Pazopanib Hydrochloride in Treating Patients With Advanced or 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