Clinical Trials Register

Summary
EudraCT Number:	2013-000665-36
Sponsor's Protocol Code Number:	UZB-MO-FC-01
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:	2013-07-16
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

Belgium - FPS Health-DGM

A.2

EudraCT number

2013-000665-36

A.3

Full title of the trial

A phase II, open label study of everolimus with fulvestrant in postmenopausal women with hormone receptor-positive HER-2 negative AI and fulvestrant treated, locally advanced or metastatic breast cancer (mBC), who progressed on or after mTor inhibitor based treatment.

A.3.1

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

Everolimus and Fulvestrant therapy in postmenopausal metastatic Breast Cancer at patient treated with fulvestrant and who progressed on or after mTor inhibitor based treatment

A.4.1

Sponsor's protocol code number

UZB-MO-FC-01

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	UZ Brussel
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	Novartis nv.sa.
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	UZ Brussel
B.5.2	Functional name of contact point	Dr Fontaine C.
B.5.3	Address:
B.5.3.1	Street Address	Laarbeeklaan 101
B.5.3.2	Town/ city	Brussels
B.5.3.3	Post code	1090
B.5.3.4	Country	Belgium
B.5.4	Telephone number	322477 64 15
B.5.5	Fax number	322477 54 60
B.5.6	E-mail	christel.fontaine@uzbrussel.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.2.1.1.1	Trade name	Afinitor 5 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.2	Product code	RAD001
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.3.9.3	Other descriptive name	EVEROLIMUS
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.2.1.1.1	Trade name	Afinitor 10 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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.3.2	Product code	RAD001
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.3.9.3	Other descriptive name	EVEROLIMUS
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.3.11 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

postmenopausal women with hormone receptor-positive, Her2 negative AI and fulvestrant treated, locally advanced or metastatic breast cancer, who progressed on prior fulvestrant and also received prior treatment with everolimus and exemestane. The treatment with fulvestrant is not required to be the last treatment administered as long as at some point in time a progression on fulvestrant has been ascertained.

E.1.1.1

Medical condition in easily understood language

Postmenopausal women with metastatic breast cancer with progression during exemestant or everolimus treatment.

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10027475
E.1.2	Term	Metastatic breast cancer
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

A phase II academic study to investigate whether the combination of everolimus and fulvestrant can restore sensibility to fulvestrant in postmenopausal women with ER+ HER2- advanced breast cancer who received a previous everolimus + exemestane treatment

E.2.2

Secondary objectives of the trial

- Determine the disease response to the combination of fulvestrant and everolimus.
- The tolerability of the combination
- Correlate the response with steady state plasma levels of everolimus (pharmacokinetic) at base line dosing and subsequent dose adaptations as determined one week after dosing initiation or subsequent dose adaptation.
- Correlation of response with the activated mTOR pathway in tumor tissue. (biomarkers).
- Correlation of early metabolic response with final outcome

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Postmenopausal women. Postmenopausal status is defined either by:
- Age ≥ 55 years and one year or more of amenorrhea
- Age < 55 years and one year or more of amenorrhea, with an estradiol assay < 20 pg/ml
- Surgical menopause with bilateral oophorectomy
2. Organ function:
- ALT/AST <2.5 ULN or <5 if hepatic metastases
- Bilirubine less than 2.5 ULN
- PLT > 100.000 10*6/L
- WBC >3.5 and ANC> 1.5 10*9 g/L
- Hb > 9.0 g/dL
- INR < 2
- Creatinine clearance > 30 ml/min or Serum creatinine < 1.5xULN
3. Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 ×ULN. In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy or other lipid lowering drugs (eg fibrates), and when the above mentioned values have been achieved
4. Written informed consent obtained before any screening procedure and according to local applications.
5. Written informed consent for the analysis of germline DNA needed for translational analysis.
6. A new biopsy of tumor tissue with consent of the patient at the moment of progressive disease is preferable with the confirmation of hormone receptor positivity. If possible also frozen, for later translational investigations. In these patients 2 samples of 10 ml EDTA tubes should be taken to make germline DNA analysis possible. If a tumor biopsy is not possible at the baseline for this study due to lack of consent of the patient or for technical or safety reasons, an earlier biopsy should be available for subsequent biomarker analysis.
7. Adult women (> 18 years of age) with metastatic advanced breast cancer who relapse after adjuvant treatment treated with maximum of 3 lines of endocrine treatment.
8. For patients who present with metastatic disease at first diagnosis up to 4 lines of hormonal treatment before inclusion in the trial are accepted
9. Patients treated with maximum 1 line of chemotherapy for advanced disease.
10. Patient with histological or cytological confirmation of estrogen-receptor positive (ER+) or progesterone receptor positive (PR+) breast cancer
11. Patient with an ECOG Performance Status < 2
12. Patients who received prior sequential, but not necessary continuous Fulvestrant and exemestane plus everolimus treatment after progression disease
13. Measurable disease is not mandatory.

