Download PDF

Clinical Trial Results:
A Phase Ib/II Randomized Study of BI 836845 in Combination with Exemestane and Everolimus Versus Exemestane and Everolimus Alone in Women with Locally Advanced or Metastatic Breast Cancer

Summary
EudraCT number	2013-001110-15
Trial protocol	ES FR BE NL SE IE AT
Global end of trial date	14 Dec 2021

Results information
Results version number	v1(current)
This version publication date	25 Dec 2022
First version publication date	25 Dec 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

1280.4

ISRCTN number

US NCT number

NCT02123823

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

24 Jan 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

25 Nov 2016

Global end of trial reached?

Yes

Global end of trial date

14 Dec 2021

Was the trial ended prematurely?

Main objective of the trial

Main objective of this trial was to determine the Maximum Tolerated Dose and Recommended Phase II Dose, and to evaluate the safety and antitumour activity, of BI 836845 and everolimus in combination with exemestane in women with HR+/HER2- advanced breast cancer.

Protection of trial subjects

All patients were free to withdraw their consent at any time during the study without penalty or prejudice. Their personal trialrelated data would be considered confidential and used by BI in accordance with the local data protection laws. The level of disclosure was explained to the patients. Their medical records could be examined by Clinical Quality Assurance auditors appointed by BI, by members of the appropriate IEC/IRB, and by inspectors from regulatory authorities. Confidentiality of patient data was ensured by the use of depersonalised patient identification codes (patient numbers). The terms and conditions of the insurance cover were available to the investigator and the patients in the Investigator Site File (ISF).

Background therapy

Evidence for comparator

Actual start date of recruitment

22 May 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 31

Country: Number of subjects enrolled

France: 34

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

Spain: 66

Country: Number of subjects enrolled

Sweden: 6

Country: Number of subjects enrolled

Austria: 4

Country: Number of subjects enrolled

Ireland: 13

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 21

Country: Number of subjects enrolled

Taiwan: 10

Country: Number of subjects enrolled

United Kingdom: 15

Worldwide total number of subjects

202

EEA total number of subjects

156

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

124

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

This is a phase Ib/II, randomized, open label study to determine the maximum tolerated dose (MTD) and the recommended phase II dose and to evaluate the anti-tumor activity of BI 836845 (xentuzumab) in combination with exemestane and everolimus versus exemestane and everolimus alone in women with locally advanced or metastatic breast cancer.

Screening details

Subjects that met eligibility criteria entered. Subjects could withdraw at any time/reason. If subject continued take drug, close monitoring was adhered to+adverse events recorded. Rules implemented in all trials whereby doses be reduced if required. If further events reported, withdrawn. Symptomatic treatment of tumour associated symptoms allowed.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Open label

Are arms mutually exclusive

Yes

xentuzumab 750mg+everolimus 10mg+exemestane 25mg - Phase Ib

Arm description

Subjects received a single dose of 750 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting 7 days before first administration of BI 836845 (xentuzumab) continously until disease progression, intolerable AEs or other reason necessitating withdrawal.

Arm type

Experimental

Investigational medicinal product name

xentuzumab (BI 836845)

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received a single oral dose once daily (qd) of 1 tablet of 25 mg exemestane starting 7 days before first administration of BI 836845 (xentuzumab) continously until disease progression, intolerable AEs or other reason necessitating withdrawal.

Investigational medicinal product name

everolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus starting 7 days before first administration of BI 836845 (xentuzumab) continously until disease progression, intolerable AEs or other reason necessitating withdrawal.

xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase Ib

Arm description

Subjects received a single dose of 1000 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting 7 days before first administration of BI 836845 (xentuzumab) continously until disease progression, intolerable AEs or other reason necessitating withdrawal.

Arm type

Experimental

Investigational medicinal product name

xentuzumab (BI 836845)

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

everolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II

Arm description

Subjects received a single dose of 1000 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting on Day 1 continously until disease progression, intolerable AEs or other reason necessitating withdrawal. Administration of xentuzumab was stopped after 28th October 2016, and participants in this group who remained in the trial could continue with everolimus 10 mg + exemestane 25 mg.

Arm type

Experimental

Investigational medicinal product name

xentuzumab (BI 836845)

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

everolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

everolimus 10 mg + exemestane 25 mg - Phase II

Arm description

Subjects received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting on Day 1 continously until disease progression, intolerable AEs or other reason necessitating withdrawal.

Arm type

Active comparator

Investigational medicinal product name

everolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

exemestane

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1 ^[1]	xentuzumab 750mg+everolimus 10mg+exemestane 25mg - Phase Ib	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase Ib	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II
Started	3	21	70	70
Treated	3	21	70	69
Completed	0	0	0	0
Not completed	3	21	70	70
Consent withdrawn by subject	-	-	7	2
Adverse event, non-fatal	-	-	3	5
Progressive disease	3	19	52	53
Lack of efficacy	-	2	8	10

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Out of 202 subjects who were enrolled in the trial, only 164 were randomized.

Baseline characteristics

Top of page

Reporting group title

xentuzumab 750mg+everolimus 10mg+exemestane 25mg - Phase Ib

Reporting group description

Reporting group title

xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase Ib

Reporting group description

Reporting group title

xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II

Reporting group description

Subjects received a single dose of 1000 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting on Day 1 continously until disease progression, intolerable AEs or other reason necessitating withdrawal. Administration of xentuzumab was stopped after 28th October 2016, and participants in this group who remained in the trial could continue with everolimus 10 mg + exemestane 25 mg.

