Pazopanib Hydrochloride Followed by Chemotherapy and Surgery in Treating Patients With Soft Tissue Sarcoma

PRIMARY OBJECTIVES:

I. To determine the absolute values and changes in standardized uptake values (SUV) by
fludeoxyglucose F18 (FDG)-positron emission tomography (PET) before and after a 14 day Run-in
period of pazopanib (pazopanib hydrochloride) versus placebo, and to compare this to the
change in SUV following pre-operative chemotherapy.

II. To evaluate the correlation between antiangiogenic activity and pazopanib drug exposure.

III. To assess the response rate by Response Evaluation Criteria In Solid Tumors (RECIST)
criteria after the 14 day Run-in period of pazopanib versus placebo and compare this to the
response rate following pre-operative chemotherapy.

SECONDARY OBJECTIVES:

I. To examine the activity of antiangiogenic therapy with pazopanib combined with
pre-operative chemotherapy for high risk extremity soft tissue sarcomas as measured by:
histological necrosis at surgery; change in plasma and tumor biomarker assays of angiogenesis

II. To evaluate the safety of sequential treatment with pazopanib and pre-operative
chemotherapy with doxorubicin (doxorubicin hydrochloride) and ifosfamide.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive pazopanib hydrochloride orally (PO) once daily (QD). Treatment
continues for 14 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO QD. Treatment continues for 14 days in the absence of
disease progression or unacceptable toxicity.

All patients then receive neoadjuvant chemotherapy comprising doxorubicin hydrochloride
intravenously (IV) continuously over days 1-3 and ifosfamide IV on days 1-5. Treatment
repeats every 21 days for 4 courses. Beginning 2-4 weeks later, all patients undergo surgery
followed by 2 more courses of chemotherapy 2-4 weeks after completion of surgery. Some
patients may also undergo adjuvant external beam radiation therapy 5 days a week for 5 days
followed by a boost. Patients treated on Arm I may resume pazopanib hydrochloride 1 week
after completion of all adjuvant therapy for up to 1 year. Treatment continues in the absence
of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Inclusion Criteria:

- Histologically or cytologically confirmed soft-tissue sarcoma, excluding alveolar and
embryonal rhabdomyosarcoma, well- and dedifferentiated adipocytic sarcomas, Ewing's,
osteosarcoma, or gastrointestinal stromal tumor; American Joint Committee on Cancer
(AJCC) (6th Edition) Stage III or T2a Stage II or Stage IV treatment naive patients
planned for resection of the primary tumor, with resectable metastatic disease

- Measurable disease greater than 5 centimeters in greatest dimension; measurable
lesions are defined as those that can be accurately measured in at least one dimension
(longest diameter for non-nodal lesions and short axis for nodal lesions to be
recorded) by chest x-ray, computed tomography (CT) scan, magnetic resonance imaging
(MRI) or with calipers by clinical exam; all tumor measurements must be recorded in
millimeters (or decimal fractions of centimeters)

- Intermediate or high grade lesions: 2 or 3 on a scale of 1-3 or grades 2 to 4 on a
scale of 1-4

- Sarcoma located on upper (includes shoulder) or lower (includes hip) extremities or on
the body wall

- Life expectancy of greater than 6 months

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Karnofsky >= 80%

- No prior chemotherapy, radiotherapy, or antiangiogenic therapy

- Absolute neutrophil count (ANC) >= 1500/uL

- Hemoglobin (Hgb) >= 9.0 g/dL

- Platelets >= 100,000/uL

- Creatinine =< 1.5 x upper limit of normal (ULN)

- Bilirubin =< 1.5 mg/dL

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 x ULN

- Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time
(PTT) within 1.2 X the ULN unless a subject is receiving Coumadin and has stable INR
which is in range for the desired level of anticoagulation

- Left ventricular ejection fraction (LVEF) >= 50%

- Blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for
eligibility; initiation or adjustment of BP medication is permitted prior to study
entry provided that the average of three BP readings on baseline assessment prior to
enrollment is less than 140/90 mmHg