E.4

Principal exclusion criteria

1. HER2-overexpressing patients by local laboratory testing (FISH positive).
2. Known hypersensitivity to mTOR inhibitors.
3. Currently receiving hormone replacement therapy.
4. Patients receiving concomitant immunosuppressive agents or chronic systemic corticosteroid use;
5. Patients with symptomatic visceral disease in need of urgent disease control: e.g. significant dyspnea related to pulmonary lymphangitic carcinomatosis or lung metastases or clinically meaningful symptomatic liver metastasis at the judgment of treating investigator.
6. Metastases estimated as more than a third of the liver as defined by sonogram and/or CT scan.
7. Symptomatic brain or other CNS metastases. Previously treated symptomatic brain metastases are allowed provided the patient is free of symptoms, prior radiotherapy for brain metastasis was more than four weeks before enrollment and the dose of corticosteroids is low and stable for at least two weeks prior to enrollment.
8. Patients with a known immunodeficiency disease.
9. Radiotherapy within four weeks prior to enrollment 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 enrollment. Patients must have recovered from radiotherapy toxicities prior to enrollment.
10. Patients with a known history of HIV seropositivity.
11. Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin and acetylsalicylic acid or equivalent, as long as the INR is ≤ 2.0)
12. Any severe and / or uncontrolled medical conditions such as:
• Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia
• Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN
• Acute and chronic, active infectious disorders and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy
• Impairment of gastrointestinal function or gastrointestinal disease that may uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
• Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, DLco, O2 saturation at rest on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates.
13. Patients who test positive for hepatitis B or C. (Patients who test negative for HBV-DNA, HBsAg, and HBcAb but positive for HBsAb with prior history of vaccination against Hepatitis B will be eligible)
14. Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itroconazole, Voriconazole, Ritinavir, Telithromycin) within the last 5 days prior to enrollment
15. History of non-compliance to medical regimens
16. Patients unwilling to or unable to comply with the protocol.
17. ECOG score >2
18. Diagnosis of concurrent malignancy within 5 years of study enrollment, except for an adequately treated cervical carcinoma in situ and a basal or squamous cell carcinoma of the skin.
19. Patients with more than one line of prior chemotherapy for advanced disease
20. Patients with more than 3 lines of endocrine treatment for metastatic disease who relapse after adjuvant treatment

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint is the 4-month clinical benefit rate (CBR) defined as the percentage of all patients with a complete or partial response or stable disease at 4 months with a duration of 16 weeks or longer, according to RECIST 1.1 criteria.
Time to overall response (CR or PR) is the time between date of randomization until first documented response (CR or PR) according to RECIST 1.1
Duration of overall response applies only to patients whose best overall response is CR or PR. The start date is the date of first documented response (CR or PR) and the date is the date of event defined as first documented progression or death due to underlying cancer. See RECISTt 1.1

E.5.1.1

Timepoint(s) of evaluation of this end point

16 weeks

E.5.2

Secondary end point(s)

- Response rate shall be evaluated using the RECIST 1.1 criteria.
- The clinicians will report all the adverse events and grading using the CTC criteria version 4.0.
- On day 8 a blood sample will be taken to measure the everolimus steady state plasma levels.
- New tumour biopsies will be analyzed by immunohistochemistry and mutational analysis to make a correlation possible between tumour response and the activation of the mTor pathway and other biomarkers.
- Early metabolic response will be determined by a Pet CT scan taken on day 14.

E.5.2.1

Timepoint(s) of evaluation of this end point

For patient s with measurable disease at screening (as per RECIST criteria), efficacy (overall tumor response and progression) will be evaluated every 2 months (screening+3 evaluations) for 6 months and afterwards every 3 months.

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

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)

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

Last Visit Last Subject

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)

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)

Standard treatment

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

2013-08-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-11-13

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