Reporting group title

everolimus 10 mg + exemestane 25 mg - Phase II

Reporting group description

Reporting group values	xentuzumab 750mg+everolimus 10mg+exemestane 25mg - Phase Ib	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase Ib	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II	Total
Number of subjects	3	21	70	70	164
Age categorical
Treated set (Phase Ib only): This patient set included all patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Randomised set (RS) (Phase II only): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with exemestane and everolimus or exemestane and everolimus alone as randomised.
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0
Adults (18-64 years)	2	9	47	44	102
From 65-84 years	1	12	22	26	61
85 years and over	0	0	1	0	1
Age Continuous
Treated set (Phase Ib only): This patient set included all patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Randomised set (RS) (Phase II only): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with exemestane and everolimus or exemestane and everolimus alone as randomised.
Units: years
arithmetic mean (standard deviation)	59.00 ± 8.00	64.33 ± 7.84	60.17 ± 9.61	60.67 ± 9.07	-
Sex: Female, Male
Treated set (Phase Ib only): This patient set included all patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Randomised set (RS) (Phase II only): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with exemestane and everolimus or exemestane and everolimus alone as randomised.
Units: Participants
Female	3	21	70	70	164
Male	0	0	0	0	0
Race (NIH/OMB)
Treated set (Phase Ib only): This patient set included all patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Randomised set (RS) (Phase II only): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with exemestane and everolimus or exemestane and everolimus alone as randomised.
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	0	0	12	12	24
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	0	0	0	0
White	3	21	53	51	128
More than one race	0	0	0	0	0
Unknown or Not Reported	0	0	5	7	12
Ethnicity (NIH/OMB)
Treated set (Phase Ib only): This patient set included all patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Randomised set (RS) (Phase II only): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab in combination with exemestane and everolimus or exemestane and everolimus alone as randomised.
Units: Subjects
Hispanic or Latino	0	2	1	5	8
Not Hispanic or Latino	3	19	62	57	141
Unknown or Not Reported	0	0	7	8	15

End points

Top of page

Reporting group title

xentuzumab 750mg+everolimus 10mg+exemestane 25mg - Phase Ib

Reporting group description

Reporting group title

xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase Ib

Reporting group description

Reporting group title

xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II

Reporting group description

Subjects received a single dose of 1000 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting on Day 1 continously until disease progression, intolerable AEs or other reason necessitating withdrawal. Administration of xentuzumab was stopped after 28th October 2016, and participants in this group who remained in the trial could continue with everolimus 10 mg + exemestane 25 mg.

Reporting group title

everolimus 10 mg + exemestane 25 mg - Phase II

Reporting group description

Subject analysis set title

xentuzumab (BI 836845)

Subject analysis set type

Full analysis

Subject analysis set description

Treatment group "xentuzumab (BI 836845) comprises all dose cohorts during the dose finding phase, that is, "xentuzumab (BI 836845) 750 mg + everolimus 10 mg + exemestane 25 mg" and "xentuzumab (BI 836845) 1000 mg + everolimus 10 mg + exemestane 25 mg". All patients were administered doses of xentuzumab (BI 836845) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course in the absence of disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting 7 days before first administration of BI 836845 (xentuzumab) continously in the absence of disease progression, intolerable AEs or other reason necessitating withdrawal.

Primary: Progression-free survival (PFS) - Phase II part

Top of page

End point title

Progression-free survival (PFS) - Phase II part ^[1]

End point description

Progression-free survival (PFS) in the phase II part is presented. PFS was defined as the time from randomisation until radiological tumour progression according to RECIST 1.1, or death from any cause, whichever occurred earlier. Clinical disease progression was not considered for determination of a PFS event, unless the outcome of the progression was death. The cut-off date was 25th November 2016. At cut-off date, xentuzumab was discontinued in all patients in the experimental arm per sponsor decision, recruitment was also terminated. Patients who discontinued xentuzumab treatment continued with everolimus 10 mg + exemestane 25 mg treatment. 99999 = not available (not calculable) Randomised set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab (BI 836845) in combination with exemestane and everolimus or exemestane and everolimus alone as randomised.

End point type

Primary

End point timeframe

From randomisation until radiological tumour progression according to RECIST 1.1, or death from any cause or data cut-off (25Nov2016), up to 32.2 months.

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only reports results for phase II of the study, therefore arms belonging to phase Ib are not reported here.

End point values	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II
Number of subjects analysed	70	70
Units: Months
median (confidence interval 95%)	7.3 (3.3 to 99999)	5.6 (3.7 to 9.1)

Log Rank analysis

Comparison groups

xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II v everolimus 10 mg + exemestane 25 mg - Phase II

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9057

Method

Logrank

Parameter type

Log hazard ratio

Point estimate

0.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.57

upper limit

1.65

Primary: Number of patients with dose limiting toxicity (DLT) - phase Ib part

Top of page

End point title

Number of patients with dose limiting toxicity (DLT) - phase Ib part ^[2] ^[3]

End point description

Number of patients with dose limiting toxicity (DLT) in phase Ib part is presented. Treated set (Phase Ib only): This patient set included all patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1).

End point type

Primary

End point timeframe

From first administration of study treatment until end of first treatment cycle, up to 28 days.

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The primary endpoint was only analysed descriptively.
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only reports results for phase II of the study, therefore arms belonging to phase Ib are not reported here.

End point values	xentuzumab 750mg+everolimus 10mg+exemestane 25mg - Phase Ib	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase Ib
Number of subjects analysed	3	6
Units: Participants	0	1

No statistical analyses for this end point

Primary: Maximum Tolerated Dose (MTD) - phase Ib part

Top of page

End point title

Maximum Tolerated Dose (MTD) - phase Ib part ^[4]

End point description

The Maximum Tolerated Dose (MTD) in this study was defined as the highest dose level examined of trial medication, at which no more than 1 out of 6 patients experienced a DLT during the MTD evaluation period. Maximum tolerated dose (MTD) set: The MTD set defined the set of patients in the Phase Ib part who were fully evaluable for determination of the MTD in the first treatment course. The MTD set was used for some safety analyses in the escalation part. The MTD evaluation period was defined as the time from the first administration of xentuzumab up to start of cycle 2. A “3+3” Phase Ib dose finding phase was performed to determine the MTD.

