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

Phase 2

Completed

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

Interventions: Drug: Medroxyprogesterone progesterone acetate (MPA)
Drug: Medroxyprogesterone with Cyclophosphamide + Methotrexate

Brief Summary: 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: 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.

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Cohort I (MPA)	Medroxyprogesterone progesterone acetate (MPA)	Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose.
Cohort II (MPA, low-dose chemotherapy)	Medroxyprogesterone with Cyclophosphamide + Methotrexate	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.

Primary Outcome Measures

Name	Time	Method
Clinical Benefit Rate (CR + PR + SD > 6 Months).	baseline through end of study, up to 3 years	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.

Secondary Outcome Measures

Name	Time	Method
Grade 3 or 4 Adverse Events Related to Treatment	baseline through end of 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.
MPA Trough Level > 50 ng/mL When Have Clinical Benefit	baseline through end of treatment	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.
MPA Trough Concentration	Cycle 1 (Day 10-14) and Cycle 2 (Day 1)	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).

Locations (7): Indiana University Melvin and Bren Simon Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Duke University Comprehensive Cancer Center
🇺🇸
Durham, North Carolina, United States
University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
University of California, San Francisco Comprehensive Cancer Center
🇺🇸
San Francisco, California, United States
University of North Carolina, Lineberger Comprehensive Cancer Center
🇺🇸
Chapel Hill, North Carolina, United States
The University of Texas M. D. Anderson Cancer Center
🇺🇸
Houston, Texas, United States