Clinical Trials Register

Summary
EudraCT Number:	2012-004860-22
Sponsor's Protocol Code Number:	IJB-BCTL:20120306
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-11-13
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2012-004860-22

A.3

Full title of the trial

The [PEARL] Study : Pet imaging as a biomarker of Everolimus Added value in hormone Refractory postmenopausaL women

A.3.1

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

A Study evaluating utility of PET imaging in patients who do not benefit of the treatment of Everolimus combined with Exemestane.

A.3.2

Name or abbreviated title of the trial where available

PEARL

A.4.1

Sponsor's protocol code number

IJB-BCTL:20120306

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	Institute Jules Bordet
B.1.3.4	Country	Belgium
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	Institut Jules Bordet
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	Novartis
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	institut Jules Bordet
B.5.2	Functional name of contact point	Andrea Gombos
B.5.3	Address:
B.5.3.1	Street Address	Boulevard de Waterloo 121
B.5.3.2	Town/ city	Brussels
B.5.3.3	Post code	1000
B.5.3.4	Country	Belgium
B.5.4	Telephone number	322541 7232
B.5.6	E-mail	andrea.gombos@bordet.be

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.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Afinitor
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	Everolimus
D.3.9.1	CAS number	159351-69-6
D.3.9.4	EV Substance Code	SUB02065MIG
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	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Everolimus
D.3.9.1	CAS number	159351-69-6
D.3.9.4	EV Substance Code	SUB02065MIG
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	5
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	Yes
D.2.1.2	Country which granted the Marketing Authorisation	Belgium
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	Aromasin
D.3.4	Pharmaceutical form	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	Exemestane
D.3.9.1	CAS number	107868-30-4
D.3.9.4	EV Substance Code	SUB07492MIG
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.3.11 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Locally advanced or metastatic endocrine receptor positive and HER2 negative breast cancer refractory to non-steroidal aromatase inhibitors (NSAI)

E.1.1.1

Medical condition in easily understood language

Locally advanced breast cancer or metastatic 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	20.0
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.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate if early metabolic response (MR) using FDG-PET/CT is associated with progression free survival (PFS) in ER+, HER2 negative ABC or MBC patients treated with exemestane plus everolimus.

E.2.2

Secondary objectives of the trial

To evaluate if early metabolic response (MR) using FDG-PET/CT is associated with overall survival (OS) in ER+, HER2 negative locally advanced or MBC patients treated with exemestane plus everolimus.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Adult women (> or =18 years of age) with locally advanced or metastatic breast cancer not amenable to
curative treatment by surgery or radiotherapy.
2. Histological or cytological confirmation of estrogen-receptor positive (ER+), HER2 negative breast cancer.
3. Postmenopausal female defined as:
o Age > or = 55 years and one year or more of amenorrhoea
o Age <55 years and one year or more of amenorrhoea, with an estradiol assay <20pg/ml
o Surgical menopause with bilateral oophorectomy
4. Breast cancer that is refractory to non-steroidal aromatase inhibitors (NSAI) (i.e. anastrozole or letrozole) defined as:
o Recurrence while on, or within 12 months of end of adjuvant treatment with anastrozole or letrozole; OR
o Progression while on, or within one month of end of anastrozole or letrozole or treatment for locally advanced or metastatic breast cancer.
5. FDG-PET measurable disease defined as: at least one target lesion fulfilling following criteria:
a.Size ≥1.5cm; AND
b.FDG-PET avid lesion with uptake above the background liver uptake as described below:
i.e. with a marked accumulation of FDG, at least 1.5-fold greater than liver SUV mean + 2 SDs (in 3cm spherical ROI in normal right lobe of liver). If liver is abnormal, target lesion should have uptake > 2.0 x SUV mean of blood pool in 1-cm-diameter ROI in descending thoracic aorta)
NB:
- The target lesion can be a bone metastasis if it fulfils the above mentioned criteria.
- In the case the target lesion is a lymph node, the small axis should be ≥ 1.5cm.
6. Radiological or clinical evidence of recurrence or progression on last systemic therapy prior to enrolment.
7. Adequate bone marrow function as shown by:
o Haemoglobin (HgB) > or = 9.0 g/dL
o ANC > or = 1,500/mm3 (> or = 1.5 x 109/L)
o Platelets > or = 100,000/mm3 (> or = 100x 109/L)
8. Adequate liver function as shown by:
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5xULN (or ≤ 5 if hepatic metastases are present)
o Total serum bilirubin ≤ 1.5 x ULN (≤ 3 ULN for patients known to have Gilbert Syndrome)
9. Adequate renal function as shown by serum creatinine ≤ 1.5 x ULN
10. Fasting serum cholesterol, triglycerides and glucose
o Fasting serum cholesterol ≤ 300 mg/dL or 7.75 mmol/L
o Fasting triglycerides ≤ 2.5 x ULN
o Fasting glucose < 1.5 x ULN
11. Eastern Co-operative Oncology Group (ECOG) performance status ≤ 2.
12. Written and signed informed consent obtained before any trial related activity.
13. Availability of a FFPE core of primary breast tumor
14. Possibility to obtainthe mandatory blood samples for the translational research studies.
15. For patients with accessible metastatic lesions, possibility to obtain biopsy (FFPE and frozen) of a metastatic lesion

