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Doxorubicin Hydrochloride Liposome, Cyclophosphamide, and Trastuzumab in Treating Patients With Stage IV Breast Cancer

Primary Purpose

HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
pegylated liposomal doxorubicin hydrochloride
cyclophosphamide
trastuzumab
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HER2-positive Breast Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm I

Arm Description

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.

Outcomes

Primary Outcome Measures

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
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).
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

Secondary Outcome Measures

Treatment-related Toxicity (Phase I)
Count of phase I participants with treatment related toxicity.
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.
Progression-free Survival (Phase II)
Kaplan-Meier estimate assessed at 18 months
Overall Survival (Phase II)
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)
Count of participants with a clinical benefit (i.e., complete response, partial response, and stable disease).

Full Information

First Posted
May 30, 2006
Last Updated
June 27, 2017
Sponsor
University of Washington
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00331552
Brief Title
Doxorubicin Hydrochloride Liposome, Cyclophosphamide, and Trastuzumab in Treating Patients With Stage IV Breast Cancer
Official Title
Phase I - II Study of Doxil® In Combination With Daily Oral Cyclophosphamide and Herceptin for Patients With HER-2/Neu Positive Disease In Patients With Metastatic Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
February 2006 (undefined)
Primary Completion Date
February 2011 (Actual)
Study Completion Date
February 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Washington
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
pegylated liposomal doxorubicin hydrochloride
Other Intervention Name(s)
CAELYX, Dox-SL, DOXIL, doxorubicin hydrochloride liposome, Evacet, LipoDox
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
CPM, CTX, Cytoxan, Endoxan, Endoxana, Enduxan
Intervention Description
Given orally
Intervention Type
Biological
Intervention Name(s)
trastuzumab
Other Intervention Name(s)
anti-c-erB-2, Herceptin, MOAB HER2, monoclonal antibody c-erb-2, monoclonal antibody HER2
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose and Optimal Tolerated Dose of Pegylated Liposomal Doxorubicin Hydrochloride (Doxil) When Given in Combination With Cyclophosphamide (Phase I)
Description
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
Title
Efficacy as Assessed by the Overall Clinical Benefit Rate
Description
Count of participants with a clinical benefit (i.e., complete response, partial response, and stable disease).
Time Frame
18 months
Title
Safety as Assessed by Grade 1, 2, 3, 4, Fatal Toxicity, Need for Dose Reduction, Treatment Interruption, or Treatment Discontinuation
Description
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
Secondary Outcome Measure Information:
Title
Treatment-related Toxicity (Phase I)
Description
Count of phase I participants with treatment related toxicity.
Time Frame
Up to 24 weeks
Title
Time to Progression (Phase II)
Description
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
Title
Progression-free Survival (Phase II)
Description
Kaplan-Meier estimate assessed at 18 months
Time Frame
18 months
Title
Overall Survival (Phase II)
Description
Kaplan-Meier estimate assessed at 18 months
Time Frame
18 months
Title
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)
Description
Count of participants with a clinical benefit (i.e., complete response, partial response, and stable disease).
Time Frame
Up to 24 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hannah Linden
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Doxorubicin Hydrochloride Liposome, Cyclophosphamide, and Trastuzumab in Treating Patients With Stage IV Breast Cancer

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