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Metronomic Chemotherapy in Combination With Bevacizumab for Advanced Breast Cancer

Phase 2
18 Years
Open (Enrolling)
Breast Cancer

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Trial Information

Metronomic Chemotherapy in Combination With Bevacizumab for Advanced Breast Cancer



- Compare the overall response rate in women with metastatic breast cancer treated with
metronomic low-dose cyclophosphamide and methotrexate with or without bevacizumab.


- Compare the progression-free survival of patients treated with these regimens.

- Compare the toxicity of these regimens in these patients.

- Correlate markers of angiogenesis, including vascular endothelial growth factor and
circulating endothelial cells, at baseline and during treatment, with response in
patients treated with these regimens.

OUTLINE: This is a randomized study. Patients are randomized to 1 of 2 treatment arms.

- Arm I: Patients receive low-dose oral cyclophosphamide once daily on days 1-28,
low-dose oral methotrexate twice daily on days 1, 2, 8, 9, 15, 16, 22 and 23, and
bevacizumab IV over 30-90 minutes on days 1 and 15.

- Arm II: Patients receive cyclophosphamide and methotrexate as in arm I. In both arms,
courses repeat every 28 days in the absence of disease progression or unacceptable

Patients in arm II who have progressive disease have the option of discontinuing treatment
or crossing over to arm I.

PROJECTED ACCRUAL: A total of 36-66 patients (18-33 per treatment arm) will be accrued for
this study within 7-12 months.

Inclusion Criteria


- Histologically or cytologically confirmed invasive breast cancer

- Metastatic (stage IV) disease confirmed by histology or cytology, physical exam,
or radiologic study

- Measurable disease

- At least one unidimensionally measurable lesion at least 20 mm by conventional
techniques OR at least 10 mm by spiral CT scan

- Measurable lesions in a previously irradiated field must have progressed after

- HER2-positive patients must have received prior trastuzumab (Herceptin^®) for
advanced disease or in the adjuvant setting

- No evidence of brain metastases by brain CT scan or MRI

- Hormone receptor status:

- Not specified



- 18 and over


- Female

Menopausal status

- Not specified

Performance status

- ECOG 0-1 OR

- Karnofsky 70-100%

Life expectancy

- More than 6 months


- Absolute neutrophil count ≥ 1,000/mm^3

- Platelet count ≥ 100,000/mm^3

- No bleeding diatheses (including hemoptysis)


- AST and ALT ≤ 4.0 times upper limit of normal (ULN)

- Bilirubin ≤ 2 times ULN


- Creatinine ≤ 2.0 mg/dL

- Urinary protein < 500 mg/24-hour-urine collection OR

- Protein urinalysis < 1+


- LVEF ≥ 50% by echocardiogram or nuclear medicine gated study

- No poorly controlled hypertension

- No prior blood clots

- No symptomatic congestive heart failure

- No unstable angina pectoris

- No cardiac arrhythmia


- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No history of grade 3 or 4 allergic reaction to compounds of similar chemical or
biological composition to cyclophosphamide or methotrexate

- No concurrent uncontrolled illness

- No active or ongoing infection

- No psychiatric illness or social situation that would preclude study compliance


Biologic therapy

- See Disease Characteristics

- No prior experimental angiogenesis inhibitors

- No concurrent filgrastim (G-CSF)

- Concurrent epoetin alfa growth factor support allowed


- Prior adjuvant chemotherapy for early-stage breast cancer allowed, including
cyclophosphamide-based chemotherapy

- No more than 1 prior chemotherapy regimen for metastatic breast cancer

- No prior oral cyclophosphamide- or methotrexate-based therapy for metastatic disease

Endocrine therapy

- Prior hormonal therapy in the adjuvant or metastatic setting or for early-stage
breast cancer allowed

- No concurrent hormonal therapy, including luteinizing hormone-releasing hormone


- See Disease Characteristics

- Prior radiotherapy in the metastatic or early-stage setting allowed

- Concurrent radiotherapy allowed


- More than 28 days since prior surgery except for venous access device or diagnostic


- Recovered from prior therapy

- No concurrent anticoagulation or chronic aspirin therapy (> 325 mg/day)

- Concurrent low-dose anticoagulation or thrombolytic agents for venous access
patency allowed

- No other concurrent investigational or experimental therapy

- No other concurrent anticancer agents or therapies

- Concurrent bisphosphonates allowed provided skeletal sites are not the primary sites
used in assessing response

- If skeletal sites are being followed for measurable response, bisphosphonates
must be initiated at least 4 weeks before study entry

Type of Study:


Study Design:

Allocation: Randomized, Primary Purpose: Treatment

Outcome Measure:

Clinical response rate (complete and partial) as measured by RECIST criteria

Safety Issue:


Principal Investigator

Harold J. Burstein, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Federal Government

Study ID:




Start Date:

November 2002

Completion Date:

Related Keywords:

  • Breast Cancer
  • recurrent breast cancer
  • stage IV breast cancer
  • Breast Neoplasms



Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Boston, Massachusetts  02115