E.4

Principal exclusion criteria

1. HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
2. Patients with only non-measurable lesions by FDG-PET/CT (e.g. pleural effusion, ascites etc.).
3. Symptomatic visceral disease for example liver, pulmonary metastases or lymphangitis carcinomatosis.
4. Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
5. Another malignancy within 5 years prior to enrolment, with the exception of adequately treated in-situ carcinoma of the cervix, uteri, basal or squamous cell carcinoma or non-melanomatous skin cancer.
6. Radiotherapy within four weeks prior to enrolment except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture, which can then be completed within two weeks prior to enrolment. Patients must have recovered from radiotherapy toxicities prior to enrolment.
7. Currently receiving hormone replacement therapy, unless discontinued prior to enrolment.
8. Symptomatic brain metastases or other central nervous system metastases which are not controlled by local treatments.
9.Patients receiving concomitant immunosuppressive agents or chronic corticosteroid use at the time of study entry except in cases outlined below:
a. Topical applications (e.g. rash)
b. Inhaled sprays (e.g. obstructive airways disease)
c. Eye drops
d.Local injections (e.g. intra-articular)
e. Stable low dose of corticosteroids for at least two weeks before enrolment
10. Patients with known HIV seropositivity. Screening for HIV infection at baseline is not required
11. Acute and chronic, active infectious disorders (except for Hepatitis B and Hepatitis C positive patients).
12. Active bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin, LMWH and acetylsalicylic acid or equivalent, as long as the INR is ≤ 2.0).
13. Any severe uncontrolled medical conditions such as:
a. Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤ 6 months prior to enrolment, uncontrolled cardiac arrhythmia
b. Uncontrolled diabetes as defined by fasting glucose > 1.5 x ULN
c. Acute and chronic, active infectious disorders and non-malignant medical illnesses that are
uncontrolled or whose control may be jeopardized by the complications of this study therapy.
d. Symptomatic deterioration of lung function
14. Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazoleonazole, Voriconazole, Ritonavir, Telithromycin) within the last 5 days prior to enrolment.
15. History of non-compliance to medical regimens.
16. Patients unwilling or unable to comply with the protocol.
17. Concurrent anti-cancer treatment in another investigational trial, including hormonal therapy, immunotherapy or targeted agents other than those administered in this study.

E.5 End points

E.5.1

Primary end point(s)

o Pilot phase: Proportion of FDG-PET/CT metabolic non-responders/FDG-PET/CT metabolic responders
o Main phase: Progression free survival based on RECIST criteria 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

o In pilot and main phases: Patients will have imaging with MRI or CT scan at baseline and every 8 weeks to assess progression according to RECIST 1.1.
o In the Pilot phase: FDG-PET/CT will aslo be performed at baseline, the end of week 2 (day 14) ,the end of week 4 (day 28)
o In the Main phase: Following the results from the Pilot phase, FDG-PET/CT will be performed at baseline and at the end of week 2 (day 14). Day 14 FDG-PET/CT was chosen for the second phase, given the high concordance between the two time points used in the pilot phase and the aim to reduce at maximum treatment exposure and costs.

E.5.2

Secondary end point(s)

o Pilot phase: Estimate the most suitable second FDG-PET/CT time point (2 weeks versus 4 weeks after initiation of treatment)
o Mainphase: Overall survival (OS)

E.5.2.1

Timepoint(s) of evaluation of this end point

o Pilot phase: at the end of the pilot pahse
o Main phase: The timepoint will be death of the patients

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

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)

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

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

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

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

This is an event driven analysis. The analysis for the primary endpoint will be performed after 42 PFS events have occurred. The study should end after a survival follow-up period of 3 years of the last subject included or will end when all OS events have been reported, whatever occurs first and the database has been fully cleaned and frozen for all analyses.

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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)

At the discretion of the physician according to local standard practice

G. Investigator Networks to be involved in the Trial

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-12-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-07-05

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