Pazopanib and ARQ 197 for Advanced Solid Tumors

NCT01468922 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 12000912-C-0009
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Solid Tumor

Keywords

Pazopanib; Tivantinib; MET Inhibitor; Advanced Cancer; Anti-Angiogenesis; Cancer; Solid Tumor; Sarcoma

Outcome Measures

Primary Outcomes (2)

• Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant

  The highest Grade 3 or 4 adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 3 is severe, and Grade 4 is life threatening.

  Time receiving study drug, up to 22 cycles

• Changes in MET and Phospho-MET Levels

  MET or phospho-MET levels (in fmol) normalized to the amount of total protein in a sample (in mg).

  MET and phospho-MET levels were measured on Cycle 1 Day 1 and Cycle 1 Day 8.

Other Outcomes (2)

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)

  Date treatment consent signed to date off study, approx 22m (month)/2 days(d); 13m/20 d; 5m/23 d; 17m./24 d; 7 m/5 d; 5m/5 d; 5m/13 d; and 23m/21d for DL1, DL2, DL3, DL3 foll/by DL2, DL4, DL4 foll/by DL3, DL 4 foll/by DL 3 foll/by DL2; & DL5 respectively.

• Pazopanib-induced Changes to Epithelial-mesenchymal Phenotype in Human Tumors

  Pre-treatment and day 8 post administration

Study Arms (1)

A/Combination pazopanib plus ARQ 197 (Tivantinib)

EXPERIMENTAL

Combination pazopanib plus ARQ197 at doses established during escalation phase

Drug: Pazopanib; Drug: ARQ 197

Interventions

Pazopanib DRUG

Vascular endothelial growth factor (VEGFR) inhibitor

Also known as: Votrient

A/Combination pazopanib plus ARQ 197 (Tivantinib)

ARQ 197 DRUG

Hepatocyte growth factor receptor (mesenchymal-epithelial transition factor \[c-MET\]) inhibitor

Also known as: Tivantinib

A/Combination pazopanib plus ARQ 197 (Tivantinib)

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Patients who are receiving any other investigational agents.
• Patients with active brain metastases or carcinomatous meningitis are excluded from this clinical trial. Patients whose brain metastatic disease status has remained stable for greater than or equal to 4 weeks following treatment of the brain metastases are eligible to participate.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib or ARQ 197.
• Eligibility of subjects receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of pazopanib or ARQ 197 will be determined following review of their cases by the Principal Investigator. Efforts should be made to switch subjects with gliomas or brain metastases who are taking enzyme inducing anticonvulsant agents to other medications.
• Certain medications that act through the cytochromes P450 (CYP450) system are specifically prohibited in subjects receiving pazopanib and ARQ 197 and others should be avoided or administered with extreme caution.
• Strong inhibitors of cytochrome P450 3A4 (CYP3A4) such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole may increase pazopanib concentrations and are prohibited; although, in exceptional circumstances they may be administered in conjunction with lowering the dose of pazopanib by 50% of what would otherwise be administered. Grapefruit juice is also an inhibitor of CYP450 and should not be taken with pazopanib.
• Strong inducers of Cytochrome P450 Family 3 Subfamily A Member 4 (CYP3A4), such as rifampin, may decrease pazopanib concentrations, are strictly prohibited.
• Medications which have narrow therapeutic windows and are substrates of CYP3A4, cytochrome P450 2D6 CYP2D6), or cytochrome P₄₅₀2C8 (CYP2C8) should be avoided and, if necessary, administered with caution.
• Inhibitors or inducers of cytochrome P450 2C19 (CYP2C19) should be avoided and, if necessary, administered with caution.
• Cardiovascular baseline corrected QT Interval (QTc) greater than or equal to 480 msec will exclude patients from entry on study. Medications that may cause QTc interval prolongation are listed, and should be avoided by patients entering on trial. Patients for whom a given medication that may cause QTc interval prolongation cannot be discontinued may be eligible at the discretion of the study principal investigator (PI). A comprehensive list of agents with the potential to cause QTc prolongation can be found at http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm. (Note: If subjects must take medications with a risk or possible risk of Torsades de Pointes, they should be watched carefully for symptoms of Torsades de Pointes, such as syncope. Performing additional electrocardiograms (EKGs) on subjects who must take one or more of these medications is not required; however, additional investigations, including EKGs, may be performed as per the treating physicians judgment.)
• Subjects with any of the following cardiovascular conditions within the past 6 months:
• cerebrovascular accident (CVA) or transient ischemic attack (TIA)
• clinically significant bradycardia or other uncontrolled cardiac arrhythmia
• admission for unstable angina or myocardial infarction
• cardiac angioplasty or stenting

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Gerritsen ME, Tomlinson JE, Zlot C, Ziman M, Hwang S. Using gene expression profiling to identify the molecular basis of the synergistic actions of hepatocyte growth factor and vascular endothelial growth factor in human endothelial cells. Br J Pharmacol. 2003 Oct;140(4):595-610. doi: 10.1038/sj.bjp.0705494. Epub 2003 Sep 22.

  PMID: 14504135 BACKGROUND

• Xin X, Yang S, Ingle G, Zlot C, Rangell L, Kowalski J, Schwall R, Ferrara N, Gerritsen ME. Hepatocyte growth factor enhances vascular endothelial growth factor-induced angiogenesis in vitro and in vivo. Am J Pathol. 2001 Mar;158(3):1111-20. doi: 10.1016/S0002-9440(10)64058-8.

  PMID: 11238059 BACKGROUND

• Van Belle E, Witzenbichler B, Chen D, Silver M, Chang L, Schwall R, Isner JM. Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis. Circulation. 1998 Feb 3;97(4):381-90. doi: 10.1161/01.cir.97.4.381.

  PMID: 9468212 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Neoplasms; Sarcoma

Interventions

pazopanib; ARQ 197

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type

Results Point of Contact

• Title: Dr. Alice Chen
• Organization: National Cancer Institute

chenali@mail.nih.gov

240-781-3274

Study Officials

• Alice P Chen, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 8, 2011
• First Posted: November 10, 2011
• Study Start: January 23, 2012
• Primary Completion: September 30, 2014
• Study Completion: February 11, 2016
• Last Updated: July 1, 2022
• Results First Posted: July 1, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)