Cyclophosphamide, Methotrexate, and Prednisolone With or Without Aromatase Inhibitor Therapy in Treating Postmenopausal Women With Metastatic Breast Cancer - Full Text View

Purpose

RATIONALE: Drugs used in chemotherapy, such as cyclophosphamide, methotrexate, and prednisolone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Estrogen can cause the growth of breast cancer cells. Hormone therapy using anastrozole, letrozole, or exemestane may fight breast cancer by lowering the amount of estrogen the body makes. It is not yet known whether giving combination chemotherapy together with aromatase inhibitor therapy is more effective than combination chemotherapy alone in treating breast cancer.

PURPOSE: This randomized phase II trial is studying giving cyclophosphamide, methotrexate, and prednisolone together with aromatase inhibitor therapy to see how well it works compared with cyclophosphamide, methotrexate, and prednisolone in treating postmenopausal women with metastatic breast cancer.

Condition	Intervention	Phase
Breast Cancer	Drug: anastrozole Drug: cyclophosphamide Drug: exemestane Drug: letrozole Drug: methotrexate Drug: prednisolone	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Masking: Open Label Primary Purpose: Treatment
Official Title:	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

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Clinical benefit response rate (complete response, partial response, or stable disease for > 24 weeks) [ Designated as safety issue: No ]

Secondary Outcome Measures:

Time to progression [ Designated as safety issue: No ]
Overall survival [ Designated as safety issue: No ]
Safety and toxicity [ Designated as safety issue: Yes ]
Correlation between tumor response and markers of angiogenesis [ Designated as safety issue: No ]
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 [ Designated as safety issue: No ]

Estimated Enrollment:	70
Study Start Date:	May 2008
Estimated Primary Completion Date:	April 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 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.	Drug: anastrozole Given as previously prescribed Drug: cyclophosphamide Given by mouth Drug: exemestane Given as previously prescribed Drug: letrozole Given as previously prescribed Drug: methotrexate Given by mouth Drug: prednisolone Given by mouth
Active Comparator: Arm II Patients receive cyclophosphamide, methotrexate, and prednisolone as in arm I.	Drug: cyclophosphamide Given by mouth Drug: methotrexate Given by mouth Drug: prednisolone Given by mouth

Arms

Assigned Interventions

Experimental: 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.

Drug: anastrozole

Given as previously prescribed

Drug: cyclophosphamide

Given by mouth

Drug: exemestane

Given as previously prescribed

Drug: letrozole

Given as previously prescribed

Drug: methotrexate

Given by mouth

Drug: prednisolone

Given by mouth

Active Comparator: Arm II

Patients receive cyclophosphamide, methotrexate, and prednisolone as in arm I.

Drug: cyclophosphamide

Given by mouth

Drug: methotrexate

Given by mouth

Drug: prednisolone

Given by mouth

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Female
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00687648

Locations

Singapore
National Cancer Centre - Singapore	Recruiting
Singapore, Singapore, 169610
Contact: Wong Nan Soon, MBBS, MRCP, FAMS 65-6-436-8088

Sponsors and Collaborators

National Cancer Centre, Singapore

Investigators

Principal Investigator:

Wong Nan Soon, MBBS, MRCP, FAMS

National Cancer Centre, Singapore

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

ClinicalTrials.gov Identifier:	NCT00687648 History of Changes
Other Study ID Numbers:	CDR0000595712, SINGAPORE-NCC0706
Study First Received:	May 30, 2008
Last Updated:	June 16, 2009
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

stage IV breast cancer
recurrent breast cancer
HER2-negative breast cancer
estrogen receptor-positive breast cancer
progesterone receptor-positive breast cancer

Additional relevant MeSH terms:

Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Methotrexate
Exemestane
Letrozole
Anastrozole
Prednisolone
Methylprednisolone Hemisuccinate
Methylprednisolone acetate
Prednisolone acetate
Methylprednisolone

Prednisolone hemisuccinate
Prednisolone phosphate
Aromatase Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Abortifacient Agents, Nonsteroidal

ClinicalTrials.gov processed this record on May 19, 2013