ARV-471 in Combination With Everolimus for the Treatment of Advanced or Metastatic ER+, HER2- Breast Cancer

Study Overview
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Brief Summary
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A phase 1b study to assess the combination of ARV-471 and everolimus in participants with advanced or metastatic ER+/HER2- breast cancer.

Detailed Description
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This is a Phase 1b study to assess the safety and tolerability of ARV-471 in combination with everolimus in participants with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced or metastatic breast cancer, who have received a prior CDK4/6 inhibitor and endocrine therapy in the advanced/metastatic setting.

Official Title
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A Phase 1b Trial of ARV-471 in Combination With Everolimus in Patients With ER+, HER2- Advanced or Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: ARV-471 in combination with Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed ER+ and HER2-advanced breast cancer (metastatic, recurrent, or unresectable) Women must be postmenopausal, or pre-/peri-menopausal women must be on ovarian suppression Measurable disease or non-measurable (evaluable) disease per RECIST v1.1 Received a minimum of 1 and up to 3 lines of anti-cancer therapy in the advanced/metastatic setting: must have received and progressed on (or were intolerant to) a CDK 4/6 inhibitor, either alone or in combination; must have received at least one endocrine therapy, either alone or in combination; may have received up to one line of chemotherapy Must be willing to use dexamethasone mouthwash for the prevention of everolimus-induced stomatitis ECOG performance status of 0 or 1 Exclusion Criteria: Untreated brain metastases or brain metastases requiring steroids above physiologic replacement doses Prior treatment with ARV-471 Prior treatment targeting mTOR (e.g. everolimus) Prior anticancer or investigational drug treatment within 28 days (fulvestrant) or 14 days (tamoxifen or aromatase inhibitor, or CDK 4/6 inhibitor) before the first dose of study drug Prior anticancer or investigational anticancer drug therapy within 28 days or 5 half-lives (whichever is shorter) before the first dose of study drug, except as mentioned above Any of the following in the previous 12 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, 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, ongoing cardiac arrythmias/dysrhythmias, atrial fibrillation Hypertension that cannot be controlled by medication (>150/90 mmHg despite optimal medical therapy) Active, uncontrolled bacterial, fungal, or viral infection, including hepatitis B virus, hepatitis C virus, known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS)-related illness Known history of drug-induced pneumonitis or other significant symptomatic deterioration of lung function Live vaccines within 14 days before the first dose of study drug Major surgery (as defined by the Investigator) within 4 weeks of first dose of study drug Radiation therapy within 4 weeks of first dose of study drug or prior irradiation to more than 25% of the bone marrow

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARV-471 and Everolimus<br>ARV-471 oral tablets in combination with everolimus administered daily in 28 day cycles | Drug: ARV-471 in combination with Everolimus<br>* ARV-471 oral tablets in combination with everolimus administered daily in 28 day cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities of ARV-471 in combination with everolimus | Dose limiting toxicities in the first 35 days of the study combination treatment characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), timing, seriousness, and relationship to study drug | 35 Days | 
| Recommended Phase 2 Dose (RP2D) for ARV-471 in combination with everolimus |  | 35 Days | 
| Number of participants with adverse events as a measure of safety and tolerability of ARV-471 in combination with everolimus | Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug combination | 28 calendar days after participant discontinues study treatment | 
| Incidence of laboratory abnormalities as a measure of safety and tolerability of ARV-471 in combination with everolimus | Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), and timing | 28 calendar days after participant discontinues study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) in participants |  | Up to approximately 1 year | 
| Clinical benefit rate (CBR) in participants. | Clinical benefit response rate based on the summation of CRs, PRs and stable disease of 24 weeks duration or longer. | Up to approximately 1 year | 
| Duration of response (DOR) in participants |  | Up to approximately 1 year | 
| Maximum plasma concentrations (Cmax) of ARV-471 and everolimus |  | At predefined intervals throughout the treatment period, up to approximately 4 weeks after last dose of investigational products | 
| Time to maximum plasma concentrations (Tmax) of ARV-471 and everolimus |  | At predefined intervals throughout the treatment period, up to approximately 4 weeks after last dose of investigational products | 
| Area under the concentration-time curve over 24 hours at steady state (AUC(0-24)) of ARV-471 and everolimus |  | At predefined intervals throughout the treatment period, up to approximately 4 weeks after last dose of investigational products | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MBC, Advanced breast cancer, Metastatic breast cancer, Endocrine therapy, Estrogen receptor, ER+, human epidermal growth factor receptor 2, HER2-, ARV-471, Everolimus, PROTAC, Vepdegestrant