Sunitinib Malate, Paclitaxel, Doxorubicin Hydrochloride, and Cyclophosphamide Before Surgery in Treating Patients With Stage IIB-IIIC Breast Cancer

Phase 2

Completed

Conditions: Stage II Breast Cancer
Inflammatory Breast Cancer
Male Breast Cancer
Stage IIIC Breast Cancer
Stage IIIA Breast Cancer
Stage IIIB Breast Cancer

Interventions: Drug: sunitinib malate
Drug: paclitaxel
Drug: doxorubicin hydrochloride
Drug: cyclophosphamide
Biological: filgrastim
Procedure: therapeutic conventional surgery
Other: laboratory biomarker analysis
Other: flow cytometry

Registration Number: NCT00513695

Lead Sponsor: University of Washington

Brief Summary: This phase II trial studies how well giving sunitinib malate together with paclitaxel, doxorubicin hydrochloride, and cyclophosphamide before surgery works in treating patients with stage IIB-IIIC breast cancer. Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor. Drugs used in chemotherapy, such as paclitaxel, doxorubicin hydrochloride, and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving sunitinib malate together with combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed

Detailed Description: PRIMARY OBJECTIVES:

I.To assess the microscopic pathologic complete response rate (pCR) in patients treated with a two part, neoadjuvant regimen consisting of daily oral sunitinib with weekly IV paclitaxel for 12 weeks followed by weekly doxorubicin and daily oral cyclophosphamide given with filgrastim (G-CSF) support for 15 weeks.

SECONDARY OBJECTIVES:

I. To assess the association between microscopic pCR and clinical complete response rate at the primary tumor site.

II. To assess the relapse rate, overall and disease-free survival in patients with breast cancer treated with neoadjuvant chemotherapy consisting of daily oral sunitinib with weekly IV paclitaxel for 12 weeks followed weekly doxorubicin and daily oral cyclophosphamide given with G-CSF support for 15 weeks.

III. To assess the toxicity associated with these regimens. IV. To explore the relationship between planned correlative laboratory and clinical studies and indicators of efficacy such as pathologic response, clinical response and relapse.

OUTLINE:

Patients receive neoadjuvant chemotherapy comprising sunitinib malate orally (PO) once daily and paclitaxel intravenously (IV) over 1 hour once weekly for 8-12 weeks in the absence of disease progression or unacceptable toxicity. Beginning within 3 weeks of completion of sunitinib malate and paclitaxel, patients receive doxorubicin IV once weekly for 15 weeks, cyclophosphamide PO once daily for 15 weeks, and filgrastim subcutaneously (SC) on days 2-7 for 16 weeks in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo surgery.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 68

Inclusion Criteria

Be informed of the investigational nature of the study and all pertinent aspects of the trial and must sign and give written consent in accordance with institutional and federal guidelines
Have a histologically-confirmed diagnosis of breast cancer that is locally advanced or inflammatory; inflammatory breast cancer is defined as erythema and peau d'orange involving half or more of the breast with a histologic diagnosis of breast cancer; the finding of focal dermal lymphatic involvement on histology does not constitute inflammatory breast cancer
Have selected stage IIB (T3, N0, M0) or IIIA (T3, N1-2, M0 or T0-2, N2, M0) disease judged primarily unresectable by an experienced breast surgeon or otherwise deemed appropriate candidates for neoadjuvant treatment or stage IIIB (T4, any N, M0) or stage IIIC (any T, N3, M0) disease
Patients must have a performance status of 0-2 by Zubrod criteria
Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
Platelet count >= 100,000 cells/mm^3
Serum creatinine =< 1.5 x institutional upper limit of normal (IULN)
Bilirubin =< 2.0
Serum glutamic oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT)/alkaline phosphatase =< 2.0 x IULN
Have a multi gated acquisition scan (MUGA) or echocardiogram scan performed within 3 months prior to enrollment and have a left ventricular ejection fraction (LVEF) % greater than the institutional lower limit of normal
Be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures

