Resumen

This is a Phase 3, open-label, randomized, clinical trial evaluating the efficacy and safety of gedatolisib plus fulvestrant with or without palbociclib for the treatment of patients with locally advanced or metastatic HR+/HER2- breast cancer following progression on or after CDK4/6 and aromatase inhibitor therapy.

Descripción detallada

This is a Phase 3, open-label, randomized clinical trial evaluating the efficacy and safety of gedatolisib plus fulvestrant with or without palbociclib for the treatment of patients with advanced (inoperable) or metastatic Hormone Receptor Positive, Human Epidermal Growth Factor Receptor 2 Negative (HR+/HER2-) breast cancer following progression on or after CDK4/6 and aromatase inhibitor therapy. Gedatolisib is an intravenously administered pan-PI3K/mTOR inhibitor. Palbociclib is a CDK4/6 inhibitor. Fulvestrant is a selective estrogen receptor degrader (SERD). Subjects will be assessed for PIK3CA status and then randomized to treatment arms according to their confirmed PIK3CA mutation status.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Histologically or cytologically confirmed diagnosis of metastatic or locally advanced breast cancer Adult females, pre- and/or post-menopausal, and adult males. Pre-menopausal (and peri-menopausal) women can be enrolled if amenable to treatment with an LHRH agonist. Patients are to have commenced concomitant treatment with LHRH agonist prior to or on Cycle 1, Day 1 and must be willing to continue on it for the duration of the study.
Negative pregnancy test for women of childbearing potential. Female subjects of childbearing potential must use an effective and/or acceptable contraceptive method from screening until 1 year after the last dose of study treatment
Confirmed diagnosis of estrogen receptor positive and/or progesterone receptor positive, as per American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines (2020), based on most recent tumor biopsy utilizing an assay consistent with local standards
Documented HER2 immunohistochemistry (IHC) negative as per ASCO-CAP 2018 guidance
Adequate archival or fresh tumor tissue for the analysis of PIK3CA mutational status
Subject must have documentation of radiological disease progression on or after the last prior treatment and also have radiologically evaluable disease (measurable and/or non-measurable) according to RECIST v1.1, per local assessment. Subjects with bone only disease must have lytic or mixed lytic/blastic lesions that can be accurately assessed; bone only blastic lesions with no soft tissue component is not allowed.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
Life expectancy of at least 3 months
Progressed during or after CDK4/6 inhibitor combination treatment with non-steroidal aromatase inhibitor (AI)
Adequate bone marrow, hepatic, renal and coagulation function

Criterios de exclusión

History of malignancies other than adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥3 years
Prior treatment with a phosphoinositide 3-kinase (PI3K) inhibitor, a protein kinase B (Akt) inhibitor, or a mechanistic target of rapamycin (mTOR) inhibitor
Prior treatment with chemotherapy and antibody drug conjugates for advanced disease is not permitted (prior adjuvant or neoadjuvant chemotherapy is permitted)
More than 2 lines of prior endocrine therapy treatment
Bone only disease that is only blastic with no soft tissue component
Subjects with type 1 diabetes or uncontrolled type 2 diabetes
Known and untreated, or active, brain or leptomeningeal metastases
a. Subjects with previously treated central nervous system (CNS) metastases may be enrolled in the study if they meet the following criteria: do not require supportive therapy with steroids; do not have seizures and do not exhibit uncontrolled neurological symptoms; stable disease confirmed by radiographic assessment within at least 4 weeks prior to enrollment
Patients with advanced, symptomatic, visceral spread that are at risk of life-threatening complication in the short-term
History of clinically significant cardiovascular abnormalities such as: Congestive heart failure (New York Heart Association (NYHA) classification ≥ II within 6 months of study entry
Myocardial infarction within 12 months of study entry
History of any uncontrolled (or untreated) clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block), supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months
Uncontrolled hypertension defined by systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥100 mmHg, with or without antihypertensive medication (initiation or adjustment of antihypertensive medication\[s\] is allowed prior to screening)
Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
i. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, or history of clinically significant/symptomatic bradycardia
ii. On screening, inability to determine the corrected QT interval using Fridericia's formula (QTcF) on the ECG (i.e., unreadable or not interpretable) or QTcF \>480 msec (determined by mean of triplicate ECGs at screening)
Known hypersensitivity to the study drugs or their components
Pregnant or breast-feeding women
Concurrent participation in another interventional clinical trial
Subjects must agree not to participate in another clinical trial (other than observational) at any time during participation in VIKTORIA-1.

Intervenciones

drug

Gedatolisib

Gedatolisib 180 mg IV given weekly for 3 weeks (Days 1, 8, 15) followed by 1 week off

drug

Palbociclib

Palbociclib 125 mg PO given daily for 3 weeks (21 days), followed by 1 week off

drug

Fulvestrant

Fulvestrant 500 mg IM (2 × 5 mL injections) given every 2 weeks during Cycle 1 (Days 1 and 15), then every 4 weeks beginning with Cycle 2 Day 1

drug

Alpelisib

Alpelisib 300 mg PO (2 × 150 mg tablets) given daily for 4 weeks (28 days)

Ubicaciones

CENIT Foundation

Buenos Aires, Argentina

Alexander Fleming Institute

Buenos Aires, Argentina

Buenos Aires British Hospital

Buenos Aires, Argentina

Center for Medical Education and Clinical Research (CEMIC)

Buenos Aires, Argentina

Fleischer Medical Center

Buenos Aires, Argentina

Medical Center Austral

Buenos Aires, Argentina

Pergamino Clinic

Buenos Aires, Argentina

Cordoba Oncology Institute (IONC)

Córdoba, Argentina

Center of Nuclear and Molecular Medicine of Entre Rios (CEMENER)

Paraná, Argentina

CEDIT Diagnostic and treatment center

Salta, Argentina

CER San Juan

San Juan, Argentina

9 of July Sanatorium

San Miguel de Tucumán, Argentina

Rosario's Oncology Institute and Medical Specialities (IOR)

Santa Fe, Argentina

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Gedatolisib

Palbociclib

Fulvestrant

Alpelisib

Ubicaciones

CENIT Foundation

Alexander Fleming Institute

Buenos Aires British Hospital

Center for Medical Education and Clinical Research (CEMIC)

Fleischer Medical Center

Medical Center Austral

Pergamino Clinic

Cordoba Oncology Institute (IONC)

Center of Nuclear and Molecular Medicine of Entre Rios (CEMENER)

CEDIT Diagnostic and treatment center

CER San Juan

9 of July Sanatorium

Rosario's Oncology Institute and Medical Specialities (IOR)

Patrocinadores