Clinical Trials Register

Summary
EudraCT Number:	2014-002001-37
Sponsor's Protocol Code Number:	009684QM
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-01-27
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2014-002001-37

A.3

Full title of the trial

Phase II window of opportunity study of short term preoperative treatment with enzalutamide (alone or in combination with exemestane) in patients with primary breast cancer.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A window of opportunity study of enzalutamide (alone or in combination with exemestane) in patients with newly diagnosed breast cancer who are awaiting surgery for their cancer.

A.3.2

Name or abbreviated title of the trial where available

ARB v1.0

A.4.1

Sponsor's protocol code number

009684QM

A.5.4

Other Identifiers

Name:

Not applicable

Number:

Not applicable

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Queen Mary University London
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Astellas Pharma Europe Ltd
B.5.2	Functional name of contact point	Suzanne Day
B.5.3	Address:
B.5.3.1	Street Address	2000 Hillswood Drive,
B.5.3.2	Town/ city	Chertsey
B.5.3.3	Post code	KT16 0RS
B.5.3.4	Country	United Kingdom

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Xtadi
D.2.1.1.2	Name of the Marketing Authorisation holder	Astellas Pharma Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Enzalutamide
D.3.2	Product code	MDV3100
D.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Enzalutamide
D.3.9.1	CAS number	915087-33-1
D.3.9.2	Current sponsor code	Enzalutamide
D.3.9.3	Other descriptive name	MDV3100, MDV-3100, MDV 3100
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	160
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Aromasin
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Exemestane
D.3.2	Product code	Not applicable
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Exemestane
D.3.9.1	CAS number	107868-30-4
D.3.9.2	Current sponsor code	Exemestane
D.3.9.3	Other descriptive name	N/A
D.3.9.4	EV Substance Code	AS4
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Exemestane
D.3.9.1	CAS number	107868-30-4
D.3.9.2	Current sponsor code	107868-30-4
D.3.9.3	Other descriptive name	N/A
D.3.9.4	EV Substance Code	AS5
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Primary breast cancer

E.1.1.1

Medical condition in easily understood language

Newly diagnosed breast cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.1
E.1.2	Level	PT
E.1.2	Classification code	10057654
E.1.2	Term	Breast cancer female
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Determine the ability of enzalutamide, when taken alone or in combination with exemestane, to affect the growth of cancer cells in patients with newly diagnosed breast cancer.

E.2.2

Secondary objectives of the trial

- Determine the effect of enzalutamide, when taken alone or in combination with exemestane, on tumour cell death.

- Establish the safety and tolerability of enzalutamide, when taken alone or in combination with exemestane, in this patient population.

- Evaluate changes in circulating hormone levels after enzalutamide administration

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent prior to admission to this study
2. Female, aged ≥18 years
3. ECOG performance status 0- 2
4. Histologically confirmed invasive primary breast cancer
5. Palpable breast tumour of any size, or tumour with an ultrasound or MRI size of at least 1.0 cm
6. Haematologic and biochemical indices within the ranges shown below at the screening visit
a) ANC ≥ 1500 cells/μl
b) Platelet count ≥ 100000/μl
c) Serum creatinine concentration < 1.5 x ULN
d) Bilirubin level < 1.5 x ULN
e) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 x ULN

Inclusion Criteria unique to the ER+ve cohort
1. ER+ve tumours defined as ≥1% of tumour cells positive for ER on IHC staining or an IHC score (Allred) of ≥3
2. Postmenopausal defined as:
a) Age ≥55 years and 1 year or more of amenorrhea
b) Age <55 years and 1 year or more of amenorrhea with LH and/or FSH levels in the postmenopausal range
c) Age <55 with prior hysterectomy but intact ovaries with LH and/or FSH levels in the postmenopausal range
d) Status after bilateral oophorectomy (≥ 28 days prior to first study treatment)

Inclusion Criteria unique to the AR+ve, TNBC cohort
1. AR positive tumours defined as any nuclear AR staining by IHC (enrolment may be based on local pathology findings; subsequent review of AR expression by central pathology laboratory will be carried out)
2. Triple-negative tumours, i.e. tumour cells are negative for
a) ER with <1% of cells positive on IHC or an IHC score (Allred) of ≤2
b) PR with <1% of tumour cells positive on IHC or an Allred score of ≤2
c) HER2 with 0, 1+ or 2+ intensity on IHC and no evidence of amplification of the HER2 gene on ISH
3. Negative serum or urine pregnancy test for women of childbearing potential within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible. Patients of childbearing potential must agree to use adequate contraception (for example, intrauterine device [IUD], birth control pills unless clinically contraindicated, or barrier device) beginning 2 weeks before the first dose of investigational medicinal product (IMP) and for 30 days after the final dose of IMP.

