Cyclophosphamide, Methotrexate, and Prednisolone With or Without Aromatase Inhibitor Therapy in Treating Postmenopausal Women With Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide, methotrexate, and prednisolone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole, letrozole, or exemestane may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether giving combination chemotherapy together with aromatase inhibitor therapy is more effective than combination chemotherapy alone in treating breast cancer. PURPOSE: This randomized phase II trial is studying giving cyclophosphamide, methotrexate, and prednisolone together with aromatase inhibitor therapy to see how well it works compared with cyclophosphamide, methotrexate, and prednisolone in treating postmenopausal women with metastatic breast cancer.

Detailed Description
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OBJECTIVES: Primary Compare the clinical benefit rate (complete response, partial response or stable disease for > 24 weeks) in postmenopausal women with metastatic breast cancer treated with metronomic chemotherapy with vs without aromatase inhibitor therapy. Secondary Compare the time to progression in these patients Compare the overall survival of these patients. Compare the safety and toxicity of these regimens in these patients. Correlate tumor response with markers of angiogenesis (circulating endothelial progenitor cells, VEGF, VEGF-C, VEGFR-2, and VEGFR-3). Determine the relative contribution of methotrexate and prednisolone to metronomic chemotherapy as assessed by change in circulating endothelial progenitor cell, VEGF, and VEGFR levels during serial addition of each drug. OUTLINE: Patients are stratified according to site of metastases (visceral vs non-visceral only) and number of lines of prior chemotherapy in the metastatic setting (0 vs 1-2). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive aromatase inhibitor (anastrozole, letrozole, or exemestane) as previously prescribed. Patients also receive oral cyclophosphamide once daily on days 1-28 and oral methotrexate twice on days 15, 16, 22, and 23 of course 1. For all subsequent courses, patients receive oral cyclophosphamide once daily and oral prednisolone once daily on days 1-28 and oral methotrexate twice on days 1, 2, 8, 9, 15, 16, 22, and 23. Treatment with cyclophosphamide, methotrexate, and prednisolone repeats every 28 days in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive cyclophosphamide, methotrexate, and prednisolone as in arm I. Patients undergo blood sample collection at baseline, in weeks 2, 4, 6, and 10, every 4 weeks until disease progression, and then at 4 weeks after disease progression. Blood samples are assessed for circulating endothelial progenitor cell levels by flow cytometry and VEGF, VEGF-C, VEGFR-2, and VEGFR-3 levels by ELISA immunoassays. After completion of study therapy, patients are followed every 3 months.

Official Title
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Randomised Phase II Study of Metronomic Chemotherapy Plus the Same Aromatase Inhibitor Compared to Metronomic Chemotherapy Alone in Women With Hormone Receptor Positive, Her-2 Non-Overexpressing Advanced Breast Cancer Whose Disease Has Progressed While Receiving an Aromatase Inhibitor, Correlating Response With Circulating Endothelial Progenitor Cells, VEGF and VEGFR

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: anastrozole
* Drug: cyclophosphamide
* Drug: exemestane
* Drug: letrozole
* Drug: methotrexate
* Drug: prednisolone


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed invasive breast cancer Metastatic disease Measurable disease, as defined by RECIST criteria Evidence of disease progression while receiving a third-generation aromatase inhibitor No extensive visceral disease (> 50% liver or lung parenchymal involvement) No pleural effusion or ascites No HER2/neu overexpression Hormone receptor status: Estrogen receptor- or progesterone receptor-positive tumor PATIENT CHARACTERISTICS: Postmenopausal, as defined by any of the following: Over 60 years of age 50-59 years of age with plasma follicle-stimulating hormone, luteinizing hormone, and estradiol in the postmenopausal range and amenorrhea for > 1 year Any age with documented bilateral oophorectomy ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%) Life expectancy > 6 months Leukocytes ≥ 3,000/μL Absolute neutrophil count ≥ 1,500/μL Platelet count ≥ 100,000/μL Total bilirubin normal AST/ALT ≤ 2.5 times upper limit of normal Creatinine normal OR creatinine clearance ≥ 60 mL/min Not pregnant Fertile patients must use effective contraception No other prior malignancies except curatively treated basal cell carcinoma of the skin or carcinoma in situ of the cervix No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, methotrexate, prednisolone, anastrozole, letrozole, or exemestane No concurrent uncontrolled illness including, but not limited to, any of the following: Ongoing or active infection Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Psychiatric illness/social situations that would limit compliance with study requirements PRIOR CONCURRENT THERAPY: No more than 2 lines of prior chemotherapy or endocrine therapy for advanced disease No other concurrent chemotherapy, immunotherapy, anticancer hormonal therapy, or anticancer surgery No other concurrent anticancer therapy No other concurrent investigational agents No concurrent combination anti-retroviral therapy for HIV-positive patients

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
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive aromatase inhibitor (anastrozole, letrozole, or exemestane) as previously prescribed. Patients also receive oral cyclophosphamide once daily on days 1-28 and oral methotrexate twice on days 15, 16, 22, and 23 of course 1. For all subsequent courses, patients receive oral cyclophosphamide once daily and oral prednisolone once daily on days 1-28 and oral methotrexate twice on days 1, 2, 8, 9, 15, 16, 22, and 23. Treatment with cyclophosphamide, methotrexate, and prednisolone repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: anastrozole<br>* Given as previously prescribed<br>Drug: cyclophosphamide<br>* Given by mouth<br>Drug: exemestane<br>* Given as previously prescribed<br>Drug: letrozole<br>* Given as previously prescribed<br>Drug: methotrexate<br>* Given by mouth<br>Drug: prednisolone<br>* Given by mouth<br>|
| Active Comparator: Arm II<br>Patients receive cyclophosphamide, methotrexate, and prednisolone as in arm I. | Drug: cyclophosphamide<br>* Given by mouth<br>Drug: methotrexate<br>* Given by mouth<br>Drug: prednisolone<br>* Given by mouth<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit response rate (complete response, partial response, or stable disease for > 24 weeks) |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression |  |  | 
| Overall survival |  |  | 
| Safety and toxicity |  |  | 
| Correlation between tumor response and markers of angiogenesis |  |  | 
| Relative contribution of methotrexate and prednisolone to metronomic chemotherapy as assessed by change in circulating endothelial progenitor cell, VEGF, and VEGFR levels during serial addition of each drug |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, recurrent breast cancer, HER2-negative breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer