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Fulvestrant and EVerolimus Plus EXemestane in Metastatic Breast Cancer (FEVEX)

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ClinicalTrials.gov Identifier: NCT02404051
Recruitment Status : Recruiting
First Posted : March 31, 2015
Last Update Posted : June 15, 2016
Sponsor:
Collaborator:
Clinical Research Technology S.r.l.
Information provided by (Responsible Party):
Consorzio Oncotech

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 Type : Interventional  (Clinical Trial)
Estimated 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 : December 2015
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : January 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ARM 1
Everolimus plus Exemestane -> progression disease (PD) -> fulvestrant (ARM 1)
Drug: Everolimus
10 mg daily tablets
Other Name: Afinitor

Drug: Exemestane
25 mg daily tablets
Other Name: Aromasin

Drug: Fulvestrant
500 mg i.m. on Days 1, 15 and 29 and every 28 days thereafter
Other Name: Faslodex

Experimental: ARM 2
Fulvestrant -> progression disease (PD) -> everolimus plus exemestane (ARM 2)
Drug: Everolimus
10 mg daily tablets
Other Name: Afinitor

Drug: Exemestane
25 mg daily tablets
Other Name: Aromasin

Drug: Fulvestrant
500 mg i.m. on Days 1, 15 and 29 and every 28 days thereafter
Other Name: Faslodex




Primary Outcome Measures :
  1. Progression-free survival (PFS1) [ Time Frame: 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).

  2. Total Progression-free survival (PFST) [ Time Frame: 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 :
  1. Response Rate [ Time Frame: 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.

  2. Clinical Benefit Rate [ Time Frame: 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.

  3. Overall Survival [ Time Frame: 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.

  4. Safety - 5D5L questionnaire [ Time Frame: up to 31 days since last treatment ]

    The overall observation period will be divided into three mutually exclusive segments per treatment phase:

    1. 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
    2. post-treatment period: starting at day 31 after last dose of study medication (phase 2)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02404051


Contacts
Contact: Clinical Research Technology 0039089301545

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

Responsible Party: Consorzio Oncotech
ClinicalTrials.gov Identifier: NCT02404051     History of Changes
Other Study ID Numbers: GIM16-FEVEX
2014-004035-38 ( EudraCT Number )
First Posted: March 31, 2015    Key Record Dates
Last Update Posted: June 15, 2016
Last Verified: June 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Consorzio Oncotech:
Breast cancer
HER2Negative
hormone receptor positive (HR+)
Metastatic
Locally Advanced
fulvestrant
everolimus
exemestane

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Fulvestrant
Exemestane
Everolimus
Sirolimus
Estradiol
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents, Hormonal
Estrogen Receptor Antagonists
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Estrogens
Hormones
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action