Estrogen Receptor-negative Breast Cancer, Progesterone Receptor-negative Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer
Conditions
Keywords
Medroxyprogesterone progesterone acetate (MPA), Cyclophosphamide plus 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.
Interventions
DRUGMedroxyprogesterone progesterone acetate (MPA)
1000 mg po daily
DRUGMedroxyprogesterone with Cyclophosphamide + Methotrexate
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
Sponsors
Translational Breast Cancer Research Consortium
Indiana University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Countries
United States
Participant flow
Recruitment details
Since there was not enough evidence of clinical benefit, this study did not go beyond the first stage in the two stage design. A total of 30 patients (14 in the MPA alone cohort and 16 in the MPA+ ldoCM cohort) were in the study before the study ended.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: MPA-Alone Medroxyprogesterone progesterone acetate (MPA) will be administered orally as a single daily dose. | 14 |
| Cohort 2: MPA+IdoCM 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. | 16 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Alternative Therapy | 0 | 1 |
| Overall Study | Prog, refract disease during active trt | 8 | 5 |
| Overall Study | Progression, relapse during active trt | 6 | 8 |
Baseline characteristics
| Characteristic | Cohort 1: MPA-Alone | Cohort 2: MPA+IdoCM | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 4 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 12 Participants | 21 Participants |
| Age, Continuous | 59.0 Years STANDARD_DEVIATION 12.78 | 56.2 Years STANDARD_DEVIATION 12.24 | 57.5 Years STANDARD_DEVIATION 12.36 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 16 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 12 Participants | 21 Participants |
| Sex: Female, Male Female | 14 Participants | 16 Participants | 30 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 14 | 12 / 16 |
| serious Total, serious adverse events | 2 / 14 | 2 / 16 |
Outcome results
Primary
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.
Time frame: baseline through end of study, up to 3 years
Population: All Patients on study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort I: MPA-Alone | Clinical Benefit Rate (CR + PR + SD > 6 Months). | 7.1 Percent of Participants |
| Cohort 2: MPA+IdoCM | Clinical Benefit Rate (CR + PR + SD > 6 Months). | 6.3 Percent of Participants |
Secondary
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.
Time frame: baseline through end of treatment
Population: All patients in the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort I: MPA-Alone | Grade 3 or 4 Adverse Events Related to Treatment | 2 participants |
| Cohort 2: MPA+IdoCM | Grade 3 or 4 Adverse Events Related to Treatment | 2 participants |
Secondary
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).
Time frame: Cycle 1 (Day 10-14) and Cycle 2 (Day 1)
Population: All patients with available data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort I: MPA-Alone | MPA Trough Concentration | Cycle 1, Day 10-14 | 14.5 ng/mL | Standard Deviation 8.9 |
| Cohort I: MPA-Alone | MPA Trough Concentration | Cycle 2, Day 1 | 52.6 ng/mL | Standard Deviation 65.3 |
| Cohort 2: MPA+IdoCM | MPA Trough Concentration | Cycle 1, Day 10-14 | 42.1 ng/mL | Standard Deviation 66.4 |
| Cohort 2: MPA+IdoCM | MPA Trough Concentration | Cycle 2, Day 1 | 66.4 ng/mL | Standard Deviation 71.5 |
Secondary
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.
Time frame: baseline through end of treatment
Population: Patients who showed clinical benefit (CR, PR, or SD \> 6 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort I: MPA-Alone | MPA Trough Level > 50 ng/mL When Have Clinical Benefit | 1 participants |
| Cohort 2: MPA+IdoCM | MPA Trough Level > 50 ng/mL When Have Clinical Benefit | 1 participants |