 1280-022 
primary endpoint analysis results
Section to be changed
5.3 Assessment of safety
Description of change
Requirements for safety assessments reduced
Rationale for change
Based on benefit-risk change after 1280-022 
primary endpoint analysis results
Section to be changed
5.4.1 Assessment of Pharmacokinetics
Description of change
PK samples are no longer collected
Rationale for change
Based on benefit-risk change after 1280-022 
primary endpoint analysis results
Section to be changed
5.4.2
Methods of sample collection
Description of change
Blood for PK and ADA is no longer collected
Rationale for change
Based on benefit-risk change after 1280-022 
primary endpoint analysis results
Section to be changed
5.5 Assessment of biomarker(s)
Description of change
biomarkers samples are no longer collected
Rationale for change
Based on benefit-risk change after 1280-022 
primary endpoint analysis results
Section to be changed
5.6.1 Assessment of Immunogenicity
Description of change
blood samples for immunogenicity assessments 
are no longer collected
Rationale for change
Based on benefit-risk change after 1280-022 
primary endpoint analysis results
Section to be changed
6.2.2.3 Cohorts D1, D2 and F
Description of change
Reference to reduced flow chart
Rationale for change
To be consistent with the revised flowcharts for 
cohorts D1, D2 and F
Section to be changed
6.2.3.1 End of treatment visit
Description of change
Sample collection details removed
Rationale for change
To be consistent with flowchart revision
Section to be changed
7.3 Planned analysis


Boehringer Ingelheim
04 Mar 2022
BI Trial No.: 1280.18
c09049566-10
Trial Protocol
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001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Description of change
Final analysis timepoint description removed
Rationale for change
To conduct final analyses before last patient out
Section to be changed
10.2.3 FLOW CHART for PK, immunogenicity, 
and biomarkers for cohort F
Description of change
Blood samples no longer collected
Rationale for change
To be consistent with the revised flowchart for 
cohort F
Section to be changed
10.2.4 FLOW CHART for PK, immunogenicity, 
and biomarkers for cohorts D1 and D2
Description of change
Blood samples no longer collected
Rationale for change
To be consistent with the revised flowchart for 
cohorts D1 and D2

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c17168379-02
BI Trial No.:
1280.18
Title:
An open label, phase Ib, dose-escalation study evaluating the 
safety and tolerability of xentuzumab and abemaciclib in patients 
with locally advanced or metastatic solid tumours and in 
combination with endocrine therapy in patients with locally 
advanced or metastatic hormone receptor-positive, HER2-, breast 
cancer, followed by expansion cohorts. 
Including Protocol Amendment 8 [c09049566-09]
Investigational
Product(s):
Xentuzumab (BI 836845)
Responsible trial 
statistician(s):
Tel.: 
Date of statistical 
analysis plan:
25 Oct 2021 SIGNED
Version:
2.0
Page 1 of 45
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.


Boehringer Ingelheim                                                                                    c17168379-02
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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
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY.........8
4.1
ADDITIONS/NEW ANALYSES.........................................................................8
4.2
CHANGES.............................................................................................................8
4.3
CLARIFICATIONS .............................................................................................8
5
ENDPOINTS ..........................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.1.1
Cohorts A, B, C, and D:....................................................................................9
5.1.2
Cohort E............................................................................................................9
5.1.3
Cohorts D1 and D2 .........................................................................................10
5.1.4
Cohort F..........................................................................................................13
5.2
SECONDARY ENDPOINTS.............................................................................13
5.2.1
Key secondary endpoints................................................................................13
5.2.2
Other secondary endpoints..............................................................................13
5.2.2.1
Cohorts A, B, C, and D.................................................................................13
5.2.2.2
Cohorts E, F, D1 and D2...............................................................................13
6
GENERAL ANALYSIS DEFINITIONS...........................................24
6.1
TREATMENTS ..................................................................................................24
6.2
IMPORTANT PROTOCOL DEVIATIONS ...................................................24
6.3
PATIENTS SETS ANALYSED.........................................................................29
6.5
POOLING OF CENTRES.................................................................................30
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................30
6.6.1
Adverse events................................................................................................31
6.6.2
Laboratory values at baseline .........................................................................31
6.6.3
PK parameters.................................................................................................31
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS..................31
6.7.1
Baseline...........................................................................................................31
6.7.2
Time windows for every RECIST assessment ...............................................32
7
PLANNED ANALYSES......................................................................33


Boehringer Ingelheim                                                                                    c17168379-02
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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........34
7.1.1
Disposition of patients ....................................................................................34
7.1.2
Important protocol deviations.........................................................................34
7.1.3
Demographic and other baseline characteristics.............................................34
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................34
7.3
TREATMENT COMPLIANCE........................................................................34
7.4
PRIMARY ENDPOINTS...................................................................................34
7.4.1
Cohorts A, B, C, and D...................................................................................34
7.4.2
Cohort E..........................................................................................................35
7.4.3
Cohorts D1 and D2 .........................................................................................35
7.4.4
Cohort F..........................................................................................................36
7.5
SECONDARY ENDPOINTS.............................................................................36
7.5.1
Key secondary endpoints................................................................................36
7.5.2
Other secondary endpoints..............................................................................36
7.5.2.1
Cohorts A, B, C and D..................................................................................36
7.5.2.2
Cohorts E and F, D1 and D2.........................................................................36
7.7
EXTENT OF EXPOSURE.................................................................................39
7.8
SAFETY ANALYSES ........................................................................................39
7.8.1
Adverse events................................................................................................39
7.8.2
Laboratory data...............................................................................................42
7.8.2.1
Laboratory data.............................................................................................42
7.8.2.2
Laboratory values of special interest ............................................................42
7.8.3
Vital signs .......................................................................................................42
8
REFERENCES.....................................................................................43
10
HISTORY TABLE...............................................................................45


Boehringer Ingelheim                                                                                    c17168379-02
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LIST OF TABLES
Table 5.1.3: 1
Derivation rules for PFS ........................................................................11
Table 5.2.2.2: 1
Derivation rules for Duration of Objective Response............................14
Table 5.2.2.2: 2
Derivation rules for Duration of Disease Control..................................16
Table 6.2: 1
Important PDs........................................................................................25
Table 6.6: 1  
Rules for imputations of missing or incomplete dates...........................30
Table 6.7.2: 1
Nominal time-points and windows for imaging ....................................32
Table 7.8.1: 1
Adverse events by user defined AE categories......................................41
Table 10: 1
History table...........................................................................................45


