A Trial Using ARV-471 or Anastrozole in Post-Menopausal Women With Breast Cancer Prior to Surgery

Study Overview
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Brief Summary
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This trial is a Phase 2 neoadjuvant study evaluating ARV-471 or anastrozole in post-menopausal women with ER+/HER2- localized breast cancer.

Detailed Description
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This is a Phase 2, open-label, randomized, non-comparative proof of concept study of ARV-471 or anastrozole in participants with ER+/HER2- breast cancer amenable to definitive surgical resection. The main goal of this study is to evaluate the biological activity of ARV-471 and anastrozole, respectively.

Official Title
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An Open-label, Randomized, Non-comparative Phase 2 Study of ARV-471 or Anastrozole in Post-menopausal Women With ER+/HER2- Breast Cancer in the Neoadjuvant Setting

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: ARV-471
* Drug: Anastrozole
* Procedure: Surgical resection of breast tumor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Post-menopausal females ≥ 18 years Histologically or cytologically confirmed ER+ and HER2- breast cancer (per local assessment). ER and HER2 status must be documented: ER+ disease, with ER staining of ≥ 10% of tumor cell nuclei by IHC per ASCO/CAP Guidelines (Allison 2020). HER2- disease by either IHC or in situ hybridization per ASCO/CAP guidelines Ki-67 score ≥ 5%, analyzed locally Clinical T1c-T4c, N0-N2, M0 breast cancer amenable to definitive surgical resection, without bilateral breast ductal carcinoma in situ or invasive breast cancer The primary tumor must be at least 1.5 cm by imaging ECOG performance status of 0 or 1 Willingness to undergo a screening biopsy, an on-treatment biopsy and surgical resection Exclusion Criteria: Any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or cervical carcinoma in situ Any of the following in the previous 6 months: Myocardial infarction; Severe unstable angina; Coronary/peripheral artery bypass graft; Symptomatic congestive heart failure (New York Heart Association class III or IV); Cerebrovascular accident; Transient ischemic attack; Symptomatic pulmonary embolism or other clinically significant episode of thromboembolism Any of the following in the previous 6 months: Congenital long QT syndrome; Torsade de Pointes; Sustained ventricular tachyarrhythmia and ventricular fibrillation; Left anterior hemiblock (bifascicular block); Ongoing cardiac dysrhythmias of NCI CTCAE ≥ Grade 2; Atrial fibrillation of any grade (≥ Grade 2 in the case of asymptomatic lone atrial fibrillation) QTcF > 470 msec Active, uncontrolled bacterial, fungal or viral infection, including HBV, HCV, and HIV or AIDS-related illness Active inflammatory gastrointestinal disease, chronic diarrhea, known uncontrolled diverticular disease, or previous gastric resection or lap band surgery Cirrhosis meeting criteria for Child Pugh B and C Prior treatment for breast cancer including systemic therapy (eg, chemotherapy, hormonal therapy), radiation, surgery, or any investigational agents Any live vaccines within 14 days of planned start of first dose of study drug. Major surgery (as defined by the Investigator) within four weeks of first dose of study drug

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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 monotherapy<br>ARV-471 taken once daily until surgical resection | Drug: ARV-471<br>* tablets<br>Procedure: Surgical resection of breast tumor<br>* Participants will have surgical resection approximately 5.5 months after starting treatment (C6D18 ± 14 days)<br>|
| Active Comparator: Anastrozole monotherapy<br>Anastrozole 1mg taken once daily until surgical resection | Drug: Anastrozole<br>* 1mg tablet<br>* Other names: Arimidex;Procedure: Surgical resection of breast tumor<br>* Participants will have surgical resection approximately 5.5 months after starting treatment (C6D18 ± 14 days)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the effects of ARV-471 and anastrozole, respectively, on Ki-67 expression in tumors after 2 weeks of treatment | Percent change in Ki-67 expression between baseline and C1D15 tumor biopsies | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety/tolerability of ARV-471 and anastrozole, respectively | Incidence of all adverse events, serious adverse events, and adverse events leading to study drug discontinuation | From signing of consent to minimum of 30 days after last administration of study drug | 
| Evaluate the pathological response of ARV-471 and anastrozole, respectively (pathologic stage) | Pathologic stage at the time of surgical resection | Approximately 5.5 months | 
| Evaluate the pathological response of ARV-471 and anastrozole, respectively (pathologic complete response rate) | pathologic complete response rate at the time of surgical resection | Approximately 5.5 months | 
| Evaluate the pathological response of ARV-471 and anastrozole, respectively (modified Pre-operative Endocrine Prognostic Index score) | modified Pre-operative Endocrine Prognostic Index score at the time of surgical resection | Approximately 5.5 months | 
| Evaluate the clinical response of ARV-471 and anastrozole, respectively (breast conserving surgery rate) | rates of breast conserving surgery | Approximately 5.5 months | 
| Evaluate the clinical response of ARV-471 and anastrozole, respectively (radiographic response) | radiographical response rate in the primary tumor during cycle 6 | Approximately 5 months | 
| Evaluate the clinical response of ARV-471 and anastrozole, respectively (caliper-based response) | Best percentage change from baseline up to C6D1 in caliper measurement of the primary tumor | Approximately 5 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Early breast cancer, Localized breast cancer, Untreated breast cancer, Pre-operative breast cancer, Treatment-naïve breast cancer, Neoadjuvant, Estrogen receptor, Estrogen receptor positive, ER+, Hormone positive, Hormone receptor positive, HR+, human epidermal growth factor receptor 2, HER2-, ARV-471, Anastrozole, Arimidex, Aromatase inhibitor, Vepdegestrant