Exclusion Criteria

Have evidence of distant metastases
Have tumors that overexpress human epidermal growth factor receptor 2 (HER2)/neu as evidenced by 3+ staining by immunohistochemistry or gene amplification by fluorescent in situ hybridization (FISH)
Have received any prior chemotherapy or hormonal therapy for breast cancer
Have received prior radiation therapy or prior definitive surgery for breast cancer
Have a clinical diagnosis of congestive heart failure or angina pectoris or any of the following within the 6 months prior to study drug administration:, myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, or pulmonary embolism
Have ongoing cardiac dysrhythmias of National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0 grade >= 2
Have uncontrolled hypertension (>150/100 mm Hg despite optimal medical therapy)
Have pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal range with medication
Have a known, active infection
Have any prior malignancy except for adequately treated basal cell or squamous cell skin cancer, any in situ cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission or any other cancer from which the patient has been disease-free for 5 years
Human immunodeficiency virus (HIV) positive
Are receiving or planning to receive any concurrent anticancer therapy while receiving protocol treatment
Are receiving or planning to receive concurrent treatment on another clinical trial (supportive care trials or non-treatment trials, e.g. quality of life (QOL) are allowed; participation in the companion imaging trial, dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and fludeoxyglucose F 18 positron emission tomography (FDG PET) with Kinetic Analysis to Monitor Breast Cancer Response to Neoadjuvant Sunitinib and Metronomic Chemotherapy is also allowed)
Be pregnant or breast feeding; female subjects must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy; all female subjects with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment; male subjects must be surgically sterile or must agree to use effective contraception during the period of therapy; the definition of effective contraception will be based on the judgment of the principal investigator or a designated associate
Have other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (neoadjuvant chemotherapy before surgery)	laboratory biomarker analysis	Patients receive neoadjuvant chemotherapy comprising sunitinib malate PO once daily and paclitaxel IV over 1 hour once weekly for 8-12 weeks in the absence of disease progression or unacceptable toxicity. Beginning within 3 weeks of completion of sunitinib malate and paclitaxel, patients receive doxorubicin IV once weekly for 15 weeks, cyclophosphamide PO once daily for 15 weeks, and filgrastim SC on days 2-7 for 16 weeks in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo surgery.
Treatment (neoadjuvant chemotherapy before surgery)	filgrastim	Patients receive neoadjuvant chemotherapy comprising sunitinib malate PO once daily and paclitaxel IV over 1 hour once weekly for 8-12 weeks in the absence of disease progression or unacceptable toxicity. Beginning within 3 weeks of completion of sunitinib malate and paclitaxel, patients receive doxorubicin IV once weekly for 15 weeks, cyclophosphamide PO once daily for 15 weeks, and filgrastim SC on days 2-7 for 16 weeks in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo surgery.
Treatment (neoadjuvant chemotherapy before surgery)	therapeutic conventional surgery	Patients receive neoadjuvant chemotherapy comprising sunitinib malate PO once daily and paclitaxel IV over 1 hour once weekly for 8-12 weeks in the absence of disease progression or unacceptable toxicity. Beginning within 3 weeks of completion of sunitinib malate and paclitaxel, patients receive doxorubicin IV once weekly for 15 weeks, cyclophosphamide PO once daily for 15 weeks, and filgrastim SC on days 2-7 for 16 weeks in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo surgery.
Treatment (neoadjuvant chemotherapy before surgery)	flow cytometry	Patients receive neoadjuvant chemotherapy comprising sunitinib malate PO once daily and paclitaxel IV over 1 hour once weekly for 8-12 weeks in the absence of disease progression or unacceptable toxicity. Beginning within 3 weeks of completion of sunitinib malate and paclitaxel, patients receive doxorubicin IV once weekly for 15 weeks, cyclophosphamide PO once daily for 15 weeks, and filgrastim SC on days 2-7 for 16 weeks in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo surgery.
Treatment (neoadjuvant chemotherapy before surgery)	sunitinib malate	Patients receive neoadjuvant chemotherapy comprising sunitinib malate PO once daily and paclitaxel IV over 1 hour once weekly for 8-12 weeks in the absence of disease progression or unacceptable toxicity. Beginning within 3 weeks of completion of sunitinib malate and paclitaxel, patients receive doxorubicin IV once weekly for 15 weeks, cyclophosphamide PO once daily for 15 weeks, and filgrastim SC on days 2-7 for 16 weeks in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo surgery.
Treatment (neoadjuvant chemotherapy before surgery)	paclitaxel	Patients receive neoadjuvant chemotherapy comprising sunitinib malate PO once daily and paclitaxel IV over 1 hour once weekly for 8-12 weeks in the absence of disease progression or unacceptable toxicity. Beginning within 3 weeks of completion of sunitinib malate and paclitaxel, patients receive doxorubicin IV once weekly for 15 weeks, cyclophosphamide PO once daily for 15 weeks, and filgrastim SC on days 2-7 for 16 weeks in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo surgery.
Treatment (neoadjuvant chemotherapy before surgery)	doxorubicin hydrochloride	Patients receive neoadjuvant chemotherapy comprising sunitinib malate PO once daily and paclitaxel IV over 1 hour once weekly for 8-12 weeks in the absence of disease progression or unacceptable toxicity. Beginning within 3 weeks of completion of sunitinib malate and paclitaxel, patients receive doxorubicin IV once weekly for 15 weeks, cyclophosphamide PO once daily for 15 weeks, and filgrastim SC on days 2-7 for 16 weeks in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo surgery.
Treatment (neoadjuvant chemotherapy before surgery)	cyclophosphamide	Patients receive neoadjuvant chemotherapy comprising sunitinib malate PO once daily and paclitaxel IV over 1 hour once weekly for 8-12 weeks in the absence of disease progression or unacceptable toxicity. Beginning within 3 weeks of completion of sunitinib malate and paclitaxel, patients receive doxorubicin IV once weekly for 15 weeks, cyclophosphamide PO once daily for 15 weeks, and filgrastim SC on days 2-7 for 16 weeks in the absence of disease progression or unacceptable toxicity. Beginning 3-6 weeks after completion of chemotherapy, patients undergo surgery.

