Pazopanib in Treating Patients With Recurrent or Metastatic Breast Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well giving pazopanib works in treating patients with recurrent or metastatic invasive breast cancer. Pazopanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the antitumor activity of pazopanib, in terms of objective response rate (partial and complete response), in patients with recurrent or metastatic invasive breast cancer. SECONDARY OBJECTIVES: I. To determine the duration of objective response, rate and duration of stable disease. II. To determine 6-month progression-free and median and overall survival rates in patients treated with this drug. III. To document the safety and tolerability of this drug in these patients. OUTLINE: This is a multicenter, open label study. Patients receive oral pazopanib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Blood samples are collected at baseline and at 1, 4, and 8 weeks for correlative laboratory studies. Blood samples are evaluated for the following tumor markers by ELISA: VEGF, bFGF, sFLT-1, sTIE-2, sE-Selectin, VCAM-1, PDGF-AA, PDGF-AB and PDGF-BB. TSP-1 in plasma is measured by Accucyte™ competitive immunoassay. After completion of study treatment, patients are followed every 3 months.

Official Title
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A Phase 2 Study of GW786034 (Pazopanib) in Patients With Recurrent and/or Metastatic Invasive Breast Carcinoma

Conditions
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Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: pazopanib hydrochloride
* Procedure: pharmacological study
* Procedure: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Criteria: No prior bevacizumab Histologically or cytologically confirmed invasive breast carcinoma (recurrent or metastatic disease) Measurable disease, defined as >= 1 unidimensionally measurable lesion >= 20 mm by conventional techniques or >= 10 mm by spiral CT scan Patients who may still benefit from hormonal therapy are ineligible (patients with hormone receptor-positive breast cancer should have received appropriate sequential hormonal therapy for metastatic disease until disease progression) Patients with HER-2 positive disease who have not yet received trastuzumab (Herceptin®) to maximal benefit are ineligible (patients with disease progression during trastuzumab therapy are eligible) No known brain metastases ECOG performance status (PS) 0-1 or Karnofsky PS 60-100% Life expectancy > 12 weeks Absolute neutrophil count >= 1,500/mm³ Platelets >=100,000/mm³ Total bilirubin normal (exception made for patients with known Gilbert's disease) AST/ALT =< 2.5 times upper limit of normal (ULN) No proteinuria > +1 on two consecutive dipsticks taken >= 1 week apart PT/INR/PTT =< 1.2 times ULN No allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib or other study agents No QTc prolongation (defined as a QTc interval >= 500 msecs) or other significant ECG abnormalities No condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, or active peptic ulcer disease) that would impair ability to swallow and retain study drug No poorly controlled hypertension (systolic blood pressure [BP] >= 140 mm Hg or diastolic BP >= 90 mm Hg) Initiation or adjustment of BP medication is allowed prior to study entry provided that the average of 3 BP readings prior to study entry is < 140/90 mm Hg No serious or non-healing wound, ulcer, or bone fracture No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the last 4 weeks No cerebrovascular accident within the last 6 months No myocardial infarction, cardiac arrhythmia, hospital admission for unstable angina within the last 12 weeks No venous thrombosis within the last 12 weeks No NYHA class III-IV heart failure Patients with a history of class II heart failure may be considered eligible provided they are asymptomatic on treatment No concurrent uncontrolled illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would preclude study compliance Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C), radiotherapy, or surgery No cardiac angioplasty or stenting within the last 12 weeks No more than 1 prior chemotherapy regimen for recurrent disease No prior surgical procedures affecting absorption No CYP2C9 substrates during or for 1-2 weeks after completion of study treatment, including any of the following: Therapeutic warfarin Low molecular weight heparin or prophylactic low-dose warfarin are allowed No CYP2C9 substrates during or for 1-2 weeks after completion of study treatment, including any of the following: Erectile dysfunction agents: sildenafil, tadalafil, or vardenafil Antiarrhythmics: bepridil, flecainide, lidocaine, mexilitine, amiodarone, or quinidine Immune modulators: cyclosporine, tacrolimus, or sirolimus Miscellaneous: theophylline, quetiapine, or risperidone No CYP2C9 substrates during or for 1-2 weeks after completion of study treatment, including any of the following: Oral hypoglycemics: glipizide, glyburide, or tolbutamide Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, or methylergonovine Neuroleptics: pimozide No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent investigational agents No other concurrent anticancer therapy WBC >= 3,000/mm³ No more than 2 prior palliative systemic chemotherapy regimens for de novo metastatic disease Creatinine normal OR creatinine clearance >= 60 mL/min At least 3 months since prior trastuzumab

Ages Eligible for Study
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Minimum Age: 18 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: Treatment (pazopanib hydrochloride)<br>Patients receive oral pazopanib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: pazopanib hydrochloride<br>* Given orally<br>* Other names: Votrient;Procedure: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Procedure: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Partial and Complete Response. | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT / MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Objective Response |  | From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 3 years | 
| Duration of Stable Disease |  | From the start of the treatment until the criteria for progression are met, assessed up to 3 years | 
| Progression-free Survival | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a nontarget lesion, or the appearance of new lesions | 6 months | 
| Overall Survival | Computed using the Kaplan-Meier method. | Up to 3 years | 
| Adverse Events Graded According to the NCI CTCAE Version 3.0 | grade 3- 4 toxicities - transaminitis, hypertension, and neutropenia in three patients each (14% each) and grade 3 gastrointestinal hemorrhage in one patient (5%). | Up to 3 years |