A Phase I and Pharmacokinetic Single Agent Study of Pazopanib in Adults With Advanced Malignancies and Varying Degrees of Liver Dysfunction
- 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.
- 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
- 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.
- 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.
- 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.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To establish the MTD and DLT of pazopanib in groups of patients with varying degrees of hepatic dysfunction (mild, moderate, and severe) to provide appropriate dosing recommendations for panzopanib in such patients.
Luigi Ferrucci, M.D.
National Institute on Aging (NIA)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|City of Hope National Medical Center||Los Angeles, California 91010|