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

Study Overview
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Brief Summary
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RATIONALE: Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide and methotrexate, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sunitinib together with combination chemotherapy may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of sunitinib when given together with cyclophosphamide and methotrexate to see how well they work in treating patients with metastatic breast cancer.

Detailed Description
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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 vascular endothelial growth factor (VEGF) levels. After completion of study treatment, patients are followed for 30 days and then every 2 months for 1 year.

Official Title
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Phase I/II Study of SU11248 (Sutent) in Combination With Metronomic Dosing of Cyclophosphamide and Methotrexate in Patients With Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: methotrexate
* Drug: sunitinib malate
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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 Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy ≥ 12 weeks Absolute Neutrophil Count (ANC) ≥ 1,000/mm³ Platelet count ≥ 100,000/mm³ Creatinine ≤ 1.5 times upper limit of normal (ULN) aspartate aminotransferase (AST) and alanine aminotransferase (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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sunitinib, Cyclophosphamide, and Methotrexate<br> | Drug: cyclophosphamide<br> <br> Drug: methotrexate<br> <br> Drug: sunitinib malate<br> <br> Other: laboratory biomarker analysis<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Sunitinib (Phase I) | Patients in each cohort were followed for DLT for at least 8 weeks (2 week lead-in with sunitinib and 6 weeks of treatment with sunitinib and metronomic cyclophosphamide and methotrexate) before opening accrual to the next dose level. Dose limiting toxicity (DLT) defined as: 1) ≥ grade 3 anemia that does not resolve with appropriate growth factors afebrile grade 4 neutropenia that does not resolve with growth factor support after ≥ 7 days 2) grade 4 neutropenia associated with fever (1 reading of oral temperature > 38.5 degrees Celsius or 3 readings of oral temperature > 38.0 degrees Celsius in a 24 hour period) 3) ≥ grade 3 thrombocytopenia 4) ≥ grade 3 non-hematologic toxicities, except those that can be controlled to grade 2 or less with appropriate treatment. 5) Inability to resume treatment with any of the study medications within 14 days of stopping due to treatment related toxicity. | 8 weeks | 
| Patients With Progression-free Survival (PFS) Greater Than or Equal to 12 Weeks (Phase II) | Progression defined as: 25% increase or an increase of 10 sq. cm (whichever is smaller) in the sum of products of measurable lesions over smallest sum observed (over baseline if no decrease), or appearance of any lesion which had disappeared, or clear worsening of any evaluable disease, or appearance of any new lesion/site, or failure to return for evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this cancer). | up to 12 weeks after treatment start date | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Per Response Evaluation Criteria in Solid Tumors (RECIST): Complete Response (CR): Complete disappearance of all measurable and evaluable disease. No new lesions. Partial Response (PR): greater than or equal to 50% decrease under baseline in the sum of the products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable: Does not qualify for complete response, partial response or progression. | until disease progression, up to 13 months post treatment | 
| Duration of Response | Duration of response refers to duration of single partial response observed per Response Evaluation Criteria in Solid Tumors (RECIST): Complete Response (CR): Complete disappearance of all measurable and evaluable disease. No new lesions. Partial Response (PR): greater than or equal to 50% decrease under baseline in the sum of the products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Stable: Does not qualify for complete response, partial response or progression. Progression: 25% increase or an increase of 10 sq. cm (whichever is smaller) in the sum of products of measurable lesions over smallest sum observed (over baseline if no decrease), OR appearance of any lesion which had disappeared, or clear worsening of any evaluable disease, or appearance of any new lesion/site, or failure to return for evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this cancer). | until disease progression up to 13 months post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent breast cancer, stage IV breast cancer, male breast cancer