I. To assess the anti-tumor activity (in terms of the tumor response rate using the RECIST criteria) of pazopanib (pazopanib hydrochloride) (GW786034) in patients with advanced malignant pheochromocytomas and paragangliomas.
SECONDARY OBJEC TIVES:
I. To assess safety profile of pazopanib. II. To assess duration of tumor response. III. To assess time to treatment failure. IV. To assess progression-free survival time. V. To assess overall survival time.
I. To examine the association between baseline CYP isoforms and the maximum pazopanib plasma level achieved during the first cycle of treatment.
II. To examine whether tumor response is associated with plasma pazopanib levels achieved during the first cycle of treatment or baseline CYP isoforms.
III. To examine whether severe toxicities leading to pazopanib dose reductions are associated maximum pazopanib level achieved during the first cycle of treatment or baseline CYP isoforms.
IV. To examine changes in urinary catecholamine and/or metanephrine levels. V. To examine whether pazopanib-induced changes in urinary catecholamine and/or metanephrine levels during the first cycle of treatment may be associated with objective tumor response.
VI. To examine associations between tumor response and somatic mutational status in archived tumors, or germline mutational status in patient's peripheral blood mononuclear cells, (presence of SDHD, SDHB, RET, VHL, neurofibromatosis type-1).
VII. To examine associations between tumor response and tumor expression levels of HIF-1a, VEGF-R (total and phospho-) and microvessel density.
OUTLINE: This is a multicenter study. Patients are stratified according to prior tyrosine kinase inhibitor (yes vs no). Patients receive pazopanib hydrochloride orally once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo urine and blood sample collection at baseline and periodically during study for correlative studies.
After completion of study therapy, patients are followed up every 3-6 months for a maximum of 3 years.
- 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
Last updated: 05/01/2013