End point type

Primary

End point timeframe

up to 28 days.

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The primary endpoint was only analysed descriptively.

End point values	xentuzumab (BI 836845)
Number of subjects analysed	9
Units: milligrams (mg)	1000

No statistical analyses for this end point

Secondary: Number of patients with objective response (OR) - phase II part

Top of page

End point title

Number of patients with objective response (OR) - phase II part ^[5]

End point description

Objective response (OR) - phase II part is presented. Objective response (OR), defined as best overall response of complete response (CR) or partial response (PR), where best overall response was determined according to RECIST 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. Randomised set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab (BI 836845) in combination with exemestane and everolimus or exemestane and everolimus alone as randomised.

End point type

Secondary

End point timeframe

From randomisation until the earliest of disease progression, death or last evaluable tumour assessment before start of subsequent anti-cancer therapy or data cut-off (25Nov2016), up to 32.2 months.

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only reports results for phase II of the study, therefore arms belonging to phase Ib are not reported here.

End point values	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II
Number of subjects analysed	70	70
Units: Participants	5	7

Logistic regression analysis

Comparison groups

xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II v everolimus 10 mg + exemestane 25 mg - Phase II

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5598

Method

Regression, Logistic

Parameter type

Log odds ratio

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

2.32

Secondary: Time to progression (TTP) - phase II part

Top of page

End point title

Time to progression (TTP) - phase II part ^[6]

End point description

Time to progression (TTP) is presented. Time to progression (TTP), defined as the time from the date of randomization until the date of the first objective tumour progression according to RECIST 1.1. 99999 = not available (not calculable) Randomised set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab (BI 836845) in combination with exemestane and everolimus or exemestane and everolimus alone as randomised. Only patients with progression were analysed.

End point type

Secondary

End point timeframe

From randomisation until the date of the first objective tumour progression according to RECIST 1.1. or data cut-off (25Nov2016), up to 32.2 months.

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only reports results for phase II of the study, therefore arms belonging to phase Ib are not reported here.

End point values	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II
Number of subjects analysed	70	70
Units: Months
median (confidence interval 95%)	7.3 (3.7 to 99999)	5.6 (5.3 to 9.1)

Log Rank analysis

Comparison groups

xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II v everolimus 10 mg + exemestane 25 mg - Phase II

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9146

Method

Logrank

Parameter type

Log hazard ratio

Point estimate

1.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.59

upper limit

1.8

Secondary: Number of patients with disease control (DC) - phase II part

Top of page

End point title

Number of patients with disease control (DC) - phase II part ^[7]

End point description

Disease control is defined as best overall response of complete response (CR) or partial response (PR), or stable disease (SD) >= 24 weeks, or Non−CR/Non−PD for >= 24 weeks. PD=Progressive disease. Randomised set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab (BI 836845) in combination with exemestane and everolimus or exemestane and everolimus alone as randomised.

End point type

Secondary

End point timeframe

From randomisation until data cut-off (25Nov2016), up to 32.2 months.

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only reports results for phase II of the study, therefore arms belonging to phase Ib are not reported here.

End point values	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II
Number of subjects analysed	70	70
Units: Participants	13	17

Logistic regression analysis

Comparison groups

xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II v everolimus 10 mg + exemestane 25 mg - Phase II

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4008

Method

Regression, Logistic

Parameter type

Log odds ratio

Point estimate

0.7

Confidence interval

level

95%

sides

2-sided

lower limit

0.31

upper limit

1.59

Secondary: Time to objective response - phase II part

Top of page

End point title

Time to objective response - phase II part ^[8]

End point description

Time to objective response is presented. Time to objective response is defined as the time from randomisation until first documented complete response (CR) or partial response (PR). Randomised set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab (BI 836845) in combination with exemestane and everolimus or exemestane and everolimus alone as randomised. Only patients with objective response were analysed.

End point type

Secondary

End point timeframe

From randomisation until first documented complete response (CR) or partial response (PR) or data cut-off (25Nov2016), up to 32.2 months.

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only reports results for phase II of the study, therefore arms belonging to phase Ib are not reported here.

End point values	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II
Number of subjects analysed	5	7
Units: Months
median (inter-quartile range (Q1-Q3))	3.7 (3.6 to 5.3)	1.8 (1.7 to 5.3)

No statistical analyses for this end point

Secondary: Duration of objective response - phase II part

Top of page

End point title

Duration of objective response - phase II part ^[9]

End point description

Duration of objective response is presented. Duration of objective response is 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 (OR). 99999 = not available (not calculable) Randomised set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab (BI 836845) in combination with exemestane and everolimus or exemestane and everolimus alone as randomised. Only patients with objective response were analysed.

End point type

Secondary

End point timeframe

From randomisation until the earliest of disease progression or death or data cut-off (25Nov2016), up to 32.2 months.

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only reports results for phase II of the study, therefore arms belonging to phase Ib are not reported here.

End point values	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II
Number of subjects analysed	5	7
Units: Months
median (inter-quartile range (Q1-Q3))	5.6 (5.6 to 5.6)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Duration of disease control - phase II part

Top of page

End point title

Duration of disease control - phase II part ^[10]

End point description

Duration of disease control is presented. Duration of disease control is defined as the time from randomisation until the earliest of disease progression or death, among patients with disease control. 99999 = not available (not calculable) Randomised set (RS): This patient set included all randomised patients in the Phase II part, regardless of whether or not they received treatment. Patients were assigned to xentuzumab (BI 836845) in combination with exemestane and everolimus or exemestane and everolimus alone as randomised. Only patients with disease control were analysed.

