The purpose of this study is to understand the safety and effects of the study medicine vepdegestrant (ARV-471/PF-07850327) given together with palbociclib in advanced breast cancer. In particular, the study will compare the combination of vepdegestrant plus palbociclib to standard of care therapy (letrozole plus palbociclib). Both letrozole and palbociclib are medicines already used for treatment of breast cancer. Vepdegestrant is a new medicine under study. This study is seeking participants who have breast cancer that: * Have a locally advanced or metastatic disease and cannot be fully cured by surgery or radiation therapy. A metastatic disease is when disease has spread to other parts of the body. * Is sensitive to hormonal therapy such as tamoxifen. This is called estrogen receptor positive disease. * Have not received any prior medicine for advanced disease. Example medications include tamoxifen or letrozole or exemestane. The study will have an open-label SLI (study lead-in) before initiation of Phase 3 trial. During SLI, two dose levels of palbociclib in combination with vepdegestrant will be explored in parallel. Assignment to the palbociclib dose is by chance. Half of the participant will receive one dose and the other half another palbociclib dose. The purpose of SLI is to determine the recommended Phase 3 dose of palbociclib to be administered in combination with vepdegestrant. In the Phase 3, half of the participants will take vepdegestrant plus palbociclib while the other half will take letrozole plus palbociclib. In both SLI and Phase 3, participants will take the study medicines by mouth, with food, once a day. Participants will take the study medicines until breast cancer increase in size or side effects become too severe. Side effects refer to unwanted reactions to medications. Participants will visit the study clinic about once every 4 weeks.
The purpose of this study is to demonstrate that vepdegestrant (ARV-471) in combination with palbociclib provides superior clinical benefit compared to letrozole in combination with palbociclib in participants with ER(+)/HER2(-) aBC who have not received any prior systemic anti-cancer therapies for their locoregionally advanced or metastatic disease. The study will have a Study Lead-in (SLI) and a Phase 3. In the SLI, 50 participants (approximately 25 each arm) will be randomly assigned on a 1:1 basis to one of the two dose levels (DLs). In the randomized Phase 3, approximately 1130 eligible participants (approximately 565 each arm) will be randomized in a 1:1 ratio to the Experimental Arm (ie, vepdegestrant plus palbociclib at RP3D determined in the SLI) or Control Arm (ie, letrozole plus palbociclib at the registered doses). Randomization will be stratified by menopausal status at study entry, visceral disease and de novo metastatic disease.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
59
Pharmaceutical form: Tablets. Route of Administration: Oral
Pharmaceutical form: Capsules. Route of Administration: Oral.
Pharmaceutical form: Capsules. Route of Administration: Orally
Pharmaceutical form: Capsules. Route of Administration: Oral.
BRCR Global
Plantation, Florida, United States
BRCR Medical Center Inc
Plantation, Florida, United States
Virginia Oncology Associates
Norfolk, Virginia, United States
Cancer Research SA
Adelaide, South Australia, Australia
Barwon Health
Geelong, Victoria, Australia
Hospital Santa Rita de Cassia
Study Lead-in (SLI): Incidence of Grade 4 neutropenia
It is defined as the number of participants with Grade 4 neutropenia AE (graded by NCI CTCAE v.5.0) with onset within the first 4 cycles divided by the number of participants.
Time frame: From randomization date up to Cycle 4 (each cycle is 28 days).
SLI: Incidence of dose reduction
It is defined as the number of participants reducing the dose of palbociclib and/or vepdegestrant due to any cause occurring within the first 4 cycles divided by the number of participants.
Time frame: From randomization date up to Cycle 4 (each cycle is 28 days).
SLI: Incidence of drug discontinuation.
It is defined as the number of participants discontinuing palbociclib and/or vepdegestrant due to any cause occurring within the first 4 cycles divided by the number of participants.
Time frame: From randomization date up to Cycle 4 (each cycle is 28 days).
Phase 3: Progression-Free Survival
Progression-free survival is defined as the time interval from the date of randomization to the date of first documented tumor progression determined by Blinded Independent Central Review (BICR) as per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) or death due to any cause, whichever come first.
