FEVEX: Fulvestrant and EVerolimus Plus EXemestane in Metastatic Breast Cancer

Sponsor

Consorzio Oncotech (Other)

Overall Status

Unknown status

CT.gov ID

NCT02404051

Collaborator

Clinical Research Technology S.r.l. (Industry)

745

Enrollment

Locations

Arms

Duration (Months)

18.2

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multi-center, randomized, open-label, parallel group study designed to evaluate efficacy and safety of fulvestrant followed, at progression, by examestane and everolimus versus examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR+ and HER2- LABC or MBC whose disease has progressed to NSAI in the adjuvant or metastatic setting.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer Breast Cancer Hormone Receptor Positive Tumor Human Epidermal Growth Factor 2 Negative Carcinoma of Breast Locally Advanced Malignant Neoplasm	Drug: Everolimus Drug: Exemestane Drug: Fulvestrant	Phase 3

Detailed Description

In this study everolimus will be administered in combination with exemestane, which is an irreversible steroidal aromatase inactivator that has demonstrated efficacy in the treatment of postmenopausal patients with ABC. Exemestane is indicated for adjuvant treatment of postmenopausal women with HR+ EBC who have received two to three years of tamoxifen and are switched to exemestane for completion of a total of five consecutive years of adjuvant hormonal therapy. It is also indicated for the treatment of ABC in postmenopausal women whose disease has progressed following tamoxifen therapy (in the USA) or following antiestrogen therapy (in Europe). In 2011, the BOLERO-2 trial reported (5; 33) a significant benefit for HR+ HER2- postmenopausal pretreated women in the ABC setting by combining everolimus with exemestane. In this randomized, double-blind, placebo-controlled trial a statistically significant improvement in PFS by adding everolimus to exemestane versus exemestane alone was reported. Adding everolimus determined a 2.4-fold prolongation in PFS from 3.2 up to 7.4 months and so lowered the risk of cancer progression by 56% for these women. These findings were confirmed by an independent assessment (4.1 vs. 11.0 months, risk reduction: 64%). The QoL data shows positive trend in the everolimus plus exemestane treatment arm.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

745 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Fulvestrant Followed by Everolimus Plus Exemestane vs Examestane and Everolimus Followed by Fulvestrant in Postmenopausal Women With HR+ and HER2- Locally Advanced (LABC) or Metastatic Breast Cancer (MBC) Previously Treated With NSAI

Study Start Date :

Dec 1, 2015

Anticipated Primary Completion Date :

Jan 1, 2018

Anticipated Study Completion Date :

Jan 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ARM 1 Everolimus plus Exemestane -> progression disease (PD) -> fulvestrant (ARM 1)	Drug: Everolimus 10 mg daily tablets Other Names: Afinitor Drug: Exemestane 25 mg daily tablets Other Names: Aromasin Drug: Fulvestrant 500 mg i.m. on Days 1, 15 and 29 and every 28 days thereafter Other Names: Faslodex
Experimental: ARM 2 Fulvestrant -> progression disease (PD) -> everolimus plus exemestane (ARM 2)	Drug: Everolimus 10 mg daily tablets Other Names: Afinitor Drug: Exemestane 25 mg daily tablets Other Names: Aromasin Drug: Fulvestrant 500 mg i.m. on Days 1, 15 and 29 and every 28 days thereafter Other Names: Faslodex

Arm

Intervention/Treatment

Experimental: ARM 1

Everolimus plus Exemestane -> progression disease (PD) -> fulvestrant (ARM 1)

Drug: Everolimus

10 mg daily tablets

Other Names:

Afinitor

Drug: Exemestane

25 mg daily tablets

Other Names:

Aromasin

Drug: Fulvestrant

500 mg i.m. on Days 1, 15 and 29 and every 28 days thereafter

Other Names:

Faslodex

Experimental: ARM 2

Fulvestrant -> progression disease (PD) -> everolimus plus exemestane (ARM 2)

Drug: Everolimus

10 mg daily tablets

Other Names:

Afinitor

Drug: Exemestane

25 mg daily tablets

Other Names:

Aromasin

Drug: Fulvestrant

500 mg i.m. on Days 1, 15 and 29 and every 28 days thereafter

Other Names:

