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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


Phase 1/Phase 2
18 Years
N/A
Not Enrolling
Both
HER2-positive Breast Cancer, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

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Trial Information

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


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.


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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose and optimal tolerated dose of pegylated liposomal doxorubicin hydrochloride (Doxil) when given in combination with cyclophosphamide (Phase I)

Outcome Time Frame:

At 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

Safety Issue:

Yes

Principal Investigator

Hannah Linden

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Authority:

United States: Institutional Review Board

Study ID:

6139

NCT ID:

NCT00331552

Start Date:

February 2006

Completion Date:

Related Keywords:

  • HER2-positive Breast Cancer
  • Male Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male

Name

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer ConsortiumSeattle, Washington  98109