End point type

Secondary

End point timeframe

From randomisation until the earliest of disease progression or death or data cut-off (25Nov2016), up to 32.2 months.

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only reports results for phase II of the study, therefore arms belonging to phase Ib are not reported here.

End point values	xentuzumab 1000mg+everolimus 10mg+exemestane 25mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II
Number of subjects analysed	13	17
Units: Months
median (inter-quartile range (Q1-Q3))	99999 (10.9 to 99999)	9.3 (9.1 to 99999)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Phase Ib: from first dose until last dose + 42 days of residual effect period, up to 54.3 months + 42 days Phase II: from first dose until last dose + 42 days of residual effect period, up to 37.7 months + 42 days

Adverse event reporting additional description

Treated set (Ib): all patients who were documented to have received and taken at least one dose of any study medication during the treatment cycles (from Day 1). Randomised set (II): all randomised patients, regardless of whether or not they received treatment. AEs were reported by initial treatment as planned in the Statistical Analysis Plan.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Xentuzumab 750mg + Ev 10mg + Ex 25mg - Phase Ib

Reporting group description

Subjects received a single dose of 750 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28- day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus (Ev) and 1 tablet of 25 mg exemestane (Ex) starting 7 days before first administration of BI 836845 (xentuzumab) continously until disease progression, intolerable AEs or other reason necessitating withdrawal.

Reporting group title

Xentuzumab 1000 mg + Ev 10 mg + Ex 25 mg - Phase Ib

Reporting group description

Subjects received a single dose of 1000 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable adverse events (AEs) or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus (Ev) and 1 tablet of 25 mg exemestane (Ex) starting 7 days before first administration of BI 836845 (xentuzumab) continously until disease progression, intolerable AEs or other reason necessitating withdrawal.

Reporting group title

Xentuzumab 1000 mg + Ev 10 mg + Ex 25 mg - Phase II

Reporting group description

Subjects received a single dose of 1000 milligram (mg) BI 836845 (xentuzumab) as a 1 hour (h) intravenous infusion once a week on Day 1, 8, 15 and 22 in a 28-day course until disease progression, intolerable AEs or other reason necessitating withdrawal. Subjects also received a single oral dose once daily (qd) of 2x 5 mg (10 mg total) tablets of everolimus and 1 tablet of 25 mg exemestane starting on Day 1 continously until disease progression, intolerable AEs or other reason necessitating withdrawal. Administration of xentuzumab was stopped after 28th October 2016, and participants in this group who remained in the trial could continue with everolimus 10 mg + exemestane 25 mg.