Faslodex

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS1) [Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months]
The number of events required for the other primary endpoint (PFS1), and the expected time needed to achieve it are derived from previous calculations. Assuming an average accrual rate of 31 pts/month (677pts/22 months), a median PFS1 of 6 months in the Fulvestrant arm (control), a Hazard ratio of 0.70 (implying that a median PFS1 of 8,6 months is expected in the experimental arm, a 2-sided significance level of 0.025 and power of 0.90, 391 events are required for PFS1, that will be achieved in about 22 months (East 6 software).
Total Progression-free survival (PFST) [Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months]
Overall study size is driven by the endpoint less frequent (PFST). Sample size is planned to identify a Hazard ratio of 0.75, assuming an overall study duration of 36 months, an accrual duration of 24 months, a 2-sided significance level of 0.025 and power of 0.80. Assuming a median PFST of 12 months in the Fulvestrant arm (control), the expected PFST in the experimental arm will be equal to 16 months and 677 subjects need to be enrolled (East 6 software) with an average accrual rate equal to 30.8 patients/month (11 months per year have been considered).

Secondary Outcome Measures

Response Rate [Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months]
Objective Response Rate (ORR), the Clinical Benefit, the overall survival, and the safety profile and the QOLof of the sequence of fulvestrant followed, at progression by exemestane and everolimus versus the sequence of examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR + and HER2- LABC or MBC previously treated with NSAI in the adjuvant or metastatic setting.
Clinical Benefit Rate [Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months]
Objective Response Rate (ORR), the Clinical Benefit, the overall survival, and the safety profile and the QOLof of the sequence of fulvestrant followed, at progression by exemestane and everolimus versus the sequence of examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR + and HER2- LABC or MBC previously treated with NSAI in the adjuvant or metastatic setting.
Overall Survival [Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months]
Objective Response Rate (ORR), the Clinical Benefit, the overall survival, and the safety profile and the QOLof of the sequence of fulvestrant followed, at progression by exemestane and everolimus versus the sequence of examestane and everolimus followed, at progression, by fulvestrant in postmenopausal women with HR + and HER2- LABC or MBC previously treated with NSAI in the adjuvant or metastatic setting.
Safety - 5D5L questionnaire [up to 31 days since last treatment]
The overall observation period will be divided into three mutually exclusive segments per treatment phase: pre-treatment period: from day of patient's informed consent to the day before first dose of study medication (phase 1) on-treatment period: from day of first dose of study medication to 30 days (minimum washout) after last dose of study medication (phase 2) or first dose of second phase treatment after cross-over post-treatment period: starting at day 31 after last dose of study medication (phase 2)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult women (≥ 18 years of age) with LABC or MBC not amenable to curative treatment by surgery or radiotherapy, refractory to NSAI
Histological or cytological confirmation of ER+ BC and/or PgR+.
Postmenopausal women.
Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to randomization
Patients must have:

At least one lesion that can be accurately measured in at least one dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mm with spiral CT or MRI
Bone lesions: lytic or mixed (lytic + sclerotic) in the absence of measurable disease as defined above.

Adequate bone marrow and coagulation according RCP
Adequate liver function, according RCP
Adequate renal function, according RCP
ECOG Performance Status ≤ 2
Written informed consent

Exclusion Criteria:

HER2-overexpressing patients by local laboratory testing (IHC3+ staining or in situ hybridization positive).
Patients who received chemotherapy for MBC
Patients who received more than one NSAI treatment for LABC or MBC
Pre-menopausal, pregnant, lactating women.
Known hypersensitivity to mTOR inhibitors
Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose galactose malabsorption.
Radiotherapy within four weeks prior to enrollment
Currently receiving hormone replacement therapy, unless discontinued prior to enrollment.
Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in some cases
Patients with symptomatic visceral disease in need of urgent disease control
Symptomatic brain or other CNS metastases.
Patients with a known history of HIV seropositivity.
Active, bleeding diathesis, or on oral anti-vitamin K medication (except cases).
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
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study treatments (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
Inability to swallow oral medications
Significant symptomatic deterioration of lung function.

