Recurrent Breast Cancer, Stage IV Breast Cancer
Conditions
Brief summary
Prolactin is a hormone produced in the pituitary gland. Previous studies have revealed that elevated levels of the hormone prolactin might be associated with an increased risk of breast cancer. Cabergoline has been shown to lower prolactin levels in the blood. The purpose of this study is to evaluate the effectiveness of cabergoline in treating metastatic breast cancer disease in those who test positive for the prolactin receptor.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate overall response rate (ORR) of cabergoline in women with metastatic breast cancer. SECONDARY OBJECTIVES: I. Evaluate the progression-free survival (PFS) and overall survival (OS). II. Evaluate toxicity. III. Correlate serum prolactin levels during therapy with response. IV. Evaluate within-patient changes in computed tomography (CT) and bone scan measurements taken at baseline and after 2 cycles of treatment. V. Evaluate within-patient changes in prolactin receptor (PRLr) expression from baseline to after 1 cycle of treatment in those patients who consent to optional repeat biopsy. OUTLINE: Patients receive cabergoline orally (PO) twice weekly for weeks 1-4. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 6 months thereafter.
Interventions
DRUGcabergoline
Given orally
Sponsors
Lynn Sage Foundation
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed metastatic breast cancer; tissue (a minimum of 3 slides) from the most recent biopsy is required for review and confirmation of eligibility; NOTE: material should ideally be from the metastatic disease, however material from the primary tumor is acceptable if that is all that is available * Patients must have stage IV breast cancer * Patients must have tumors (primary or metastatic) that stain positively for the prolactin receptor * Patients may have measurable or evaluable disease * Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \> 20 mm with conventional techniques or as \> 10 mm with spiral CT scan * Evaluable disease is disease that does not meet the criteria for measurable disease; examples would include patients with effusions or bone-only disease * Women of childbearing potential must commit to the use of effective barrier (non-hormonal) contraception while on study * Patients must have a life expectancy of greater than 12 weeks * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 * Patients may have had a prior diagnosis of cancer if it has been \> 5 years since their last treatment * Leukocytes \>= 3,000/uL (microliter) * Absolute neutrophil count \>= 1,500/uL * Platelets \>= 100,000/uL * Child Pugh score =\< 10 * Patients must be able to swallow and retain oral medication * All patients must have given signed, informed consent prior to registration on study
Exclusion criteria
* Women who are pregnant or lactating are not eligible for study treatment * Patients who are undergoing concomitant radiotherapy are NOT eligible for participation * Patients who are receiving any other investigational agents or concurrent anticancer therapy are NOT eligible for participation; previous systemic treatment is allowed with a 2 week washout period prior to registration * Patients who are taking any herbal (alternative) medicines are NOT eligible for participation; patients must be off any such medications by the time of registration * Patients who are receiving concomitant D2-antagonists (such as phenothiazines, butyrophenones, thioxanthenes, or metoclopramide) are NOT eligible for participation; patients must be off any such medications by the time of registration * Patients with known brain metastases are NOT eligible for participation * Patients with any of the following conditions or complications are NOT eligible for participation: * Uncontrolled hypertension * Known hypersensitivity to ergot derivatives * History of cardiac valvular disorders, as suggested by anatomical evidence of valvulopathy of any valve (to be determined by pre-treatment evaluation including echocardiographic demonstration of valve leaflet thickening, valve restriction, or mixed valve restriction-stenosis) * History of pulmonary, pericardial, cardiac valvular, or retroperitoneal fibrotic disorders * Gastrointestinal (GI) tract disease resulting in an inability to take oral medication * Malabsorption syndrome * Require intravenous (IV) alimentation * History of prior surgical procedures affecting absorption * Uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) at 2 Months | After 8 weeks (2 cycles) of treament | Overall Response Rate (ORR) is defined as the number of patients that achieved Complete Response (CR) or Partial Response (PR) and will be assessed after 8 weeks (2 cycles) of therapy using CT scan images and RECIST guidelines. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LD. Progressive Disease (PD): At least a 20% increase in the sum o the LD of target lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LD since the treatment started |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Toxicity | After every 4 weeks (1 cycle) during treatment for up to 20 cycles and 30 days post last treatment | Toxicity will be assessed at the beginning of each cycle (1 cycle equals 28 days) during treatment and 30 days post last treatment during treatment. Toxicity will be assessed according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE Grades 1 through 4 adverse events that were determined to be at least possibly related to treatment are combined and reported below. |