- Eligibility of subjects receiving any medications or substances known to affect or
with the potential to affect the activity or pharmacokinetics of pazopanib will be
determined following review of their cases by the Principal Investigator

- Women of child-bearing potential and men must agree to use adequate contraception

- A female is eligible to enter and participate in this study if she is of
non-childbearing potential (i.e., physiologically incapable of becoming pregnant) or
if she is of childbearing potential

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Subjects with known brain metastases and/or unresectable sarcoma

- Uncontrolled intercurrent illness including, active serious infection, symptomatic
congestive heart failure, unstable angina pectoris, cardiac ventricular arrhythmia
requiring anti-arrhythmic therapy, serious hepatic impairment, or psychiatric
illness/social situations that would limit compliance with study

- Pregnant or lactating women

- Subjects with no additional active malignancy within the last 3 years

- Subjects receiving other investigational agents

- Subjects with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to pazopanib or other agents used in the study

- Subjects who have both bilirubin > ULN and AST/ALT > ULN

- Subjects with a urine protein/creatinine ratio greater than 1

- Subjects with a baseline corrected QT (QTc) of equal to or greater than 480 msecs or
other significant electrocardiogram (ECG) abnormalities

- Certain medications that act through the cytochrome P450 (CYP450) system are
specifically prohibited in subjects receiving pazopanib and others should be avoided
or administered with extreme caution and require principal investigator (PI) approval

- Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin,
atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
telithromycin, voriconazole may increase pazopanib concentrations and are
prohibited; grapefruit juice is also an inhibitor of CYP450 and should not be
taken with pazopanib

- Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib
concentrations, are prohibited

- Medications which have narrow therapeutic windows and are substrates of CYP3A4,
CYP2D6, or CYP2C8 should be avoided and, if necessary, administered with caution

- Pazopanib, 800 mg once daily, has no effect on CYP2C9, CYP1A2, or CYP2C19 in vivo
but does in vitro; therefore, therapeutic doses of warfarin, a substrate of
CYP2C9, and omeprazole, a substrate of CYP2C19 are permitted; caffeine, a
substrate of CYP1A2, is also permitted

- Certain medications that are associated with a risk for QTc prolongation and/or
Torsades de Pointes, although not prohibited, should be avoided or replaced with
medications that do not carry these risks, if possible

- Subjects who require heparin other than low-molecular weight heparin

- Subjects with any condition that may impair the ability to swallow or absorb oral
medications/investigational product including:

- Any lesion, whether induced by tumor, radiation or other conditions, which makes
it difficult to swallow capsules or pills

- Prior surgical procedures affecting absorption including, but not limited to
major resection of stomach or small bowel

- Active peptic ulcer disease, not on a proton pump inhibitor

- Malabsorption syndrome

- Subjects with any condition that may increase the risk of gastrointestinal bleeding or
gastrointestinal perforation, including

- Active peptic ulcer disease, not on a proton pump inhibitor

- Known intraluminal metastatic lesions

- Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or

- Other gastrointestinal conditions which increase the risk of perforation

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal
abscess within 28 days prior to beginning study treatment

- Subjects with any of the following cardiovascular conditions within the past 6 months:

- Cerebrovascular accident (CVA) or transient ischemic attack (TIA)

- Cardiac arrhythmia

- Admission for unstable angina

- Cardiac angioplasty or stenting

- Coronary artery bypass graft surgery

- Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been
treated with therapeutic anticoagulation for less than 6 weeks

- Arterial thrombosis

- Symptomatic peripheral vascular disease

- Class III or IV heart failure as defined by the New York Heart Association (NYHA)
functional classification system; a subject who has a history of Class II heart
failure and is asymptomatic on treatment may be considered eligible

- History of hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to
first dose of study drug

- History of serious or non-healing wound, ulcer, or bone fracture

- Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral
therapy are ineligible

- Subjects with severe hepatic impairment

- Bilirubin > 3 x ULN, regardless of any level of ALT