Boehringer Ingelheim                                                                                    c17168379-02
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2
LIST OFABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Transaminase
BI
Boehringer Ingelheim
CR
COVID-19
CTL
Complete response
Coronavirus Disease 2019
Clinical Trial Leader
DC
Disease control
ECG
Electrocardiogram
FDA
Food and Drug Administration
ICH
International Conference on Harmonisation
IPD
Important Protocol Deviation
ITT
KM
Intent-to-Treat
Kaplan-Meier
LLT
Lowest Level Term
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
OR
Objective response
OS
Overall Survival
PD
PD
Progressive Disease
Protocol Deviation
PFS
Progression Free Survival
PK
Pharmacokinetics
PR
Partial response
RP2D
Recommended Phase II Dose
RS
Randomised Set
SAE
Serious Adverse Event


Boehringer Ingelheim                                                                                    c17168379-02
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Term
Definition / description
SD
Stable Disease
SDL
Subject Data Listings
SIR
Synoptic Interim Report
SOC
System Organ Class
SOP
Standard Operating Procedure
TSAP
Trial Statistical Analysis Plan


Boehringer Ingelheim                                                                                    c17168379-02
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3
INTRODUCTION
As per ICH E9, 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 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 (see in section “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, randomisation. This TSAP follows Boehringer 
Ingelheims (BI) internal reference (1).
The trial consists of three parts. Part 1 includes a dose finding cohort A and part 2 includes 
three dose finding cohorts B, C and D and one expansion cohort E.  Part 3 includes cohort D1, 
D2 and F.
The TSAP describes the analysis for all the cohorts of the trial. After each of dose finding 
cohort (cohorts A, B, C and D), safety analyses were performed and documented.(see Section 
9.1).
SAS Version 9.4 or later version will be used for all analyses unless otherwise specified.


Boehringer Ingelheim                                                                                    c17168379-02
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4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY
4.1
ADDITIONS/NEW ANALYSES
The following additions/new analyses 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 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 MAR 20).
4.2
CHANGES
Not applicable.
4.3
CLARIFICATIONS
The following points warrant further clarification:

The terms “progression”, “progressive disease” (PD) and “disease progression” will 
be used interchangeably within this document.

The terms “treatment cycle” or “treatment course” will be used interchangeably 
throughout this document.

The terms “study medication” and “trial medication” will be used interchangeably 
throughout this document.

If not stated otherwise, date of randomisation will be replaced by first treatment 
administration of any study medication in the outputs (i.e. including the run-in period)


Boehringer Ingelheim                                                                                    c17168379-02
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5
ENDPOINTS
5.1
PRIMARY ENDPOINTS
5.1.1
Cohorts A, B, C, and D:
The primary endpoint is the maximum tolerated dose (MTD) of trial medications based on 
the occurrence of dose limiting toxicity (DLT) during the first treatment course. The planned 
treatment course consists of 28 days.
MTD:
The MTD is defined as the highest dose with less than 25% risk of the true DLT rate being 
above 33%. The MTD evaluation period is defined as the time from the first administration of 
any study medication up to start of cycle 2. That means that the exact duration of this period 
will be derived for each patient. If the patient experiences any delay after planned 28 days of 
cycle 1 but prior to the start of cycle 2, this delay will be also considered as MTD 
evaluationperiod. 
5.1.2
Cohort E 
The primary endpoint for the expansion part cohort E is objective response (OR).
Objective response (OR)
OR is defined as best overall response of complete response (CR) or partial response (PR), 
where best overall response is determined according to Response Evaluation Criteria In Solid 
Tumours (RECIST) version 1.1 from date of first treatment administration until the earliest of 
disease progression, death or last evaluable tumour assessment before start of subsequent 
anti-cancer therapy.
Best overall response
An adequate RECIST tumour assessment includes an assessment of target lesions (only for 
patients with measurable disease at baseline), as well as radiological tests to evaluate non-
target lesions if any and to search for new lesions. In case no RECIST tumour evaluation has 
been performed, the assessment will be set to missing. 
Best overall response is calculated based on the “overall” visit response from each 
assessment. Best overall response represents the best response a patient has had during 
his/her time in the study until progression, last evaluable assessment in the absence of 
progression or the start of subsequent anti-cancer therapy. For patients whose progression 
event is death, best overall response will be calculated based on data until the last evaluable 
RECIST assessment prior to death. (note that no confirmation is required for best overall 
response)
The following categories of best overall response will be derived:

Complete response (CR)

Partial response (PR) – possible only for patients with measurable disease at baseline

Stable disease (SD) – possible only for patients with measurable disease at baseline


Boehringer Ingelheim                                                                                    c17168379-02
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o
Subcategory “SD >= Week 24” for breast cancer and “SD>=6 weeks” for 
NSCLC: calculated from randomization/treatment start until the earliest of 
disease progression, death or last evaluable tumour assessment before start of 
subsequent anti-cancer therapy. Here SD >= Week 24 includes SD >=161 
days taking into account allowable CTP window. 

Non-CR/Non-PD – possible only for patients with non-measurable disease at baseline
o
Subcategory “Non−CR / Non−PD >= Week 24” for breast cancer and 
“Non−CR / Non−PD >= 6 weeks” for NSCLC: calculated from 
randomization/treatment start until the earliest of disease progression, death or 
last evaluable tumour assessment before start of subsequent anti-cancer 
therapy. Here Non−CR / Non−PD >= Week 24 includes Non−CR / Non−PD 
>=161 days taking into account allowable CTP window. 

Progressive disease (PD) in the absence of CR or PR or SD or Non-CR/Non-PD

Not evaluable (NE) - means no evidence of CR or PR or SD or Non-CR/Non-PD or 
PD 
o
Subcategory ‘Missing post-baseline image’: in case no post-baseline image 
has been performed.
The Week 24 tumour assessment was chosen to coincide with the minimum required duration 
of SD or Non-CR/Non-PD (24 weeks), in order to include all Week 24 assessments allowable 
per protocol the cut-off of >=161 days has been implemented.
5.1.3
Cohorts D1 and D2
The primary endpoint for expansion part cohort D1 and D2 is Progression-free survival (PFS)
status at 18th month (PFS18).
PFS18 is defined as the PFS status of a patient who is alive without disease progression at 18 
months after first treatment administration, where progression is determined according to 
RECIST 1.1.
PFS is defined as the time from first treatment administration until tumour progression 
according to RECIST 1.1 or death from any cause, whichever occurs earlier.
Tumour assessments will be performed at screening and then every 8 weeks after start of the
first treatment course until week 48 and every 12 weeks thereafter. 
For each follow-up imaging time-point an overall tumour response will be determined 
according to RECIST 1.1. The overall tumour response for each imaging time-point will be 
selected from the following categories: Complete Response (CR); Partial Response (PR); 
Stable Disease (SD); Progressive Disease (PD); Non-CR/Non-PD; or Not Evaluable (NE).
For details on the imaging process and RECIST evaluation, see Section 5.2 and Section 10.4 
of the CTP.
Derivation of endpoint PFS
Derivations below are described in days. However, the endpoints below will be presented in 
months in the statistical tables produced for the Clinical Trial Report (CTR).