Reporting group title

everolimus 10 mg + exemestane 25 mg - Phase II

Reporting group description

Serious adverse events	Xentuzumab 750mg + Ev 10mg + Ex 25mg - Phase Ib	Xentuzumab 1000 mg + Ev 10 mg + Ex 25 mg - Phase Ib	Xentuzumab 1000 mg + Ev 10 mg + Ex 25 mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	10 / 21 (47.62%)	20 / 70 (28.57%)	29 / 69 (42.03%)
number of deaths (all causes)	0	2	9	11
number of deaths resulting from adverse events	0	0	2	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Burkitt's lymphoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Lymphangiosis carcinomatosa
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	3 / 3 (100.00%)	5 / 21 (23.81%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 6	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Metastases to peritoneum
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Sarcoma uterus
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	3 / 69 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral venous disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Feeling cold
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	2 / 69 (2.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	2 / 69 (2.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	2 / 70 (2.86%)	5 / 69 (7.25%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Pneumothorax
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reexpansion pulmonary oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Neutrophil count decreased
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Brain contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral infarction
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial aneurysm
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 3 (33.33%)	0 / 21 (0.00%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis chronic
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	2 / 70 (2.86%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	2 / 69 (2.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
Renal failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	2 / 69 (2.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	2 / 70 (2.86%)	2 / 69 (2.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scrub typhus
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	2 / 70 (2.86%)	2 / 69 (2.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Xentuzumab 750mg + Ev 10mg + Ex 25mg - Phase Ib	Xentuzumab 1000 mg + Ev 10 mg + Ex 25 mg - Phase Ib	Xentuzumab 1000 mg + Ev 10 mg + Ex 25 mg - Phase II	everolimus 10 mg + exemestane 25 mg - Phase II
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	21 / 21 (100.00%)	70 / 70 (100.00%)	68 / 69 (98.55%)
Vascular disorders
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	4 / 70 (5.71%)	1 / 69 (1.45%)
occurrences all number	0	3	5	1
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	9 / 21 (42.86%)	8 / 70 (11.43%)	7 / 69 (10.14%)
occurrences all number	0	36	14	15
Lymphoedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	7 / 70 (10.00%)	2 / 69 (2.90%)
occurrences all number	0	1	10	5
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 3 (100.00%)	9 / 21 (42.86%)	23 / 70 (32.86%)	24 / 69 (34.78%)
occurrences all number	8	35	56	49
Calcinosis
subjects affected / exposed	1 / 3 (33.33%)	0 / 21 (0.00%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	0	0	0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	5 / 70 (7.14%)	6 / 69 (8.70%)
occurrences all number	0	0	5	7
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	9 / 21 (42.86%)	19 / 70 (27.14%)	17 / 69 (24.64%)
occurrences all number	0	19	26	25
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	5 / 69 (7.25%)
occurrences all number	0	0	1	5
Mucosal dryness
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	2 / 70 (2.86%)	1 / 69 (1.45%)
occurrences all number	0	3	2	1
Mucosal inflammation
subjects affected / exposed	3 / 3 (100.00%)	10 / 21 (47.62%)	27 / 70 (38.57%)	22 / 69 (31.88%)
occurrences all number	5	33	61	46
Oedema peripheral
subjects affected / exposed	1 / 3 (33.33%)	5 / 21 (23.81%)	11 / 70 (15.71%)	16 / 69 (23.19%)
occurrences all number	2	6	18	21
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	7 / 21 (33.33%)	10 / 70 (14.29%)	7 / 69 (10.14%)
occurrences all number	1	9	12	8
Reproductive system and breast disorders
Vulvovaginal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	4 / 70 (5.71%)	0 / 69 (0.00%)
occurrences all number	0	0	6	0
Respiratory, thoracic and mediastinal disorders
Aphonia
subjects affected / exposed	1 / 3 (33.33%)	0 / 21 (0.00%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	0	0	0
Dysphonia
subjects affected / exposed	1 / 3 (33.33%)	0 / 21 (0.00%)	2 / 70 (2.86%)	2 / 69 (2.90%)
occurrences all number	1	0	2	2
Cough
subjects affected / exposed	1 / 3 (33.33%)	10 / 21 (47.62%)	25 / 70 (35.71%)	18 / 69 (26.09%)
occurrences all number	1	18	34	36
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	6 / 21 (28.57%)	12 / 70 (17.14%)	18 / 69 (26.09%)
occurrences all number	1	9	15	28
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	4 / 70 (5.71%)	5 / 69 (7.25%)
occurrences all number	0	0	6	5
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	9 / 21 (42.86%)	13 / 70 (18.57%)	12 / 69 (17.39%)
occurrences all number	0	11	16	15
Interstitial lung disease
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	0 / 70 (0.00%)	5 / 69 (7.25%)
occurrences all number	0	2	0	5
Nasal dryness
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	3	0	0
Pneumonitis
subjects affected / exposed	1 / 3 (33.33%)	9 / 21 (42.86%)	7 / 70 (10.00%)	8 / 69 (11.59%)
occurrences all number	3	22	10	11
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	5 / 70 (7.14%)	2 / 69 (2.90%)
occurrences all number	0	1	9	2
Psychiatric disorders
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	8 / 70 (11.43%)	8 / 69 (11.59%)
occurrences all number	0	4	8	8
Sleep disorder
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences all number	0	2	1	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 3 (33.33%)	5 / 21 (23.81%)	18 / 70 (25.71%)	11 / 69 (15.94%)
occurrences all number	1	20	29	24
Aspartate aminotransferase increased
subjects affected / exposed	1 / 3 (33.33%)	4 / 21 (19.05%)	14 / 70 (20.00%)	14 / 69 (20.29%)
occurrences all number	1	9	23	25
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 3 (33.33%)	2 / 21 (9.52%)	1 / 70 (1.43%)	2 / 69 (2.90%)
occurrences all number	1	4	1	4
Blood creatine phosphokinase increased
subjects affected / exposed	2 / 3 (66.67%)	7 / 21 (33.33%)	11 / 70 (15.71%)	7 / 69 (10.14%)
occurrences all number	8	24	22	19
Blood cholesterol increased
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	1 / 70 (1.43%)	6 / 69 (8.70%)
occurrences all number	0	3	1	13
Blood creatinine increased
subjects affected / exposed	1 / 3 (33.33%)	5 / 21 (23.81%)	3 / 70 (4.29%)	4 / 69 (5.80%)
occurrences all number	2	13	3	5
Blood glucose increased
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	1 / 70 (1.43%)	1 / 69 (1.45%)
occurrences all number	0	2	1	1
Blood iron decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	1 / 70 (1.43%)	2 / 69 (2.90%)
occurrences all number	0	4	5	3
Blood phosphorus decreased
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	3 / 70 (4.29%)	2 / 69 (2.90%)
occurrences all number	0	4	4	2
Blood triglycerides increased
subjects affected / exposed	1 / 3 (33.33%)	2 / 21 (9.52%)	5 / 70 (7.14%)	2 / 69 (2.90%)
occurrences all number	2	13	6	2
Haemoglobin decreased
subjects affected / exposed	0 / 3 (0.00%)	4 / 21 (19.05%)	2 / 70 (2.86%)	1 / 69 (1.45%)
occurrences all number	0	12	12	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	5 / 21 (23.81%)	8 / 70 (11.43%)	7 / 69 (10.14%)
occurrences all number	0	13	12	18
Low density lipoprotein increased
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	3 / 70 (4.29%)	1 / 69 (1.45%)
occurrences all number	0	7	5	2
Neutrophil count decreased
subjects affected / exposed	1 / 3 (33.33%)	4 / 21 (19.05%)	8 / 70 (11.43%)	2 / 69 (2.90%)
occurrences all number	1	14	20	4
Platelet count decreased
subjects affected / exposed	2 / 3 (66.67%)	4 / 21 (19.05%)	14 / 70 (20.00%)	3 / 69 (4.35%)
occurrences all number	9	5	23	6
Weight decreased
subjects affected / exposed	1 / 3 (33.33%)	11 / 21 (52.38%)	6 / 70 (8.57%)	9 / 69 (13.04%)
occurrences all number	1	25	9	17
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	1 / 70 (1.43%)	1 / 69 (1.45%)
occurrences all number	0	2	1	1
Infusion related reaction
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	2 / 70 (2.86%)	0 / 69 (0.00%)
occurrences all number	0	3	4	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	4 / 70 (5.71%)	5 / 69 (7.25%)
occurrences all number	0	2	4	6
Dysgeusia
