Clinical Trials Register

Summary
EudraCT Number:	2013-000898-68
Sponsor's Protocol Code Number:	2013/VCC/0008
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2014-01-15
Trial 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

2013-000898-68

A.3

Full title of the trial

A phase 1b/2 randomised placebo controlled trial of fulvestrant +/- AZD5363 in
postmenopausal women with advanced breast cancer previously treated with a third generation aromatase inhibitor.

A.3.1

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

Fulvestrant +/- Akt inhibition in advanced aromatase inhibitor resistant breast cancer

A.3.2

Name or abbreviated title of the trial where available

FAKTION

A.4.1

Sponsor's protocol code number

2013/VCC/0008

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	Velindre NHS Trust
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	Clinical Trials Awards and Advisory Committee, Cancer Research UK
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	AstraZeneca
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Wales Cancer Trials Unit
B.5.2	Functional name of contact point	Tracie Madden
B.5.3	Address:
B.5.3.1	Street Address	Wales Cancer Trials Unit
B.5.3.2	Town/ city	School of Medicine Cardiff University
B.5.3.3	Post code	CF14 4YS
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02920687953
B.5.5	Fax number	02920687501
B.5.6	E-mail	MaddenTA1@cf.ac.uk

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	No
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	AZD5363
D.3.2	Product code	AZD5363
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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	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	No
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	AZD5363
D.3.2	Product code	AZD5363
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.3.11 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
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Estrogen receptor positive advanced breast cancer

E.1.1.1

Medical condition in easily understood language

Breast cancer cells which have the estrogen receptor (ER positive or ER+).

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	18.0
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.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10070575
E.1.2	Term	Estrogen receptor positive breast cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10006187
E.1.2	Term	Breast cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10070577
E.1.2	Term	Oestrogen receptor positive breast cancer
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

Phase 1 safety run in: To assess the safety and appropriate dose level of the trial drug AZD5363 in combination with fulvestrant.

Randomised Phase 2:
• To assess the efficacy of AZD5363 in combination with fulvestrant compared with fulvestrant plus placebo in women with ER positive cancers resistant to aromatase inhibitor therapy.

• To examine the relative effectiveness of fulvestrant treatment plus AZD5363 compared to fulvestrant plus placebo in patients with and without activation of the tumour PI3K/Akt/PTEN pathway.

E.2.2

Secondary objectives of the trial

Phase 1 safety run in: To make a preliminary assessment of the anti-tumour activity of AZD5363 in combination with fulvestrant

Randomised Phase 2:
• To assess the safety and tolerability of AZD5363 in combination with fulvestrant compared with fulvestrant plus placebo
• To examine the effectiveness of fulvestrant plus AZD5363 vs fulvestrant plus placebo in sub-populations of patients with and without activation of the tumour PI3K/Akt/PTEN pathway

Both phases:
• To assess how AZD5363 treatment may affect the blood concentration of fulvestrant
• To store genetic samples for future translational research, aimed at the identification of markers which may predict the response to treatment

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Provision of informed consent prior to any study specific procedures.
2. Adult female patients, aged ≥ 18 years.
3. Postmenopausal patients.
4. Histological confirmation of ER+ve breast cancer on primary tumour at diagnosis or on biopsy of a metastasis.
5. Histological confirmation of HER2 negative breast cancer on primary tumour at diagnosis or on biopsy of a metastasis.
6. Clinical or histological confirmation of metastatic or locally advanced disease not amenable to curative surgical resection
7. ECOG performance status 0 to 2 with no deterioration over the previous 2 weeks
8. Minimum life expectancy of 12 weeks.
9. Measurable or non-measurable disease
10.Progressive disease whilst receiving a third generation aromatase inhibitor for locally advanced or metastatic BC or relapsed with metastatic disease whilst receiving a third generation AI in the adjuvant setting. The AI does not need to be the last treatment immediately prior to recruitment.
11.No more than 3 prior lines of endocrine therapy for ABC. If an attempt to downstage a locally advanced tumour with endocrine therapy was made in the absence of MBC, and the tumour operated upon, then this does not count as a line of therapy for ABC. In contrast, if the tumour remained inoperable then this treatment should be included as a line of therapy for ABC.
12.No more than 1 line of cytotoxic chemotherapy for ABC (Adjuvant and neo-adjuvant chemotherapy are not classed as lines of chemotherapy for ABC). A chemotherapy regimen used to treat ABC but that was discontinued due to toxicity, during, or within 6 weeks of the first dose, with a maximum of one cycle delivered and no evidence of disease progression clinically or radiologically at the time subsequent therapy was initiated, is not considered a line of therapy).
13.Suitable for further endocrine therapy according to the treating clinician.
14.Radiological or objective clinical evidence of recurrence or progression on or after the last systemic therapy prior to enrolment.
15.Provision of archival tumour sample for PIK3CA mutation and PTEN by IHC testing. If insufficient tumour available contact WCTU for further information.
16.Provision of baseline plasma sample for PIK3CA mutation testing on cfDNA.
17.Patient has adequate bone marrow and organ function
18.Patients with type II diabetes mellitus that is well controlled by dietary measures alone and have an HgA1c < 8% are eligible to participate.