E.4

Principal exclusion criteria

1. Inflammatory breast cancer
2. Treatment with any of the following medications within 4 weeks before the baseline diagnostic biopsy is taken:
a) Oestrogens, including hormone replacement therapy;
b) Androgens (testosterone, dihydroepiandrosterone, etc.);
c) Any approved or investigational agent that blocks androgen synthesis or targets the AR (e.g., abiraterone acetate, ARN-509, bicalutamide, enzalutamide, ODM-201, TAK-448, TAK-683, TAK-700)
3. Previous systemic or local treatment for the new primary breast cancer currently under investigation (including surgery, radiotherapy, cytotoxic and endocrine treatments); prior treatment for previous breast cancer or other neoplasms is allowed as long as it was completed at least 1 year prior to inclusion into this trial.
4. History of seizure or any condition that may predispose to seizure; history of loss of consciousness or transient ischemic attack within 12 months before day 1.
5. Significant cardiovascular disease, such as
a) History of myocardial infarction, acute coronary syndromes or coronary angioplasty/stenting/bypass grafting within the past 6 months.
b) Congestive heart failure New York Heart Association (NYHA) Class III or IV or history of congestive heart failure NYHA class III or IV, unless an echocardiogram or multigated acquisition scan performed within 3 months before day 1 reveals a left ventricular ejection fraction ≥ 45%;
c) History of clinically significant ventricular arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, torsade de pointes);
6. Hypersensitivity to the active pharmaceutical ingredient or any of the excipients of the IMPs, including Labrasol, butylated hydroxyanisole, and butylated Hydroxytoluene
7. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an IMP, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
8. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
9. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug ≤30 days prior to study entry depending on the half-life of the investigational drug and/or guidance issued by the ARB IMP manufacturer. Please contact the ARB Coordinating team for further information.

E.5 End points

E.5.1

Primary end point(s)

ER positive cohort: The difference in geometric mean change (post treatment - pre treatment) in Ki67 expression between the two treatment arms.

AR positive, triple negative breast cancer cohort: Individual anti-proliferative response (RRδKi67), defined as a ≥50% fall in Ki67 expression over the course of the study treatment.

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary endpoint will be evaluated on breast cancer tumour samples collected prior to the start of study treatment and on completion of study treatment.

E.5.2

Secondary end point(s)

1. Secondary Ki67 analyses:
- Geometric mean change in Ki67 expression at the end of study treatment (Mean ΔKi67) (TNBC-cohort).
- Geometric mean Ki67 expression at the end of study treatment (Mean Ki67post).
- Individual end-of treatment anti-proliferative response (RRKi67-Post), defined as the natural logarithm of percentage positive Ki67 of less than 1 at the end of study treatment
- Individual anti-proliferative response (RRΔKi67), defined as a ≥50% fall in Ki67 expression over the course of the study treatment (ER+ve cohort.

2. Changes in Caspase-3 IHC assessment between pre- and post-treatment tumour samples:
- Geometric mean change in Caspase-3 between end-of-treatment and pre-treatment tumour samples (Mean ΔCaspase-3).
- Individual apoptotic response (RRΔCaspase-3), defined as a ≥50% increase in Caspase-3 over the course of the study treatment.

3. Safety:
- Incidence of serious adverse events (SAEs)
- Incidence of grade 3 and 4 adverse events (AEs) (CTCAE, version 4.03)
- Incidence of all AEs of all grades
- Clinically significant changes in vital signs and clinical laboratory results during and following study drug administration

4. Plasma levels of estrone, estrodiol, androstenedione, dihydroepiandrosterone, DHT, total/free testosterone, and sex-hormone binding globulin in blood samples taken prior to and after treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Secondary Ki67 analysis will be carried out on breast cancer tumour samples collected prior to the start of study treatment and on completion of study treatment.

2. Changes in Caspase-3 will be investigated on breast cancer tumour samples collected prior to the start of study treatment and on completion of study treatment.

3. Safety will be evaluated based on adverse events reported on the pre-treatment, post-treatment and safety visits.

4. Circulating hormone levels will be measured on blood samples collected prior to the start of study treatment and on completion of study treatment.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of the trial is defined as 12 months after the last patient visit takes place in both cohorts.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1