HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer
Conditions
Brief summary
Drugs used in chemotherapy, such as doxorubicin hydrochloride liposome and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving more than one drug (combination chemotherapy) together with trastuzumab may be a better way to block tumor growth.
Detailed description
PRIMARY OBJECTIVES: I. To determine the optimal tolerated dose of Doxil when given in combination with daily oral cyclophosphamide in patients with stage IV breast cancer. (Phase I) II. To determine the efficacy (overall clinical response rate) of the optimal tolerated dose of Doxil when given in combination with daily oral cyclophosphamide and herceptin (for HER2 neu positive patients) in patients with stage IV breast cancer. (Phase II) SECONDARY OBJECTIVES: I. To assess the treatment related toxicity associated with each dose level of this regimen and assess efficacy (overall clinical response rate). (Phase I) II. To assess the safety (treatment related toxicity) of the optimal tolerated dose of Doxil when given in combination with daily oral cyclophosphamide and herceptin (for HER2 neu positive patients) in patients with stage IV breast cancer. (Phase II) III. To assess time to progression and overall survival following treatment with Doxil and daily oral cyclophosphamide and herceptin (for HER2 neu positive patients). (Phase II) IV. To compare the response rate in patients who are heavily pretreated to the response rate in patients who are less heavily pretreated. OUTLINE: This is a phase I, dose-escalation study of pegylated doxorubicin HCl liposome followed by a phase II feasibility study. Patients receive oral cyclophosphamide once daily on days 1-28 and pegylated doxorubicin HCl liposome IV over 90 minutes on day 1. Treatment repeats every 4-6 weeks in the absence of disease progression or unacceptable toxicity. Some patients with HER2/neu 3+ disease may also receive trastuzumab IV over 30-90 minutes weekly or every 3 weeks at the discretion of the treating physician. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Interventions
DRUGpegylated liposomal doxorubicin hydrochloride
Given IV
DRUGcyclophosphamide
Given orally
BIOLOGICALtrastuzumab
Given IV
Sponsors
National Cancer Institute (NCI)
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must satisfy either a or b: a) Measurable disease by RECIST criteria; x-rays, scans or physical examinations used for tumor assessment must have been completed within 30 days prior to registration; any non-measurable disease must be assessed within 42 days prior to registration; b) Non-measurable disease only, but MUC-1 antigen level (either CA 27-29 or CEA) is \> 2X ULN AND MUC-1 antigen has been documented to have increased by 1.5X prior to registration; x-rays, scans or other tests for assessment of non-measurable disease must have been performed within 42 days prior to registration * ECOG performance status of =\< 2 * ANC \>= 1,500 cells/mm\^3 * Platelet count \>= 100,000 cells/mm\^3 * Hemoglobin \>= 9.0g/dL * Creatinine =\< 2.5 mg/dL * In the absence of liver metastases, AST / ALT, alkaline phosphatase and total bilirubin must not exceed 2 x upper limit of normal (i.e., must be =\< 2 x upper limit of normal) * In the presence of liver metastases, AST / ALT, alkaline phosphatase and total bilirubin must not exceed 3 x upper limit of normal (i.e., must be =\< 3 x upper limit of normal) * Have a MUGA scan or 2-d echocardiogram indicating an ejection fraction of \>= 50% within 42 days prior to first dose of study drug (the method used at baseline must be used for later monitoring) * Use an adequate contraceptive method (e.g., abstinence, intrauterine device, barrier device with spermicide or surgical sterilization) during treatment and for three months after completing treatment if of reproductive potential * Be informed of the investigational nature of this study and provide written informed consent in accordance with institutional and federal guidelines prior to study specific screening procedures
Exclusion criteria
* Pregnant or lactating women * History of hypersensitivity reactions attributed to a conventional formulation of doxorubicin HCL or the components of Doxil * Patients who are HER2-neu positive with cardiac disease that would preclude the use of Doxil or Herceptin are not eligible, including active cardiac disease (i.e., angina pectoris that requires the use of antianginal medication, cardiac arrhythmia requiring medication, severe conduction abnormality, clinically significant valvular disease, cardiomegaly on chest x-ray, ventricular hypertrophy on EKG, uncontrolled hypertension \[diastolic greater than 100 mm/Hg or systolic \> 200 mm/hg\], current use of digitalis or beta blockers for CHF, clinically significant pericardial effusion) and history of cardiac disease (i.e., myocardial infarction documented as a clinical diagnosis or by EKG or any other test, documented congestive heart failure, documented cardiomyopathy, documented arrhythmia or cardiac valvular disease that requires