Metronomic Capecitabine Plus Aromatase Inhibitor for First Line Treatment in HR(+), Her2(-) Metastatic Breast Cancer

Study Overview
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Brief Summary
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The study is designed to compare the clinical benefit following treatment with aromatase inhibitor in combination with metronomic capecitabine versus aromatase inhibitor alone in women with hormone receptor-positive, Her2-negative advanced breast cancer who have not received prior systemic anti-cancer therapies for their advanced/metastatic disease.

Detailed Description
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Initial endocrine therapy (ET) is a common choice for hormone receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer (MBC) patients for its good tolerability, low toxicity and durable response. The median time to progression (TTP) of initial ET in HR+, HER2- metastatic patients is about 9 months with aromatase inhibitors (AIs). However, all metastatic patients receiving ET will develop resistance to the conventional endocrine treatments ultimately. So some novel agents, like palbociclib and everolimus, are approved to be effective in improving the efficacy of standard ET. But the fact we have to face is either palbociclib or everolimus is focusing on a single checkpoint of pathway that responsible for resistance of ET. In clinical, there are some patients without an activation of resistance-related pathways have poor response to endocrine therapy. And the mechanisms of resistance to endocrine therapy is complicated and not fully understood. So far, these novel agents have not completely solved the clinical problems of secondary drug-resistance. Maybe a broad spectrum anti-cancer therapy with low toxicity and good tolerability is more practical and promising in the near future. Metronomic chemotherapy is administration of low-dose chemotherapy to induce disease control in metastatic cancer patients, which has low-incidence of adverse effects. More and more evidences showed activity of metronomic therapy in breast cancer. Metronomic therapy with or without endocrine therapy in both metastatic and neoadjuvant setting showed considerable efficacy. Although the concept of combination of chemotherapy and endocrine therapy simultaneously was large abandoned because of previous using tamoxifen and intravenous chemotherapy showing no additional benefit, with better understanding of the biology of endocrine therapy and metronomic chemotherapy, it's worth to evaluate whether endocrine therapy plus low-dose metronomic chemotherapy brings a better clinical benefit rate without sacrificing the quality of patients' life. In this phase III study, we investigate the efficacy and safety of low-dose capecitabine plus AI to treat metastatic HR+, HER2- postmenopausal breast cancer patients.

Official Title
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A Phase 3 Randomized Controlled Study of Metronomic Capecitabine Combined With Aromatase Inhibitor Versus Aromatase Inhibitor Alone for First Line Treatment in Hormone Receptor-positive, Her2-negative Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Aromatase Inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult women with locoregionally recurrent or metastatic disease not amenable to curative therapy Confirmed diagnosis of ER positive/Her2-negative breast cancer No prior systemic anti-cancer therapy for advanced ER+ disease Any menopausal status On a luteinizing hormone releasing hormone (LHRH) agonist for at least 28 days, if pre-/peri-menopausal, and willing to switch to goserelin (Zoladex ®) at time of randomization Measurable disease defined by RECIST version 1.1, or bone-only disease Eastern Cooperative Oncology Group (ECOG) 0-1 Adequate organ and marrow function Resolution of all toxic effects of prior therapy or surgical procedures Patient must agree to provide tumor tissue from metastatic tissue at baseline Exclusion Criteria: Patients with advanced, symptomatic, visceral spread that are at risk of life threatening complication in the short term Known uncontrolled or symptomatic central nervous system metastases Second primary malignancy(except in situ carcinoma of the cervix or adequately treated nonmelanomatous carcinoma of the skin) Serious uncontrolled intercurrent infections or intercurrent medical or psychiatric illness

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capecitabine+Aromatase inhibitor<br>Capecitabine, 625mg/m2, orally twice daily in combination with an aromatase inhibitor (Anastrozole 1 mg, orally once daily or Letrozole 2.5mg, orally once daily or Exemestane 25mg, orally once daily) | Drug: Capecitabine<br>* Capecitabine, 625mg/m2, orally twice daily (continuously)<br>* Other names: xeloda;Drug: Aromatase Inhibitor<br>* Aromatase Inhibitor (Anastrozole, 1mg, orally once daily or Letrozole, 2.5mg, orally once daily or Exemestane , 25mg, orally once daily)<br>* Other names: exemestane;|
| Active Comparator: Aromatase inhibitor<br>Aromatase inhibitor (Anastrozole 1 mg, orally once daily or Letrozole 2.5mg, orally once daily or Exemestane 25mg, orally once daily) | Drug: Aromatase Inhibitor<br>* Aromatase Inhibitor (Anastrozole, 1mg, orally once daily or Letrozole, 2.5mg, orally once daily or Exemestane , 25mg, orally once daily)<br>* Other names: exemestane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progress-free survival | Time from randomization to the first documentation of objective tumor progression or to death due to any cause. | Baseline up to approximately 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from randomization to date of death due to any cause. | Baseline until death (up to approximately 48 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metronomic capecitabine, aromatase inhibitor, first line treatment, metastatic breast cancer