E.4

Principal exclusion criteria

1. Previous treatment with fulvestrant or inhibitors of the PI3K/mTOR/Akt pathway to treat breast cancer
2. Clinically significant abnormalities of glucose metabolism as defined by any of the following:
a. Diagnosis of diabetes mellitus type I;
b. Glycosylated haemoglobin (HbA1C) ≥8.0% at screening (64 mmol/mol)
(conversion equation for HbA1C [IFCC-HbA1C (mmol/mol) = [DCCT-HbA1C(%) – 2.15] x 10.929)
c. Fasting Plasma Glucose ≥ 7.0mmol/L (126 mg/dL) at screening. Fasting is defined as no caloric intake for at least 8 hours.
3. Rapidly progressive visceral disease not suitable for further endocrine therapy
4. Last dose chemotherapy, immunotherapy targeted therapy, biologic therapy or tumour embolisation must be more than 21 days (more than 6 weeks for nitrosurea or mitomycin C) prior to the first dose of study treatment (fulvestrant).
5. Last dose of palliative radiotherapy must be more than 7 days prior to the first dose of study treatment (fulvestrant)
6. Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment (fulvestrant).
7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
8. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
9. Any of the following cardiac criteria:
a. Mean resting corrected QT interval (QTc) >470 msec obtained from 3 consecutive ECGs.
b. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block.
c. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval.
d. Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure NYHA Grade 2.
e.Uncontrolled hypotension
f.Cardiac ejection fraction outside institutional range of normal or <50% (whichever is higher) as measured by echocardiogram or MUGA scan.
10.With the exception of alopecia, any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment.
11.Elevated Alkaline phosphatase (ALP) is not exclusionary if due to the presence of bone metastasis or if liver function is otherwise considered adequate in the investigator’s judgement.
12.Proteinuria
13.Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD5363
14.History of hypersensitivity to active or inactive excipients of AZD5363 or fulvestrant
15.Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
16.Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
17.Evidence of dementia, altered mental status or any psychiatric condition that would prohibit understanding or rendering of informed consent.
18.Participation in another clinical study with an investigational product (IP) during the last 30 days.
19.Known immunodeficiency syndrome.
20.Inability or unwillingness to comply with study procedures, including the inability to take regular oral medication.
21.Concomitant medication unsuitable for combination with trial medication including certain commonly used antiemetics and statins. Treatment with coumarins such as warfarin is not permitted in the study.

E.5 End points

E.5.1

Primary end point(s)

To establish the anti-tumour activity of the combination of AZD5363 with fulvestrant as measured by progression-free survival (PFS) compared with fulvestrant and placebo. This is the time from randomisation to any disease progression and/or any death, defined according to strict RECIST v1.1 criteria. Lesions will be compared to baseline measurements to assess progression.

E.5.1.1

Timepoint(s) of evaluation of this end point

From date of randomisation until the date of first documented disease progression or date of death from any cause, whichever comes first, assessed up to 6 months after the last patient is randomised.

E.5.2

Secondary end point(s)

- Safety, tolerability and feasibility of use (the number of patients with adverse events and the number of patients requiring dose modifications)
- Objective response rate and clinical benefit as assessed by RECIST 1.1 criteria
- Overall survival, time from randomisation to death with those still alive censored at date last seen
- The influence of mutational status of PIK3CA and the presence of complete loss of PTEN on outcome in the two treatment groups
- Fulvestrant pharmacokinetics
- Samples collected for future translational research (exploratory biomarkers)

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to 12 months after the last patient is randomised except for:
- Fulvestrant pharmacokinetics will be evaluated at cycle 1 day 15, cycle 2 day 1 and cycle 3 day 1;
- Samples collected for future translational research (exploratory biomarkers)at baseline, week 8 and upon disease progression.

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase 1b, to ensure the proposed dose is safe to use in combination with fulvestrant.

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

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

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

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

Yes

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 study end date is deemed to be the date of last data capture. This will be the last patient’s study visit, or when 98 disease progression events have been reported, whichever is later.

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1