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This phase II, open-label, single-arm, study investigates the clinical benefit of everolimus combined with endocrine therapy (ET) in hormone receptor-positive (HR+), metastatic breast cancer (MBC) patients who progressed on prior PI3K inhibitor therapy (+ ET). The trial aims to determine if sequential inhibition of the PI3K/AKT/mTORC1 pathway retains efficacy post-PI3K inhibitor resistance, hypothesizing that everolimus will demonstrate a response rate exceeding the historical 9.5% observed in the BOLERO2 trial.
Detailed Description The study employs a two-stage design to evaluate the primary endpoint of clinical response rate (complete/partial response per RECIST v1.1). Stage 1 will enroll 19 patients with measurable disease; if no responses are observed, the trial terminates. If ≥1 response occurs, 24 additional patients will be enrolled (total N=43), with success defined as ≥2 responses. Secondary endpoints include progression-free survival (PFS), clinical benefit rate (CBR), and biomarker analysis via longitudinal ctDNA profiling to identify genomic drivers of resistance/sensitivity. Eligible participants receive everolimus (10 mg/day) + ET until progression, unacceptable toxicity, or withdrawal. Tumor assessments occur every 8 weeks, with toxicity monitoring.
Study Design
Intervention Model: Single-group assignment
Primary Purpose: Treatment
Phase: II
Allocation: Non-randomized
Masking: None (open-label)
Outcome Measures
Primary: Objective response rate (ORR).
Secondary:
PFS (time from treatment initiation to progression/death).
CBR (proportion with CR/PR or stable disease ≥24 weeks).
Biomarker correlation (e.g., ESR1 mutations, PTEN alterations) via ctDNA analysis.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| HR+MBC post Alpelisib | Patients with HR+MBC post Alpelisib treatment who are scheduled to receive Everolimus with endocrine therapy, an additional blood sample is collected for biomarker evaluation. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Everolimus (Afinitor) tablets with endocrine therapy | Drug | Patients receive standard of care treatment as prescribed by their treating physician. This study only observes the outcomes and does not alter the treatment regimen, dosing, or schedule." |
| Measure | Description | Time Frame |
|---|---|---|
| ORR | Objective response rate -best response rate in the first scan 8-12 weeks from day1 | Response rate- From enrollment to the first scan at 8-12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| PFS | Time from Day 1 to progression, an average of 16 weeks | From date of enrollment until the date of first documented progression, assessed up to 24 months. |
| CBR Clinical Benefit Rate | Proportion with CR/PR or stable disease ≥24 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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HR+ MBC post CDK 4/6 inhibitors and anti PI3K inhibitor.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Breast Cancer coordinator Breast Cancer coordinator | Contact | 972-03-6974092 | hananm@tlvmc.gov.il |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ichilov-Sourasky Medical Center | Recruiting | Tel Aviv | Israel |
Individual participant data will not be made available outside the primary research group to protect participant privacy and maintain confidentiality.
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| Blood draw for biomarker and genetic analysis | Procedure | "A supplementary blood sample is collected from participants to analyze genetic and molecular biomarkers, aiming to identify potential correlations between these markers and clinical response to the standard treatment." |
|
| Through the end of the study, assessed up to 24 months. |
| ID | Term |
|---|---|
| D000068338 | Everolimus |
| D013607 | Tablets |
| D001800 | Blood Specimen Collection |
| D015415 | Biomarkers |
| D005820 | Genetic Testing |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
| D013048 | Specimen Handling |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D011677 | Punctures |
| D013514 | Surgical Procedures, Operative |
| D008919 | Investigative Techniques |
| D001685 | Biological Factors |
| D005821 | Genetic Techniques |
| D033142 | Genetic Services |
| D006296 | Health Services |
| D005159 | Health Care Facilities Workforce and Services |
| D003954 | Diagnostic Services |
| D011314 | Preventive Health Services |
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