| Change in Within-patient Imaging Measurements at Baseline and After 2 Cycles | At baseline and at 8 weeks | At baseline and after 2 cycles changes CT and bone scan measurements will be evaluated. |
| Progression Free Survival (PFS) | From start of treatment until progression of disease or death | Progression Free Survival (PFS) will be measured from time of treatment initiation until first documentation of progression of disease or death from any cause. |
| Correlate Tissue Prolactin Biomarkers With Response to Therapy | At baseline | Baseline tumor tissue was analyzed for prolactin receptor (PRLr) expression and was provided with an IHC-based Allred score of 0 to 300 based on percentage intensity where lower scores indicate less PRLr expression and high scores indicate more PRLr expression. Only the malignant epithelium was scored. The score was correlated with best response of patient. |
| Overall Survival (OS) | From the start of treatment until death from any cause. Median follow up time of 6.817 months (95%CI 0.22-26.18) | Overall Survival (OS) is defined from the first day of treatment until death from any cause. |
| Change in Prolactin Receptor Expression Measurements at Baseline and After 1 Cycle | At baseline and after 4 weeks (1 cycle) | Evaluate prolactin expression in biopsy tissue taken at baseline and after 4 weeks (1 cycle) of treatment. |
Countries
United States
Participant flow
Recruitment details
The study opened for accrual on November 29, 2012 with an accrual goal of up to 20 patients. The first patient starting treatment February 11, 2013. Accrual was suspended twice during the study; May 28 2014 reopening June 11, 2014 and July 24 2015, reopening August 27 2015. The study was closed October 21, 2015 with 20 patients enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Cabergoline) Patients receive cabergoline oral (PO) twice weekly for weeks 1-4. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
cabergoline: Given orally | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 1 |
| Overall Study | Progressive Disease | 12 |
Baseline characteristics
| Characteristic | Treatment (Cabergoline) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 20 |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 4 / 20 |
Outcome results
Primary
Overall Response Rate (ORR) at 2 Months
Overall Response Rate (ORR) is defined as the number of patients that achieved Complete Response (CR) or Partial Response (PR) and will be assessed after 8 weeks (2 cycles) of therapy using CT scan images and RECIST guidelines. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LD. Progressive Disease (PD): At least a 20% increase in the sum o the LD of target lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LD since the treatment started
Time frame: After 8 weeks (2 cycles) of treament
Population: 2 patients did not reach 8 week response time point and were determined not to be evaluable for this objective.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Cabergoline) | Overall Response Rate (ORR) at 2 Months | 0 Participants |
Secondary
Change in Prolactin Receptor Expression Measurements at Baseline and After 1 Cycle
Evaluate prolactin expression in biopsy tissue taken at baseline and after 4 weeks (1 cycle) of treatment.
Time frame: At baseline and after 4 weeks (1 cycle)
Population: No data collected as no patients completed repeat biopsy after 1 cycle of treatment.
Secondary
Change in Within-patient Imaging Measurements at Baseline and After 2 Cycles
At baseline and after 2 cycles changes CT and bone scan measurements will be evaluated.
Time frame: At baseline and at 8 weeks
Population: This data was not collected and analysed as it was decided that it was not meaningful on its own.
Secondary
Correlate Tissue Prolactin Biomarkers With Response to Therapy
Baseline tumor tissue was analyzed for prolactin receptor (PRLr) expression and was provided with an IHC-based Allred score of 0 to 300 based on percentage intensity where lower scores indicate less PRLr expression and high scores indicate more PRLr expression. Only the malignant epithelium was scored. The score was correlated with best response of patient.
Time frame: At baseline
Population: Only 9 patients had sufficient baseline tissue to be analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Treatment (Cabergoline) | Correlate Tissue Prolactin Biomarkers With Response to Therapy | Stable Disease | 170 score on a scale |
| Treatment (Cabergoline) | Correlate Tissue Prolactin Biomarkers With Response to Therapy | Progressive Disease | 220 score on a scale |
Secondary
Overall Survival (OS)
Overall Survival (OS) is defined from the first day of treatment until death from any cause.
Time frame: From the start of treatment until death from any cause. Median follow up time of 6.817 months (95%CI 0.22-26.18)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cabergoline) | Overall Survival (OS) | 10.41 Months |
Secondary
Progression Free Survival (PFS)
Progression Free Survival (PFS) will be measured from time of treatment initiation until first documentation of progression of disease or death from any cause.
