Resumen

Este es un estudio de fase 3, de un solo brazo y abierto que evalúa la efectividad de TOL2506 para suprimir la función ovárica en mujeres premenopáusicas con cáncer de mama RH+, HER2 negativo. El estudio también tiene como objetivo evaluar la seguridad de TOL2506 en hombres con cáncer de mama RH+, HER2 negativo. El Período de Cribado se llevará a cabo en dos partes: 1) un cribado inicial abreviado en el que se determinará el estado premenopáusico antes de la quimioterapia neoadyuvante o adyuvante (si está planificada) y 2) la evaluación de cribado completa realizada después de la quimioterapia neoadyuvante o adyuvante (o para los sujetos que ingresan al estudio sin haber recibido quimioterapia). Tras el Período de Cribado, los sujetos elegibles ingresarán al Período de Tratamiento de 48 semanas en uno de 2 grupos: los que recibirán tamoxifeno de forma concomitante con TOL2506, o los que iniciarán terapia con un IA (letrozol, anastrozol o exemestano) comenzando 6 semanas después de la primera administración de TOL2506, tras confirmar que se han alcanzado niveles de estradiol (E2) < 20 pg/mL (niveles de testosterona < 50 ng/dL en hombres). Después de la Semana 12, se permitirá a los sujetos cambiar de un IA a tamoxifeno o de tamoxifeno a IA a discreción del Investigador; sin embargo, no se permite un cambio 28 días antes de una visita de dosificación (p. ej., Semana 24, 36 y 48, donde se extraerá una muestra de sangre predosis para análisis de FK y FD). Al finalizar el Período de Tratamiento, tras completar la Visita de Fin de Estudio (Visita 9, Semana 48), los sujetos podrán ser elegibles para participar en un Estudio de Extensión de Seguridad bajo un Protocolo separado.

Elegibilidad

Edad mínima: 18 YearsEdad máxima: 49 YearsSexo: ALL

Criterios de inclusión

Female
Able to understand the investigational nature of this study and provide written informed consent prior to the participation in the trial
Age 18 to 49, inclusive
Diagnosis of Stage I, II, or III HR+, HER2-negative breast cancer (ER\>1% and/or, PR\>1%, HER2-negative per ASCO CAP guidelines)
Is a candidate for endocrine therapy + ovarian suppression LH \> 4 IU/L within 28 days prior to Day 1
Is premenopausal as defined by:
E2 \> 30 pg/mL
follicle stimulating hormone (FSH) \< 40 IU/L
regular menses (eg, menstrual cycle length of 21 to 35 days) Note: premenopausal status must be determined before neo/adjuvant chemotherapy in patients for which it is planned or prior to Day 1 in patients who did not have prior chemotherapy. If premenopausal status was not determined prior to chemotherapy, E2 and FSH must meet the above criteria when measured 2 weeks or more after the end of the final cycle of chemotherapy.