medication or is medically significant) * Has anthracycline resistant disease defined as a) If anthracycline was given for non-metastatic disease: The cumulative dose of anthracycline exceeds 360 mg/m\^ 2 for doxorubicin or 540 mg/m\^2 for epirubicin AND the disease-free interval from discontinuation of anthracycline to diagnosis of metastatic disease is \< 12 months; b) If anthracycline was given for metastatic disease: The cumulative dose of anthracycline exceeds 360 mg/m\^2 for doxorubicin or 540 mg/m\^2 for epirubicin AND the patient's disease progressed on anthracycline given as palliative therapy * Except for the following no other malignancy is allowed: synchronous ipsilateral breast cancer of the same subtype (ER/PR, HER-2/neu), adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer or other stage I or II cancer from which the patient has been disease free for at least 5 years * Any life-threatening illness other than the malignancy for which they are being treated * Mental illness * Have a life expectancy of less than 4 months * Unwillingness to participate or inability to comply with the protocol for the duration of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose and Optimal Tolerated Dose of Pegylated Liposomal Doxorubicin Hydrochloride (Doxil) When Given in Combination With Cyclophosphamide (Phase I) | Up to 24 weeks | The dose level in which 2 or more patients develop treatment-related toxicity of grade 3 or higher OR require a dose adjustment following the first course of treatment |
| Efficacy as Assessed by the Overall Clinical Benefit Rate | 18 months | Count of participants with a clinical benefit (i.e., complete response, partial response, and stable disease). |
| Safety as Assessed by Grade 1, 2, 3, 4, Fatal Toxicity, Need for Dose Reduction, Treatment Interruption, or Treatment Discontinuation | Periodically during study treatment, up to 24 weeks | Count of participants with grade 1, 2, 3, 4, fatal toxicity, need for dose reduction, treatment interruption, or treatment discontinuation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (Phase II) | 18 months | Kaplan-Meier estimate assessed at 18 months |
| Progression-free Survival (Phase II) | 18 months | Kaplan-Meier estimate assessed at 18 months |
| Comparison of Clinical Benefit Rate in 2 Subgroups--heavily Pre-treated (1 or More Regimens for Advanced Disease) vs Less Heavily Pre-treated (no Regimens for Advanced Disease) (Phase II) | Up to 24 weeks | Count of participants with a clinical benefit (i.e., complete response, partial response, and stable disease). |
| Time to Progression (Phase II) | Up to 2 years | Median time to progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions or new effusions. |
| Treatment-related Toxicity (Phase I) | Up to 24 weeks | Count of phase I participants with treatment related toxicity. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I: Cyclophosphamide, Doxil, Trastuzumab Patients receive oral cyclophosphamide once daily on days 1-28 and pegylated doxorubicin HCl liposome IV over 90 minutes on day 1. Treatment repeats every 4-6 weeks in the absence of disease progression or unacceptable toxicity. Some patients with HER2/neu 3+ disease may also receive trastuzumab IV over 30-90 minutes weekly or every 3 weeks at the discretion of the treating physician.
pegylated liposomal doxorubicin hydrochloride: Given IV
cyclophosphamide: Given orally
trastuzumab: Given IV | 6 |
| Phase II: Cyclophosphamide, Doxil, Trastuzumab Patients receive oral cyclophosphamide once daily on days 1-28 and pegylated doxorubicin HCl liposome IV over 90 minutes on day 1. Treatment repeats every 4-6 weeks in the absence of disease progression or unacceptable toxicity. Some patients with HER2/neu 3+ disease may also receive trastuzumab IV over 30-90 minutes weekly or every 3 weeks at the discretion of the treating physician.
pegylated liposomal doxorubicin hydrochloride: Given IV
cyclophosphamide: Given orally
trastuzumab: Given IV | 24 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 3: Phase II | Neurological Symptoms | 1 | 0 |
| Period 3: Phase II | Severe Nausea | 1 | 0 |
Baseline characteristics
| Characteristic | Phase II: Cyclophosphamide, Doxil, Trastuzumab | Total | Phase I: Cyclophosphamide, Doxil, Trastuzumab |
|---|---|---|---|
| Age, Continuous | 57 years | 56.5 years | 49.5 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 30 Participants | 6 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 | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 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 | 21 Participants | 25 Participants | 4 Participants |
| Sex: Female, Male Female | 23 Participants | 29 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 1 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 | 27 / 27 | 3 / 3 |
| serious Total, serious adverse events | 0 / 27 | 0 / 3 |
Outcome results
Primary
Efficacy as Assessed by the Overall Clinical Benefit Rate
Count of participants with a clinical benefit (i.e., complete response, partial response, and stable disease).
