Clinical Trials Register

Summary
EudraCT Number:	2011-006312-31
Sponsor's Protocol Code Number:	D3610C00002
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-02-27
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

Czechia - SUKL

A.2

EudraCT number

2011-006312-31

A.3

Full title of the trial

A Phase I/II, Multicentre, Study Comprising a Safety Run-In of AZD5363 when Combined with Paclitaxel in Patients with Advanced or Metastatic Breast Cancer; Followed by a Randomised Expansion of AZD5363 when Combined with Paclitaxel vs. Paclitaxel plus Placebo in Patients with ER-Positive Advanced or Metastatic Breast Cancer, Stratified by PIK3CA Mutation Status (BEECH).

Multicentrická studie fáze I/II sestávající z Run-in fáze hodnocení bezpečnosti podání AZD5363 v kombinaci s paclitaxelem u pacientů s pokročilým nebo metastatickým karcinomem prsu, která je následována randomizovaným rozšířením porovnávajícím podání AZD5363 v kombinaci s paclitaxelem oproti paclitaxelu s placebem u pacientů, rozdělených podle ne/přítomnosti mutace PIK3CA, s ER pozitivním pokročilým nebo metastatickým nádorem prsu (BEECH).

A.3.1

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

Investigating safety, tolerability and efficacy of AZD5363 when combined with paclitaxel in breast cancer patients.

Hodnocení bezpečnosti podání AZD5363 v kombinaci s paclitaxelem u pacientů s pokročilým nebo metastatickým karcinomem prsu.

A.4.1

Sponsor's protocol code number

D3610C00002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01226316

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	AstraZeneca AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Astrazeneca
B.5.2	Functional name of contact point	information Centre
B.5.6	E-mail	Informationcenter@astrazeneca.com

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 80 mg film-coated tablet
D.3.2	Product code	AZD5363
D.3.4	Pharmaceutical form	Film-coated 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	not available
D.3.9.1	CAS number	1143532-39-1
D.3.9.2	Current sponsor code	AZD5363
D.3.9.3	Other descriptive name	4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxy-propyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-caroxamide
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	200
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 200 mg film-coated tablet
D.3.2	Product code	AZD5363
D.3.4	Pharmaceutical form	Film-coated 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	not available
D.3.9.1	CAS number	1143532-39-1
D.3.9.2	Current sponsor code	AZD5363
D.3.9.3	Other descriptive name	4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxy-propyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-caroxamide
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	200
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	Film-coated 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

Advanced or metastatic breast cancer, ER+ve advanced or metastatic breast cancer, safety and tolerability, pharmacokinetics, pharmacodynamics, tumour response, PIK3CA

E.1.1.1

Medical condition in easily understood language

Advanced breast cancer, side effects, changes in blood levels of drug, effect of drug on body and cancer, breast cancer, an error in the genetic code of an enzyme which drives cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part A. Safety run-in: To assess the safety and tolerability of two intermittent dosing schedules of AZD5363 when combined with weekly paclitaxel in patients with advanced or metastatic breast cancer; and to recommend, by assessment of dose limiting toxicities and other safety, tolerability, pharmacokinetic and pharmacodynamic data, a dose and schedule of AZD5363 for further study when combined with weekly paclitaxel.
Part B. Randomised expansion: To assess the relative efficacy of AZD5363 when combined with weekly paclitaxel compared with weekly paclitaxel plus placebo by assessment of progression-free survival in the overall advanced or metastatic Estrogen Receptor positive breast cancer population and in a Phosphoinositide 3-kinase (PIK3CA) mutation-positive sub-population.

E.2.2

Secondary objectives of the trial

Part A:To assess anti-tumour activity of AZD5363+paclitaxel by objective response rate and % of patients without progressive disease at 12 w.
Part B:To assess relative efficacy of AZD5363+paclitaxel vs.paclitaxel+placebo by objective response rate at 12 w., best objective response, durable response rate and duration of response.To assess relative antitumour activity of AZD5363+paclitaxel vs.paclitaxel+placebo by change in tumour size at 12 w.To compare overall survival in patients treated with AZD5363+paclitaxel vs. paclitaxel+placebo by time to death.To further assess safety and tolerability of AZD5363+paclitaxel vs.paclitaxel+placebo.To investigate effects on patients' quality of life of AZD5363+paclitaxel vs.paclitaxel+placebo by changes from baseline, using a patient questionnaire.
PartsA and B:To assess PK ofAZD5363 and paclitaxel alone and in combination.To assess relationship between plasma AZD5363 exposure and concentrations of plasma biomarkers; toxicity burden of diarrhoea.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Provision of informed consent
Female Patients
Aged at least 18 years
Histological or cytological confirmation of breast cancer with evidence of advanced or metastatic disease (must be ER+ve, HER2-ve, in Part B).
World Health Organisation (WHO) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.

