Pazopanib and ARQ 197 for Advanced Solid Tumors
- Pazopanib is an anticancer drug that blocks the growth of new blood vessels in tumors. It has been approved to treat renal cell cancer. ARQ 197 is an experimental drug that blocks a protein called 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.
- To test the safety and effectiveness of pazopanib and ARQ 197 for advanced solid tumors.
- Individuals at least 18 years of age who have advanced solid tumors that have not responded to earlier treatments.
- 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....
Drug: ARQ 197
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase Ib Study of the Combination of Pazopanib, an Oral VEGFR Inhibitor, and ARQ 197 (Tivantinib), an Oral MET Inhibitor, in Patients With Refractory Advanced Solid Tumors|
- Safety and tolerability of combination [ Time Frame: First cycle ] [ Designated as safety issue: Yes ]
- Changes in MET and phospho-MET [ Time Frame: Start of second cycle ] [ Designated as safety issue: No ]
|Study Start Date:||October 2011|
|Estimated Study Completion Date:||March 2016|
|Estimated Primary Completion Date:||March 2016 (Final data collection date for primary outcome measure)|
Combination pazopanib plus ARQ197 at doses established during escalation phase
VEGFR inhibitorDrug: ARQ 197
- 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 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 MET inhibitor ARQ 197 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.
- 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, 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 HGF, soluble MET (sMET), VEGF-A, and soluble VEGFR2 (sVEGFR2) prior to and following administration of the study drugs.
- Determine polymorphisms in the CYP2C19 and correlate these with the observed toxicities, and the PK of ARQ 197.
- Evaluate antitumor activity of the combination of pazopanib and ARQ 197 in patients with refractory advanced solid tumors.
-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.
- 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 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01468922
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Alice P Chen, M.D.||National Cancer Institute (NCI)|