A Study to Learn About a New Medicine Called ARV-471 (PF-07850327) in People Who Have Advanced Metastatic Breast Cancer.

Study Overview
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Brief Summary
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A study to learn about a new medicine called ARV-471 (PF-07850327) in people who have advanced metastatic breast cancer.

Detailed Description
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The purpose of this study is to learn about the safety and effects of the study medicine ARV-471 (PF-07850327, vepdegestrant) compared to fulvestrant (FUL) in participants with advanced breast cancer. Advanced breast cancer is difficult to cure or control with treatment. The cancer may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body, i.e. bones, lungs, brain, or liver. FUL is a medicine already used for treatment of breast cancer while ARV-471 is a new medicine. This study is seeking participants with breast cancer who: have cancer that has come back in the place where it started or spread to nearby tissue, lymph nodes, or distant parts of the body. cannot be fully cured by surgery or radiation therapy. Radiation therapy is the use of high-energy radiation such as x-rays, gamma rays and other sources to kill cancer cells and shrink tumors. respond to hormonal or endocrine therapy (which target hormones and/or activity of hormone receptors) such as tamoxifen or aromatase inhibitors (this is called estrogen receptor positive disease) have received one line of CDK4/6 inhibitor therapy (for example palbociclib, ribociclib or abemaciclib) in combination with endocrine therapy (for example letrozole) for advanced cancer. are allowed up to one other endocrine therapy (for example exemestane) for advanced cancer. Half of the participants will be given ARV-471 while the other half of the participants will be given FUL. Participants who get ARV-471 will take ARV-471 by mouth with food, one time a day. During the first treatment cycle participants who will get FUL will be given FUL by shots into the muscles on Day 1 and again 2 weeks later. After the first month, FUL shots will be given on the first day of each new treatment cycle. One treatment cycle is 28 days. Participants will receive the study medicine until their breast cancer worsens or side effects become too severe. Participants will have visits at the study clinic about every 4 weeks.

Official Title
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A PHASE 3, RANDOMIZED, OPEN-LABEL, MULTICENTER TRIAL OF ARV-471 (PF-07850327) VS FULVESTRANT IN PARTICIPANTS WITH ESTROGEN RECEPTOR-POSITIVE, HER2-NEGATIVE ADVANCED BREAST CANCER WHOSE DISEASE PROGRESSED AFTER PRIOR ENDOCRINE BASED TREATMENT FOR ADVANCED DISEASE (VERITAC-2)

Conditions
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Advanced Breast Cancer

Intervention / Treatment
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* Drug: ARV-471
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants with loco-regional recurrent or metastatic breast disease not amenable to surgical resection or radiation therapy Confirmed diagnosis of ER+/HER2- breast cancer Prior therapies for locoregional recurrent or metastatic disease must fulfill all the following criteria: One line of CDK4/6 inhibitor therapy in combination with endocrine therapy. Only one line of CDK4/6 inhibitor is allowed in any setting. ≤ 1 endocrine therapy in addition to CDK4/6 inhibitor with ET Most recent endocrine treatment duration must have been given for ≥6 months prior to disease progression. This may be the endocrine treatment component of the CDK4/6 inhibitor line of therapy. Radiological progression during or after the last line of therapy. 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 0-1 Participants should be willing to provide blood and tumor tissue Exclusion Criteria: Participants with advanced, symptomatic visceral spread, that are at risk of life-threatening complications in the short term Prior treatment with: ARV-471, fulvestrant, elacestrant, mTOR, PI3K, AKT pathway inhibitors, PARP inhibitor for any setting other investigational agents (including novel endocrine therapy any SERDs, SERCAs, CERANs) for any setting prior chemotherapy for advanced/metastatic disease Inadequate liver, kidney and bone marrow function Active brain metastases Participants with significant concomitant illness