subjects affected / exposed	1 / 3 (33.33%)	8 / 21 (38.10%)	10 / 70 (14.29%)	9 / 69 (13.04%)
occurrences all number	1	8	14	10
Headache
subjects affected / exposed	0 / 3 (0.00%)	5 / 21 (23.81%)	17 / 70 (24.29%)	10 / 69 (14.49%)
occurrences all number	0	7	26	15
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 3 (100.00%)	13 / 21 (61.90%)	16 / 70 (22.86%)	16 / 69 (23.19%)
occurrences all number	11	48	48	35
Iron deficiency anaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences all number	0	11	2	0
Leukopenia
subjects affected / exposed	1 / 3 (33.33%)	6 / 21 (28.57%)	7 / 70 (10.00%)	5 / 69 (7.25%)
occurrences all number	1	23	7	19
Lymphopenia
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	6 / 70 (8.57%)	6 / 69 (8.70%)
occurrences all number	0	24	7	33
Neutropenia
subjects affected / exposed	1 / 3 (33.33%)	8 / 21 (38.10%)	20 / 70 (28.57%)	11 / 69 (15.94%)
occurrences all number	4	26	57	29
Thrombocytopenia
subjects affected / exposed	1 / 3 (33.33%)	4 / 21 (19.05%)	17 / 70 (24.29%)	10 / 69 (14.49%)
occurrences all number	1	14	40	37
Eye disorders
Visual acuity reduced
subjects affected / exposed	1 / 3 (33.33%)	0 / 21 (0.00%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences all number	1	0	1	0
Xerophthalmia
subjects affected / exposed	1 / 3 (33.33%)	0 / 21 (0.00%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	0	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 3 (33.33%)	4 / 21 (19.05%)	11 / 70 (15.71%)	6 / 69 (8.70%)
occurrences all number	1	12	12	7
Abdominal pain upper
subjects affected / exposed	1 / 3 (33.33%)	5 / 21 (23.81%)	6 / 70 (8.57%)	6 / 69 (8.70%)
occurrences all number	2	5	9	7
Aphthous ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	1 / 70 (1.43%)	4 / 69 (5.80%)
occurrences all number	0	0	2	4
Constipation
subjects affected / exposed	1 / 3 (33.33%)	3 / 21 (14.29%)	15 / 70 (21.43%)	7 / 69 (10.14%)
occurrences all number	2	3	29	7
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	12 / 21 (57.14%)	31 / 70 (44.29%)	23 / 69 (33.33%)
occurrences all number	0	53	73	39
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	3 / 70 (4.29%)	7 / 69 (10.14%)
occurrences all number	0	2	3	7
Dyspepsia
subjects affected / exposed	1 / 3 (33.33%)	2 / 21 (9.52%)	5 / 70 (7.14%)	2 / 69 (2.90%)
occurrences all number	1	3	5	2
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	3 / 70 (4.29%)	2 / 69 (2.90%)
occurrences all number	0	3	3	4
Mouth ulceration
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	3 / 70 (4.29%)	12 / 69 (17.39%)
occurrences all number	0	6	4	17
Nausea
subjects affected / exposed	1 / 3 (33.33%)	9 / 21 (42.86%)	24 / 70 (34.29%)	16 / 69 (23.19%)
occurrences all number	3	23	40	24
Odynophagia
subjects affected / exposed	1 / 3 (33.33%)	1 / 21 (4.76%)	3 / 70 (4.29%)	2 / 69 (2.90%)
occurrences all number	1	1	3	2
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	8 / 21 (38.10%)	24 / 70 (34.29%)	26 / 69 (37.68%)
occurrences all number	0	24	67	53
Tooth loss
subjects affected / exposed	1 / 3 (33.33%)	0 / 21 (0.00%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	0	0	0
Toothache
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	0 / 70 (0.00%)	3 / 69 (4.35%)
occurrences all number	0	3	0	3
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	7 / 21 (33.33%)	14 / 70 (20.00%)	15 / 69 (21.74%)
occurrences all number	3	18	22	20
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 3 (33.33%)	2 / 21 (9.52%)	3 / 70 (4.29%)	4 / 69 (5.80%)
occurrences all number	1	2	3	4
Dermatitis
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences all number	0	4	1	0
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	8 / 70 (11.43%)	6 / 69 (8.70%)
occurrences all number	0	4	9	8
Eczema
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	3 / 70 (4.29%)	0 / 69 (0.00%)
occurrences all number	0	3	3	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 21 (0.00%)	5 / 70 (7.14%)	5 / 69 (7.25%)
occurrences all number	0	0	6	6
Nail disorder
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	5 / 70 (7.14%)	1 / 69 (1.45%)
occurrences all number	0	2	7	1
Nail dystrophy
subjects affected / exposed	0 / 3 (0.00%)	5 / 21 (23.81%)	2 / 70 (2.86%)	4 / 69 (5.80%)
occurrences all number	0	7	2	4
Onychoclasis
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	3 / 70 (4.29%)	4 / 69 (5.80%)
occurrences all number	0	1	3	4
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	6 / 21 (28.57%)	14 / 70 (20.00%)	15 / 69 (21.74%)
occurrences all number	0	10	15	16
Rash
subjects affected / exposed	2 / 3 (66.67%)	6 / 21 (28.57%)	25 / 70 (35.71%)	23 / 69 (33.33%)
occurrences all number	4	9	42	50
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	3 / 70 (4.29%)	4 / 69 (5.80%)
occurrences all number	0	1	4	5
Urticaria
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	2 / 70 (2.86%)	0 / 69 (0.00%)
occurrences all number	0	2	2	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 3 (0.00%)	4 / 21 (19.05%)	1 / 70 (1.43%)	3 / 69 (4.35%)
occurrences all number	0	9	1	3
Urinary incontinence
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	2	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 3 (33.33%)	4 / 21 (19.05%)	11 / 70 (15.71%)	17 / 69 (24.64%)
occurrences all number	1	7	22	27
Back pain
subjects affected / exposed	0 / 3 (0.00%)	6 / 21 (28.57%)	12 / 70 (17.14%)	13 / 69 (18.84%)
occurrences all number	0	6	16	17
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	5 / 70 (7.14%)	4 / 69 (5.80%)
occurrences all number	0	3	6	5
Muscle spasms
subjects affected / exposed	1 / 3 (33.33%)	4 / 21 (19.05%)	8 / 70 (11.43%)	1 / 69 (1.45%)
occurrences all number	2	5	8	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	4 / 21 (19.05%)	8 / 70 (11.43%)	5 / 69 (7.25%)
occurrences all number	0	5	12	7
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	6 / 70 (8.57%)	4 / 69 (5.80%)
occurrences all number	0	3	6	5
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	8 / 70 (11.43%)	7 / 69 (10.14%)
occurrences all number	0	3	11	8
Pain in jaw
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	2 / 70 (2.86%)	3 / 69 (4.35%)
occurrences all number	0	2	2	3
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	4 / 70 (5.71%)	3 / 69 (4.35%)
occurrences all number	0	1	7	5
Cystitis
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	4 / 70 (5.71%)	0 / 69 (0.00%)
occurrences all number	0	2	5	0
Diverticulitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 21 (0.00%)	0 / 70 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	2 / 70 (2.86%)	1 / 69 (1.45%)
occurrences all number	0	4	3	2
Gingivitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	3 / 70 (4.29%)	4 / 69 (5.80%)
occurrences all number	0	2	3	4
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	5 / 21 (23.81%)	12 / 70 (17.14%)	12 / 69 (17.39%)
occurrences all number	0	12	18	14
Oral herpes
subjects affected / exposed	0 / 3 (0.00%)	1 / 21 (4.76%)	2 / 70 (2.86%)	4 / 69 (5.80%)
occurrences all number	0	1	2	4
Paronychia
subjects affected / exposed	1 / 3 (33.33%)	0 / 21 (0.00%)	0 / 70 (0.00%)	1 / 69 (1.45%)
occurrences all number	1	0	0	1
Rhinitis
subjects affected / exposed	1 / 3 (33.33%)	2 / 21 (9.52%)	2 / 70 (2.86%)	3 / 69 (4.35%)
occurrences all number	2	2	3	3
Tooth abscess
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	2 / 70 (2.86%)	1 / 69 (1.45%)
occurrences all number	0	2	3	2
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	5 / 70 (7.14%)	10 / 69 (14.49%)
occurrences all number	0	6	6	15
Tooth infection
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	1 / 70 (1.43%)	1 / 69 (1.45%)
occurrences all number	0	2	1	2
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	6 / 21 (28.57%)	7 / 70 (10.00%)	9 / 69 (13.04%)
occurrences all number	0	6	13	11
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 3 (33.33%)	13 / 21 (61.90%)	18 / 70 (25.71%)	22 / 69 (31.88%)
occurrences all number	1	28	25	35
Hypercholesterolaemia
subjects affected / exposed	1 / 3 (33.33%)	5 / 21 (23.81%)	7 / 70 (10.00%)	6 / 69 (8.70%)
occurrences all number	4	36	16	9
Hyperglycaemia
subjects affected / exposed	3 / 3 (100.00%)	11 / 21 (52.38%)	18 / 70 (25.71%)	17 / 69 (24.64%)
occurrences all number	8	44	41	36
Hypertriglyceridaemia
subjects affected / exposed	0 / 3 (0.00%)	3 / 21 (14.29%)	5 / 70 (7.14%)	10 / 69 (14.49%)
occurrences all number	0	12	8	12
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	4 / 21 (19.05%)	4 / 70 (5.71%)	5 / 69 (7.25%)
occurrences all number	0	6	7	7
Hypocalcaemia
subjects affected / exposed	1 / 3 (33.33%)	4 / 21 (19.05%)	7 / 70 (10.00%)	4 / 69 (5.80%)
occurrences all number	3	9	12	6
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 21 (9.52%)	1 / 70 (1.43%)	0 / 69 (0.00%)
occurrences all number	0	2	1	0
Hypophosphataemia
subjects affected / exposed	1 / 3 (33.33%)	7 / 21 (33.33%)	11 / 70 (15.71%)	8 / 69 (11.59%)
occurrences all number	1	26	34	16

