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Clinical Trial Results:
A Phase 1b/2 Randomized Study of MEDI-573 in Combination with an Aromatase Inhibitor (AI) Versus AI Alone in Women with Metastatic Breast Cancer (MBC)

Summary
EudraCT number	2011-000198-29
Trial protocol	ES DE HU BE GB
Global end of trial date	28 Jun 2019

Results information
Results version number	v1(current)
This version publication date	14 Jun 2020
First version publication date	14 Jun 2020
Other versions

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

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Trial information

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Sponsor protocol code

CD-ON-MEDI-573-1030

ISRCTN number

US NCT number

NCT01446159

WHO universal trial number (UTN)

Sponsor organisation name

MedImmune, LLC

Sponsor organisation address

One MedImmune Way, Gaithersburg, United States, 20878

Public contact

Mohammed Dar, One MedImmune Way, +1 301-398-1894, information.center@astrazeneca.com

Scientific contact

Mohammed Dar, MedImmune, LLC, +1 301-398-1894, information.center@astrazeneca.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

20 Aug 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

28 Jun 2019

Global end of trial reached?

Yes

Global end of trial date

28 Jun 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study is to evaluate the safety and tolerability of 3 dose levels of MEDI-573 in combination with an AI in participants with HR+, HER2-negative MBC.

Protection of trial subjects

The conduct of this clinical study met all local and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonization guideline: Good Clinical Practice, and applicable regulatory requirements. Participants signed an informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Jun 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 99

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

Hungary: 4

Country: Number of subjects enrolled

Spain: 15

Country: Number of subjects enrolled

Germany: 6

Country: Number of subjects enrolled

France: 3

Country: Number of subjects enrolled

Israel: 19

Country: Number of subjects enrolled

Canada: 9

Country: Number of subjects enrolled

Poland: 2

Country: Number of subjects enrolled

Belgium: 22

Worldwide total number of subjects

183

EEA total number of subjects

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted across 10 countries (Belgium, Canada, France, Germany, Hungary, Israel, Spain, Poland, United Kingdom, USA).

Screening details

A total of 187 participants were screened in the study. Of which, 183 participants were treated with study drugs.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

MEDI-573 10 mg/kg + aromatase inhibitor (AI)

Arm description

Participants enrolled in Phase 1b of the study and received intravenous infusion of MEDI-573 10 mg/kg on Day 1 of each 21-day cycle and AI of the investigator’s choice (letrozole, anastrozole, or exemestane) orally once daily until unacceptable toxicity, documentation of disease progression, or withdrawal for other reasons.

Arm type

Experimental

Investigational medicinal product name

MEDI-573

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Intravenous (IV) infusion of MEDI-573 10 mg/kg on Day 1 of each 21-day cycle until unacceptable toxicity, documentation of disease progression, or withdrawal for other reasons.

Investigational medicinal product name

Aromatase inhibitor

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

AI of the investigator’s choice (letrozole, anastrozole, or exemestane) orally once daily until unacceptable toxicity, documentation of disease progression, or withdrawal for other reasons.

MEDI-573 30 mg/kg + AI

Arm description

Participants enrolled in Phase 1 b of the study and received intravenous infusion of MEDI-573 30 mg/kg on Day 1 of each 21-day cycle and AI (letrozole, anastrozole, or exemestane) orally once daily until unacceptable toxicity, documentation of disease progression, or withdrawal for other reasons.

Arm type

Experimental

Investigational medicinal product name

Aromatase inhibitor

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

AI of the investigator’s choice (letrozole, anastrozole, or exemestane) orally once daily until unacceptable toxicity, documentation of disease progression, or withdrawal for other reasons.

Investigational medicinal product name

MEDI-573

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

IV infusion of MEDI-573 10 mg/kg on Day 1 of each 21-day cycle until unacceptable toxicity, documentation of disease progression, or withdrawal for other reasons.

MEDI-573 45 mg/kg + AI

Arm description

Participants received intravenous infusion of MEDI-573 45 mg/kg on Day 1 of each 21-day cycle and AI (letrozole, anastrozole, or exemestane) orally once daily until unacceptable toxicity, documentation of disease progression, or withdrawal for other reasons. Three participants were enrolled in Phase 1b and 89 were enrolled in Phase 2 of the study.

Arm type

Experimental

Investigational medicinal product name

MEDI-573

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

IV infusion of MEDI-573 10 mg/kg on Day 1 of each 21-day cycle until unacceptable toxicity, documentation of disease progression, or withdrawal for other reasons.

Investigational medicinal product name

Aromatase inhibitor

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

AI of the investigator’s choice (letrozole, anastrozole, or exemestane) orally once daily until unacceptable toxicity, documentation of disease progression, or withdrawal for other reasons.

Aromatase Inhibitor

Arm description

Participants enrolled in Phase 2 of the study and received oral AI (letrozole, anastrozole, or exemestane) once daily until unacceptable toxicity, documentation of disease progression, or withdrawal for other reasons.

Arm type

Active comparator

Investigational medicinal product name

Aromatase Inhibitor

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

aromatase inhibitor

Number of subjects in period 1	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Started	3	3	92	85
Completed	0	0	21	23
Not completed	3	3	71	62
Adverse event, serious fatal	2	3	43	36
Consent withdrawn by subject	1	-	14	11
Not specified	-	-	13	13
Lost to follow-up	-	-	1	2

Baseline characteristics

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Reporting group title

MEDI-573 10 mg/kg + aromatase inhibitor (AI)

Reporting group description

Reporting group title

MEDI-573 30 mg/kg + AI

Reporting group description

Reporting group title

MEDI-573 45 mg/kg + AI

Reporting group description

Reporting group title

Aromatase Inhibitor

Reporting group description

Reporting group values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor	Total
Number of subjects	3	3	92	85	183
Age categorical
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	1	49	44	96
From 65-84 years	1	2	41	40	84
85 years and over	0	0	2	1	3
Age Continuous
Units: Years
arithmetic mean (standard deviation)	66.3 ( 12.3 )	61.0 ( 8.7 )	63.2 ( 10.5 )	63.3 ( 11.0 )	-
Sex: Female, Male
Units: Participants
Female	3	3	92	85	183
Male	0	0	0	0	0
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	0	0	0	1	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	1	0	6	1	8
White	2	3	84	82	171
More than one race	0	0	0	0	0
Unknown or Not Reported	0	0	2	1	3
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	7	6	13
Not Hispanic or Latino	3	3	85	79	170
Unknown or Not Reported	0	0	0	0	0

