Pazopanib to Treat Adults With Advanced Cancers and Varying Degrees of Liver Function
Condition: Neoplasms; Lymphoma
MeSH terms: Lymphoma
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

        -  Pazopanib is an experimental drug that was designed to enter cancer cells and block the
           activity of proteins that are important for cancer cell growth and survival.

        -  This is the first study in which pazopanib is given to patients with different degrees
           of liver function. The safe dose for patients with normal liver function is already
           known.

      Objectives:

        -  To determine the safety and side effects of pazopanib given at different dose levels to
           patients with cancer who have different degrees of liver function.

        -  To find out how much pazopanib is in the blood at specific times.

        -  To determine if pazopanib is effective in treating advanced cancer in patients with
           different degrees of liver function.

      Eligibility:

      - Patients 18 years of age and older with an advanced solid tumor or lymphoma that cannot be
      treated successfully with standard therapies and who have normal or abnormal liver function.

      Design:

        -  Treatment:

        -  Patients are divided into 4 groups, based on their liver function. The first three
           patients in each group receive a low dose of pazopanib. The next three in each group
           receive a higher dose of pazopanib if no serious side effects were reported in the
           previous three. The dose is increased in succeeding groups of three patients until the
           maximum study dose is reached.

        -  Patients take pazopanib once a day by mouth in 21-day treatment cycles. Treatment
           continues until the cancer worsens, the patient develops severe side effects, the
           patient no longer wants to continue the study, or the doctor removes the patient from
           the study for other reasons.

        -  Monitoring:

        -  Blood pressure: Patients monitor and record their blood pressure twice a day after
           starting treatment.

        -  Blood tests: Patients have weekly routine blood tests. In addition, at week 3 of the
           first cycle and again after the highest safe dose has been determined, several blood
           samples are collected at frequent intervals to determine how the body handles the drug.

        -  Imaging studies: X-rays or scans or both are done to measure the extent of disease every
           3 cycles.

        -  Physical examinations are done at periodic intervals.
    

Detailed description: 
      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.
    

Intervention name(s): Pazopanib; Pazopanib (GW786034)(GW786034)
Intervention type(s): Drug; Drug
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Pazopanib; Tyrosine Kinase Inhibitor; Advanced Cancer; Pharmacokinetics; Cancer; Solid Tumor; Lymphoma