Resumen

Este estudio de Fase III, aleatorizado, abierto y multicéntrico evaluará la eficacia y seguridad de giredestrant más everolimus en comparación con la terapia endocrina a elección del médico más everolimus en participantes con cáncer de mama localmente avanzado o metastásico, receptor de estrógeno (RE) positivo y receptor 2 del factor de crecimiento epidérmico humano (HER2) negativo, que han recibido tratamiento previo con inhibidores de quinasas dependientes de ciclina 4/6 (CDK4/6i) y terapia endocrina, ya sea en el contexto localmente avanzado/metastásico o adyuvante.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Locally advanced unresectable or metastatic adenocarcinoma of the breast, not amenable to treatment with curative intent
Documented estrogen receptor-positive (ER+) tumor and HER2-negative tumor, assessed locally
Ability to provide a blood sample for circulating-tumor deoxyribonucleic acid (ctDNA) Estrogen Receptor 1 (ESR1) mutation status determination by central testing
Prior endocrine therapy (ET) in combination with cyclin-dependent kinase 4/6 inhibitors in either setting as follows:
Metastatic setting: Disease progression after ≥6 months on ET plus CDK4/6 inhibitor in the locally advanced or metastatic setting. If ET plus CDK4/6 inhibitor is not the most recent therapy, then patient must also have had disease progression after ≥4 months on most recent ET
Adjuvant Setting: Relapse either while taking or within 12 months of exposure to combination adjuvant ET and CDK4/6 inhibitor. Patients must have taken at least 12 months of adjuvant ET, 6 months of which was in combination with a CDK4/6 inhibitor.
Measurable disease as defined per RECIST v.1.1 or evaluable bone metastases. Patients with evaluable bone disease in the absence of measurable disease outside of the bone must have at least one predominantly lytic bone lesion confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) which can be followed
Eastern Cooperative Oncology Group Performance Status 0-1
For women who are premenopausal or perimenopausal and for men: treatment with approved luteinizing hormone-releasing hormone (LHRH) agonist therapy for the duration of study treatment

Criterios de exclusión

Prior treatment with another oral selective estrogen receptor degrader (SERD), proteolysis targeting chimera (PROTAC), complete estrogen receptor antagonist (CERAN), novel oral selective estrogen receptor modulator (SERM), or everolimus in any setting. Prior fulvestrant is allowed if treatment was terminated at least 28 days prior to randomization. Prior treatment with tamoxifen is allowed.
Progression on more than 2 prior lines of systemic endocrine therapy in the locally advanced unresectable or metastatic breast cancer setting
Prior chemotherapy for locally advanced unresectable or metastatic disease
Treatment with strong Cytochrome P450 3A4 (CYP3A4) inhibitors or inducers within 14 days or 5 drug elimination half-lives (whichever is longer) prior to randomization
Treatment with any investigational therapy within 28 days prior to initiation of study treatment
Major surgery, chemotherapy, radiotherapy, or other anti-cancer therapy within 14 days prior to randomization
History of any other malignancy other than breast cancer within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, papillary thyroid cancer treated with surgery, Stage I endometrial cancer, or other non-breast cancers at very low risk of recurrence
Advanced, symptomatic, visceral spread that is at risk of life-threatening complications in the short term
Known active uncontrolled or symptomatic central nervous system (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease
Active cardiac disease or history of cardiac dysfunction
Known clinically significant history of liver disease consistent with Child-Pugh Class B or C including active viral or other hepatitis virus, current alcohol abuse, or cirrhosis
Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper gastrointestinal (GI) surgery including gastric resection
Interstitial lung disease or severe dyspnea at rest or requiring oxygen therapy
Serious infection requiring oral or intravenous (IV) antibiotics, or other clinically significant infection, within 14 days prior to randomization
Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
Known allergy or hypersensitivity to any of the study drugs or any of their excipients
For premenopausal or perimenopausal women and for men: known hypersensitivity to LHRH agonists
Pregnant or breastfeeding