End points

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Reporting group title

MEDI-573 10 mg/kg + aromatase inhibitor (AI)

Reporting group description

Reporting group title

MEDI-573 30 mg/kg + AI

Reporting group description

Reporting group title

MEDI-573 45 mg/kg + AI

Reporting group description

Reporting group title

Aromatase Inhibitor

Reporting group description

Primary: Phase 1b and Phase 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

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End point title

Phase 1b and Phase 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs) ^[1]

End point description

An Adverse Event (AE) is any unfavourable and unintended sign, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. A serious adverse event (SAE) is an AE that results in death, initial or prolonged inpatient hospitalization, life-threatening, persistent or significant disability/incapacity, congenital anomaly/birth defect, or an important medical event. TEAEs and TESAEs are defined as AEs and SAEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 60 days after the last study drug or until the participants started another anticancer therapy, whichever occurs first (approximately 8 years). Safety population included all participants who received any study therapy and were analysed per the treatment they actually received was considered for this end point.

End point type

Primary

End point timeframe

From the start of study treatment (Day 1) through 60 days after the last dose of treatment or until the participants started another anticancer therapy, whichever occurs first (approximately 8 years)

Notes
[1] - 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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	3	3	92	85
Units: Participants
Any TEAEs	3	3	90	82
Any TESAEs	2	0	21	16

No statistical analyses for this end point

Primary: Phase 1b: Number of Participants with dose-limiting toxicities (DLTs)

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End point title

Phase 1b: Number of Participants with dose-limiting toxicities (DLTs) ^[2] ^[3]

End point description

The AEs that occurred during Cycle 1 (Days 1 to 21) and were suspected of having a causal relationship to MEDI-573 and were >= Grade 3 in severity were considered as DLTs. Evaluable population included all participants in Phase 1b of the study, who received at least 1 full cycle of MEDI-573 and completed the safety follow-up through the DLT evaluation period (Days 1 to 21 of Cycle 1) was considered for this end point.

End point type

Primary

End point timeframe

Up to Day 21 of Cycle 1

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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
[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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI
Number of subjects analysed	3	3	3
Units: Participants	0	0	0

No statistical analyses for this end point

Primary: Phase 1b: Number of DLTs

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End point title

Phase 1b: Number of DLTs ^[4] ^[5]

End point description

End point type

Primary

End point timeframe

Up to Day 21 of Cycle 1

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: Statistical analysis was not applicable since there were no inferential statistics, only descriptive statistics were performed for this end point.
[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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI
Number of subjects analysed	3	3	3
Units: DLT events	0	0	0

No statistical analyses for this end point

Primary: Phase 2: Progression-free Survival (PFS)

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End point title

Phase 2: Progression-free Survival (PFS) ^[6]

End point description

Progression-free survival (PFS) was defined as the time from the randomization until the first documentation of disease progression or death due to any cause, whichever occurred first. The PFS was censored on the date of the last tumor assessment documenting absence of tumor progression for participants who had no documented progression and were still alive prior to data cut-off, dropout, or the initiation of alternate anticancer treatment. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as >= 20% increase in the sum of diameters of target lesions and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of non-target lesions or a new lesion. The Intent-to-Treat (ITT) population included all participants who enrolled in Phase 2 and received any study therapy and were analysed per their randomized treatment group was considered for this end point.

End point type

Primary

End point timeframe

From Day 1 until disease progression or death due to any cause, whichever occurred first (Approximately 8 years)

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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	89	85
Units: Months
median (confidence interval 95%)	12.65 (8.15 to 15.54)	11.33 (8.54 to 15.54)

Statistical analysis

Comparison groups

Aromatase Inhibitor v MEDI-573 45 mg/kg + AI

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

P-value

= 0.86

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.991

Confidence interval

level

95%

sides

2-sided

lower limit

0.689

upper limit

1.429

Secondary: Phase 1b and Phase 2: Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs

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End point title

Phase 1b and Phase 2: Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs

End point description

An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation were reported as AEs. The TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 60 days after the last study drug or until the participants started another anticancer therapy, whichever occurs first (approximately 8 years). Safety population was considered for this end point.

End point type

Secondary

End point timeframe

From the start of study treatment (Day 1) through 60 days after the last dose of treatment or until the participants started another anticancer therapy, whichever occurs first (approximately 8 years)

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	3	3	92	85
Units: Participants
Anemia	1	1	17	10
Eosinophilia	0	0	1	0
Leukopenia	0	0	0	3
Lymphopenia	0	0	1	2
Neutropenia	1	1	3	4
Pancytopenia	0	0	0	1
Thrombocytopenia	0	2	1	3
Granulocyte count decreased	0	1	0	0
Hemoglobin decreased	0	1	1	0
Lymphocyte count decreased	0	0	2	1
Monocyte count decreased	0	0	1	0
Neutrophil count decreased	0	0	2	0
Neutrophil count increased	0	0	1	0
Platelet count decreased	0	0	4	1
White blood cell count decreased	0	0	2	1
Alanine aminotransferase increased	2	0	8	4
Aspartate aminotransferase increased	2	1	6	4
Blood albumin decreased	0	0	1	0
Blood albumin increased	0	1	0	0
Blood alkaline phosphatase increased	0	1	5	5
Blood bicarbonate decreased	0	0	1	0
Blood bilirubin increased	0	0	0	1
Blood chloride decreased	0	0	1	0
Blood creatine increased	0	1	1	0
Blood creatinine decreased	0	0	0	1
Blood creatinine increased	0	1	8	2
Blood glucose increased	0	0	1	1
Blood lactate dehydrogenase increased	0	0	1	1
Blood magnesium decreased	0	1	0	0
Blood potassium decreased	0	0	1	0
Blood sodium decreased	0	1	0	0
Blood triglycerides increased	0	0	1	2
Blood urea increased	0	0	1	0
Blood uric acid increased	0	0	3	1
Gamma-glutamyl transferase decreased	0	1	0	0
Gamma-glutamyl transferase increased	1	1	9	4
Protein total decreased	0	1	0	1
Leukocytosis	0	0	0	1
Neutrophilia	0	0	1	0

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Number of Participants With Abnormal Vital Signs Reported as TEAEs

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End point title

Phase 1b and Phase 2: Number of Participants With Abnormal Vital Signs Reported as TEAEs

End point description

An abnormal vital signs that were judged by the investigator to be medically significant were reported as AEs. The TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 60 days after the last study drug or until the participants started another anticancer therapy, whichever occurs first (approximately 8 years). Safety population was considered for this end point.

End point type

Secondary

End point timeframe

From the start of study treatment (Day 1) through 60 days after the last dose of treatment or until the participants started another anticancer therapy, whichever occurs first (approximately 8 years)

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	3	3	92	85
Units: Participants
Bradycardia	1	0	1	1
Palpitations	1	0	1	2
Pyrexia	0	0	10	6
Temperature intolerance	0	0	1	1
Body temperature increased	0	0	1	0
Aspiration	0	0	1	0
Dyspnoea	2	0	18	14
Hypertension	0	0	8	13
Hypotension	1	0	1	0
Orthostatic hypotension	0	0	1	0

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Number of Participants with Abnormal Electrocardiogram (ECG) Reported as TEAEs

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End point title

Phase 1b and Phase 2: Number of Participants with Abnormal Electrocardiogram (ECG) Reported as TEAEs

End point description

An abnormal ECG findings that were judged by the investigator to be medically significant were reported as AEs. The TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 60 days after the last study drug or until the participants started another anticancer therapy, whichever occurs first (approximately 8 years). Safety population was considered for this end point.

End point type

Secondary

End point timeframe

From the start of study treatment (Day 1) through 60 days after the last dose of treatment or until the participants started another anticancer therapy, whichever occurs first (approximately 8 years)

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	3	3	92	85
Units: Participants
Sinus bradycardia	1	0	2	0
Sinus tachycardia	0	0	0	1
Supraventricular tachycardia	0	0	0	2
Tachycardia	0	0	1	2
Angina pectoris	0	0	0	1
Arrhythmia	0	0	0	1
Atrial fibrillation	0	0	1	2
Atrial flutter	0	0	0	1
Atrioventricular block first degree	0	0	1	0
Bradycardia	1	0	1	1
Cardiac failure	0	0	1	0
Cardiac valve disease	0	0	1	0
Palpitation	1	0	1	2
Ventricular extrasystoles	0	0	1	0

No statistical analyses for this end point

Secondary: Phase 2: Number of Participants With Best Overall Tumor Response

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End point title

Phase 2: Number of Participants With Best Overall Tumor Response ^[7]

End point description

Tumor evaluation was based on RECIST v1.1 by CT or MRI scan as: Complete Response (CR): Disappearance of all target and non-target lesions and no new lesions; Partial Response (PR): >= 30% decrease in the sum of diameters of target lesions (compared to baseline) and no new lesions; Stable disease (SD): Neither sufficient shrinkage to qualify as a response nor sufficient growth to qualify as progression; Progressive Disease (PD): >= 20% increase in the sum of diameters of target lesions and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of non-target lesions or a new lesion; not evaluable (NE): either no or only a subset of lesion measurements are made at an assessment. Participants enrolled in Phase 2 and were the part of IIT population were analysed.

End point type

Secondary

End point timeframe

From Day 1 until disease progression or death due to any cause, whichever occurred first (Approximately 8 years)

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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	89	85
Units: Participants
CR	1	2
PR	23	21
SD	48	46
PD	15	12
NE	2	4

No statistical analyses for this end point

Secondary: Phase 2: Objective Response Rate (ORR)

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End point title

Phase 2: Objective Response Rate (ORR) ^[8]

End point description

The ORR was defined as percentage of participants with confirmed complete response or confirmed partial response, where CR was defined as disappearance of all target and non-target lesions and no new lesions and PR was definded as >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. Participants enrolled in Phase 2 and were the part of IIT population were analysed.

End point type

Secondary

End point timeframe

From Day 1 until disease progression or death due to any cause, whichever occurred first (Approximately 8 years)

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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	89	85
Units: Percentage of participants
number (confidence interval 95%)	27.0 (18.1 to 37.4)	27.1 (18.0 to 37.8)

No statistical analyses for this end point

Secondary: Phase 2: Time to Response

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End point title

Phase 2: Time to Response ^[9]

End point description

Time to response was measured from treatment start to the first documentation of disease response and was evaluated only in participants who achieved objective response (confirmed CR or confirmed PR. The CR was defined as disappearance of all target and non-target lesions and no new lesions and PR was defined as >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. Participants enrolled in Phase 2 and were the part of IIT population were analysed.

End point type

Secondary

End point timeframe

From Day 1 until disease progression or death due to any cause, whichever occurred first (Approximately 8 years)

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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	89	85
Units: Months
median (full range (min-max))	4.22 (1.7 to 18.0)	3.98 (1.9 to 16.8)

No statistical analyses for this end point

Secondary: Phase 2: Duration of Response (DR)

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End point title

Phase 2: Duration of Response (DR) ^[10]

End point description

Duration of response (DR) is measured from the first documentation of disease response to the first documented progressive disease and was evaluated only in participants who achieved objective response (confirmed CR or confirmed PR). The CR was defined as disappearance of all target and non-target lesions and no new lesions and PR was defined as >= 30% decrease in the sum of diameters of Target Lesions (compared to baseline) and no new lesions. Participants enrolled in Phase 2 and were the part of IIT population were analysed.

End point type

Secondary

End point timeframe

From Day 1 until disease progression or death due to any cause, whichever occurred first (Approximately 8 years)

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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	89	85
Units: Months
median (full range (min-max))	14.55 (4.5 to 58.8)	17.18 (2.1 to 45.1)

No statistical analyses for this end point

Secondary: Phase 2: Time to Progression (TTP)

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End point title

Phase 2: Time to Progression (TTP) ^[11]

End point description

Time to progression was measured from treatment start until the first documentation of disease progression. The PD was defined as >= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of >=5mm (compared to the previous minimum sum) or progression of non-target lesions or a new lesion. Participants enrolled in Phase 2 and were the part of IIT population were analysed.