Time frame: From start of treatment until progression of disease or death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Cabergoline) | Progression Free Survival (PFS) | 1.84 Months |
Secondary
Treatment Toxicity
Toxicity will be assessed at the beginning of each cycle (1 cycle equals 28 days) during treatment and 30 days post last treatment during treatment. Toxicity will be assessed according to the National Cancer Institute's Common Toxicity Criteria for adverse events version 3.0 (CTCAE v3.0). In general adverse events (AEs) will be graded according to the following: Grade 1 Mild AE Grade 2 Moderate AE Grade 3 Severe AE Grade 4 Life-threatening or disabling AE Grade 5 Death related to AE Grades 1 through 4 adverse events that were determined to be at least possibly related to treatment are combined and reported below.
Time frame: After every 4 weeks (1 cycle) during treatment for up to 20 cycles and 30 days post last treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Cabergoline) | Treatment Toxicity | Nausea | 6 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Fatigue | 5 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Hyponatremia | 3 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Alkaline Phosphatase increased | 3 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Aspartate Aminotansferase increased | 2 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Hyperglycemia | 2 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Hypokalemia | 2 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Vomiting | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Pain in extremity | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Acute Kidney Injury | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Alanine Aminotranserase increased | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Arthralgia | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Creatinine increased | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Diarrhea | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Dizziness | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Dry eye | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Hyperkalemia | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Hypernatremia | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Hypocalcemia | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Hypoglycemia | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Insomnia | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | Pain | 1 participants |
| Treatment (Cabergoline) | Treatment Toxicity | White Blood Cell decreased | 1 participants |
Post Hoc
Best Overall Response
Best Overall Response is defined as patients best response to treatment from treatment initiation until the end of treatment as assessed by RECIST guidelines of CT scans. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LD. Progressive Disease (PD): At least a 20% increase in the sum o the LD of target lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LD since the treatment started
Time frame: From the start of treatment until the end of treatment up to a maximum of 20 cycles (1 cycle = 4 weeks)
Population: 1 patient died on treatment 7 days after starting and was not included in this outcome measure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Cabergoline) | Best Overall Response | Partial Response | 1 Participants |
| Treatment (Cabergoline) | Best Overall Response | Stable Disease | 5 Participants |
| Treatment (Cabergoline) | Best Overall Response | Progressive Disease | 13 Participants |
Post Hoc
Change in Serum Prolactin Levels From Baseline and After 2 Cycles of Treatment
Serum prolactin measurements were taken at baseline and after completion of two cycles of treatment. The mean drop was calculated for all patients, and for patients with best response of Stable Disease and Progressive Disease.
Time frame: At baseline and after 2 cycles of treatment where 1 cycle =4 weeks
Population: Serum prolactin at baseline and after 2 cycles of treatment were only available for 12 patients.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Treatment (Cabergoline) | Change in Serum Prolactin Levels From Baseline and After 2 Cycles of Treatment | All | -9.425 ng/ml |
| Treatment (Cabergoline) | Change in Serum Prolactin Levels From Baseline and After 2 Cycles of Treatment | Stable Disease | -8.72 ng/ml |
| Treatment (Cabergoline) | Change in Serum Prolactin Levels From Baseline and After 2 Cycles of Treatment | Progressive Disease | -9.93 ng/ml |
Post Hoc
Clinical Benefit Rate (CBR) After 2 Cycles of Treatment
Clinical Benefit Rate (CBR) is defined as the number of patients with Complete Response (CR), Partial Response (PR), or Stable Disease (SD) and is assessed by RECIST guidelines for measurements of CT scan at 8 weeks (2 cycles) of treatment. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LD. Progressive Disease (PD): At least a 20% increase in the sum o the LD of target lesions, taking as reference the smallest sum of LD recorded since the treatment started or the appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of LD since the treatment started
Time frame: After 8 weeks (2 cycles) of treatment
Population: 2 patients did not reach the 8 week response assessment time point.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Cabergoline) | Clinical Benefit Rate (CBR) After 2 Cycles of Treatment | 6 Participants |
Post Hoc
Disease Control at 12 Months
Number of patients without progressive disease as assessed by CT scan and RECIST guidelines at 12 months of treatment.
Time frame: At 12 months from start of treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (Cabergoline) | Disease Control at 12 Months | 2 Participants |