Fulvestrant and EVerolimus Plus EXemestane in Metastatic Breast Cancer

Breast Cancer Clinical Trial

— FEVEX  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02404051
• Other study ID #: GIM16-FEVEX
• Secondary ID: 2014-004035-38
• Status: Recruiting
• Phase: Phase 3
• First received: January 26, 2015
• Last updated: June 14, 2016
• Start date: December 2015
• Est. completion date: January 2019

Study information

• Verified date: June 2016
• Source: Consorzio Oncotech
• Contact: Clinical Research Technology
• Phone: 0039089301545
• Is FDA regulated: No
• Health authority: Italy: The Italian Medicines Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 745
• Est. completion date: January 2019
• Est. primary completion date: January 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Adult women (= 18 years of age) with LABC or MBC not amenable to curative treatment by surgery or radiotherapy, refractory to NSAI

2. Histological or cytological confirmation of ER+ BC and/or PgR+.

3. Postmenopausal women.

4. Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to randomization

5. 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.

6. Adequate bone marrow and coagulation according RCP

7. Adequate liver function, according RCP

8. Adequate renal function, according RCP

9. ECOG Performance Status = 2

10. Written informed consent

Exclusion Criteria:

1. HER2-overexpressing patients by local laboratory testing (IHC3+ staining or in situ hybridization positive).

2. Patients who received chemotherapy for MBC

3. Patients who received more than one NSAI treatment for LABC or MBC

4. Pre-menopausal, pregnant, lactating women.

5. Known hypersensitivity to mTOR inhibitors

6. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose galactose malabsorption.

7. Radiotherapy within four weeks prior to enrollment

8. Currently receiving hormone replacement therapy, unless discontinued prior to enrollment.

9. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use, at the time of study entry except in some cases

10. Patients with symptomatic visceral disease in need of urgent disease control

11. Symptomatic brain or other CNS metastases.

12. Patients with a known history of HIV seropositivity.

13. Active, bleeding diathesis, or on oral anti-vitamin K medication (except cases).

14. 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.

15. 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

16. Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme CYP3A

17. History of non-compliance to medical regimens.

18. 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms
• Hormone Receptor Positive Tumor
• Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
• Locally Advanced Malignant Neoplasm
• Metastatic Breast Cancer
• Neoplasms

Intervention

Drug:
• Everolimus
10 mg daily tablets
• Exemestane
25 mg daily tablets
• Fulvestrant
500 mg i.m. on Days 1, 15 and 29 and every 28 days thereafter

Locations

Country	Name	City	State
Italy	ASL19 - Ospedale Cardinal Massaia	Asti
Italy	Azienda Ospedaliera Policlinico di Bari	Bari
Italy	Istituto Tumori Giovanni Paolo II	Bari
Italy	Azienda Ospedaliera "G. Rummo"	Benevento
Italy	Ospedale Fatebenefratelli `Sacro Cuore di Gesù` di Benevento	Benevento
Italy	A.O. Ospedale Papa Giovanni XXIII	Bergamo
Italy	Presidio Ospedaliero Antonio Perrino	Brindisi
Italy	Azienda Ospedaliera - A. Businco - A.S.L. N. 8	Cagliari
Italy	Fondazione del Piemonte per l' Oncologia - Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.)	Candiolo
Italy	ASL di Taranto - Polo Occidentale	Castellaneta
Italy	A.O.R.N.A.S. Garibaldi Nesima di Catania	Catania
Italy	Fondazione per la Ricerca e la Cura dei Tumori T. Campanella - Campus S. Venuta	Catanzaro
Italy	Azienda Ospedaliera S. Croce e Carle	Cuneo
Italy	Ospedale Infermi di Rimini	Faenza
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	Azienda Ospedaliero - Universitaria Ospedali Riuniti di Foggia	Foggia
Italy	I.R.C.C.S. A.O.U San Martino - IST	Genova
Italy	Ospedale Civile di guastalla	Guastalla
Italy	Ospedale Civile San Salvatore - Università degli Studi L'Aquila	L'Aquila
Italy	Presidio Ospedaliero "Renzetti"	Lanciano
Italy	Ospedale Vito Fazzi	Lecce
Italy	Ospedale di Macerata	Macerata
Italy	AO Papardo	Messina
Italy	AORN . Ospedali dei colli Monaldi-Cotugno	Napoli
Italy	Azienda Ospedaliera `A. Cardarelli` (AORN)	Napoli
Italy	Azienda Ospedaliera Universitaria Federico II	Napoli
Italy	Istituto Nazionale per lo studio dei Tumori - Fondazione `Pascale`	Napoli
Italy	A.O.U. `Maggiore della Carità`	Novara
Italy	A.O.U.P. `Paolo Giaccone`	Palermo
Italy	Azienda Ospedaliera S. Chiara	Pisa
Italy	Ospedale F. Lotti	Pontedera
Italy	Ospedale di Ravenna	Ravenna
Italy	Campus Biomedico di Roma	Roma
Italy	Istituto Regina Elena per lo studio e la cura dei tumori - Oncologia A	Roma
Italy	Istituto Regina Elena per lo studio e la cura dei tumori - Oncologia B	Roma
Italy	Azienda Ospedaliera `San Giovanni di Dio e Ruggi D'Aragona`	Salerno
Italy	IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico `Casa Sollievo della Sofferenza`	San Giovanni rotondo
Italy	Azienda Ospedaliera Universitaria di Sassari	Sassari
Italy	Azienda Ospedaliero Universitaria ´S. Maria della Misericordia´ di Udine	Udine
Italy	"Ospedale Borgo Roma Verona Sezione di Oncologia Medica"	Verona
Italy	Ospedale Sacro Cuore Don Calabria di Negrar	Verona

Sponsors (2)

Lead Sponsor	Collaborator
Consorzio Oncotech	Clinical Research Technology

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS1)	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).	Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months	No
Primary	Total Progression-free survival (PFST)	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).	Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months	No
Secondary	Response Rate	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.	Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months	No
Secondary	Clinical Benefit Rate	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.	Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months	No
Secondary	Overall Survival	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.	Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months	Yes
Secondary	Safety - 5D5L questionnaire	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)	up to 31 days since last treatment	Yes