End point type

Secondary

End point timeframe

From Day 1 until disease progression or death due to any cause, whichever occurred first (Approximately 8 years)

Notes
[11] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	89	85
Units: Months
median (confidence interval 95%)	14.39 (8.34 to 18.69)	11.33 (8.54 to 17.97)

No statistical analyses for this end point

Secondary: Phase 2: Overall Survival (OS)

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End point title

Phase 2: Overall Survival (OS) ^[12]

End point description

Overall survival (OS) was measured from treatment start until death. Participants enrolled in Phase 2 and were the part of IIT population were analysed.

End point type

Secondary

End point timeframe

From Day 1 until disease progression or death due to any cause, whichever occurred first (Approximately 8 years)

Notes
[12] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	89	85
Units: Months
median (full range (min-max))	39.39 (0.3 to 73.2)	38.34 (0.3 to 51.6)

No statistical analyses for this end point

Secondary: Phase 2: Change in Tumor Size

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End point title

Phase 2: Change in Tumor Size ^[13]

End point description

Participants enrolled in Phase 2 and were the part of IIT population were analysed.

End point type

Secondary

End point timeframe

From Day 1 until disease progression or death due to any cause, whichever occurred first (Approximately 8 years)

Notes
[13] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	89	85
Units: Centimeters
arithmetic mean (standard deviation)	-36.2 ( 35.8 )	-26.8 ( 37.2 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to Day 21 (AUC0-day21) of MEDI-573 for Cycle 1

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End point title

Phase 1b and Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to Day 21 (AUC0-day21) of MEDI-573 for Cycle 1 ^[14]

End point description

The ITT population was considered for this analysis. Participants who received MEDI-573 were analysed.

End point type

Secondary

End point timeframe

Cycle 1 Days 1, 2, 8, 15, and 21 (Cycle 2 Day 1, pre-dose)

Notes
[14] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI
Number of subjects analysed	3	3	92
Units: μg·day/mL
arithmetic mean (standard deviation)	1430 ( 867 )	4500 ( 725 )	7990 ( 1590 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MEDI-573 for Cycle 1

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End point title

Phase 1b and Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MEDI-573 for Cycle 1 ^[15]

End point description

The ITT population was considered for this analysis. Participants who received MEDI-573 were analysed.

End point type

Secondary

End point timeframe

Cycle 1 Days 1, 2, 8, 15, and 21 (Cycle 2 Day 1, pre-dose)

Notes
[15] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI
Number of subjects analysed	3	3	92
Units: μg·day/mL
arithmetic mean (standard deviation)	1500 ( 955 )	4930 ( 691 )	9570 ( 2310 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Dose-Normalised Area Under the Serum Concentration-time Curve From Time Zero to Infinity (DN AUC0-inf) of MEDI-573 for Cycle 1

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End point title

Phase 1b and Phase 2: Dose-Normalised Area Under the Serum Concentration-time Curve From Time Zero to Infinity (DN AUC0-inf) of MEDI-573 for Cycle 1 ^[16]

End point description

The ITT population was considered for this analysis. Participants who received MEDI-573 were analysed.

End point type

Secondary

End point timeframe

Cycle 1 Days 1, 2, 8, 15, and 21 (Cycle 2 Day 1, pre-dose)

Notes
[16] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI
Number of subjects analysed	3	3	92
Units: day·kg·μg/mL/mg
arithmetic mean (standard deviation)	150 ( 95.5 )	164 ( 23.0 )	213 ( 51.3 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Maximum Observed Serum Concentration (Cmax) of MEDI-573 for Cycle 1

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End point title

Phase 1b and Phase 2: Maximum Observed Serum Concentration (Cmax) of MEDI-573 for Cycle 1 ^[17]

End point description

The ITT population was considered for this analysis. Participants who received MEDI-573 were analysed.

End point type

Secondary

End point timeframe

Cycle 1 Days 1, 2, 8, 15, and 21 (Cycle 2 Day 1, pre-dose)

Notes
[17] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI
Number of subjects analysed	3	3	92
Units: μg/mL
arithmetic mean (standard deviation)	269 ( 74.1 )	624 ( 210 )	1070 ( 253 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-573 for Cycle 1

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End point title

Phase 1b and Phase 2: Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-573 for Cycle 1 ^[18]

End point description

The ITT population was considered for this analysis. Participants who received MEDI-573 were analysed.

End point type

Secondary

End point timeframe

Cycle 1 Days 1, 2, 8, 15, and 21 (Cycle 2 Day 1, pre-dose)

Notes
[18] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI
Number of subjects analysed	3	3	92
Units: Day
median (full range (min-max))	0.04 (0 to 0.09)	0.07 (0.06 to 0.08)	0.07 (0.03 to 0.17)

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Systemic Clearance (CL) of MEDI-573 for Cycle 1

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End point title

Phase 1b and Phase 2: Systemic Clearance (CL) of MEDI-573 for Cycle 1 ^[19]

End point description

The CL is a quantitative measure of the rate at which a drug substance is removed from the body. The total systemic clearance after intravenous dose was estimated by dividing the total administered dose by AUC(0-infinity). The ITT population was considered for this analysis. Participants who received MEDI-573 were analysed.

End point type

Secondary

End point timeframe

Cycle 1 Days 1, 2, 8, 15, and 21 (Cycle 2 Day 1, pre-dose)

Notes
[19] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI
Number of subjects analysed	3	3	92
Units: mL/day/kg
arithmetic mean (standard deviation)	8.29 ( 3.86 )	6.17 ( 0.889 )	4.96 ( 1.13 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Terminal Half life (t1/2) of MEDI-573 for Cycle 1

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End point title

Phase 1b and Phase 2: Terminal Half life (t1/2) of MEDI-573 for Cycle 1 ^[20]

End point description

The elimination half-life (t1/2) is the time measured for the serum concentration of MEDI-573 to decrease by 1 half to its original concentration. The ITT population was considered for this analysis. Participants who received MEDI-573 were analysed.

