Clinical trial NCT02404051: Fulvestrant and EVerolimus Plus EXemestane in Metastatic Breast Cancer
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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Metastatic Breast Cancer
Breast Cancer
Hormone Receptor Positive Tumor
Human Epidermal Growth Factor 2 Negative Carcinoma of Breast
Locally Advanced Malignant Neoplasm
Keywords: Breast cancer
HER2Negative
hormone receptor positive (HR+)
Metastatic
Locally Advanced
fulvestrant
everolimus
exemestane
Lead sponsor: Consorzio Oncotech
Sponsor class: OTHER
Collaborators: name: Clinical Research Technology S.r.l.
First posted: 2015-03-31
Enrollment: 745
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Progression-free survival (PFS1)
timeFrame: Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months
measure: Total Progression-free survival (PFST)
timeFrame: Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months
Secondary outcomes:
measure: Response Rate
timeFrame: Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months
measure: Clinical Benefit Rate
timeFrame: Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months
measure: Overall Survival
timeFrame: Time elapsed from randomization to progression or death for any cause whichever occurred first assessed up to 30 months
measure: Safety - 5D5L questionnaire
timeFrame: up to 31 days since last treatment
Other outcomes:
Locations:
city: Asti
country: Italy
facility: ASL19 - Ospedale Cardinal Massaia
city: Bari
country: Italy
facility: Azienda Ospedaliera Policlinico di Bari
city: Bari
country: Italy
facility: Istituto Tumori Giovanni Paolo II
city: Benevento
country: Italy
facility: Azienda Ospedaliera "G. Rummo"
city: Benevento
country: Italy
facility: Ospedale Fatebenefratelli 'Sacro Cuore di Gesù' di Benevento
city: Bergamo
country: Italy
facility: A.O. Ospedale Papa Giovanni XXIII
city: Brindisi
country: Italy
facility: Presidio Ospedaliero Antonio Perrino
city: Cagliari
country: Italy
facility: Azienda Ospedaliera - A. Businco - A.S.L. N. 8
city: Candiolo
country: Italy
facility: Fondazione del Piemonte per l' Oncologia - Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.)
city: Castellaneta
country: Italy
facility: ASL di Taranto - Polo Occidentale
city: Catania
country: Italy
facility: A.O.R.N.A.S. Garibaldi Nesima di Catania
city: Catanzaro
country: Italy
facility: Fondazione per la Ricerca e la Cura dei Tumori T. Campanella - Campus S. Venuta
city: Cuneo
country: Italy
facility: Azienda Ospedaliera S. Croce e Carle
city: Faenza
country: Italy
facility: Ospedale Infermi di Rimini
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Foggia
country: Italy
facility: Azienda Ospedaliero - Universitaria Ospedali Riuniti di Foggia
city: Genova
country: Italy
facility: I.R.C.C.S. A.O.U San Martino - IST
city: Guastalla
country: Italy
facility: Ospedale Civile di guastalla
city: L'Aquila
country: Italy
facility: Ospedale Civile San Salvatore - Università degli Studi L'Aquila
city: Lanciano
country: Italy
facility: Presidio Ospedaliero "Renzetti"
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi
city: Macerata
country: Italy
facility: Ospedale di Macerata
city: Messina
country: Italy
facility: AO Papardo
city: Napoli
country: Italy
facility: AORN . Ospedali dei colli Monaldi-Cotugno
city: Napoli
country: Italy
facility: Azienda Ospedaliera 'A. Cardarelli' (AORN)
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria Federico II
city: Napoli
country: Italy
facility: Istituto Nazionale per lo studio dei Tumori - Fondazione 'Pascale'
city: Novara
country: Italy
facility: A.O.U. 'Maggiore della Carità'
city: Palermo
country: Italy
facility: A.O.U.P. 'Paolo Giaccone'
city: Pisa
country: Italy
facility: Azienda Ospedaliera S. Chiara
city: Pontedera
country: Italy
facility: Ospedale F. Lotti
city: Ravenna
country: Italy
facility: Ospedale di Ravenna
city: Roma
country: Italy
facility: Campus Biomedico di Roma
city: Roma
country: Italy
facility: Istituto Regina Elena per lo studio e la cura dei tumori - Oncologia A
city: Roma
country: Italy
facility: Istituto Regina Elena per lo studio e la cura dei tumori - Oncologia B
city: Salerno
country: Italy
facility: Azienda Ospedaliera 'San Giovanni di Dio e Ruggi D'Aragona'
city: San Giovanni rotondo
country: Italy
facility: IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico 'Casa Sollievo della Sofferenza'
city: Sassari
country: Italy
facility: Azienda Ospedaliera Universitaria di Sassari
city: Udine
country: Italy
facility: Azienda Ospedaliero Universitaria ´S. Maria della Misericordia´ di Udine
city: Verona
country: Italy
facility: "Ospedale Borgo Roma Verona Sezione di Oncologia Medica"
city: Verona
country: Italy
facility: Ospedale Sacro Cuore Don Calabria di Negrar
Study officials:
affiliation: Dipartimento di Medicina Clinica e Chirurgia Oncologia Università degli Studi di Napoli "Federico II"
name: Sabino De Placido, MD
role: PRINCIPAL_INVESTIGATOR
References: