Randomised Phase II Study of Metronomic Chemotherapy Plus the Same Aromatase Inhibitor Compared to Metronomic Chemotherapy Alone in Women With Hormone Receptor Positive, Her-2 Non-Overexpressing Advanced Breast Cancer Whose Disease Has Progressed While Receiving an Aromatase Inhibitor, Correlating Response With Circulating Endothelial Progenitor Cells, VEGF and VEGFR
18 Years
N/A
Female
Breast Cancer
Trial Information
Randomised Phase II Study of Metronomic Chemotherapy Plus the Same Aromatase Inhibitor Compared to Metronomic Chemotherapy Alone in Women With Hormone Receptor Positive, Her-2 Non-Overexpressing Advanced Breast Cancer Whose Disease Has Progressed While Receiving an Aromatase Inhibitor, Correlating Response With Circulating Endothelial Progenitor Cells, VEGF and VEGFR
OBJECTIVES:
Primary
- Compare the clinical benefit rate (complete response, partial response or stable
disease for > 24 weeks) in postmenopausal women with metastatic breast cancer treated
with metronomic chemotherapy with vs without aromatase inhibitor therapy.
Secondary
- Compare the time to progression in these patients
- Compare the overall survival of these patients.
- Compare the safety and toxicity of these regimens in these patients.
- Correlate tumor response with markers of angiogenesis (circulating endothelial
progenitor cells, VEGF, VEGF-C, VEGFR-2, and VEGFR-3).
- Determine the relative contribution of methotrexate and prednisolone to metronomic
chemotherapy as assessed by change in circulating endothelial progenitor cell, VEGF,
and VEGFR levels during serial addition of each drug.
OUTLINE: Patients are stratified according to site of metastases (visceral vs non-visceral
only) and number of lines of prior chemotherapy in the metastatic setting (0 vs 1-2).
Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive aromatase inhibitor (anastrozole, letrozole, or exemestane) as
previously prescribed. Patients also receive oral cyclophosphamide once daily on days
1-28 and oral methotrexate twice on days 15, 16, 22, and 23 of course 1. For all
subsequent courses, patients receive oral cyclophosphamide once daily and oral
prednisolone once daily on days 1-28 and oral methotrexate twice on days 1, 2, 8, 9,
15, 16, 22, and 23. Treatment with cyclophosphamide, methotrexate, and prednisolone
repeats every 28 days in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive cyclophosphamide, methotrexate, and prednisolone as in arm I.
Patients undergo blood sample collection at baseline, in weeks 2, 4, 6, and 10, every 4
weeks until disease progression, and then at 4 weeks after disease progression. Blood
samples are assessed for circulating endothelial progenitor cell levels by flow cytometry
and VEGF, VEGF-C, VEGFR-2, and VEGFR-3 levels by ELISA immunoassays.
After completion of study therapy, patients are followed every 3 months.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Histologically confirmed invasive breast cancer
- Metastatic disease
- Measurable disease, as defined by RECIST criteria
- Evidence of disease progression while receiving a third-generation aromatase
inhibitor
- No extensive visceral disease (> 50% liver or lung parenchymal involvement)
- No pleural effusion or ascites
- No HER2/neu overexpression
- Hormone receptor status:
- Estrogen receptor- or progesterone receptor-positive tumor
PATIENT CHARACTERISTICS:
- Postmenopausal, as defined by any of the following:
- Over 60 years of age
- 50-59 years of age with plasma follicle-stimulating hormone, luteinizing
hormone, and estradiol in the postmenopausal range and amenorrhea for > 1 year
- Any age with documented bilateral oophorectomy
- ECOG performance status (PS) 0-2 (Karnofsky PS 60-100%)
- Life expectancy > 6 months
- Leukocytes ≥ 3,000/μL
- Absolute neutrophil count ≥ 1,500/μL
- Platelet count ≥ 100,000/μL
- Total bilirubin normal
- AST/ALT ≤ 2.5 times upper limit of normal
- Creatinine normal OR creatinine clearance ≥ 60 mL/min
- Not pregnant
- Fertile patients must use effective contraception
- No other prior malignancies except curatively treated basal cell carcinoma of the
skin or carcinoma in situ of the cervix
- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to cyclophosphamide, methotrexate, prednisolone, anastrozole,
letrozole, or exemestane
- No concurrent uncontrolled illness including, but not limited to, any of the
following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness/social situations that would limit compliance with study
requirements
PRIOR CONCURRENT THERAPY:
- No more than 2 lines of prior chemotherapy or endocrine therapy for advanced disease
- No other concurrent chemotherapy, immunotherapy, anticancer hormonal therapy, or
anticancer surgery
- No other concurrent anticancer therapy
- No other concurrent investigational agents
- No concurrent combination anti-retroviral therapy for HIV-positive patients
Type of Study:
Interventional
Study Design:
Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Clinical benefit response rate (complete response, partial response, or stable disease for > 24 weeks)
Safety Issue:
No
Principal Investigator
Wong Nan Soon, MBBS, MRCP, FAMS
Investigator Role:
Principal Investigator
Investigator Affiliation:
National Cancer Centre, Singapore
Authority:
Unspecified
Study ID:
CDR0000595712
NCT ID:
NCT00687648
Start Date:
May 2008
Completion Date:
Related Keywords:
- Breast Cancer
- stage IV breast cancer
- recurrent breast cancer
- HER2-negative breast cancer
- estrogen receptor-positive breast cancer
- progesterone receptor-positive breast cancer
- Breast Neoplasms
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