End point type

Secondary

End point timeframe

Cycle 1 Days 1, 2, 8, 15, and 21 (Cycle 2 Day 1, pre-dose)

Notes
[20] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI
Number of subjects analysed	3	3	92
Units: Day
arithmetic mean (standard deviation)	4.38 ( 1.07 )	5.91 ( 2.09 )	8.45 ( 2.23 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Concentration of insulin-like growth factor (IGF) I and IGF-II

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End point title

Phase 1b and Phase 2: Concentration of insulin-like growth factor (IGF) I and IGF-II

End point description

The mean concentration profiles of both IGF-I and IGF-II post administration of MEDI-573 in plasma were evaluated during treatment. Safety population was analysed for this end point. Participants with free IGF concentration were analysed. The “n” denotes the number of participants who were analysed for the specific endpoint. The arbitrary numbers “9999" signifies that standard deviation was not calculated as only one participant was evaluable for the specified arm.

End point type

Secondary

End point timeframe

Baseline (Cycle1 Day1 pre-dose), end of treatment (EOT), and 60 days post last dose (Approximately 8 years)

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Number of subjects analysed	3	3	92	85
Units: ng/mL
arithmetic mean (standard deviation)
Baseline Free IGF-I (n=3, 3, 82, 78)	2.57 ( 0.712 )	1.25 ( 0.635 )	3.49 ( 4.39 )	1.89 ( 1.24 )
Baseline Free IGF-II (n=3, 3, 84, 78	3.81 ( 1.66 )	3.07 ( 0.709 )	3.01 ( 1.20 )	3.03 ( 1.12 )
EOT Free IGF-I (n=2, 2, 40, 38)	0.724 ( 0.421 )	0.313 ( 0.0 )	0.346 ( 0.130 )	2.32 ( 3.64 )
EOT Free IGF-II (n=2, 2, 40, 38)	0.625 ( 0.0 )	0.625 ( 0.0 )	0.641 ( 0.102 )	3.12 ( 1.22 )
60 days post last dose Free IGF-I (n=1, 2, 21, 22)	1.54 ( 99999 )	1.33 ( 0.3 )	1.02 ( 1.29 )	4.62 ( 8.52 )
60days post last dose Free IGF-II (n=1, 2, 21, 22)	1.49 ( 99999 )	0.625 ( 0.0 )	0.984 ( 0.734 )	3.38 ( 1.51 )

No statistical analyses for this end point

Secondary: Phase 1b and Phase 2: Number of participants With Positive Anti-drug Antibodies (ADA) to MEDI-573

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End point title

Phase 1b and Phase 2: Number of participants With Positive Anti-drug Antibodies (ADA) to MEDI-573 ^[21]

End point description

Participants With Positive ADA to MEDI-573 are reported. Participants who received MEDI-573 and were analysed per the treatment they actually received were analysed for this outcome measure.

End point type

Secondary

End point timeframe

Pre-infusion on Day 1 of each cycle, End of Treatment, Day 30, 60 and 90 post treatment (approximately 8 years)

Notes
[21] - 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: Only those baseline period arms for which analysis was planned were reported in the end point.

End point values	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI
Number of subjects analysed	3	3	92
Units: Participants	0	0	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug (Day 1) through 60 days after the last dose of treatment or until the participants started another anticancer therapy, whichever occurs first (approximately 8 years)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

MEDI-573 10 mg/kg + aromatase inhibitor (AI)

Reporting group description

Reporting group title

MEDI-573 30 mg/kg + AI

Reporting group description

Reporting group title

MEDI-573 45 mg/kg + AI

Reporting group description

Reporting group title

Aromatase Inhibitor

Reporting group description

Serious adverse events	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	21 / 92 (22.83%)	16 / 85 (18.82%)
number of deaths (all causes)	2	3	43	36
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BREAST CANCER METASTATIC
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	1 / 85 (1.18%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
INTRADUCTAL PROLIFERATIVE BREAST LESION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
LUNG ADENOCARCINOMA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
OVARIAN CANCER METASTATIC
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
RECTAL NEOPLASM
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
UTERINE CANCER
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (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
Vascular disorders
EMBOLISM
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
HYPOTENSION
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (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
General disorders and administration site conditions
CHEST PAIN
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (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
PYREXIA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
Reproductive system and breast disorders
OVARIAN CYST
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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, thoracic and mediastinal disorders
ASPIRATION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
EMPHYSEMA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
PLEURAL EFFUSION
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	2 / 85 (2.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMOTHORAX
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (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
PULMONARY EMBOLISM
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
Psychiatric disorders
MENTAL STATUS CHANGES
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
PSYCHOTIC DISORDER
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
SUICIDE ATTEMPT
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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 / 1	0 / 0
Injury, poisoning and procedural complications
ACETABULUM FRACTURE
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
CERVICAL VERTEBRAL FRACTURE
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
SUBDURAL HAEMATOMA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
Cardiac disorders
ATRIAL FIBRILLATION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
ATRIAL FLUTTER
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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 FAILURE
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
SINUS BRADYCARDIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (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
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	2 / 85 (2.35%)
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
Nervous system disorders
ALTERED STATE OF CONSCIOUSNESS
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
CEREBRAL HAEMORRHAGE
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
PARTIAL SEIZURES
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
Blood and lymphatic system disorders
FEBRILE NEUTROPENIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (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
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
DIARRHOEA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
DYSPHAGIA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
GASTRIC ULCER PERFORATION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
INTESTINAL MASS
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
PANCREATITIS ACUTE
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
SMALL INTESTINAL OBSTRUCTION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
VOMITING
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 92 (3.26%)	0 / 85 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
BILIARY DILATATION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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 / 1	0 / 0
Renal and urinary disorders
HYDRONEPHROSIS
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
BACK PAIN
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
FLANK PAIN
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
PAIN IN EXTREMITY
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
DEVICE RELATED INFECTION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
DIVERTICULITIS
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
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
WOUND INFECTION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
Metabolism and nutrition disorders
DEHYDRATION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
HYPERGLYCAEMIA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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
HYPONATRAEMIA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (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

