Pazopanib and ARQ 197 for Advanced Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01468922
First received: November 8, 2011
Last updated: August 2, 2014
Last verified: April 2014
  Purpose

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. 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.

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....

Condition Intervention Phase
Sarcoma
Stomach Neoplasms
Neoplasms
Drug: Pazopanib
Drug: ARQ 197
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Safety and tolerability of combination [ Time Frame: First cycle ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Changes in MET and phospho-MET [ Time Frame: Start of second cycle ] [ Designated as safety issue: No ]

Estimated Enrollment: 56
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)
Arms Assigned Interventions
Experimental: A
Combination pazopanib plus ARQ197 at doses established during escalation phase
Drug: Pazopanib
VEGFR inhibitor
Drug: ARQ 197
MET inhibitor

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 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.

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, 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.

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 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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • ELIGIBILITY CRITERIA:
  • Patients with histologically confirmed (by the Laboratory of Pathology, NIH) solid tumors that have progressed following at least one line of standard therapy or for whom no standard treatment options exist.
  • Patients must have measurable or evaluable disease.
  • Patients enrolling in the expansion cohorts must have disease amenable to biopsy, and be willing to undergo pre-and post-treatment biopsies.
  • Patients must have completed any chemotherapy, radiation therapy, or biologic therapy greater than or equal to 4 weeks prior to entering the study (6 weeks for nitrosoureas or mitomycin C). Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in a phase 0 or equivalent study. Patients must have recovered to eligibility levels from prior toxicity or adverse events. Treatment with bisphosphonates is permitted.
  • Patients who have had prior treatment with any anti-angiogenic therapy and/or c-MET inhibitor are eligible in the dose escalation phase unless the antiangiogenic therapy and/or c-MET inhibitor were administered within the 4 weeks prior to entering the study. In the expansion phase, prior c-MET inhibitor is not allowed, and anti-angiogenic therapy is allowed unless it was administered within the 3 months prior to entering the study.
  • Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of pazopanib in combination with ARQ 197 in patients less than 18 years of age, children are excluded from this study.
  • Life expectancy greater than 3 months.
  • ECOG performance status 0 or 1.
  • Patients must have normal organ and marrow function as defined below:

    • Absolute neutrophil count greater than or equal to 1,500/microL
    • Platelets greater than or equal to 100,000/microL
    • Total bilirubin less than or equal to 1.5 X institutional ULN
    • AST (SGOT)/ALT (SGPT) less than or equal to 2.5 X institutional ULN
    • Creatinine less than or equal to 1.5 mg/dL (133 mcmol/L); OR
    • Measured creatinine greater than or equal to 60 mL/minute for patients with clearance creatinine levels greater than 1.5 mg/dL
    • Urine protein/creatinine ratio less than 1 OR 24-hour urine protein less than 1 gram
  • Subjects who have both bilirubin greater than ULN and AST/ALT greater than ULN are not eligible.
  • Subjects in the expansion cohort must have PT/INR/PTT less than or equal to 1.2 X institutional ULN, except patients with confirmed positive lupus anticoagulant test.
  • Subjects must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90 mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication is permitted prior to study entry provided that the average of three BP readings at a visit prior to enrollment is less than 140/90 mmHg.
  • The effects of study drugs on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 2 months after dosing with study drugs ceases. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Women of child-bearing potential must have a negative pregnancy test prior to entry.
  • Patients must be able to swallow whole tablets or capsules. Nasogastric or G-tube administration is not allowed.
  • Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

  • 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 enzymeinducing anticonvulsant agents to other medications.
  • Certain medications that act through the 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 CYP3A4 such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinivir, retonavir, 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 CYP3A4, such as rifampin, may decrease pazopanib concentrations, are strictly prohibited.
    • Medications which have narrow therapeutic windows and are substrates of CYP3A4, CYP2D6, or CYP2C8 should be avoided and, if necessary, administered with caution.
    • Inhibitors or inducers of CYP2C19 should be avoided and, if necessary, administered with caution.
  • Cardiovascular baseline 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 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 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 physician s 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
  • coronary artery bypass graft surgery
  • pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks
  • arterial thrombosis
  • symptomatic peripheral vascular disease
  • Class III or IV heart failure as defined by the NYHA functional classification system. A subject who has a history of Class II heart failure and is asymptomatic on treatment may be considered eligible

    • History of serious or non-healing wound, ulcer, or bone fracture.
    • Patients who received major surgery within the past 4 weeks
    • Subjects with any condition that may impair the ability to swallow or absorb oral medications/investigational product including:
  • any lesion, whether induced by tumor, radiation or other conditions, which makes it difficult to swallow capsules or pills
  • prior surgical procedures affecting absorption including, but not limited to major resection of stomach or small bowel
  • active peptic ulcer disease
  • malabsorption syndrome

    -Subjects with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including

  • active peptic ulcer disease
  • known intraluminal metastatic lesions
  • inflammatory bowel disease (e.g., ulcerative colitis, Crohn s disease) or other gastrointestinal conditions which increase the risk of perforation
  • history of abdominal fistula, gastrointestinal perforation or intraabdominal abscess within 28 days prior to beginning study treatment

    • History of hemoptysis in excess of 2.5 mL (1/2 teaspoon ) within 8 weeks prior to first dose of study drug.
    • Urine protein/creatinine ratio should be screened by urine analysis. If protein is 1+ or higher, 24-hour urine protein should be obtained and the level should be less than 1g for patient enrollment. Patients with less than 1+ proteinuria are eligible following initial determination by urinalysis within 1 week prior to enrollment and do not need the urinalysis repeated.
    • Patients with clinically significant intercurrent illnesses, including but not limited to, life threatening infection, psychiatric illness/social situations that would limit compliance with study requirements will not be eligible to participate.
    • Pregnant women are excluded from this study because the effects of the study drugs on the developing fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study drugs, breastfeeding should be discontinued prior to the first dose of study drug and women should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.
    • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for PK interactions.
    • Patients who require use of coumarin-derivative anticoagulants such as warfarin are excluded. Low molecular weight heparin is permitted for prophylactic use, but not therapeutic use.

INCLUSION OF WOMEN AND MINORITIES:

Both men and women of all races and ethnic groups are eligible for this trial.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01468922

Contacts
Contact: Ramya Antony (301) 594-4949 parthasarathyr@mail.nih.gov
Contact: Shivaani Kummar, M.D. (301) 435-0517 kummars@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Shivaani Kummar, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT01468922     History of Changes
Other Study ID Numbers: 120009, 12-C-0009
Study First Received: November 8, 2011
Last Updated: August 2, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Pazopanib
Tivantinib
MET Inhibitor
Advanced Cancer
Anti-Angiogenesis
Cancer
Solid Tumor
Sarcoma

Additional relevant MeSH terms:
Neoplasms
Stomach Neoplasms
Sarcoma
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Stomach Diseases
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on August 27, 2014