Medroxyprogesterone +/- Cyclophosphamide & Methotrexate in Hormone Receptor-Negative Recurrent/Metastatic Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the impact of MPA alone and in combination with low dose oral chemotherapy in patients with ER- and PR- advanced breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] >= 6 months) of medroxyprogesterone acetate (MPA) monotherapy and MPA + low dose oral cyclophosphamide and methotrexate (ldoCM) in patients with refractory hormone receptor negative metastatic breast cancer. SECONDARY OBJECTIVES: I. To evaluate the toxicity of MPA and MPA + ldoCM in this patient population. II. To explore the relationship between MPA trough level and clinical benefit. III. To explore genetic determinants of MPA bioavailability and trough concentration. IV. To explore potential surrogates of biologic activity including Nm-23 expression in primary tumor, change in Nm-23 expression in skin, change in plasma thrombospondin (TSP)-1, change in plasma plasminogen activator inhibitor (PAI)-1 antigen and activity. OUTLINE: Patients are assigned to 1 of 2 treatment arms. COHORT I: Patients receive MPA orally (PO) once daily (QD). COHORT II: Patients receive MPA as in Cohort I, cyclophosphamide PO QD, and methotrexate PO twice daily (BID) on days 1 and 2 of every week. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Official Title
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MPA Revisited: A Phase II Study of Anti-Metastatic, Anti-Angiogenic Therapy in Postmenopausal Patients With Hormone Receptor Negative Breast Cancer. A Translational Breast Cancer Research Consortium (TBCRC) Trial

Conditions
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Estrogen Receptor-negative Breast Cancer, Progesterone Receptor-negative Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: Medroxyprogesterone progesterone acetate (MPA)
* Drug: Medroxyprogesterone with Cyclophosphamide + Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the breast with measurable locally recurrent or metastatic disease Primary tumor must be ER negative and PR negative Patients must be post-menopausal Patients may have had up to 3 prior chemotherapy regimens for recurrent/metastatic disease Adequate organ function as evidenced by laboratory studies outlined in section 3.6 of the protocol Patients with treated, asymptomatic brain metastases are eligible provided chronic steroid therapy is not required Exclusion Criteria: Patients must not have extensive pleural effusion or ascites Patients must not have history of DVT or pulmonary embolism w/in past 12 mo Patients must not have had chemotherapy or hormonal therapy within 2 weeks of study entry Patients must not have had radiation therapy within 1 week of study entry.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort I (MPA)<br>Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. | Drug: Medroxyprogesterone progesterone acetate (MPA)<br>* 1000 mg po daily<br>* Other names: Provera Dosepak;|
| Experimental: Cohort II (MPA, low-dose chemotherapy)<br>Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. Cyclophosphamide will be administered orally as a single daily dose. Methotrexate will be administered twice daily on days 1 and 2 of each week. | Drug: Medroxyprogesterone with Cyclophosphamide + Methotrexate<br>* Medroxyprogesterone Acetate Dose 1000 mg po daily Cyclophosphamide Dose 50 mg po daily Methotrexate Dose 2.5 mg po daily Days 1 and 2 of each week<br>* Other names: MTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CR + PR + SD > 6 Months). | To determine the clinical benefit rate (Complete Response + Partial Response + Stable Disease > 6 months) per Response Evaluation Criteria in Solid tumors (RECIST version 1.0). of MPA monotherapy and MPA + low dose oral cyclophosphamide and methotrexate (ldoCM) in patients with refractory hormone receptor negative metastatic breast cancer. This will show the percent of patients who had Clinical Benefit and the Exact 95% Confidence Interval. | baseline through end of study, up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade 3 or 4 Adverse Events Related to Treatment | To evaluate the toxicity of MPA and MPA + ldoCM in this patient population by the number of patients who have grade 3 or 4 adverse events that are related to treatment. | baseline through end of treatment | 
| MPA Trough Level > 50 ng/mL When Have Clinical Benefit | To explore the relationship between MPA trough level and clinical benefit. This is done by seeing if the MPA concentrations remained > 50 ng/mL after initial dose escalation for those patients who showed clinical benefit. The number shows how many of the patients who showed clinical benefit had MPA concentrations > 50 ng/mL. | baseline through end of treatment | 
| MPA Trough Concentration | To explore genetic determinants of MPA bioavailability and trough concentration by showing average MPA levels at cycle 1 (Day 10-14) and cycle 2 (Day 1). | Cycle 1 (Day 10-14) and Cycle 2 (Day 1) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Medroxyprogesterone progesterone acetate (MPA), Cyclophosphamide plus Methotrexate