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

Non-serious adverse events	MEDI-573 10 mg/kg + aromatase inhibitor (AI)	MEDI-573 30 mg/kg + AI	MEDI-573 45 mg/kg + AI	Aromatase Inhibitor
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	90 / 92 (97.83%)	82 / 85 (96.47%)
Vascular disorders
HOT FLUSH
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	13 / 92 (14.13%)	30 / 85 (35.29%)
occurrences all number	1	1	22	46
HYPERTENSION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	8 / 92 (8.70%)	13 / 85 (15.29%)
occurrences all number	0	0	17	24
PERIPHERAL COLDNESS
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	1	0	0	0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	19 / 92 (20.65%)	13 / 85 (15.29%)
occurrences all number	1	0	33	18
FATIGUE
subjects affected / exposed	2 / 3 (66.67%)	3 / 3 (100.00%)	41 / 92 (44.57%)	27 / 85 (31.76%)
occurrences all number	3	6	96	38
MUCOSAL INFLAMMATION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 92 (7.61%)	0 / 85 (0.00%)
occurrences all number	0	0	9	0
OEDEMA PERIPHERAL
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	9 / 92 (9.78%)	10 / 85 (11.76%)
occurrences all number	0	0	16	20
PAIN
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 92 (2.17%)	1 / 85 (1.18%)
occurrences all number	1	0	2	1
PYREXIA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	9 / 92 (9.78%)	6 / 85 (7.06%)
occurrences all number	0	0	11	11
SWELLING
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
occurrences all number	1	0	0	1
Reproductive system and breast disorders
ATROPHIC VULVOVAGINITIS
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 92 (1.09%)	1 / 85 (1.18%)
occurrences all number	1	0	1	1
BREAST HAEMORRHAGE
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	0	1	0	0
BREAST PAIN
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 92 (4.35%)	5 / 85 (5.88%)
occurrences all number	0	0	5	9
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	19 / 92 (20.65%)	11 / 85 (12.94%)
occurrences all number	0	1	27	16
DYSPNOEA
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	18 / 92 (19.57%)	14 / 85 (16.47%)
occurrences all number	2	0	21	23
DYSPNOEA EXERTIONAL
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 92 (3.26%)	2 / 85 (2.35%)
occurrences all number	1	0	7	2
EPISTAXIS
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 92 (5.43%)	2 / 85 (2.35%)
occurrences all number	0	0	5	5
OROPHARYNGEAL PAIN
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 92 (6.52%)	4 / 85 (4.71%)
occurrences all number	0	0	7	4
Psychiatric disorders
ANXIETY
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	10 / 92 (10.87%)	8 / 85 (9.41%)
occurrences all number	0	1	13	10
CONFUSIONAL STATE
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 92 (1.09%)	0 / 85 (0.00%)
occurrences all number	0	1	1	0
DEPRESSION
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	11 / 92 (11.96%)	4 / 85 (4.71%)
occurrences all number	1	1	12	4
ENURESIS
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	1	0	0	0
INSOMNIA
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	10 / 92 (10.87%)	13 / 85 (15.29%)
occurrences all number	0	1	12	14
TACHYPHRENIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	1	0	0	0
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	8 / 92 (8.70%)	4 / 85 (4.71%)
occurrences all number	2	0	13	5
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	6 / 92 (6.52%)	4 / 85 (4.71%)
occurrences all number	7	1	14	7
BLOOD ALBUMIN INCREASED
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	0	1	0	0
BLOOD ALKALINE PHOSPHATASE INCREASED
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	5 / 92 (5.43%)	5 / 85 (5.88%)
occurrences all number	0	1	11	10
BLOOD CHOLESTEROL INCREASED
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 92 (2.17%)	2 / 85 (2.35%)
occurrences all number	1	0	3	3
BLOOD CREATINE INCREASED
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 92 (1.09%)	0 / 85 (0.00%)
occurrences all number	0	1	1	0
BLOOD CREATININE INCREASED
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	8 / 92 (8.70%)	2 / 85 (2.35%)
occurrences all number	0	1	38	2
BLOOD MAGNESIUM DECREASED
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	0	1	0	0
BLOOD SODIUM DECREASED
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	0	1	0	0
GAMMA-GLUTAMYLTRANSFERASE DECREASED
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	0	1	0	0
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	9 / 92 (9.78%)	4 / 85 (4.71%)
occurrences all number	1	3	41	5
GRANULOCYTE COUNT DECREASED
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	0	2	0	0
HAEMOGLOBIN DECREASED
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 92 (1.09%)	0 / 85 (0.00%)
occurrences all number	0	1	4	0
PROTEIN TOTAL DECREASED
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	1 / 85 (1.18%)
occurrences all number	0	1	0	2
WEIGHT DECREASED
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	6 / 92 (6.52%)	5 / 85 (5.88%)
occurrences all number	0	2	10	7
WEIGHT INCREASED
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 92 (5.43%)	3 / 85 (3.53%)
occurrences all number	0	0	5	3
Injury, poisoning and procedural complications
FALL
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 92 (3.26%)	6 / 85 (7.06%)
occurrences all number	0	0	4	6
Cardiac disorders
BRADYCARDIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 92 (1.09%)	1 / 85 (1.18%)
occurrences all number	1	0	1	1
PALPITATIONS
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 92 (1.09%)	2 / 85 (2.35%)
occurrences all number	1	0	1	3
SINUS BRADYCARDIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 92 (2.17%)	0 / 85 (0.00%)
occurrences all number	1	0	2	0
Nervous system disorders
DIZZINESS
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	16 / 92 (17.39%)	9 / 85 (10.59%)
occurrences all number	2	0	25	12
DYSGEUSIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	13 / 92 (14.13%)	8 / 85 (9.41%)
occurrences all number	1	0	16	8
HEADACHE
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	20 / 92 (21.74%)	19 / 85 (22.35%)
occurrences all number	0	1	29	27
NEUROPATHY PERIPHERAL
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	2 / 92 (2.17%)	2 / 85 (2.35%)
occurrences all number	3	0	2	3
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	17 / 92 (18.48%)	10 / 85 (11.76%)
occurrences all number	2	3	48	18
INCREASED TENDENCY TO BRUISE
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	1 / 85 (1.18%)
occurrences all number	1	0	0	1
LYMPHADENOPATHY
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 92 (1.09%)	1 / 85 (1.18%)
occurrences all number	1	0	1	1
NEUTROPENIA
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 92 (3.26%)	4 / 85 (4.71%)
occurrences all number	6	1	6	8
THROMBOCYTOPENIA
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 92 (1.09%)	3 / 85 (3.53%)
occurrences all number	0	3	2	11
Eye disorders
DRY EYE
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 92 (5.43%)	6 / 85 (7.06%)