Intervenciones

drug

Giredestrant

Participants will receive treatment with giredestrant 30 milligrams (mg) orally once a day (QD) on Days 1-28 of each 28-day cycle until unacceptable toxicity or disease progression as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).

drug

Exemestane

If exemestane is chosen as the physician's choice of endocrine therapy, the participant will receive exemestane at a dose of 25 mg orally once a day (QD) on Days 1-28 of each 28-day cycle or as per local label, until unacceptable toxicity or disease progression as determined by investigator according to RECIST v1.1.

drug

Fulvestrant

If fulvestrant is chosen as the physician's choice of endocrine therapy, the participant will receive fulvestrant in the clinic at a dose of 500 mg intramuscularly on Day 1 and Day 15 of Cycle 1, then Day 1 of each cycle thereafter (1 cycle is 28 days) or as per local prescribing information, until unacceptable toxicity or disease progression as determined by investigator according to RECIST v1.1.

drug

Tamoxifen

If tamoxifen is chosen as the physician's choice of endocrine therapy, the participant will receive tamoxifen at a dose of 20 mg orally QD on Days 1-28 of each 28-day cycle or as per local prescribing information, until unacceptable toxicity or disease progression as determined by investigator according to RECIST v1.1.

drug

Everolimus

Participants will receive treatment with everolimus 10 mg orally QD during each 28-day cycle until unacceptable toxicity or disease progression as determined by the investigator according to RECIST v1.1.

drug

LHRH Agonist

Only premenopausal/perimenopausal female participants and male participants will receive a luteinizing hormone-releasing hormone (LHRH) agonist on Day 1 of each 28-day treatment cycle. The investigator will determine and supply the appropriate LHRH agonist locally approved for use in breast cancer.

drug

Dexamethasone Mouth Rinse

A compounded alcohol-free mouthwash of dexamethasone (0.5 mg in 5 mL) will be supplied, where feasible. It is strongly recommended for prophylaxis or treatment of stomatitis/mucositis. Participants should use the alcohol-free mouthwash of dexamethasone four times QD for 8 weeks started concurrently with study treatment, and use it reactively thereafter with the first appearance of symptoms.

Ubicaciones

Instituto de Oncología Ángel H. Roffo

Agronomía, Ciudad Autónoma de BuenosAires, Argentina

Fundación CENIT para la Investigación en Neurociencias

Recoleta, Ciudad Autónoma de BuenosAires, Argentina

Consultorios Médicos Dr. Doreski

Ciudad Autonoma Buenos Aires, Argentina

Centro Medico Privado CEMAIC

Córdoba, Argentina

Fundacion Centro Oncologico de Integracion Regional (COIR)

Mendoza, Argentina

Instituto Medico de la Fundacion Estudios Clinicos

Rosario, Argentina

Hospital Provincial del Centenario

Rosario, Argentina

Instituto de Oncologia de Rosario

Rosario, Argentina

Centro Polivalente de Asistencia e Investigacion Clinica - CER San Juan

San Juan, Argentina

Organizacion Medica de Investigacion

San Nicolás, Argentina

Centro de Investigación Clínica ? Clínica Viedma

Viedma, Argentina

Resumen

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Giredestrant

Exemestane

Fulvestrant

Tamoxifen

Everolimus

LHRH Agonist

Dexamethasone Mouth Rinse

Ubicaciones

Instituto de Oncología Ángel H. Roffo

Fundación CENIT para la Investigación en Neurociencias

Consultorios Médicos Dr. Doreski

Centro Medico Privado CEMAIC

Fundacion Centro Oncologico de Integracion Regional (COIR)

Instituto Medico de la Fundacion Estudios Clinicos

Hospital Provincial del Centenario

Instituto de Oncologia de Rosario

Centro Polivalente de Asistencia e Investigacion Clinica - CER San Juan

Organizacion Medica de Investigacion

Centro de Investigación Clínica ? Clínica Viedma

Patrocinadores