Boehringer Ingelheim                                                                                    c17168379-02
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For patients with 'event' as an outcome for PFS:  (according to RECIST version 1.1)

PFS [days] = date of outcome - date of the first treatment administration + 1.
For patients with 'censored' as an outcome for PFS: (according to RECIST version 1.1)

PFS (censored) [days] = date of outcome - date of the first treatment administration + 1.
The censoring rules for PFS (i.e. outcome and date of outcome) are given in Table 5.1.3:1. 
Clinical disease progression will not be considered for determination of a PFS event, unless 
the outcome of the progression is death.
If patients would have their radiological examinations over a number of days, i.e. target 
lesions assessed on day x, non-target lesions assessed on day y and new lesion (if applicable) 
on day z, the following rules will be applied:

If the overall response is PD, the earliest date of multiple assessments will be taken.

If the overall response is SD, Non-CR/Non-PD, PR, CR or NE, the latest of multiple 
assessment dates will be taken to censor the patients.
Imaging assessments for which NE is assigned as the overall response at an imaging time-
point are considered to be missed assessments. Please note that NE does not indicate lack of 
progression.
Table 5.1.3: 1
Derivation rules for PFS
Situation
Outcome 
(event or 
censored)
Date of outcome
No baseline radiological assessment
Patient with death on or 
before the second 
planned radiological 
assessment
Event 
Date of death
Patient without death or 
patient with death after 
second performed 
radiological assessment
Censored
Date of randomisation (or first 
treatment administration, in non-
randomised trials)
Without post-baseline radiological assessments
Vital status is unknown 
or patient is known to be 
alive
Censored
Date of of randomisation (or first 
treatment administration, in non-
randomised trials)


Boehringer Ingelheim                                                                                    c17168379-02
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Situation
Outcome 
(event or 
censored)
Date of outcome
Death prior or on the 
second planned 
radiological assessment
Event
Date of death
Death beyond the second 
planned radiological 
assessment
Censored
Date of of randomisation (or first 
treatment administration, in non-
randomised trials)
With baseline and post-baseline radiological assessments BUT no other anti-cancer 
therapy
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


Boehringer Ingelheim                                                                                    c17168379-02
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Situation
Outcome 
(event or 
censored)
Date of outcome
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 (or first 
treatment administration, in non-
randomised trials)
In order to identify that consecutive imaging time-points are missing for a given patient, a 
nominal time point [8, 16, 24, 32, 40, 48, and then every 12 weeks thereafter] will be 
assigned to each and every image. This is achieved by creating windows for every RECIST 
assessment. The windows are defined in Table 6.7.2: 1.
5.1.4
Cohort F
The primary endpoint for the expansion part cohort F is disease control (DC).
Disease control (DC)
DC is defined as best overall response of complete response (CR) or partial response (PR) or 
confirmed stable disease (SD) (i.e. lasting till at least Week 24, 161 days taking into account 
allowable CTP window) where best overall response is defined according to RECIST version 
1.1 from first treatment administration until the earliest of disease progression, death or last 
evaluable tumour assessment before start of subsequent anti-cancer therapy.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Other secondary endpoints
5.2.2.1
Cohorts A, B, C, and D
There are no secondary endpoints.
5.2.2.2
Cohorts E, F, D1 and D2
Time to OR


Boehringer Ingelheim                                                                                    c17168379-02
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Time to objective response is defined as the time from first treatment administration until first 
documented CR or PR.
Time to objective response will only be calculated for patients with an objective response:

Time to OR [days] = date of first documented CR or PR - date of first treatment 
administration +1
Duration of OR
Duration of objective response is defined as the time from first documented CR or PR until 
the earliest of disease progression or death among patients with objective response.
Duration of objective response will only be calculated for patients with an objective response. 
For patients with disease progression or death:

Duration of objective response [days] = date of outcome – date of first assessment 
indicating OR + 1.
For patients without disease progression or death:

Duration of objective response (censored) [days] = date of outcome – date of first 
assessment indicating objective response + 1
The censoring rules for duration of OR are given in Table 5.2.2.2: 1.
Table 5.2.2.2: 1
Derivation rules for Duration of Objective Response
Situation
Outcome (event or 
censored)
Date of outcome
No other anti-cancer therapy
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 assessments
Death but no progression, zero 
or one missed radiological 
assessment prior to death
Event
Date of death


Boehringer Ingelheim                                                                                    c17168379-02
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Situation
Outcome (event or 
censored)
Date of outcome
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, no more 
than one consecutively missed 
radiological assessments prior 
to start of subsequent anti-
cancer therapy 
Censored
Date of last radiological assessment before 
initiation of subsequent anti-cancer therapy
Only radiological assessments after first assessment indicating objective response will be 
taken into consideration.
Disease control (DC) (Cohorts E, D1 and D2 only)
For breast cancer, DC is defined as best overall response of CR or PR, or SD ≥Week 24
(>=161 days taking into account allowable CTP window), or Non-CR/Non-PD for ≥Week 
24 (>=161 days taking into account allowable CTP window) where best overall response is 
defined according to RECIST version 1.1 from date of randomisation until the earliest of 
disease progression, death or last evaluable tumour assessment before start of subsequent 
anti-cancer therapy.
For NSCLC, DC is defined as best overall response of CR or PR, or SD ≥6 weeks, or 
Non−CR / Non−PD >= 6 weeks where best overall response is defined according to RECIST 
version 1.1 from date of randomisation until the earliest of disease progression, death or last 
evaluable tumour assessment before start of subsequent anti-cancer therapy.
Duration of DC
Duration of disease control is defined as the time from first treatment administration until the 
earliest of disease progression or death, among patients with disease control.
Duration of disease control will only be calculated for patients with a disease control. For 
patients with disease progression or death:

Duration of disease control [days] = date of outcome – date of the first treatment 
administration + 1.
For patients without disease progression or death:

Duration of disease control (censored) [days] = date of outcome – date of the first 
treatment administration + 1.
The censoring rules for duration of DC are given in Table 5.2.2.2: 2.


Boehringer Ingelheim                                                                                    c17168379-02
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Table 5.2.2.2: 2
Derivation rules for Duration of Disease Control
Situation
Outcome (event or 
censored)
Date of outcome
With baseline and post-baseline radiological assessments BUT no other anti-cancer therapy
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 assessments
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 (or first treatment 
administration, in non-randomised trials)
Progression-free survival (PFS)
The derivation of endpoint PFS refers to Section 5.1.3.
Last evaluable imaging


Boehringer Ingelheim                                                                                    c17168379-02
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An evaluable radiological image for the censoring of PFS is an image for which an overall 
response assessment of SD, Non-CR/Non-PD, PR or CR has been assigned. This is used for 
censoring of patients without progression at end of trial, or censoring prior to missed 
assessments, or censoring prior to subsequent anti-cancer therapy
Objective response (OR) (Cohorts F, D1 and D2 only)
The definition for OR is the same as the primary endpoint for cohort E , refer to Section 
5.1.2.


