Pazopanib and ARQ 197 for Advanced Solid Tumors
Condition: Solid Tumor
MeSH terms: Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      Background:

      - Pazopanib is an anticancer drug that blocks the growth of new blood vessels in tumors. It
      has been approved to treat renal cell cancer and soft tissue sarcomas in patients who have
      received prior chemotherapy. ARQ 197 (Tivantinib) is an experimental drug that blocks a
      protein called mesenchymal-epithelial transition factor (c-MET), which cancer cells need to
      grow. Studies suggest that some drugs that block blood vessel growth can increase the
      production of c-MET in tumors, which helps cancer cells keep growing. Blocking both blood
      vessel growth and c-MET with pazopanib and ARQ 197 may help kill cancer cells faster. This
      study will use these drugs to treat solid tumors that have not responded to earlier
      treatments.

      Objectives:

      - To test the safety and effectiveness of pazopanib and ARQ 197 for advanced solid tumors.

      Eligibility:

      - Individuals at least 18 years of age who have advanced solid tumors that have not responded
      to earlier treatments.

      Design:

        -  Participants will be screened with a physical exam and medical history. They will also
           have blood and urine tests, and imaging studies.

        -  The study drugs will be given in 4-week cycles of treatment. Participants will take
           pazopanib once a day and ARQ 197 twice a day by mouth. Some participants will start with
           pazopanib or ARQ 197 alone for the first week. Then they will take both drugs together
           for the rest of the study.

        -  Participants will be monitored with frequent blood tests and imaging studies. Optional
           tumor samples may be collected during different treatment cycles.
    

Detailed description: 
      Background:

        -  Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) signal
           transduction pathways have synergistic effects on promoting angiogenesis and growth
           factor expression. Hypoxia caused by treatment with VEGF inhibitors results in the
           upregulation of mesenchymal-epithelial transition factor (c-MET), the receptor for HGF.
           In a mouse model, combined blockade of VEGFR and c-MET significantly prolonged survival
           compared with inhibition of either target alone.

        -  We hypothesize that co-administration of the putative hepatocyte growth factor receptor
           (MET) inhibitor ARQ 197 (Tivantinib) will prevent the adaptive response to hypoxia
           resulting from treatment with the VEGFR inhibitor pazopanib, and conversely, that
           co-administration of pazopanib will prevent the effect of increased VEGF and reduced
           thrombospondin 1 in tumors after treatment with ARQ 197. Therefore, the combination of
           these agents may result in improved antitumor effects.

      Objectives:

        -  Establish the safety and tolerability of the combination of pazopanib with ARQ 197 in
           patients with refractory advanced solid tumors.

        -  Establish the maximum tolerated dose (MTD) of the combination of pazopanib with ARQ 197
           in patients with refractory advanced solid tumors.

        -  Evaluate changes in MET and phospho-MET following treatment with pazopanib and ARQ 197
           in patients with refractory advanced solid tumors.

        -  Determine the pharmacokinetics (PK) of pazopanib and ARQ 197.

        -  Determine and compare levels of total MET, phospho MET, Hypoxia-Inducible Factor
           (HIF)-1, and epithelial-mesenchymal transition markers (e-cadherin, beta catenin) in
           tumor biopsy samples prior to and following administration of the study drugs.

        -  Determine and compare levels of circulating levels of hepatocyte growth factor (HGF),
           soluble MET (sMET), vascular endothelial growth factor A (VEGF-A), and soluble vascular
           endothelial growth factor receptor 2 (VEGFR2) (sVEGFR2) prior to and following
           administration of the study drugs.

        -  Determine polymorphisms in the cytochrome P450 2C19 (CYP2C19) and correlate these with
           the observed toxicities, and the pharmacokinetics (PK) of ARQ 197.

        -  Evaluate antitumor activity of the combination of pazopanib and ARQ 197 in patients with
           refractory advanced solid tumors.

      Eligibility:

      -Adults with advanced, refractory solid tumors. Patients enrolling in the expansion cohorts
      must have advanced sarcoma, gastric cancer, and MET-expressing malignancies, have disease
      amenable to biopsy, and be willing to undergo pre-and post-treatment biopsies.

      Study Design:

        -  ARQ 197 will be administered orally twice daily and pazopanib orally once daily, in
           28-day cycles.

        -  Dose escalation will proceed using the traditional 3+3 design.

        -  Once the maximum tolerated dose (MTD) is established, an additional cohort will be
           accrued for pharmacodynamic (PD) studies in tumor biopsies (required in the expansion
           phase). For the first week, patients will receive pazopanib alone to compare PK and PD
           results; combination therapy will be given from week 2 onwards.
    

Intervention name(s): Pazopanib; ARQ 197
Intervention type(s): Drug; Drug
Intervention description(s): Vascular endothelial growth factor (VEGFR) inhibitor; Hepatocyte growth factor receptor (mesenchymal-epithelial transition factor [c-MET]) inhibitor
Other intervention name(s): Votrient; Tivantinib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Pazopanib; Tivantinib; MET Inhibitor; Advanced Cancer; Anti-Angiogenesis; Cancer; Solid Tumor; Sarcoma