Pazopanib to Treat Adults With Advanced Cancers and Varying Degrees of Liver Function

Background:

• Pazopanib is a potent, multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-alpha, PDGFR-beta, and c-kit with the potential to inhibit angiogenesis, lymphangiogenesis, and tumor growth that may have an advantage over agents with a narrower kinase specificity profile.
• Pazopanib has shown activity in renal cell cancer with tumor shrinkage and stable disease; Phase I, II, and III trials as single therapy and in combination with lapatinib are ongoing or planned in patients with various solid tumors.
• Pazopanib appears to be well tolerated at doses from 50 mg three times weekly to 2000 mg daily; the most common adverse events are hypertension, diarrhea, nausea, fatigue, and hair depigmentation.

Objectives:

• To establish the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of pazopanib in groups of patients with varying degrees of hepatic dysfunction (mild, moderate, and severe) in order to provide appropriate dosing recommendations for pazopanib in such patients.
• To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of pazopanib and metabolites (GSK1071306, GSK1268992, GSK1268997, and GW700201) in patients with varying degrees of hepatic dysfunction.
• To document the non-DLTs associated with administration of pazopanib in patients with hepatic dysfunction.
• To explore correlations of the Child-Pugh classification of hepatic dysfunction with the observed toxicities, plasma PK, and PD of pazopanib administration.
• To document any antitumor activity associated with pazopanib treatment of patients enrolled on this study.

Eligibility:

• Adult patients must have histologically or cytologically confirmed solid tumor or lymphoma that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
• Patients must have adequate renal and bone marrow function.

Study Design:

• Patients will be stratified into four cohorts according to their hepatic function.
• Pazopanib will be administered orally once daily on days 1-21 of a 21-day cycle.
• Blood samples for PK will be collected from all patients.
• A minimum of 2 and a maximum of 12 patients will be accrued in each liver dysfunction group at each dose, with 12 patients entered at the recommended dose level in each group. At least 12 patients will be accrued in the normal liver function group. The estimated maximum accrual is 132 patients, including all centers.

• INCLUSION CRITERIA:

For patients at the NCI, histological or cytological confirmation of solid tumor or lymphoma diagnosis will be performed at the NCI Laboratory of Pathology.

Exclusion criteria

Patients who have had prior treatment with pazopanib will not be eligible for this study.

Patients with abnormal liver function except grade 4 AST, grade 4 ALT, and grade 4 bilirubin will be eligible and will be grouped according to the criteria in Section 5.1. For assessing hepatic dysfunction, greater than 35 percent of the total bilirubin must be direct bilirubin.