Sunitinib, Cyclophosphamide, and Methotrexate in Treating Patients With Metastatic Breast Cancer

OBJECTIVES:

Primary

- To determine the maximum tolerated dose of the combination of metronomic dose
cyclophosphamide and methotrexate with continuous dosing sunitinib malate. (Phase I)

- To determine the time to disease progression in patients with metastatic breast cancer
treated with metronomic dose chemotherapy with cyclophosphamide and methotrexate
combined with continuous dosing of sunitinib malate. (Phase II)

Secondary

- To determine the response rate in patients receiving this treatment.

- To determine the duration of response in patients receiving this treatment.

- To determine the toxicity of this regimen in these patients.

- To determine the feasibility by assessment of toxicities of this regimen and number of
voluntary withdrawals from the study.

- To correlate outcome measures with possible surrogate markers including serial
measurements of circulating tumor cells and circulating endothelial cells.

OUTLINE: This is a dose-escalation study of sunitinib malate.

- Phase I: Patients receive oral sunitinib malate once daily. Beginning 14 days later,
patients also receive oral cyclophosphamide once daily on days 1-21 and oral
methotrexate twice daily on days 1, 2, 8, 9, 15, and 16. Treatment with sunitinib
malate, cyclophosphamide, and methotrexate repeats every 21 days* in the absence of
disease progression or unacceptable toxicity.

- Phase II: Patients receive sunitinib malate at the maximum tolerated dose determined in
phase I and cyclophosphamide and methotrexate as in phase I.

NOTE: *Course 1 includes 2 weeks of sunitinib malate alone followed by sunitinib malate,
cyclophosphamide, and methotrexate for 21 days

Blood samples are collected periodically for measurement of circulating tumor cells,
circulating endothelial cells, and VEGF levels.

After completion of study treatment, patients are followed for 30 days and then every 2
months for 1 year.

DISEASE CHARACTERISTICS:

- Pathologically confirmed diagnosis of breast cancer with documented progressive
disease

- Metastatic disease

- Measurable disease as defined by RECIST criteria or evaluable disease

- Must have received at least one prior chemotherapy regimen for metastatic breast
cancer

- Patients refusing all other chemotherapy for breast cancer may enroll without
prior treatment

- Patients with HER2-overexpression disease must have been previously treated with
trastuzumab (Herceptin®)

- Patients with stable brain metastases are eligible

- Hormone receptor status not specified

PATIENT CHARACTERISTICS:

- Menopausal status not specified

- ECOG performance status 0-2

- Life expectancy ≥ 12 weeks

- ANC ≥ 1,000/mm³

- Platelet count ≥ 100,000/mm³

- Creatinine ≤ 1.5 times upper limit of normal (ULN)

- AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver metastases)

- Total bilirubin ≤ 1.5 times ULN

- Able to take oral medications and maintain hydration

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 6 months after
treatment

- No severe concurrent illness including, but not limited to, any of the following:

- Congestive heart failure

- Significant cardiac disease

- Uncontrolled hypertension

- Must be able to read and speak English

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- At least 2 weeks since prior treatment, including chemotherapy, hormonal therapy,
trastuzumab (Herceptin®), or other targeted therapies

- Prior bevacizumab allowed if discontinued for any reason other than toxicity

- No potent inducers or inhibitors of CYP3A4 enzymes that effect the metabolism of
sunitinib malate

- No prior sunitinib malate

- No other concurrent investigational therapy

- No concurrent radiotherapy

- Concurrent bisphosphonates allowed