occurrences all number	0	0	6	7
PHOTOPSIA
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	0	1	0	0
VISION BLURRED
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 92 (5.43%)	2 / 85 (2.35%)
occurrences all number	1	0	9	2
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 92 (7.61%)	7 / 85 (8.24%)
occurrences all number	0	0	8	9
ABDOMINAL PAIN UPPER
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 92 (5.43%)	6 / 85 (7.06%)
occurrences all number	0	0	6	9
CONSTIPATION
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	21 / 92 (22.83%)	23 / 85 (27.06%)
occurrences all number	4	1	27	32
DIARRHOEA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	30 / 92 (32.61%)	22 / 85 (25.88%)
occurrences all number	3	0	50	39
DRY MOUTH
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 92 (5.43%)	8 / 85 (9.41%)
occurrences all number	1	0	7	13
DYSPEPSIA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 92 (6.52%)	6 / 85 (7.06%)
occurrences all number	0	0	6	8
HAEMATOCHEZIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	1	0	0	0
NAUSEA
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	34 / 92 (36.96%)	30 / 85 (35.29%)
occurrences all number	1	3	53	46
PROCTALGIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	1	0	0	0
STOMATITIS
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 92 (6.52%)	4 / 85 (4.71%)
occurrences all number	0	0	11	9
VOMITING
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	14 / 92 (15.22%)	15 / 85 (17.65%)
occurrences all number	0	0	20	21
Skin and subcutaneous tissue disorders
ALOPECIA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	8 / 92 (8.70%)	11 / 85 (12.94%)
occurrences all number	0	0	10	12
ECCHYMOSIS
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 92 (1.09%)	0 / 85 (0.00%)
occurrences all number	2	0	3	0
NIGHT SWEATS
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 92 (3.26%)	0 / 85 (0.00%)
occurrences all number	1	0	3	0
PRURITUS
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	13 / 92 (14.13%)	7 / 85 (8.24%)
occurrences all number	1	0	15	9
RASH
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	11 / 92 (11.96%)	10 / 85 (11.76%)
occurrences all number	0	0	12	15
SKIN MASS
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	1	0	0	0
Renal and urinary disorders
BLADDER SPASM
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	1	0	0	0
DYSURIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 92 (1.09%)	1 / 85 (1.18%)
occurrences all number	1	0	1	1
POLLAKIURIA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 92 (2.17%)	6 / 85 (7.06%)
occurrences all number	0	0	2	7
URINARY HESITATION
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	28 / 92 (30.43%)	35 / 85 (41.18%)
occurrences all number	2	1	60	73
BACK PAIN
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	29 / 92 (31.52%)	21 / 85 (24.71%)
occurrences all number	0	1	49	33
BONE LOSS
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	0	1	0	0
BONE PAIN
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	9 / 92 (9.78%)	9 / 85 (10.59%)
occurrences all number	3	0	9	11
FLANK PAIN
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 92 (2.17%)	1 / 85 (1.18%)
occurrences all number	1	0	2	1
GROIN PAIN
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 92 (2.17%)	1 / 85 (1.18%)
occurrences all number	0	1	2	1
MUSCLE SPASMS
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	10 / 92 (10.87%)	8 / 85 (9.41%)
occurrences all number	0	2	12	14
MUSCULOSKELETAL CHEST PAIN
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	12 / 92 (13.04%)	11 / 85 (12.94%)
occurrences all number	4	1	15	14
MUSCULOSKELETAL PAIN
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	10 / 92 (10.87%)	11 / 85 (12.94%)
occurrences all number	2	0	13	12
MYALGIA
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	9 / 92 (9.78%)	10 / 85 (11.76%)
occurrences all number	5	1	10	11
NECK PAIN
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 92 (6.52%)	7 / 85 (8.24%)
occurrences all number	0	0	7	8
PAIN IN EXTREMITY
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	14 / 92 (15.22%)	18 / 85 (21.18%)
occurrences all number	0	0	20	43
Infections and infestations
BRONCHITIS
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 92 (2.17%)	6 / 85 (7.06%)
occurrences all number	0	0	2	7
DEVICE RELATED INFECTION
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	0	1	0	0
FUNGAL SKIN INFECTION
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	2 / 85 (2.35%)
occurrences all number	0	1	0	3
INFLUENZA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 92 (2.17%)	0 / 85 (0.00%)
occurrences all number	1	0	2	0
LIP INFECTION
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 92 (0.00%)	0 / 85 (0.00%)
occurrences all number	0	3	0	0
NAIL INFECTION
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 92 (1.09%)	0 / 85 (0.00%)
occurrences all number	0	1	1	0
SINUSITIS
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 92 (4.35%)	3 / 85 (3.53%)
occurrences all number	0	1	4	4
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	9 / 92 (9.78%)	10 / 85 (11.76%)
occurrences all number	0	0	11	13
URINARY TRACT INFECTION
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	26 / 92 (28.26%)	17 / 85 (20.00%)
occurrences all number	1	1	48	26
VIRAL UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 92 (6.52%)	7 / 85 (8.24%)
occurrences all number	0	0	7	7
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	19 / 92 (20.65%)	14 / 85 (16.47%)
occurrences all number	1	0	24	16
DEHYDRATION
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 92 (1.09%)	2 / 85 (2.35%)
occurrences all number	0	1	2	2
DIABETES MELLITUS
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 92 (3.26%)	0 / 85 (0.00%)
occurrences all number	1	0	5	0
HYPERGLYCAEMIA
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	10 / 92 (10.87%)	8 / 85 (9.41%)
occurrences all number	0	5	38	12
HYPERKALAEMIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 92 (5.43%)	3 / 85 (3.53%)
occurrences all number	1	0	5	13
HYPERMAGNESAEMIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 92 (2.17%)	3 / 85 (3.53%)
occurrences all number	1	0	2	6
HYPERURICAEMIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 92 (5.43%)	2 / 85 (2.35%)
occurrences all number	1	0	6	3
HYPOCALCAEMIA
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	7 / 92 (7.61%)	1 / 85 (1.18%)
occurrences all number	3	0	15	1
HYPOKALAEMIA
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	10 / 92 (10.87%)	4 / 85 (4.71%)
occurrences all number	0	0	18	12
HYPOMAGNESAEMIA
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	6 / 92 (6.52%)	1 / 85 (1.18%)
occurrences all number	1	1	9	2
HYPONATRAEMIA
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	3 / 92 (3.26%)	4 / 85 (4.71%)
occurrences all number	5	0	16	7
HYPOPHOSPHATAEMIA
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 92 (2.17%)	0 / 85 (0.00%)
occurrences all number	3	0	2	0

