Breast Cancer
Conditions
Keywords
Advanced breast cancer, Metastatic breast cancer, MBC, Endocrine therapy, Estrogen receptor, ER+, human epidermal growth factor receptor 2, HER2-, ARV-471, Everolimus, PROTAC, Vepdegestrant
Brief summary
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
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.
Interventions
DRUGARV-471 in combination with Everolimus
ARV-471 oral tablets in combination with everolimus administered daily in 28 day cycles
Sponsors
Pfizer
Arvinas Estrogen Receptor, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose limiting toxicities of ARV-471 in combination with everolimus | 35 Days | 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 |
| 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 | 28 calendar days after participant discontinues study treatment | Adverse events as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study drug combination |
| Incidence of laboratory abnormalities as a measure of safety and tolerability of ARV-471 in combination with everolimus | 28 calendar days after participant discontinues study treatment | Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v5.0), and timing |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | — |
| Overall response rate (ORR) in participants | Up to approximately 1 year | — |
| 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 | — |
| Clinical benefit rate (CBR) in participants. | Up to approximately 1 year | Clinical benefit response rate based on the summation of CRs, PRs and stable disease of 24 weeks duration or longer. |
| 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 | — |
Countries
Spain, United States
Outcome results
None listed