Criterios de exclusión

Body mass index (BMI) \< 18.00 kg/m2 or \> 35.00 kg/m2
Breastfeeding
Life expectancy \< 12 months
Eastern Cooperative Oncology Group (ECOG) performance status ≥ 3
Unacceptable hepatic function as determined by any of the following:
Alanine aminotransferase (ALT) ≥ 2X upper limit of normal (ULN)
Aspartate aminotransferase (AST) ≥ 2X ULN
Bilirubin ≥ 2X ULN
Alkaline phosphatase ≥ 2X ULN
Severe hepatic impairment (Child-Pugh Class C)
Unacceptable renal function as determined by any of the following:
Creatinine ≥ 3X ULN
Creatinine clearance ≤ 30 mL/minute
Creatinine clearance ≤ 60 mL/minute in subjects with bone density 1.5 standard deviations below the young adult normal mean
History of significantly abnormal ECG or screening 12-lead ECG demonstrating any of the following:
HR \> 100 BPM
QRS \> 120 msec
QTc \> 450 msec
PR \> 220 msec
Prior (within 28 days prior to Day 1) and/or concomitant use of medications known to prolong the QT/QTc interval
Prior use of tamoxifen, other SERMs (eg, raloxifene) or antagonists (eg, fulvestrant), aromatase inhibitor, mammalian target of rapamycin (mTOR) inhibitors, or hormone replacement therapy within 3 months before breast cancer diagnosis
Concomitant use of anticancer mediations other than those specified for use by the protocol
Prior neoadjuvant or adjuvant endocrine therapy since diagnosis of breast cancer
History of treatment for osteopenia/osteoporosis or baseline bone mineral density Z-score ≤ -2.0
Prior (within 6 months prior to Day 1) or current use of drugs known to increase bone mineral density (ie, bisphosphonates, denosumab, teriparatide, abaloparatide, romosozumab) or use of supplements known to increase bone mineral density (ie, calcitonin, fluoride, strontium) within 28 days prior to Day 1
Low trauma fracture(s) occurring within 12 months prior to subject's first visit (defined as a fracture that results from a fall from a standing height or less, excluding fingers, toes, face and skull)
Conditions that preclude bone mineral density measurement (lumbar spine/bilateral hip surgery with hardware in place, abdominal clips, umbilical ring \[not willing to remove\] or weight that exceeds the DEXA machine limitation)
Any other medical condition or serious illness, presence of a second malignancy under current treatment or follow-up, or the presence of clinically significant findings on the physical exam, laboratory testing, medical history (including conditions that may be associated with low bone mass), that in the opinion of the Investigator may interfere with trial conduct, subject safety, or interpretation of study results
Already receiving and/or previously received GnRH analogs within 1 year before breast cancer diagnosis
Psychiatric, addictive, or other disorders that would preclude study compliance
Use of medications that may impact subject safety and/or affect the PK of the drug and hormonal assessments including but not limited to:
Oral or transdermal hormonal therapy within 30 days prior to subject's first visit
Estrogen, progesterone, or androgens within 30 days prior to subject's first visit
Hormonal contraceptives within 30 days prior to subject's first visit
Medications known to result in clinically important decreases in bone mass taken within 6 months prior to subject's first visit
Known hypersensitivity, idiosyncratic, or allergic reactions to GnRH, GnRH agonist/analogs or to any of the components of the IP
Sexually active with a male partner and not willing to use non-hormonal contraceptive methods throughout the study
Is of childbearing potential with a positive serum pregnancy test at Screening or urine pregnancy test at Day 1
Exposure to any investigational agent within 30 days prior to the first dose of TOL2506

Intervenciones

drug

TOL2506

Leuprolide Acetate for injectable suspension, 30 mg. Subcutaneous injection every 3 months.

drug

Tamoxifen

20 mg once daily or 10 mg 2 times daily - either tablet or solution

drug

Letrozole Tablets

One 2.5 mg tablet taken orally once daily

drug

Anastrozole Tablets

One 1 mg tablet taken orally once daily

drug

Exemestane Tablets

One 25 mg tablet taken orally once daily

Ubicaciones

Hospital Britanico de Buenos Aires

Buenos Aires, Buenos Aires F.D., Argentina

Instituto Oncologico de Cordoba (IONC)

Córdoba, Córdoba Province, Argentina

Centro Privado de RMI Rio Cuarto

Río Cuarto, Córdoba Province, Argentina

Instituto Medico de la Fundacion Estudios Clinicos

Rosario, Santa Fe Province, Argentina

Hospital Provincial del Centenario

Rosario, Santa Fe Province, Argentina

Hospital Aleman

Buenos Aires, Argentina

Fundacion CENIT

CABA, Argentina

Sanatorio Allende- Sede Nueva Cordoba

Córdoba, Argentina

Resumen

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

TOL2506

Tamoxifen

Letrozole Tablets

Anastrozole Tablets

Exemestane Tablets

Ubicaciones

Hospital Britanico de Buenos Aires

Instituto Oncologico de Cordoba (IONC)

Centro Privado de RMI Rio Cuarto

Instituto Medico de la Fundacion Estudios Clinicos

Hospital Provincial del Centenario

Hospital Aleman

Fundacion CENIT

Sanatorio Allende- Sede Nueva Cordoba

Patrocinadores