Hepatic-related exclusion criteria:

History of liver disease, such as cirrhosis or chronic active hepatitis B and C.
Presence of Hepatitis B surface antigen (HbsAg) and/or of Hepatitis B Virus - Deoxyribonucleic acid (HBV-DNA)
Presence of anti-HCV and/or HCV-RNA-PCR
History of, or current alcohol misuse/abuse within the past 12 months
Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A within the last 5 days prior to enrollment.
History of non-compliance to medical regimens.
Patients unwilling to or unable to comply with the protocol

Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A
History of non-compliance to medical regimens.
Patients unwilling to or unable to comply with the protocol.

Screening for hepatitis B

Prior to enrollment, peculiar patients should be tested for hepatitis B viral load and serologic markers, that is, HBV-DNA, HBsAg, HBsAb, and HBcAb:

Screening for hepatitis C Patients with any of the following risk factors for hepatitis C should be tested

Contacts and Locations

Locations

	Site	City	Country
1	ASL19 - Ospedale Cardinal Massaia	Asti	Italy
2	Azienda Ospedaliera Policlinico di Bari	Bari	Italy
3	Istituto Tumori Giovanni Paolo II	Bari	Italy
4	Azienda Ospedaliera "G. Rummo"	Benevento	Italy
5	Ospedale Fatebenefratelli 'Sacro Cuore di Gesù' di Benevento	Benevento	Italy
6	A.O. Ospedale Papa Giovanni XXIII	Bergamo	Italy
7	Presidio Ospedaliero Antonio Perrino	Brindisi	Italy
8	Azienda Ospedaliera - A. Businco - A.S.L. N. 8	Cagliari	Italy
9	Fondazione del Piemonte per l' Oncologia - Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.)	Candiolo	Italy
10	ASL di Taranto - Polo Occidentale	Castellaneta	Italy
11	A.O.R.N.A.S. Garibaldi Nesima di Catania	Catania	Italy
12	Fondazione per la Ricerca e la Cura dei Tumori T. Campanella - Campus S. Venuta	Catanzaro	Italy
13	Azienda Ospedaliera S. Croce e Carle	Cuneo	Italy
14	Ospedale Infermi di Rimini	Faenza	Italy
15	Azienda Ospedaliera Universitaria Careggi	Firenze	Italy
16	Azienda Ospedaliero - Universitaria Ospedali Riuniti di Foggia	Foggia	Italy
17	I.R.C.C.S. A.O.U San Martino - IST	Genova	Italy
18	Ospedale Civile di guastalla	Guastalla	Italy
19	Ospedale Civile San Salvatore - Università degli Studi L'Aquila	L'Aquila	Italy
20	Presidio Ospedaliero "Renzetti"	Lanciano	Italy
21	Ospedale Vito Fazzi	Lecce	Italy
22	Ospedale di Macerata	Macerata	Italy
23	AO Papardo	Messina	Italy
24	AORN . Ospedali dei colli Monaldi-Cotugno	Napoli	Italy
25	Azienda Ospedaliera 'A. Cardarelli' (AORN)	Napoli	Italy
26	Azienda Ospedaliera Universitaria Federico II	Napoli	Italy
27	Istituto Nazionale per lo studio dei Tumori - Fondazione 'Pascale'	Napoli	Italy
28	A.O.U. 'Maggiore della Carità'	Novara	Italy
29	A.O.U.P. 'Paolo Giaccone'	Palermo	Italy
30	Azienda Ospedaliera S. Chiara	Pisa	Italy
31	Ospedale F. Lotti	Pontedera	Italy
32	Ospedale di Ravenna	Ravenna	Italy
33	Campus Biomedico di Roma	Roma	Italy
34	Istituto Regina Elena per lo studio e la cura dei tumori - Oncologia A	Roma	Italy
35	Istituto Regina Elena per lo studio e la cura dei tumori - Oncologia B	Roma	Italy
36	Azienda Ospedaliera 'San Giovanni di Dio e Ruggi D'Aragona'	Salerno	Italy
37	IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico 'Casa Sollievo della Sofferenza'	San Giovanni rotondo	Italy
38	Azienda Ospedaliera Universitaria di Sassari	Sassari	Italy
39	Azienda Ospedaliero Universitaria ´S. Maria della Misericordia´ di Udine	Udine	Italy
40	"Ospedale Borgo Roma Verona Sezione di Oncologia Medica"	Verona	Italy
41	Ospedale Sacro Cuore Don Calabria di Negrar	Verona	Italy