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Solid TumorPhase 1NCT01468922

Pazopanib and ARQ 197 for Advanced Solid Tumors

A Phase 1 study testing Pazopanib and ARQ 197 in people with Solid Tumor, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 120 years
Conditions the study is for
Solid Tumor
What is being tested?
Pazopanib and ARQ 197
Could I receive a placebo?
No, everyone receives an active treatment
How many people
32 participants
Where
1 siteUnited States
Study dates
23 Jan 2012to 11 Feb 2016
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 120 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

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

Who cannot join

  • 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.
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  • 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
  • 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 New York Heart Association (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.
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic (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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

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

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.
Read more

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.
Read the 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.
Conditions
Solid Tumor
Being tested
Pazopanib, ARQ 197
Keywords
Pazopanib, Tivantinib, MET Inhibitor, Advanced Cancer, Anti-Angiogenesis, Cancer, Solid Tumor, Sarcoma
Medical subject headings
Neoplasms, Sarcoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PazopanibDrug

    Also called Votrient

    Vascular endothelial growth factor (VEGFR) inhibitor

  • ARQ 197Drug

    Also called Tivantinib

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

Study groups in NCT01468922
Study groupRoleWhat they receive
A/Combination pazopanib plus ARQ 197 (Tivantinib)ExperimentalCombination pazopanib plus ARQ197 at doses established during escalation phase
Receives: Drug: Pazopanib; Drug: ARQ 197

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Time receiving study drug, up to 22 cycles

  2. 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).

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Nov 2011 (estimated)
  2. Study start23 Jan 2012
  3. Primary completion30 Sep 2014
  4. Study completion11 Feb 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
32 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01468922
Sponsor's protocol ID
120009
Other IDs
12-C-0009
Status last verified
Jun 2022
First submitted
8 Nov 2011
Last updated
1 Jul 2022
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 14504135

  • 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.

    PubMed 11238059

  • 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.

    PubMed 9468212

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Pazopanib and ARQ 197 in people with Solid Tumor, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 38 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Jul 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Jul 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Grade 3 or 4 Adverse Events, Highest Occurrence Per Participant (time frame: Time receiving study drug, up to 22 cycles). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01468922, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jul 2022.

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