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

Phase 1

Terminated

Conditions: Breast Cancer

Interventions: Drug: cyclophosphamide
Drug: methotrexate
Drug: sunitinib malate
Other: laboratory biomarker analysis

Registration Number: NCT00616122

Lead Sponsor: University of California, San Francisco

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 32

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sunitinib, Cyclophosphamide, and Methotrexate	sunitinib malate	-
Sunitinib, Cyclophosphamide, and Methotrexate	laboratory biomarker analysis	-
Sunitinib, Cyclophosphamide, and Methotrexate	methotrexate	-
Sunitinib, Cyclophosphamide, and Methotrexate	cyclophosphamide	-

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose of Sunitinib (Phase I)	8 weeks	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.
Patients With Progression-free Survival (PFS) Greater Than or Equal to 12 Weeks (Phase II)	up to 12 weeks after treatment start date	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).

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate	until disease progression, up to 13 months post treatment	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.
Duration of Response	until disease progression up to 13 months post treatment	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).