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

07 May 2015

Several clarifications for accuracy, corrections, and terminology updates were made. The criteria for safety was updated adding the determination of MTD (synopsis). It was clarified that PK sampling should be taken before and at the end of xentuzumab infusion. Circulating tumour cells assessments were added for the Phase II part. cfDNA tests and CTC tests were added to the criteria for efficacy section. Sample for future companion diagnostics development was included in the flowchart for Phase II part. Text was added to clarify that a central independent review of tumour images may be conducted at a later time. The benefit-risk assessment was improved by providing more detailed information. For the inclusion criteria, Criterion 4: “aged >=18 years old” was added to the criterion, and “women” was changed to “female patients”. For the exclusion criteria, Criterion 2 was updated from: “Prior treatment with exemestane” To “Prior treatment with exemestane (except adjuvant exemestane stopped >12 months prior to start of study treatment as long as patient did not recur during or within 12 months after the end of adjuvant exemestane)”, for consistency with clinical practice. Restrictions regarding concomitant treatment were updated reflect updates to the Afinitor SmPC and dose modification recommendations for exemestane were made according to EU label (US label information was taken out). Management of expected adverse events and management of infection text were updated in line with the updated Afinitor SmPC. DLT was deleted as an endpoint from the endpoints of safety section, as it is a formal endpoint.

30 Mar 2016

Corrections and clarifications were made. Inclusion Criterion 4 was reworded for consistency with current postmenopausal status definition at participating investigational sites. A recommendation to monitor weight loss was added. The following wording was added to improve accuracy of assessment of efficacy for these particular cases: “Patients who discontinue the trial for any reason other than imaging based progressive disease should have a tumour assessment (RECIST 1.1) performed at EOTV (exception to this are patients who have already had tumour assessment within 28 days of EOT visit)”. Pneumonitis was added as an AESI to closely monitor these AEs. Phosphorus was added to the assessment of safety parameters based on the everolimus SmPC update. Definitions of the primary and secondary endpoints were updated in line with BI standards. The changes were to wording; there were no changes regarding content. Exemptions to SAE reporting were added. PD is already reported as a clinical trial endpoint and therefore does not need to be reported as an (S)AE. This is the common procedure in most oncology trials. Further endpoints for the Phase Ib part were added. Derivation of PFS and censoring rules were added in line with BI standards. More detailed description of the two prespecified analyses performed by the DMC were added.