Boehringer Ingelheim                                                                                    c17168379-02
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Boehringer Ingelheim                                                                                    c17168379-02
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Boehringer Ingelheim                                                                                    c17168379-02
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Boehringer Ingelheim                                                                                    c17168379-02
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Boehringer Ingelheim                                                                                    c17168379-02
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Boehringer Ingelheim                                                                                    c17168379-02
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Boehringer Ingelheim                                                                                    c17168379-02
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6
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For all cohorts: Patients will be analysed according to the cohort initially assigned. All 
planned analysis will be presented by this cohort, unless specified otherwise. Handling of 
patients where cohort assignment has not been followed will be handled on a case-by-case 
basis, to be agreed at report planning meetings or DBL meeting (but prior to database lock).
For Cohort A, B,  C and D, different dose levels of Xentuzumab and Abemaciclib will arise. 
The data will be presented for all cohorts separately. To justify the MTD determination, 
DLTs occurring during the MTD evaluation period will be presented separately from those 
occurring during the complete on-treatment period.
For the on-treatment period and the MTD evaluation period, the initial trial medication 
assigned at the beginning of the first treatment cycle will be used as label of the analysing 
treatment.
For safety summaries data recorded during the Residual Effect Period (REP) will be 
considered as on-treatment. For this trial, the length of the REP is 42 days.
The actual study periods and treatment codes are defined in a document entitled “4-12-01-
sdtm-trial-arms-trial-elements-trial-visits”, which can be found in Data Management and 
Statistics (DMS) folder, Section 4, within BIRDS.
Patients in cohorts E and F are on continuous daily abemaciclib for a 9-days run-in period. 
For these patients, the on-treatment period is considered to the start of run-in period.
6.2
IMPORTANT PROTOCOL DEVIATIONS
No per protocol set (PPS) analysis will be performed for this study, hence, no patient will be 
excluded from the analyses (except those with missing informed consent or not adhering to 
age limit). However patients with potentially important protocol deviations (IPDs) will be 
documented. The following list of potentially IPDs in Table 6.2: 1 will be used; note that this 
is a working list and may not be finalised until the final Blinded Report Planning Meeting 
(BRPM) or DBL meeting (but prior to database lock for the primary analysis). Potentially 
important protocol deviations will be handled according to BI standards (8).
During the study conduct, protocol deviation should be monitored and guidance for 
improving / teaching the respective sites should be discussed during the study Medical 
Quality Review Meetings (MQRMs).
A frequency table of the iPDs will be produced. In addition, a frequency table of all COVID-
19 related non-important and important PDs will be produced.


Boehringer Ingelheim                                                                                    c17168379-02
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Table 6.2: 1
Important PDs
Category
/Code
Description
Requirements
Exclude
d from
A 
[1]
Entrance criteria not 
met
A1
Diagnosis of trial disease 
questionable
Cohort A and E: Inclusion criteria 
IN6 is not met.
or
Cohort B, C, D, F, D1 and D2: 
Inclusion criteria IN6-8 is not met.
None


Boehringer Ingelheim                                                                                    c17168379-02
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Category
/Code
Description
Requirements
Exclude
d from
A2
Prohibited baseline 
condition, diagnosis or 
treatment
All Cohorts: Inclusion criteria IN3-
5 is not met
or
Cohort A: Inclusion criteria IN7-8 
is not met
or
Cohort B, C, D, F, D1 and D2: 
Inclusion criteria IN9-12 is not met
or
Cohort E: Inclusion criteria IN7-9 
not met
or
Cohort F: Inclusion criteria IN13-
14 not met
or
All cohorts: At least one of 
exclusion criteria EX1, EX3, EX5-
6, EX10, EX12-13, EX15-19, 
EX21, EX25  is met.
or
Prohibited medication use (or 
surgery) before the treatment 
period of the trial, that is,
All cohorts: At least one of 
exclusion criteria EX4, EX7-9, 
EX11, EX20, EX22-24 is met
None
A3
Laboratory result 
indicating inadequate 
organ function at 
screening
All cohorts: Exclusion criteria 
EX14 is met
or
Both screening and baseline 
(defined in Section 6.7 of this 
document) laboratory results are 
missing.
None


Boehringer Ingelheim                                                                                    c17168379-02
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Category
/Code
Description
Requirements
Exclude
d from
B 
[1]
Legal Criteria
B1
Informed consent not 
available / not done
Written informed consent is not 
available/done
All
B2
Informed consent too late
Inclusion criterion IN2 is not met.
None
B3
Age limit for patient 
inclusion not adhered to
Inclusion criterion IN1 is not met.
All
C 
[2]
Trial medication and 
randomisation
C1 
[2]
Time window deviation
for procedures performed 
at screening
Assessment at screening not within 
28 days prior to first treatment.
Create listing, decision at MQRM / 
RPM.
None
C2 
[2]
Trial medication not given 
according to protocol
Dose reduction scheme not 
followed (see CTP Section 
4.1.4.2);
Administration of trial 
medication(s) not compliant 
Indicated by medical review (i.e. 
where Administration of 
xentuzumab according to the 
protocol = ‘No’ and associated 
comments, or compliance data 
from letrozole, anastrozole, 
fulvestrant or abemaciclib with 
associated comments)
Please note: This excludes the 
investigational treatment given 
outside the boundaries specified in 
the CTP (covered in Category C3).
None


Boehringer Ingelheim                                                                                    c17168379-02
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Category
/Code
Description
Requirements
Exclude
d from
C3 
[1]
Infusion time for the 
investigational treatment 
outside of CTP specific 
boundaries
Infusion duration of xentuzumab 
given < 50 minutes or > 200 
minutes (infusion time should be 
from 60 to 180 minutes, but the 
thresholds above are accepted).
The exact duration of the infusion 
should be calculated taking 
interruptions into account.
In case of missing administration 
times, the deviation will not be 
considered important if 
administration according to 
protocol = ‘Yes’
None
C4 
[2]
Patient assignment not 
followed
Patients do not receive the initial 
treatment they were allocated to
None
C4.
1
Randomisation not 
followed
This dose not apply for this trial
None
C4.
2
Treatment allocation not 
followed
Patients do not receive the initial 
treatment they were allocated to
None
D 
[2]
Concomitant medication
D1
Prohibited treatment 
during trial conduct phase
All cohorts: At least one of 
exclusion criteria EX2, EX26-27 is 
met
or
Indicated by medical review of 
concomitant therapy use during 
study treatment.
None
E 
[2]
Missing Data
E1
Imaging assessments not 
done according to CTP 
instructions
Imaging assessment should be 
performed at screening and several 
time points thereafter (see TSAP 
Section 6.7.2).
None
E2
Pregnancy test not done 
according to CTP 
instructions
Only for Studies where pregnancy 
tests are required
None