Primary Outcome Measures

Name	Time	Method
Microscopic Pathologic CR (pCR) Rate	At the time of surgery	Defined as no evidence of microscopic invasive tumor present at primary tumor site in the surgical specimen and calculated with exact 90% binomial confidence interval.

Secondary Outcome Measures

Name	Time	Method
Relapse Rate	Up to two years	Cumulative incidence rate of relapse, assessed at two years. Death is considered a competing risk.
Overall Survival	Up to 2 years	Kaplan-Meier estimate from the start of protocol therapy until the date of death from any cause or the last date the patient was known to be alive, assessed at two years.
Clinical Complete Response and Correlation With Plasma VEGF, Soluble VCAM (sVCAM), and Circulating Endothelial Cells (CECs) Levels	At baseline, after week 12 of therapy, and prior to surgery
Time to Disease Progression	Up to 2 years	Median time to disease progression, at two years, as defined by clear increase in disease sites present at registration or development of new disease sites.
Number and Percent of Subjects Reporting Adverse Events	28 days after the last dose of study drug	See Adverse Events section for more details.

Trial Locations

Locations (7): Skagit Valley Hospital
🇺🇸
Mount Vernon, Washington, United States
Olympic Medical Center
🇺🇸
Port Angeles, Washington, United States
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
🇺🇸
Seattle, Washington, United States
Saint Luke's Mountain States Tumor Institute
🇺🇸
Boise, Idaho, United States
Katmai Oncology Group
🇺🇸
Anchorage, Alaska, United States
Arizona Cancer Center
🇺🇸
Tucson, Arizona, United States
Anchorage Oncology Centre
🇺🇸
Anchorage, Alaska, United States