E.4

Principal exclusion criteria

Clinically significant abnormalities of glucose metabolism.
Spinal cord compression or brain metastases unless asymptomatic, treated and stable (not requiring steroids).
Evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses or active infections including hepatitis B, C and HIV.
Any prior exposure to agents which inhibit AKT as the primary phamacological activity.
Part A: more than two prior courses of chemotherapy (including taxanes) for advanced or metastatic breast cancer.
Part B: any prior chemotherapy for advanced or metastatic breast cancer.

E.5 End points

E.5.1

Primary end point(s)

Part A: Safety and tolerability of AZD5363 when combined with paclitaxel, in terms of numbers of patients with adverse events and serious adverse events.
Part B: Relative efficacy of AZD5363, compared to placebo, when combined with paclitaxel, by assessment of progression-free survival.

E.5.1.1

Timepoint(s) of evaluation of this end point

Regular assessments, to include vital signs, clinical chemistry, haematology and ECGs, will be conducted from screening, throughout the period that patients receive AZD5363/placebo and paclitaxel, up to 28-days following discontinuation of study treatments. Tumour assessments by RECIST 1.1 will be conducted at baseline and every 12 weeks up to disease progression or withdrawal of consent. Recording of adverse events will be conducted from screening, throughout the period that patients receive AZD5363/placebo and paclitaxel, up to 28-days following discontinuation of study treatments. In Part B, serious adverse events that are considered related to study procedures will be recorded up to disease progression.

E.5.2

Secondary end point(s)

Part A: Preliminary anti-tumour activity of AZD5363 when combined with paclitaxel, by assessment of overall response rate (ORR) and percentage of patients without progressive disease at 12 weeks.
Part B: Relative efficacy of AZD5363, compared to placebo, when combined with paclitaxel, by assessment of ORR at 12 weeks, best objective response (BOR), duration of response (DoR) and durable response rate (DRR).
Part B: Relative anti-tumour activity of AZD5363, compared to placebo, when combined with paclitaxel, by comparison of change in tumour size at 12 weeks.
Part B: Safety and tolerability of AZD5363 when combined with paclitaxel,in terms of numbers of patients with adverse events and serious adverse events.
Part B: Effect on patient's quality of life (QoL) due to receipt of AZD5363 when combined with paclitaxel, by assessing changes from baseline score in a patient-completed QoL questionnaire (EORTC QLQ-30 / BR-23).
Parts A and B: Assessment of the plasma concentration profile of AZD5363 when combined with paclitaxel.
Parts A and B: Assessment of the plasma concentration (PK) profile of paclitaxel alone and when combined with AZD5363
Parts A and B: Assessment of the pharmacokinetic/pharmacodynamic relationship between plasma concentration of AZD5363 and plasma concentrations of pharmacodynamic biomarkers and correlation with anti-tumour activity.
Parts A and B: To assess the toxicity burden associated with diarrhoea in relation to the number of episodes, duration of episodes and variations in intensity within episodes of the event's occurrence.
Part B: Overall survival of patients treated with AZD5363, compared to
placebo, when in combination with paclitaxel by assessment of time to
death.

E.5.2.1

Timepoint(s) of evaluation of this end point

Regular assessments, including vital signs, clinical chemistry, haematology and ECGs, will be conducted from screening to 28-days after discontinuation of study treatments. Multiple blood samples for PK/PD assessments will be taken during the first 28-day cycle. Blood sampling for: glycosylated haemoglobin, lipids, circulating tumour cells, and assessment of: MUGA/Echo, QoL and RECIST 1.1, will be conducted every 12 weeks from baseline to disease progression or withdrawal of consent. Adverse events will be recorded from screening to 28-days after discontinuation of study treatments. Part B: serious adverse events that are considered related to study procedures will be recorded up to disease progression; patients will be followed for survival status to death or withdrawal of consent.

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

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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

Interventional

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

Yes

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

Yes

E.8.2.3.1

Comparator description

paclitaxel

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

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Bulgaria

Canada

Czech Republic

France

Japan

Korea, Republic of

Mexico

Peru

Singapore

Spain

United Kingdom

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

Last Subject Last Visit

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.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

140

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

140

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

140

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Standard of Care.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-02-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-10

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-10-03

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