Boehringer Ingelheim                                                                                    c17168379-02
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Category
/Code
Description
Requirements
Exclude
d from
F 
[2]
Trial Specific protocol 
deviations
F1
Other protocol deviations 
affecting patient rights or 
safety
Manual PDs will be collectively 
captured.
None
Q
[2]
Non-important COVID-19 
related
Q1
Missed examination
With inactived forms or records, 
but without inactived visit date
None
Q2
Missed visit
With inactived visit date
None
[1] IPD will be derived automatically
[2] IPD will be identified via individual review at MQRM/RPM/DBLM.
6.3
PATIENTS SETS ANALYSED
The following analysis sets will be defined for this trial:

Enrolled set (ENR)
This patient set includes all patients with informed consent given. The enrolled set will be 
used for patient disposition tables.

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 during the treatment cycles (including run-in period).
The TS will be used for all planned safety and efficacy analyses. 

MTD Set (MS)
The MTD set defines the set of patients in the dose-finding cohorts (cohorts A,B,C and D) of 
the trial that are fully evaluable for determination of the MTD in the first treatment course. 
The MTD set will be used for some safety analyses for dose-finding cohorts, this is specified 
in the technical TSAP.
Patients in the TS who were replaced within the MTD period in the dose-finding cohorts 
(cohorts A,B,C and D) of the trial will be excluded from the determination of the MTD. 
Patients in the TS who entered in an expansion cohorts will be also excluded from the 
determination of the MTD. Replacement of patients in the dose-finding cohorts of the study 
is defined in Section 3.3.5 of the CTP. The final list of replaced patients is supplied by the 
Clinical Trial Leader (CTL) no later than the last report planning meeting before the database 
lock for the safety analysis.

Pharmacokinetic set (PKS)


Boehringer Ingelheim                                                                                    c17168379-02
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This patient set includes all patients in the treated set who have at least one valid drug plasma 
concentration available. The decision whether a concentration is considered valid or not will 
in general be made at the RPM before Database Lock (DBL) or URPM and documented 
within the respective meeting minutes. Values to be excluded from analyses identified during 
analysis would be documented within the respective QC forms. The PKS will be used for the 
PK analyses of the trial.
No per protocol population will be used for analyses. 
6.5
POOLING OF CENTRES
This section is not applicable because there are no inferential statistics, and therefore there is 
no statistical model in which centre/country can be included.
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.
Missing dates that affect the evaluation of endpoints specified in previous sections of this 
TSAP will be imputed utilising a “worst case” approach, which will be applied on a case-by-
case basis (depending on the affected endpoint) and agreed to by the trial team members at 
the final BRPM before database lock at the latest.
The rules in the Table 6.6: 1 below have been agreed by the trial and project teams, and will 
be used in this trial, if applicable.
Table 6.6: 1
Rules for imputations of missing or incomplete dates
Date
Imputation rule
Date of birth
In case only the year is given: 1st of January 
Date of death
Date last known to be alive.
If only year and month are given: this will be imputed with 1st  
of the month for the analysis of OS
Date of first histological 
diagnosis
1st of month if day is missing
1st of January if month also missing
Date of first appearance or 
recurrence of metastasis
1st of month if day is missing
1st of January if month also missing
Date of start of concomitant 
medication
No imputation required


Boehringer Ingelheim                                                                                    c17168379-02
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Date of end of concomitant 
medication
No imputation required
Date of start of subsequent 
anti-cancer therapy 
(imputation required only 
for censoring of PFS)
If the day (respectively day and month) of the start date of 
subsequent anti-cancer therapy is missing, then the first of the 
month (respectively 1st January) will be imputed unless this 
date leads to a date before the stop date of study medications. 
In this case, the study medications stop date + 1 day will be 
imputed.   Additionally, all imputed start dates of subsequent 
anti-cancer therapy should be before death date if available.
Date of end of treatment 
(only for patients still 
ongoing at time of 
snapshot/interim DBL)
Date of snapshot
If date of death before this date, use date of death
6.6.1
Adverse events
Missing or incomplete AE dates are imputed according to BI standards (5).
6.6.2
Laboratory values at baseline
For missing laboratory data at Cycle 1 Visit 1 of Cohort A, B, C, D, D1, D2 and F or at Day 1 
Run-in period of Cohort E (before the very first administration of study medication) data 
from preceding visits will be used.
6.6.3
PK parameters
Missing data and outliers of PK data are handled according to BI standards (2) and as 
described in Section 7.5 of the clinical trial protocol.
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS
6.7.1
Baseline
The last measurement observed prior to start of trial medication will be assigned to baseline. 
Note that for some trial procedures (for example body weight, vital signs, laboratory tests) 
this may be the value measured on the same day trial medication was started. In these cases it 
will be assumed that the measurements were taken prior to the intake of any study 
medication. For tumour assessment, baseline evaluations must be based on Magnetic 
Resonance Imaging (MRI) or Computed Tomography scans 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.
Unless otherwise specified, baseline is defined as the latest time-point before the very first 
administration of any study medication. The run-in period in Cohort E is considered as time 
with study medication. If this criterion is not fulfilled then no baseline will be derived .
Laboratory values:


Boehringer Ingelheim                                                                                    c17168379-02
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Baseline is defined as the latest time-point before the very first administration of any study 
medication.
If any of these times are missing and the date of laboratory value is equal to the date of first 
study drug administration, then the laboratory assessment will be considered as according to 
protocol, i.e. as prior to first study medication.
6.7.2
Time windows for every RECIST assessment
In order to identify whether consecutive imaging time-points are missing for a given patient, 
a nominal time point [8, 16, 24, 32, 40, 48, 60 weeks and every 12 weeks thereafter] will be 
assigned to each and every image. This is achieved by creating windows for every RECIST 
assessment. The windows are defined in Table 6.7.2: 1 below. Day 1 corresponds to the date 
of first drug intake of any trial medication (excluding run-in period).
Table 6.7.2: 1
Nominal time-points and windows for imaging
Nominal time-point [weeks 
from start of therapy]
Due date of scans [days]
Window [days]
8
57
1 to =< 85
16
113
86 to =< 141
24
169
142 to =< 197
32
225
198 to =< 253
40
281
254 to =<309
48
337
310 to =<379
60
421
380 to =<463
every 12 week interval
etc [1]
etc [1]
[1] Due date of imaging = (nominal time point * 7) + 1. To calculate the lower bound of the window, 
use the middle point between the due date of the previous time point and the current due date + 1. To 
calculate the upper bound of the window, use the middle point between the due date of the next time 
point and the current due date.
If a patient does not have an image in one of the windows described above, he/she will be 
said to have 'missed an assessment' for that time-point. 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 a PD has been recorded earlier then PD will be used.