Time frame: From randomization date, every 12 weeks, to date of first documentation of progression or death, up to approximately 4 years.
SLI and Phase 3. Objective Response Rate
Objective response rate is defined as the proportion of participants who have a confirmed CR or PR, as best overall response determined by Investigators (SLI) or by BICR (Phase 3) as per RECIST version 1.1, from the date of randomization to the date of disease progression or death due to any cause, whichever occurs first.
Time frame: From randomization date, every 12 weeks, to the date of progression or death (up to approximately 4 years).
SLI and Phase 3: Duration of Response
Duration of response is defined as the time from first documented evidence of CR or PR until progressive disease (PD) determined by Investigators (SLI) or by BICR (Phase 3) as per RECIST version 1.1 or death due to any cause, whichever occurs first.
Time frame: From the date of the first objective response, every 12 weeks, to the date of disease progression or death (up to approximately 4 years).
SLI and Phase 3: Clinical Benefit Rate
Clinical benefit rate is defined as the proportion of participants who have a confirmed CR, PR at any time or SD or non CR/non PD for at least 24 weeks determined by Investigators (SLI) or by BICR (Phase 3) as per RECIST version 1.1, from the date of randomization until disease progression or death due to any cause, whichever occurs first.
Time frame: Every 12 weeks From randomization date, every 12 week, to the date of progression or death (up to approximately 4 years).
Phase 3: Overall Survival
Overall survival is defined as the time interval from the date of randomization to the date of documented death, due to any cause.
Time frame: From randomization date, every 3 months, to date of death (up to approximately 6 years)
SLI and Phase 3: Incidence of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
It is defined as the number of participants with TEAEs and SAEs divided by the number of participants. AEs and SAEs will be graded according to NCI CTCAE V5.0.
Time frame: From baseline to date to end of treatment (up to approximately 4 years)
SLI and Phase 3: Incidence of laboratory abnormalities
It is defined as the number of participants with laboratory abnormalities divided by the number of participants. Laboratory abnormalities will be graded according to NCI CTCAE V5.0.
Time frame: From baseline to end of treatment (up to approximately 4 years)
SLI and Phase 3: Incidence of Electrocardiogram (ECG) Abnormalities
It is defined as the number of participants with ECG abnormalities divided by the number of participants. ECG abnormalities will be graded according to NCI CTCAE V5.0.
Time frame: From baseline up to the end of treatment (up to approximately 4 years)
SLI and Phase 3: Plasma concentrations of vepdegestrant and palbociclib
Plasma concentrations of vepdegestrant and palbociclib
Time frame: From randomization date up to Cycle 5 (each cycle is 28 days)
Phase 3: Health state utility and health status will be assessed using the European Quality of Life Group questionnaire with 5 dimensions and 5 levels per dimension (EQ-5D-5L)
Change from baseline between treatment comparison in Quality of Life using the EQ-5D 5L questionnaire.
Time frame: From baseline, each cycle up to cycle 3, then every odd cycle to end of treatment (up to approximately 4 years). Each cycle is 28 days
Phase 3: Disease-related Quality of Life will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30)
Change from baseline between treatment comparison in Quality of Life using the EORTC QLQ-C30 questionnaire.
Time frame: From baseline, each cycle up to Cycle 3, then every odd cycle to end of treatment (up to approximately 4 years). Each cycle is 28 days.
Phase 3: Disease- and treatment-related Quality of Life will be assessed using the European Organization for Research and Treatment of Cancer (EORTC) breast cancer module (QLQ-BR23) questionnaire.
Change from baseline between treatment comparison in Quality of Life Using the EORTC QLQ-BR23 (Breast) questionnaire.
Time frame: From baseline, each cycle up to Cycle 3, then every odd cycle to end of treatment (up to approximately 4 years). Each cycle is 28 days.
Phase 3: Changes from baseline in plasma ctDNA (Circulating Deoxyribonucleic Acid)
Quantitative changes from baseline
Time frame: From baseline to end of treatment (up to approximately 4 years)
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Vitória, Espírito Santo, Brazil
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Porto Alegre, Rio Grande do Sul, Brazil
Centro de Pesquisa Clínica - Área Administrativa
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