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: ARV-471<br> | Drug: ARV-471<br>* orally, once daily on a 28-day continuous dosing schedule<br>* Other names: PF-07850327;|
| Active Comparator: Fulvestrant<br> | Drug: Fulvestrant<br>* intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle starting from C2D1 (28-day cycle)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | 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) assessment as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) or death due to any cause, whichever come first. | From randomization date (every 8 weeks for the first 48 weeks and then every 12 weeks thereafter) to date of first documentation of progression OR death (approximately 2 years). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | 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 (approximately 3 years) | 
| Objective Response Rate (ORR) | Objective response rate is defined as the proportion of participants who have a confirmed CR or PR, as best overall response assessed by BICR as per RECIST 1.1, from the date of randomization to the date of disease progression, death due to any cause, whichever occurs first. | From randomization date (every 8 weeks during the first 48 weeks and then every 12 weeks) to the date of progression OR death (approximately to 2 years). | 
| Duration of response (DR) | Duration of response is defined as the time from first documented evidence of CR or PR until progressive disease (PD) as determined by BICR assessment as per RECIST 1.1 or death due to any cause, whichever occurs first. | From the date of the first objective response (every 8 weeks during the first 48 weeks and then every 12 week) to the date of disease progression or death (approximately to 2 years). | 
| 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 nonCR/non PD for at least 24 weeks determined by BICR assessment as per RECIST 1.1, from the date of randomization until disease progression, death due to any cause, whichever occurs first. | From randomization date (every 8 weeks during the first 48 weeks and then every 12 weeks) to the date of progression or death (approximately to 2 years). | 
| Number of participants with treatment emergent adverse events (TEAEs), serious adverse events (SAEs), electrocardiogram (ECG) and laboratory abnormalities | Incidence of participants with TEAEs, SAEs ECGs and laboratory abnormalities. TEAE/SAE and laboratory abnormalities will be graded according to NCI CTCAE V5. | From screening until 28 days after the last dose (approximately 2 years). | 
| QT Interval (QTc) | Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) are performed. | From baseline to end of treatment (approximately 2 years). | 
| Plasma Concentration Versus Time of ARV-471 | Plasma concentrations of ARV-471 | From randomization date up to cycle 7 (each cycle is 28 days). | 
| 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 and time to deterioration between treatment comparison in Quality of Life using the EQ-5D 5L questionnaire. | From screening and every cycle until cycle 6 (each cycle is 28 days), and then every other cycle until 28 days after the last dose (approximately 2 years). | 
| 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 and time to deterioration between treatment comparison in Quality of Life using the EORTC QLQ-C30 questionnaire. | From screening and every cycle until cycle 6 (each cycle is 28 days), and then every other cycle until 28 days after the last dose (approximately 2 years). | 
| 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 and time to deterioration between treatment comparison in Quality of Life Using the EORTC QLQ-BR23 (Breast) questionnaire. | From screening and every cycle until cycle 6 (each cycle is 28 days), and then every other cycle until 28 days after the last dose (approximately 2 years). | 
| Clinical Pain and its impact on functioning will be assessed using Brief Pain Inventory Short Form (BPI-SF) questionnaire. | Change from baseline and time to deterioration between treatment comparison in Brief Pain Inventory Short Form questionnaire. | From screening and every cycle until cycle 6 (cycle=28 days) and then every other cycle until 28 days after the last dose (appr. 2 yrs).The modified BPI-SF (worst pain severity and pain interference) daily from baseline until the EOT (appr 2 yrs) | 
| circulating deoxyribonucleic acid (DNA) | Quantitative changes from baseline | From baseline to end of treatment (approximately 2 years). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ER(+)/HER2(-) Advanced Breast Cancer, Advanced cancer of the breast, Breast neoplasm, Breast tumor, Breast cancer, Fulvestrant, Estrogen receptor positive, Metastatic breast cancer, ER degrader, PROTAC, Hormone Therapy, Hormone positive breast cancer, Endocrine therapy, Recurrent breast cancer, HR+, HER2-negative, Vepdegestrant