Boehringer Ingelheim                                                                                    c17168379-02
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7
PLANNED ANALYSES
The labelling and display format of statistical parameters will follow BI standards (9).
Unless otherwise specified, outputs will be displayed separately for each cohort of the trial.
Descriptive statistics for continuous variables will generally contain N (number of patients in 
that patient set with non-missing values), Mean, Standard Deviation, Minimum (Min), Q1 
(25th percentile), Median, Q3 (75th percentile), Maximum (Max). In general, means, standard 
deviations, medians, Q1 and Q3 will be presented to one more decimal place than the raw 
data. Minima and maxima will be presented to the same number of decimal places as the raw 
data.
For time-to-event analysis tables, the set of statistics is: number of patients [N (%)], Number 
of patients with event [N (%)], Number of patients censored [N (%)], <Time to event> 
[months] followed by P25 (25th percentile), Median, P75 (75th percentile). If not specified 
otherwise, the duration as well as time to event will be displayed in months.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group total. Percentages will be rounded to one decimal place.
In general a category “missing” will be displayed, if there are missing data for the 
corresponding variable. Percentages will also generally be based on all patients in the 
respective patient set whether they have non-missing values or not.
Sort order for general categorical variables: If categories correspond to the collected 
categories on the eCRF and the table shells do not explicitly specify the ordering, the “default 
ordering” defined by the eCRF is to be used in such cases. If categories are derived the 
ordering as specified in the table shell document should be used; in general ordinal data (e.g. 
categorised continuous data) are to be displayed in ascending order.
The denominator of the main categories is defined by the number of patients in the used 
patient set. The main categories define the denominators of the subcategories. Subcategories 
should be indented and “[N (%)]” to be displayed only for the main category.
If a table includes only categorical data, “[N (%)]” is to be displayed in the column header.
In general, a “Total” column will not be displayed for post-baseline displays. Tables that 
display the status of patients for a primary or secondary endpoint with number of events and 
number censored will contain a total column.
Abbreviations (e.g., Wors.) or acronyms (e.g., PD) should not be displayed in tables and 
patients data listings without any explanation. They will be either spelled out in the table or 
explained in footnotes (whatever is more reasonable from the programming point of view).
If applicable, conversion from days to weeks, months and years will be as follows:

Weeks = days ÷ 7

Months = days × 12 ÷ 365.25

Years = days ÷ 365.25


Boehringer Ingelheim                                                                                    c17168379-02
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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.1.1
Disposition of patients
For patient disposition the standard descriptive table from the EOT catalogue will be 
populated. Additionally, patients with discontinuations by initial treatment and the reasons 
will be listed and tabulated, overall and for each treatment separately. The same output will 
also contain an overview of discontinued and non-discontinued, as well as completed and 
non-completed patients (see CTP Section 6.2.3.3).
7.1.2
Important protocol deviations
A table and a listing of patients with important protocol deviations based on Table 6.2: 1 will 
be created in Section 10.1.3 and Appendices 10.10.3 respectively, of the CTR.
7.1.3
Demographic and other baseline characteristics
Standard descriptive analysis and summary tables for all patients treated by initial treatment 
will be created for demographic data, oncological history and baseline conditions.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Concomitant diseases will 
be coded similarly as adverse events based on the most current Medical Dictionary for 
Regulatory Activities (MedDRA) version. Concomitant therapies will be coded according to 
World Health Organisation - Drug Dictionary (WHO-DD). Concomitant therapies (CT) will 
be classified according to the Anatomical, Therapeutic, Chemical (ATC) classification 
system. The third ATC level will be used to categorise CTs by therapy type. In situations 
where a medical product may be used for more than one equally important indication, there 
are often several classification alternatives. As appropriate, patients receiving CTs with more 
than one possible ATC level-three category will be counted more than once; footnotes will 
clarify this possible double counting in tables.
Concomitant medications will be presented according to whether they are concomitant with 
the reception of study medication, or whether they were given prior to study medication. In 
case start and stop dates of the medications are completely missing, they are assigned as 
given prior to study medication.
7.3
TREATMENT COMPLIANCE
Compliance will not be analysed separately, but assessed in terms of exposure (including 
dose intensity). Refer to Section 7.7 for further details on exposure analysis.
7.4
PRIMARY ENDPOINTS
7.4.1
Cohorts A, B, C, and D
The primary endpoints are the MTD and the occurrence of DLT. The MTD is determined 
from the occurrences of DLTs during the MTD evaluation period (this period is defined in 


Boehringer Ingelheim                                                                                    c17168379-02
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Section 5.1.1). An overall summary of the DLTs (see CTP Section 5.3.7 for definitions of 
DLT) which occurred during the MTD evaluation period and the on-treatment period will be 
provided for each dose cohort.
Patients that were treated but replaced for the MTD evaluation (see CTP Section 3.3.5) will 
be excluded from the MTD determination. Replacement of patients will be determined on a 
case by case basis; exclusion of these patients from the MTD evaluation will be confirmed by 
the trial team at the report planning meeting prior to database lock.
The analysis of the MTD is based on a BLRM guided by the escalation with overdose control 
principle. The MTD is defined as the highest dose for a given schedule that is expected to 
cause less than 25% risk of the true DLT rate being above or equal to 33% during the MTD 
evaluation period. Estimation of the MTD during the dose escalation phase of the study will 
be based upon the estimation of the posterior probability of the incidence of DLT in toxicity 
categories during the MTD evaluation period for all evaluable patients. The model to be used 
is specified in CTP Section 7.
The posterior probabilities that the toxicity rates of each dose level fall into the categories
specified in CTP Section 7 will be displayed.
At the end of each dose finding cohort, a safety analysis will be performed to determine the 
RP2D. The results will be documented for internal use and communication with the 
participating investigators (see also in Section 9.1).
7.4.2
Cohort E
Objective response (OR)
OR as assessed by investigators is defined as a best overall response of CR or PR and will be 
analysed. Descriptive statistics including number of treated patients, number of patients with 
objective response as best overall response and the corresponding percentages will be 
presented and evaluated.
7.4.3
Cohorts D1 and D2
PFS status at 18th month (PFS18)
PFS18 is defined as the PFS status of a patient who is alive without disease progression at 18 
months after first treatment administration, where progression is determined according to 
RECIST 1.1.
Descriptive statistics including number of treated patients, number of patients being absence 
of disease progression or death at 18th month and the corresponding percentages will be 
presented and evaluated.
Kaplan-Meier (KM) estimates will be used to display the distribution of PFS for cohort D1 
and D2 separately on a KM curve. To support the plot, estimated survival probabilities at
specific time points of interest (6 months, 12 months and 18 months) will be tabulated. In 
addition, the survival distribution will be used to provide estimates of the median, 25th and 
75th percentiles.


