Everolimus Combined With Anti-estrogen Therapy in Hormone-Receptor-Positive HER-2 Negative Advanced Breast Cancer

Study Overview
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Brief Summary
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Many patients with ER-positive or PR-positive breast cancer are treated with endocrine therapy. Although most ER/PR-positive tumors initially respond to hormonal therapy, patients often experience disease progression. Everolimus, in combination with exemestane, has shown activity in endocrine-resistant disease. This study will evaluate the efficacy of Everolimus+ anti-estrogen therapy in patients with ER-positive metastatic breast cancer who have progressed after receiving anti-estrogen therapy.

Detailed Description
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This is a multi-centered, open-labeled, Phase II study on metastastic breast cancer (MBC). The patient population includes locally recurrent or MBC patients with cytologically or histologically confirmed hormone receptor-positive breast cancer who have demonstrated disease progression on prior anti-estrogen therapy or therapies. Investigators propose to evaluate the efficacy of Everolimus in patients with ER-positive (estrogen receptor-positive) metastatic breast cancer who have progressed on anti-estrogen therapy. Forty-six (46) patients are planned for enrollment in the trial.

Official Title
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Phase II Open Label Study of Everolimus in Combination With Anti-estrogen Therapy in Hormone Receptor-Positive HER2-Negative Advanced Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Everolimus
* Drug: Exemestane
* Drug: Tamoxifen
* Drug: Fulvestrant
* Drug: Anastrozole
* Drug: Letrozole
* Drug: Toremifine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of unresectable, locally recurrent or MBC. ER and/or PR-positive tumors with staining by immunohistochemistry (IHC) based on the most recent biopsy. Only 1 previous chemotherapy regimen for MBC. Patients progressing while receiving adjuvant endocrine therapy or progressing <12 months from completion of adjuvant endocrine therapy are eligible. Progressed on anti-estrogen therapy (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy) defined as: Recurrence while on, or within 12 months of end of anti-estrogen therapy for early stage breast cancer, or Progression while on, or within one month of anti-estrogen therapy for locally advanced or metastatic breast cancer. Note: No washout for anti-estrogen therapy required. Anti-estrogen therapy does not have to be the last treatment prior to study entry. Post-menopausal or pre/peri-menopausal women on tamoxifen. LHRH agonists may be used to render ovarian suppression with postmenopausal ranges of estradiol or FSH per institutional guidelines. HER2-negative breast cancer, defined as follows: Fluorescent In Situ Hybridization (FISH)-negative (FISH ratio <2.0), or IHC 0-1+, or IHC 2-3+ AND FISH-negative (FISH ratio <2.0). Measureable disease as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 or evaluable bone lesions, lytic or mixed, in absence of measureable disease by RECIST criteria. Adequate hematologic, hepatic and renal function. International normalized ratio (INR) ≤1.5 or prothrombin time (PT)/partial thromboplastin time (PTT) within normal limits (WNL) of the institution (if patient is not on anti-coagulation therapy). Age ≥ 18 years. ECOG Performance Status score of 0-2. Life expectancy of ≥ 12 weeks. Exclusion Criteria: Previous therapy or known intolerance/hypersensitivity with any approved or investigational mTOR inhibitor (e.g., temsirolimus, everolimus, sirolimus). Patients who are ≤21 days after their most recent chemotherapy and have not recovered from side effects. Use of an investigational drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of everolimus. For investigational drugs for which 5 half-lives is ≤21 days, a minimum of 10 days between termination of the investigational drug and administration of everolimus is required. Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days for metastatic disease prior to first dose of everolimus or has not recovered from side effects of such therapy. Previously untreated brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if there is no evidence of central nervous system (CNS) disease progression, and at least 2 weeks have elapsed since treatment. Patients are not permitted to receive enzyme inducing anti-epileptic drugs (EIAEDs) during the study and should not be receiving chronic corticosteroid therapy for CNS metastases. Patients with known active hepatitis B (HBV) or hepatitis C (HCV) infection. Patients with risk factors for hepatitis must have HBV DNA and HCV RNA testing by PCR, and are ineligible if these tests are positive. Patients receiving immunization with attenuated live vaccines within 1 week of study entry or during study period. NOTE: There are additional inclusion/exclusion criteria. The study center will determine patient eligibility and respond to any questions.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: everolimus<br>Everolimus will be administered at a dose of 10 mg PO daily combined with any one of the following anti-estrogen therapies on which the patient most recently progressed (tamoxifen, fulvestrant, anastrozole, letrozole, exemestane, toremifine, or LHRH agonists in conjunction with anti-estrogen therapy). Anti-estrogen therapy will be administered at the US Food and Drug Administration (FDA) prescribed doses. | Drug: Everolimus<br> <br> * Other names: Afinitor;Drug: Exemestane<br>* Anti-estrogen therapy<br>Drug: Tamoxifen<br>* Anti-estrogen therapy<br>Drug: Fulvestrant<br>* Anti-estrogen therapy<br>Drug: Anastrozole<br>* Anti-estrogen therapy<br>Drug: Letrozole<br>* Anti-estrogen therapy<br>Drug: Toremifine<br>* Anti-estrogen therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival (PFS) | PFS is defined as the time from Day 1 of study drug administration to disease progression as defined by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 criteria, or death on study. Participants who are alive and free from disease progression will be censored at the date of last radiologic tumor assessment. Participants who receive non-protocol therapy (subsequent therapy) prior to incurring an event will be censored at the date of last tumor assessment prior to the start of subsequent therapy. Participants who do not have a post-baseline tumor assessment will be censored at the date of first treatment (Day 1). | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events (AEs) as a Measure of Safety and Tolerability | Assessments were made through analysis of the reported incidence of treatment-emergent AEs. All participants who received at least one dose of protocol treatment were followed for safety. Adverse events were collected from day of first dose to 30 days after last protocol treatment and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. | Up to 20 months | 
| Number of Patients With an Objective Response (CR or PR) Also Called the Overall Response Rate (ORR). | Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST version 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters. | every 8 weeks until discontinuation, up to 20 months | 
| Number of Participants With CR, PR, or 6 Months of SD Also Called Clinical Benefit Rate (CBR) | The proportion of patients with Complete Response (CR) or Partial Response (PR) or 6 months or more of Stable Disease (SD). A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters. SD is not meeting the criteria for PR or a 20% increase in target lesions called Progressive Disease (PD). | Up to 20 months | 
| Median Time From First Occurrence of CR or PR to Disease Progression or Death Also Called Duration of Response (DOR) | Only those patients who achieved Complete Response or Partial Response will be included in the summaries of DOR. DOR is defined as time from first date of response of CR or PR to disease progression or death as defined by RECIST v1.1 criteria. Participants who are alive and free from disease progression will be censored at the date of last tumor assessment. Patients who receive non-protocol therapy (subsequent therapy) prior to incurring an event will be censored at the date of last tumor assessment prior to the start of subsequent therapy. A CR is the complete disappearance of all target lesions. A PR is a decrease of 30% or more of the diameter(s) of all target lesions from the baseline sum of diameters. | every 8 weeks until discontinuation, up to 20 months | 
| Median Overall Survival (OS) | Defined as the time from date of first study treatment to date of death due to any cause. Patients who are alive will be censored at the date of last known date alive. | up to 3 years from first treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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everolimus, ER-Positive Breast Cancer, HER2-Negative Breast Cancer, anti-estrogen therapy, PR-Positive Breast Cancer, Afinitor