Time frame: 18 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Efficacy as Assessed by the Overall Clinical Benefit Rate | Partial response | 6 Participants |
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Efficacy as Assessed by the Overall Clinical Benefit Rate | Stable disease | 15 Participants |
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Efficacy as Assessed by the Overall Clinical Benefit Rate | Progressive disease | 7 Participants |
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Efficacy as Assessed by the Overall Clinical Benefit Rate | Complete response | 0 Participants |
Primary
Maximum Tolerated Dose and Optimal Tolerated Dose of Pegylated Liposomal Doxorubicin Hydrochloride (Doxil) When Given in Combination With Cyclophosphamide (Phase I)
The dose level in which 2 or more patients develop treatment-related toxicity of grade 3 or higher OR require a dose adjustment following the first course of treatment
Time frame: Up to 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Maximum Tolerated Dose and Optimal Tolerated Dose of Pegylated Liposomal Doxorubicin Hydrochloride (Doxil) When Given in Combination With Cyclophosphamide (Phase I) | 30 mg/m^2 |
Primary
Safety as Assessed by Grade 1, 2, 3, 4, Fatal Toxicity, Need for Dose Reduction, Treatment Interruption, or Treatment Discontinuation
Count of participants with grade 1, 2, 3, 4, fatal toxicity, need for dose reduction, treatment interruption, or treatment discontinuation
Time frame: Periodically during study treatment, up to 24 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Safety as Assessed by Grade 1, 2, 3, 4, Fatal Toxicity, Need for Dose Reduction, Treatment Interruption, or Treatment Discontinuation | Discontinued due to toxicity | 8 Participants |
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Safety as Assessed by Grade 1, 2, 3, 4, Fatal Toxicity, Need for Dose Reduction, Treatment Interruption, or Treatment Discontinuation | Grade 3 adverse events | 14 Participants |
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Safety as Assessed by Grade 1, 2, 3, 4, Fatal Toxicity, Need for Dose Reduction, Treatment Interruption, or Treatment Discontinuation | Grade 4 adverse events | 3 Participants |
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Safety as Assessed by Grade 1, 2, 3, 4, Fatal Toxicity, Need for Dose Reduction, Treatment Interruption, or Treatment Discontinuation | At least one dose held or reduced | 18 Participants |
Secondary
Comparison of Clinical Benefit Rate in 2 Subgroups--heavily Pre-treated (1 or More Regimens for Advanced Disease) vs Less Heavily Pre-treated (no Regimens for Advanced Disease) (Phase II)
Count of participants with a clinical benefit (i.e., complete response, partial response, and stable disease).
Time frame: Up to 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Comparison of Clinical Benefit Rate in 2 Subgroups--heavily Pre-treated (1 or More Regimens for Advanced Disease) vs Less Heavily Pre-treated (no Regimens for Advanced Disease) (Phase II) | 9 Participants |
| Doxil 35 mg/m^2 | Comparison of Clinical Benefit Rate in 2 Subgroups--heavily Pre-treated (1 or More Regimens for Advanced Disease) vs Less Heavily Pre-treated (no Regimens for Advanced Disease) (Phase II) | 7 Participants |
Secondary
Overall Survival (Phase II)
Kaplan-Meier estimate assessed at 18 months
Time frame: 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Overall Survival (Phase II) | 0.49 survival probability |
Secondary
Progression-free Survival (Phase II)
Kaplan-Meier estimate assessed at 18 months
Time frame: 18 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Progression-free Survival (Phase II) | 0.16 progression free survival probability |
Secondary
Time to Progression (Phase II)
Median time to progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions or new effusions.
Time frame: Up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Time to Progression (Phase II) | 6.3 months |
Secondary
Treatment-related Toxicity (Phase I)
Count of phase I participants with treatment related toxicity.
Time frame: Up to 24 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Treatment-related Toxicity (Phase I) | Grade 2 Neutropenia | 0 Participants |
| Phase I: Cyclophosphamide, Doxil, Trastuzumab | Treatment-related Toxicity (Phase I) | Grade 3 Neutropenia | 0 Participants |
| Doxil 35 mg/m^2 | Treatment-related Toxicity (Phase I) | Grade 2 Neutropenia | 1 Participants |
| Doxil 35 mg/m^2 | Treatment-related Toxicity (Phase I) | Grade 3 Neutropenia | 1 Participants |