Boehringer Ingelheim                                                                                    c17168379-02
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7.4.4
Cohort F
Disease control (DC)
DC as assessed by investigators is defined as a best overall response of CR or PR or SD and 
will be analysed. Descriptive statistics including number of treated patients, number of 
patients with objective response as best overall response and the corresponding percentages 
will be presented and evaluated.
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
Other secondary endpoints
7.5.2.1
Cohorts A, B, C and D
This section is not applicable as no secondary endpoint has been specified in the protocol.
7.5.2.2
Cohorts E and F, D1 and D2
Disease control (Cohorts E, D1 and D2 only)
Disease control (DC) is defined as best overall response of complete response (CR) or partial 
response (PR) or stable disease (SD) (defined in Section 5.2.2.2). Only descriptive statistics 
are planned for this section of the report.
Time to OR
For patients with objective response, time to objective response will be shown on patient 
level. A set of summary statistics for time to objective response on cohort level will also be 
produced.
Duration of OR
KM estimates will be calculated for each treatment group to provide estimates of the median, 
25th and 75th percentiles and their corresponding 95% CIs.
Duration of DC
Duration of DC will be analysed similarly to Duration of OR, see above.
Progression free survival
Kaplan-Meier estimates and 95% CIs ( based on Greenwood's method) will be calculated. 
Furthermore progression free survival times on patient level will be shown and if applicable 
descriptive statistics including, but not limited to, the lower quartile (P25), Median and the 
upper quartile (P75) will be computed.
Objective response (Cohorts F, D1 and D2 only)
OR as assessed by investigators is defined as a best overall response of CR or PR and will be 
analysed. Descriptive statistics including number of treated patients, number of patients with 


Boehringer Ingelheim                                                                                    c17168379-02
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objective response as best overall response and the corresponding percentages will be 
presented and evaluated.


Boehringer Ingelheim                                                                                    c17168379-02
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Boehringer Ingelheim                                                                                    c17168379-02
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7.7
EXTENT OF EXPOSURE
The variables defined in Section 5.4.2 will be summarised descriptively for each dose cohort.
Appropriate summaries of exposure before and from the start of the COVID-19 disruption
will also be produced.
7.8
SAFETY ANALYSES
All safety analyses will be performed on the TS (unless otherwise specified; for example, the 
MTD Set will be used for some safety outputs). Patients in the dose finding cohorts who were 
replaced within or before the first treatment cycle will be excluded from the determination of 
the MTD.
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature. All analyses will be based on the number 
of patients with AEs (not the number of AEs).
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE event 
provided that all of the following applies:

All AE attributes are identical (Lowest Level Term (LLT), Common Terminology 
Criteria for Adverse Events (CTCAE) grade, action taken with trial medication, 
therapy required, seriousness, reason for seriousness, relationship, outcome, AE of 
special interest)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)
For further details on summarisation of AE data, please refer to (5) and (6).
Adverse events will be coded with the most recent version of MedDRA. The severity of AEs 
will be scaled according to CTCAE (CTCAE version 4.03 (11)).
The analyses of adverse events will be based on the concept of treatment-emergent adverse 
events. That means that all adverse events with an onset between first treatment 
administration until end of the REP will be assigned as ‘on treatment’. All adverse events 
occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after the residual effect period will be assigned to ‘post-treatment’; these AEs will 
be displayed in listings only. First drug intake includes the run-in period for Cohort E and F. 
Adverse events will be displayed by the initial dose of study medication administered on the 
first day of treatment .
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarised by treatment, primary system organ class and preferred 
term. Similar summaries will be produced for the BIcMQ SARS-COV-2-infections.


Boehringer Ingelheim                                                                                    c17168379-02
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Separate tables will be provided for patients with drug-related adverse events, adverse events 
leading to dose reduction, adverse events leading to discontinuation, serious adverse events, 
serious drug-related serious adverse events, adverse events leading to death, other significant 
adverse events, adverse events of special interest, and adverse events fulfilling the DLT 
definition.
Sorting order:
In tables presenting System Organ Classes (SOCs) and Preferred Terms (PTs), SOCs will be 
sorted alphabetically and PTs (within SOC) by descending frequency.
Reporting of CTCAE grades in tables:
In tables showing AEs by worst CTCAE grade, AEs with missing CTCAE grade will only be 
displayed under the category "All grades", but no category "Missing grade" will be displayed. 
Therefore the categories "Grade 1" to "Grade 5" might not add up to the category "All 
grades"; a footnote will explain this handling.
Displaying of CTCAE grades in AE tables (Section 15) will be “All grades”, “Grade 1”, 
“Grade 2”, “Grade 3”, “Grade 4”, and “Grade 5” separately. In the appendix (Section 
16.1.13.1, the categorisation “All grades”, “Grade 1/2”, “Grade 3/4/5”, will be used.
Listings of adverse events
Adverse events will be reported with start and end day as calculated from the first day of 
treatment with study medication. This includes the run-in period for the Cohort E and F.
Incidence and severity of adverse events
The incidence of AEs overall (irrespective of relatedness to study medication), related AEs, 
and serious AEs (SAE) will be reported by severity according to CTCAE grades.
Other significant adverse events
Other significant AEs are defined as serious and non-serious AEs that lead to dose reduction 
or permanent discontinuation of study medication. Their incidence will be reported by 
severity according to CTCAE grades.
A listing of patients who developed ‘other significant’ AEs will be provided and a flag for 
serious and non-serious will be included.
AEs leading to dose reduction or permanent discontinuation will include:

AEs leading to dose reduction of xentuzumab

AEs leading to dose reduction of abemaciclib

AEs leading to permanent discontinuationof xentuzumab

AEs leading to permanent discontinuationof abemaciclib
AEs leading to death
AEs leading to death during the on-treatment period will be tabulated in a separate table. In 
this table no CTCAE grades will be shown. For fatal AEs without CTCAE grade 5 or missing 


