A Study of ARV-471 (PF-07850327) Plus Palbociclib Versus Letrozole Plus Palbociclib in Participants With Estrogen Receptor Positive, Human Epidermal Growth Factor Negative Advanced Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to understand the safety and effects of the study medicine ARV-471 (PF-07850327) given together with palbociclib in advanced breast cancer. In particular, the study will compare the combination of ARV-471 plus palbociclib to standard of care therapy (letrozole plus palbociclib). Both letrozole and palbociclib are medicines already used for treatment of breast cancer. ARV-471 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 ARV-471 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 ARV-471. In the Phase 3, half of the participants will take ARV-471 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.

Detailed Description
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The purpose of this study is to demonstrate that 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, ARV-471 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.

Official Title
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A PHASE 3, RANDOMIZED, OPEN-LABEL, MULTICENTER STUDY OF ARV-471(PF-07850327) PLUS PALBOCICLIB VERSUS LETROZOLE PLUS PALBOCICLIB FOR THE TREATMENT OF PARTICIPANTS WITH ESTROGEN RECEPTOR-POSITIVE, HER2-NEGATIVE BREAST CANCER WHO HAVE NOT RECEIVED ANY PRIOR SYSTEMIC ANTI-CANCER TREATMENT FOR ADVANCED DISEASE (VERITAC-3)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: ARV-471 (PF-07850327)
* Combination Product: Palbociclib
* Drug: Letrozole
* Combination Product: Palbociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants with loco-regional recurrent or metastatic disease not amenable to curative treatment Confirmed diagnosis of ER+/HER2- breast cancer No prior systemic treatment for loco-regional recurrent or metastatic disease Measurable disease evaluable per Response Evaluation Criterion in Solid Tumors (RECIST) v.1.1 or non-measurable bone-only disease Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Phase 3 only: Participants should be willing to provide blood and tumor tissue Exclusion Criteria: Disease recurrence while on, or within 12 months of completion of adjuvant endocrine therapy Prior treatment with cyclin dependent kinase 4/6 inhibitors (CDK4/6i), fulvestrant, elacestrant and other investigational drugs including novel endocrine therapies, any selective estrogen receptor degraders (SERDs), covalent antagonists (SERCAs) and complete ER antagonists (CERANs). Inadequate liver, kidney and bone marrow function Impaired cardiovascular function or clinically significant cardiovascular diseases Refractory nausea and vomiting, inability to swallow capsules and tablets whole, chronic gastrointestinal diseases, significant gastric (total or partial) or bowel resection that would preclude adequate absorption of study interventions. Current use or anticipated need for food, herbal supplements or drugs that are known strong CYP3A4 inhibitors or inducers.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (Investigational Arm)<br>Participants will receive: ARV-471, orally, once daily, continuously, in a 28-day cycle, plus Palbociclib, orally, once daily for 21 consecutive days followed by 7 days off treatment in a 28 day cycle | Drug: ARV-471 (PF-07850327)<br>* Pharmaceutical form: Tablets. Route of Administration: Oral<br>* Other names: Vepdegestrant;Combination Product: Palbociclib<br>* Pharmaceutical form: Capsules. Route of Administration: Oral.<br>* Other names: IBRANCE®;|
| Active Comparator: Arm B (Comparator Arm):<br>Participants will receive: Letrozole, orally, once daily, continuously, in a 28-day cycle, plus Palbociclib, orally, once daily for 21 consecutive days followed by 7 days off treatment, in a 28-day cycle. | Drug: Letrozole<br>* Pharmaceutical form: Capsules. Route of Administration: Orally<br>* Other names: FEMARA®;Combination Product: Palbociclib<br>* Pharmaceutical form: Capsules. Route of Administration: Oral.<br>* Other names: IBRANCE®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 ARV-471 due to any cause occurring within the first 4 cycles divided by the number of participants. | 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 ARV-471 due to any cause occurring within the first 4 cycles divided by the number of participants. | 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. | From randomization date, every 12 weeks, to date of first documentation of progression or death, up to approximately 4 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | From baseline up to the end of treatment (up to approximately 4 years) | 
| SLI and Phase 3: Plasma concentrations of ARV-471 and palbociclib | Plasma concentrations of ARV-471 and palbociclib | 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. | 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. | 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. | 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 | From baseline to end of treatment (up to approximately 4 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced tumor of the breast, Advanced cancer of the breast, Breast neoplasm, Breast tumor, Breast cancer, ER positive, Estrogen receptor positive, HER2-negative, Metastatic breast cancer, Palbociclib, Letrozole, ARV-471, Vepdegestrant