15 Dec 2016

On 18 Oct 2016, the DMC had the meeting for the pre-specified interim analysis of efficacy after 33% of the required number of outcome events had been reached. At that time, 32 patients in the Xe1000+Ev10+Ex25 arm and 36 patients in the control arm were still on randomised treatment. The DMC recommendation letter was received on 20 Oct 2016, in which they recommended terminating the trial for the following reasons: the benefit-risk balance of xentuzumab in combination with exemestane and everolimus was no longer favourable for patients with HR+/HER2– locally advanced or metastatic breast cancer. The change in benefit-risk balance was a result of lack of efficacy; there were no important differences in safety between treatment arms. The DMC recommendation was evaluated by the benefit risk evaluation committee (BREC), and a decision was taken on 25 Oct 2016 to discontinue administration of xentuzumab permanently in the 1280.4 study. BI informed the investigators, ethics committees, and health authorities of the decision to discontinue xentuzumab treatment in trial 1280.4 on 28 Oct 2016. Further enrolment was terminated; however, the trial itself was not to be terminated. An exception was provided only for the patient ongoing in the Phase Ib part of the study. This patient experienced a partial response, had been on therapy for more than 20 months and no remarkable safety issues had been identified. The duration of response for this patient was also considered exceptional relative to published historical information for the background therapy (everolimus + exemestane). Only after reconsenting was the patient allowed to remain on treatment under the supervision of the treating physician. At the time of writing this CTR, this patient has been on treatment with xentuzumab + everolimus + exemestane for more than 42 months.

15 Dec 2016

Amendment 3 continued: Amendment 3 was implemented to reflect the sponsor decision to discontinue xentuzumab on 28 Oct 2016. The amendment introduced several changes as a result of the discontinuation of xentuzumab including: Termination of the collection of samples for pharmacokinetics, biomarkers, circulating tumour cells and antidrug antibodies, after xentuzumab was discontinued. Safety lab and ECGs were to be performed as indicated in the approved label of everolimus / exemestane or according local practice after xentuzumab discontinuation. A new flowchart for the Phase II part was added. Clarified that blinding of the project team could no longer remain after xentuzumab discontinuation. Clarification than despite xentuzumab discontinuation, patients could continue on everolimus and exemestane. Added that cfDNA is obtained at the time of xentuzumab discontinuation for patients in the experimental arm. Clarification that analysis after 90 PFS events made no sense after the xentuzumab discontinuation. The analyses for the primary endpoint were to be done with data obtained up to 4 weeks after xentuzumab discontinuation.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Xentuzumab (Xen) stopped per sponsor decision 28Oct2016; patients (p) could continue with everolimus+exemestane. P attend for an end of Xen visit (EoXV, same procedures as end of trial visit). Recruitment stopped but study completed per protocol.

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Clinical trials

Clinical Trial Results:
A Phase Ib/II Randomized Study of BI 836845 in Combination with Exemestane and Everolimus Versus Exemestane and Everolimus Alone in Women with Locally Advanced or Metastatic Breast Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-free survival (PFS) - Phase II part

Primary: Progression-free survival (PFS) - Phase II part

Primary: Number of patients with dose limiting toxicity (DLT) - phase Ib part

Primary: Number of patients with dose limiting toxicity (DLT) - phase Ib part

Primary: Maximum Tolerated Dose (MTD) - phase Ib part

Primary: Maximum Tolerated Dose (MTD) - phase Ib part

Secondary: Number of patients with objective response (OR) - phase II part

Secondary: Number of patients with objective response (OR) - phase II part

Secondary: Time to progression (TTP) - phase II part

Secondary: Time to progression (TTP) - phase II part

Secondary: Number of patients with disease control (DC) - phase II part

Secondary: Number of patients with disease control (DC) - phase II part

Secondary: Time to objective response - phase II part

Secondary: Time to objective response - phase II part

Secondary: Duration of objective response - phase II part

Secondary: Duration of objective response - phase II part

Secondary: Duration of disease control - phase II part

Secondary: Duration of disease control - phase II part

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Phase Ib/II Randomized Study of BI 836845 in Combination with Exemestane and Everolimus Versus Exemestane and Everolimus Alone in Women with Locally Advanced or Metastatic Breast Cancer

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-free survival (PFS) - Phase II part

Primary: Progression-free survival (PFS) - Phase II part

Primary: Number of patients with dose limiting toxicity (DLT) - phase Ib part

Primary: Number of patients with dose limiting toxicity (DLT) - phase Ib part

Primary: Maximum Tolerated Dose (MTD) - phase Ib part

Primary: Maximum Tolerated Dose (MTD) - phase Ib part

Secondary: Number of patients with objective response (OR) - phase II part

Secondary: Number of patients with objective response (OR) - phase II part

Secondary: Time to progression (TTP) - phase II part

Secondary: Time to progression (TTP) - phase II part

Secondary: Number of patients with disease control (DC) - phase II part

Secondary: Number of patients with disease control (DC) - phase II part

Secondary: Time to objective response - phase II part

Secondary: Time to objective response - phase II part

Secondary: Duration of objective response - phase II part

Secondary: Duration of objective response - phase II part

Secondary: Duration of disease control - phase II part

Secondary: Duration of disease control - phase II part

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase Ib/II Randomized Study of BI 836845 in Combination with Exemestane and Everolimus Versus Exemestane and Everolimus Alone in Women with Locally Advanced or Metastatic Breast Cancer