Resumen

El propósito de este estudio es recopilar datos adicionales de seguridad y eficacia de la combinación de ribociclib + letrozol en hombres y mujeres pre/posmenopáusicas con cáncer de mama avanzado HR+HER2- sin tratamiento hormonal previo para enfermedad avanzada.

Descripción detallada

Este fue un estudio de Fase IIIb abierto, de brazo único y multicéntrico. El estudio se compuso de 2 fases: Fase Central y Fase de Extensión. En la Fase Central se recopilaron datos de seguridad y eficacia. El tratamiento del estudio durante la Fase Central se proporcionó hasta la progresión de la enfermedad, muerte, toxicidades inaceptables, decisión del médico, decisión del sujeto/tutor, desviación del protocolo, terminación del estudio por el patrocinador, pérdida de seguimiento, problemas técnicos o hasta 18 meses después de la última visita del último paciente. En el caso de que los pacientes aún estuvieran obteniendo beneficio al final de la Fase Central y ribociclib no estuviera aprobado, disponible o reembolsado, los pacientes fueron transferidos a la Fase de Extensión y continuaron recibiendo el tratamiento del estudio hasta la progresión, intolerancia, muerte o decisión del médico/paciente. Solo se recopilaron datos de seguridad y beneficio clínico (según la evaluación del investigador) en la Fase de Extensión. Durante la Fase de Extensión, si ribociclib obtenía la aprobación local y el reembolso, los pacientes debían ser transferidos a prescripción. Los pacientes que completaron la Fase de Extensión y continuaron obteniendo beneficio clínico del tratamiento según la evaluación del investigador recibieron ribociclib por prescripción (si estaba aprobado y reembolsado), otro programa de acceso postestudio u otro(s) programa(s) de acceso/apoyo a medicamentos. Subestudio canadiense: este subestudio fue un estudio exploratorio multicéntrico canadiense de recolección de muestras correlativas que tuvo como objetivo comprender mejor los mecanismos de respuesta y resistencia a ribociclib en combinación con letrozol. Este subestudio estuvo disponible para todos los sujetos canadienses inscriptos en el estudio principal y no alteró el tratamiento planificado.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Male or female advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy.
In the case of women, both pre/perimenopausal and postmenopausal patients were allowed to be included in this study; menopausal status was relevant for the requirement of goserelin to be used concomitantly with ribociclib and letrozole.
Postmenopausal status was defined either by: I).Prior bilateral oophorectomy OR ii). Age ≥ 60 OR iii). Age \< 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifen, or ovarian suppression) and FSH and estradiol in the postmenopausal range per local normal range. If patient was taking tamoxifen or toremifene and age \< 60, then FSH and plasma estradiol levels would be in post-menopausal range per local normal range (NCCN Guidelines version 2.2017).
Note: For women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol were needed to ensure menopausal status.
Premenopausal status was defined as either: I).Patient had last menstrual period within the last 12 months OR ii). If on tamoxifen or toremifene within the past 14 days, plasma estradiol and FSH must be in the premenopausal range per local normal range OR iii). In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the premenopausal range per local normal range.
Perimenopausal status was define as neither premenopausal nor postmenopausal
Patient had a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer by local laboratory.
Patient had HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test was required by local laboratory testing.
Patient had an Eastern Cooperative Oncology Group (ECOG) performance status ≤2
Patient had adequate bone marrow and organ function as defined by ALL of the following laboratory values (as assessed by local laboratory):
Absolute neutrophil count ≥ 1.5 × 10\^9/L
Platelets ≥ 100 × 10\^9/L
Hemoglobin ≥ 9.0 g/dL
Potassium, sodium, calcium corrected for serum albumin and magnesium within normal limits or corrected to within normal limits with supplements before first dose of the study medication
INR ≤1.5
Serum creatinine \<1.5 mg/dl or creatinine clearance≥50 mL/min
In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be below 2.5 × ULN. If the patient had liver metastases, ALT and AST should be \< 5 × ULN.
Total serum bilirubin \< ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin within normal range in patients with well-documented Gilbert's Syndrome
Patient must have had a 12-lead ECG with ALL of the following parameters at screening:
QTcF interval at screening \<450 msec (using Fridericia's correction)
Resting heart rate ≥ 50 bpm

Criterios de exclusión

Patient who received any CDK4/6 inhibitor
Patient who received any prior systemic hormonal therapy for advanced breast cancer; no more than one prior regimen of chemotherapy for the treatment of metastatic disease was permitted. Note:
Patients who received (neo) adjuvant therapy for breast cancer were eligible. If the prior neo (adjuvant) therapy included letrozole or anastrozole the disease free interval had to be greater than 12 months from the completion of treatment until study entry.
Patients who received ≤ 28 days of letrozole or anastrozole for advanced disease prior to inclusion in this trial were eligible.
Any prior (neo) adjuvant anti-cancer therapy or prior chemotherapy for metastatic disease had to be stopped at least 5 half-lives or 7 days, whichever was longer, before study inclusion.
Patient was concurrently using other anti-cancer therapy.

Intervenciones

drug

Ribociclib

Ribociclib was centrally supplied to the investigators and administered orally once a day on days 1-21 of each 28 day cycle at a starting dose of 600 mg daily

drug

Letrozole

Letrozole was procured locally and administered orally once a day on a continuous daily schedule at a dose of 2.5 mg

drug

Goserelin

Goserelin was procured locally and administered in men and premenopausal women as an injectable subcutaneous implant administered on day 1 starting at Cycle 1 and then every 28 days at a dose of 3.6 mg (cycle = 28 days)

drug

Leuprolide

Leuprolide was procured locally and administered in men and premenopausal women as an injectable intramuscular depot administered on day 1 starting at Cycle 1 and then every 28 days at a dose of 7.5 mg (cycle= 28 days)

Ubicaciones

Novartis Investigative Site

CABA, Buenos Aires, Argentina

Novartis Investigative Site

CABA, Buenos Aires, Argentina

Novartis Investigative Site

Rosario, Santa Fe Province, Argentina

Novartis Investigative Site

San Miguel de Tucumán, Tucumán Province, Argentina

Novartis Investigative Site

La Rioja, Argentina

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Ribociclib

Letrozole

Goserelin

Leuprolide

Ubicaciones

Novartis Investigative Site

Novartis Investigative Site

Novartis Investigative Site

Novartis Investigative Site

Novartis Investigative Site

Patrocinadores