A Phase 2 Study of Pazopanib (GW786034) in Patients With Advanced and Progressive Malignant Pheochromocytoma or Paraganglioma

Inclusion Criteria:

- Histologically or cytologically confirmed unresectable malignant secretory or
non-secretory pheochromocytoma or paraganglioma

- Patients with secretory disease must receive alpha- and beta-adrenergic blockade
for at least 7 days before pazopanib hydrochloride (GW786034) administration

- Objective evidence of tumor progression in the 6-month period prior topazopanib
hydrochloride initiation as assessed by:

- Unequivocal progression of objectively measured disease on successive
appropriate imaging (e.g., CT scan)

- In cases of uncertainty of tumor progression, the Principal Investigator of the
study will be available to assist in decisions

- Measurable disease

- At least one non-nodal lesion whose longest diameter can be accurately measured as >=
2.0 cm with chest x-ray, or as >= 1.0 cm with CT scan, CT component of a PET/CT, or
MRI and/or a lymph node whose short axis must be > 1.5 cm when assessed by CT scan
(CT scan slice thickness recommended to be no greater than 5 mm)

- Note: Tumor lesions in a previously irradiated area are not considered
measurable disease

- Life expectancy > 24 weeks

- ECOG performance status ≤ 2

- Leukocytes >= 3,000/uL

- ANC ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 9 g/dL (5.6 mmol/L) transfusion not permitted ≤ 7 days of screening

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (except in cases of Gilbert
syndrome, where indirect bilirubin may be elevated, but the direct bilirubin remains
within 1.5 times ULN)*

- AST/ALT ≤ 2.5 times ULN*

- Alkaline phosphatase ≤ 2.5 times ULN

- Creatinine ≤ 1.5 mg/dL (133 μmol/L) or normal OR creatinine clearance ≥ 50 mL/min

- Urine protein/creatinine ratio ≤ 1 OR 24-hour urine < 1 gram

- Less than +1 proteinuria (< 30 mg/dL) on 2 consecutive assessments taken ≥ 1
week apart required

- PT/INR/PTT ≤ 1.2 times ULN (unless the patient is receiving coumadin and has stable
INR that is within range for the desired level of coagulation)

- Blood pressure (BP) < 140 mm Hg (systolic) and < 90 mm Hg (diastolic)

- Negative serum pregnancy test

- Not pregnant or nursing

- No men or women of childbearing potential who are unwilling to employ adequate
contraception

- Willingness to donate blood and tissue for correlative marker studies

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to pazopanib hydrochloride or other agents used in the study

- No QTc prolongation (defined as a QTc interval ≥ 480 msec) 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, prior surgical procedures
affecting absorption, or active peptic ulcer disease) that impairs their ability to
swallow and retain pazopanib hydrochloride

- None of the following conditions:

- Active peptic ulcer disease

- Known intraluminal bowel metastatic lesions

- Inflammatory bowel disease (e.g., ulcerative colitis, Crohn disease) or other
gastrointestinal conditions which increase the risk of perforation

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess ≤ 28 days prior to registration

- Serious or non-healing wound, ulcer, or bone fracture

- None of the following conditions ≤ 6 months from registration:

- 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 < 6 weeks

- Arterial thrombosis

- Symptomatic peripheral vascular disease

- Class III or IV heart failure as defined by the NYHA functional classification
system

- A subject who has a history of class II heart failure and is asymptomatic
on treatment may be considered eligible

- No hemoptysis in excess of 2.5 mL (½ teaspoon ) ≤ 8 weeks prior to registration

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements

- Not requiring heparin other than low-molecular weight heparin

- Recovered from prior therapy

- An unlimited number of prior chemotherapeutic or biologic therapies for this disease
allowed

- Prior antiangiogenic therapies (e.g., tyrosine kinase inhibitors) allowed

- More than 4 weeks since prior chemotherapy/systemic therapy (6 weeks for nitrosoureas
or mitomycin C)

- More than 4 weeks since prior radiotherapy

- More than 4 weeks since prior surgery

- No prior pazopanib hydrochloride

- No other concurrent investigational agents

- No concurrent CYP interactive medications such as:

- Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin,
atazanavir, indinavir, nefazodone, nelfinavir, retonavir, saquinavir,
telithromycin, voriconazole, or grapefruit juice

- Strong inducers of CYP450 such as rifampin

- No concurrent medications that are associated with a risk of QTc prolongation and/or
Torsades de Pointes

- No HIV-positive patients on combination antiretroviral therapy

- Not receiving any medications or substances known to affect or with the potential to
affect the activity or pharmacokinetics of pazopanib