Pazopanib in Treating Patients With Recurrent or Metastatic Breast Cancer

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.

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