Boehringer Ingelheim                                                                                    c17168379-02
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grade, the grade will be imputed as CTCAE grade 5. Reported fatal AEs that occurred in the 
post-treatment period will be listed within the listing containing all post-treatment AEs.
Protocol-specified Adverse Events of Special Interest (AESI)
Protocol-specified AESIs are specified in the CTP Section 5.3.6.1. Their incidence will also 
be reported. DLTs are considered as AESIs only in the dose finding cohorts.
Adverse events by user defined AE categories (UDAEC)
User defined adverse events categories (UDAEC) as defined on project level by the 
pharmacovigilance working group will be derived and the latest version will be used for the 
analysis. Details of the current version are presented below in the table below.
Table 7.8.1: 1
Adverse events by user defined AE categories
SSC
Group#
Hepatic impairment
Drug related hepatic disorders – comprehensive search 
(SMQ)
Hyperglycaemia narrow
Hyperglycaemia/new onset diabetes mellitus (SMQ) -
narrow
Infusion related reaction
Hypersensitivity (SMQ) - broad
Non-infectious pneumonitis
Interstitial lung disease (SMQ) - narrow 
Renal insufficiency
Acute renal failure (SMQ) -  broad and narrow; Proteinuria
(SMQ)-broad and narrow;  Glomerulonephritis and 
nephrotic syndrome:HLT
Weight loss
Weight loss (BIcMQ) – broad and narrow
Neutropenia
Haematopoietic leukopenia (SMQ) – narrow
Stomatitis
Stomatitis (BIcMQ) – broad and narrow
Asthenia
MedDRA PTs: Asthenia, Fatigue, Lethargy, Malaise, and 
Decreased activity
Haemorrhage
Haemorrhage laboratory terms (SMQ)-narrow;
Haemorrhage terms (excl laboratory terms) (SMQ)-broad 
and narrow
Anemia
Haematopoietic erythropenia (SMQ) – broad and narrow
Thrombocytopenia
Haematopoietic thrombocytopenia (SMQ) - narrow
Thromboembolism
Embolic and thrombotic events,
vessel type unspecified and mixed arterial and venous 
(SMQ)-broad and narrow
Bradycardia
Torsade de pointes/QT prolongation (SMQ), PT of 
Bradycardia
Rash
BIcMQ: Skin eruptions (subsearch2: Skin rash potentially
related to drug use [broad and narrow])
#
This column indicates whether the Term(s) provided in the first column are MedDRA preferred terms 
(PT), Standardised MedDRA Queries (SMQ) or BI customised MedDRA Queries (BIcMQ).
The incidence of AE by UDAEC will be analysed.


Boehringer Ingelheim                                                                                    c17168379-02
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7.8.2
Laboratory data
7.8.2.1
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (7). The same on-treatment periods as considered for the analysis of adverse events 
will be applied for laboratory values except for that the baseline laboratory value will be 
included in the 'on-treatment' period. Patients having at least one post-baseline laboratory 
value will be displayed in the descriptive analyses.
Descriptive statistics, including change from baseline and frequency of patients with 
transitions relative to the reference range, will be provided. CTCAE grades for applicable 
laboratory parameters will be calculated according to CTCAE version 4.03 (11). The 
following outputs will be presented:

Worst CTCAE grade experienced during the on-treatment phase.

Transitions of CTCAE grade from baseline to worst laboratory value, from worst to 
last laboratory value during the on-treatment phase, and from baseline to last 
laboratory value.
Patients with missing CTCAE grade at baseline or no baseline value but post baseline values 
will be displayed in the category “Missing CTCAE grade at baseline”. Laboratory values 
without CTCAE grading will be compared to their reference ranges and frequency tables will 
be provided for the number of patients within and outside the reference range at baseline and 
the last measurement on treatment.
Analysis of potentially clinically significant abnormal laboratory values, and handling of 
CTCAE grade -1 and -9 laboratory parameters, are described in the SOP for "Display and 
analysis of laboratory data" (7), Reference Document 9.
7.8.2.2
Laboratory values of special interest
Hepatic enzyme elevations (potential Hy’s law cases):
These are defined as those cases where a combination of all of the following events occurred: 
any on-treatment value of ALT and/or AST > 3ULN with total bilirubin ≥2ULN and ALKP 
< 2 ULN. The events can occur in any order, but must occur within 14 days of the previous 
event, i.e. the second event must occur within 14 days of the first event, and the third event 
must occur within 14 days of the second event, etc.
Patients with missing laboratory values for liver enzymes will be excluded from these 
analyses but will be presented separately in a listing. Tabulations of hepatic enzyme 
elevations and liver laboratory values (see Section 5.3.6.1 of the CTP), including flags of true 
DILI cases, are created in accordance with the Food and Drug Administration (FDA) DILI 
guidance (10). Tabulations of hepatic enzyme elevations and liver laboratory values (see 
Section 5.3.6.1 of the CTP), including flags of true DILI cases, are created in accordance with 
the Food and Drug Administration (FDA) DILI guidance (10).
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.


Boehringer Ingelheim                                                                                    c17168379-02
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8
REFERENCES
1
001-MCG-160_RD-06: "Trial Statistical Analysis Plan - Template", 
current version; IDEA for CON.
2
001-MCS-36-472: "Standards and processes for analyses performed 
within Clinical Pharmacokinetics/Pharmacodynamics (3.0)", current 
version; IDEA for CON.
3
Tolaney, S. M., et al. "biomarkers Exploratory biomarkers in MONARCH 
1, a phase II study of abemaciclib monotherapy in hormone-receptor 
positive (HR) HER2-metastatic breast cancer (MBC)." (2016): LBA12.
4
Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga 
A, Quarmby V, Richards S, Schneider CK, Subramanyam M, Swanson S, 
Vethelyi D, Yim S. 
Assessment and reporting of the clinical immunogenicity of therapeutic 
proteins and peptides-harmonized terminology and tactical 
recommendations. AAPS J 16 (4), 658 - 673 (2014)
5
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON.
6
001-MCG-156: "Handling and summarisation of adverse event data for 
clinical trial reports and integrated summaries", current version; IDEA for 
CON.
7
001-MCG-157: "Display and Analysis of Laboratory Data", current 
version, IDEA for CON.
8
001-MCS-50-413: “Handling of Protocol Violations in Clinical Trials and 
Projects”, current version; IDEA for CON.
9
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", 
current version; IDEA for CON.
10
Guidance for industry: drug-induced liver injury: premarketing clinical 
evaluation U.S. Departement of Health and Human Services, Food and 
Drug Administration, Center for Drug Evaluation and Research (CDER), 
Center for Biologics Evaluation and Research (CBER), 2009.
11
Common terminology criteria for adverse events (CTCAE): version 4.0 
(NIH publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 
2010), revised June 2010, reprinted June 2010).  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf (2010)


Boehringer Ingelheim                                                                                    c17168379-02
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Boehringer Ingelheim                                                                                    c17168379-02
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10 HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
28-APR-17
None
This is the initial TSAP describing 
treatment setup and IPD.
1.0
12-APR-18
All 
sections
Core TSAP
2.0
25-Oct-21
All 
sections
Update for cohorts D1, D2 and interim 
CTR