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

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.

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