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Were there any global substantial amendments to the protocol? Yes

07 Feb 2012

Sections of clinical experience with medi-573, research hypothesis, research hypothesis were updated. Primary objective was updated for the number of dose levels to be tested from 2 to 3. The text of Phase 1b (Dose-evaluation Phase) was modified to account for the addition of a 45 mg/kg plus AI treatment arm. Phase 2 (Randomization Phase) was changed to a 2-arm structure to test 45 mg/kg MEDI-573 plus AI versus AI alone. Addition of a 45 mg/kg arm in Phase 1b and Phase 2, based on PK and pharmacodynamic experience. Inclusion criteria added for participants with metastases to bone, clarified that HER2 negativity assessment, added the definition of postmenopausal, and added the age limit for participants enrolled in Japan. Exclusion criteria changed for the washout period following tamoxifen or an AI prior to receiving the first dose of MEDI-573, clarified the exclusion of participants with active brain metastases, known central nervous system metastases, and leptomeningeal carcinomatosis; text was modified for participants with a history of allergy or reaction attributed to compounds of chemical/biologic composition similar to MEDI-573 or AI, for history of another invasive malignancy, and had poorly controlled diabetes mellitus. Modified the randomization text. Added the text related to dairy for AI intake. Clarified the for MEDI-573 infusion timing. Updated the “Schedule of Study Procedures” table. Added additional physical examination details. Planned analyses text was changed to specify that the primary analysis of PFS and safety were performed after 122 PFS events had occurred. Modified sample size and power calculations.

05 Dec 2012

Randomization statement was added for participants with bone-only disease. Inclusion criteria were updated for participants with bone metastases and method of determining HER2 status. Exclusion criteria were updated for prior adjuvant therapy with an AI and/or tamoxifen and participants with evidence of spinal canal involvement. Added treatment window period to infusion times for potential overfill and for collection of vital signs. Updated permitted concomitant medications section. Updated the “Schedule of Study Procedures” table. Screening section was modified for laboratory results, pregnancy tests, and archival tumor samples. Modified the statements related to Cycle 1 Day 1 and Cycle 2 and Every Cycle Thereafter assessments. Added the description of assessments required after 2 years on study for participants who remain on study drug or s who were discontinued study drug.

25 Jul 2016

Updated the text to include the results from the completed FTIH study (CP-184) and the primary analysis of CD-ON-MEDI-573-1030 study. Updated “End of study” to clarify the follow-up procedures for participants who discontinued treatment or for participants who were on treatment at the end of 36 months. Updated the “Schedule of Study Procedures” table.

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.

None reported

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Clinical trials

Clinical Trial Results: A Phase 1b/2 Randomized Study of MEDI-573 in Combination with an Aromatase Inhibitor (AI) Versus AI Alone in Women with Metastatic Breast Cancer (MBC)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b and Phase 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Primary: Phase 1b and Phase 2: Number of Participants with Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)

Primary: Phase 1b: Number of Participants with dose-limiting toxicities (DLTs)

Primary: Phase 1b: Number of Participants with dose-limiting toxicities (DLTs)

Primary: Phase 1b: Number of DLTs

Primary: Phase 1b: Number of DLTs

Primary: Phase 2: Progression-free Survival (PFS)

Primary: Phase 2: Progression-free Survival (PFS)

Secondary: Phase 1b and Phase 2: Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs

Secondary: Phase 1b and Phase 2: Number of Participants With Abnormal Clinical Laboratory Results Reported as TEAEs

Secondary: Phase 1b and Phase 2: Number of Participants With Abnormal Vital Signs Reported as TEAEs

Secondary: Phase 1b and Phase 2: Number of Participants With Abnormal Vital Signs Reported as TEAEs

Secondary: Phase 1b and Phase 2: Number of Participants with Abnormal Electrocardiogram (ECG) Reported as TEAEs

Secondary: Phase 1b and Phase 2: Number of Participants with Abnormal Electrocardiogram (ECG) Reported as TEAEs

Secondary: Phase 2: Number of Participants With Best Overall Tumor Response

Secondary: Phase 2: Number of Participants With Best Overall Tumor Response

Secondary: Phase 2: Objective Response Rate (ORR)

Secondary: Phase 2: Objective Response Rate (ORR)

Secondary: Phase 2: Time to Response

Secondary: Phase 2: Time to Response

Secondary: Phase 2: Duration of Response (DR)

Secondary: Phase 2: Duration of Response (DR)

Secondary: Phase 2: Time to Progression (TTP)

Secondary: Phase 2: Time to Progression (TTP)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Change in Tumor Size

Secondary: Phase 2: Change in Tumor Size

Secondary: Phase 1b and Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to Day 21 (AUC0-day21) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to Day 21 (AUC0-day21) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Dose-Normalised Area Under the Serum Concentration-time Curve From Time Zero to Infinity (DN AUC0-inf) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Dose-Normalised Area Under the Serum Concentration-time Curve From Time Zero to Infinity (DN AUC0-inf) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Maximum Observed Serum Concentration (Cmax) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Maximum Observed Serum Concentration (Cmax) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Time to Reach Maximum Observed Serum Concentration (Tmax) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Systemic Clearance (CL) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Systemic Clearance (CL) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Terminal Half life (t1/2) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Terminal Half life (t1/2) of MEDI-573 for Cycle 1

Secondary: Phase 1b and Phase 2: Concentration of insulin-like growth factor (IGF) I and IGF-II

Secondary: Phase 1b and Phase 2: Concentration of insulin-like growth factor (IGF) I and IGF-II

Secondary: Phase 1b and Phase 2: Number of participants With Positive Anti-drug Antibodies (ADA) to MEDI-573

Secondary: Phase 1b and Phase 2: Number of participants With Positive Anti-drug Antibodies (ADA) to MEDI-573

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 1b/2 Randomized Study of MEDI-573 in Combination with an Aromatase Inhibitor (AI) Versus AI Alone in Women with Metastatic Breast Cancer (MBC)