Tivantinib in Treating Patients With Previously Treated Malignant Mesothelioma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01861301
First received: May 20, 2013
Last updated: October 2, 2014
Last verified: July 2014
  Purpose

This phase II trial studies how well tivantinib works in treating patients with previously treated malignant mesothelioma. Tivantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
Epithelial Mesothelioma
Recurrent Malignant Mesothelioma
Sarcomatous Mesothelioma
Stage II Malignant Mesothelioma
Stage III Malignant Mesothelioma
Stage IV Malignant Mesothelioma
Drug: tivantinib
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study of ARQ 197 in Patients With Previously-Treated Malignant Mesothelioma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Objective radiologic response rate (complete or partial response) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Time to disease progression [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Analyzed using the Kaplan-Meier method.

  • Overall survival [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Analyzed using the Kaplan-Meier method.

  • Incidence of adverse events, graded per NCI CTCAE version 4 [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]
    Toxicity will be summarized by type and grade.


Other Outcome Measures:
  • Change in baseline levels of continuous or ordinal markers (e.g., serum HGF/MET IHC) between responders and non-responders [ Time Frame: Baseline to 1 year ] [ Designated as safety issue: No ]
    Fisher's exact test will be performed for binary variables (e.g., presence/absence of MET gene amplification). Paired t-tests or Wilcoxon signed-ranks test, whichever is appropriate, will be used to examine the changes with treatment in the laboratory correlates that are continuous and McNemar's test will be used for binary markers.

  • Change in serum HGF or MET IHC and tumor size change (percent reduction in sum of longest diameters) [ Time Frame: Baseline to 1 year ] [ Designated as safety issue: No ]
    Will be evaluated by Spearman's rank correlation coefficient.

  • Association between baseline HGF, MET gene amplification, MET IHC and PFS [ Time Frame: Baseline to 1 year ] [ Designated as safety issue: No ]
    Will be evaluated using the Cox regression model.


Estimated Enrollment: 49
Study Start Date: January 2013
Estimated Primary Completion Date: February 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (tivantinib)
Patients receive tivantinib PO BID. Treatment continues in the absence of disease progression or unacceptable toxicity.
Drug: tivantinib
Given PO
Other Name: ARQ 197
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the objective response rate of patients with malignant mesothelioma who are treated with ARQ 197 (tivantinib).

SECONDARY OBJECTIVES:

I. To determine the progression-free survival of patients with malignant mesothelioma who are treated with ARQ 197.

II. To determine the toxicity experienced by patients with malignant mesothelioma who are treated with ARQ 197.

III. To determine median and overall survival of patients with malignant mesothelioma who are treated with ARQ 197.

TERTIARY OBJECTIVES:

I. To determine the frequency of mesenchymal-epithelial transition (MET) gene amplification in malignant mesothelioma patient tumor samples, and to correlate the results with MET immunohistochemistry (IHC).

II. To determine whether MET gene amplification results in increased sensitivity to ARQ 197 as observed by improved clinical outcomes (response rate [RR] and progression free survival [PFS]) compared to those without MET gene over-expression/amplification.

III. To determine whether high baseline serum hepatocyte growth factor (HGF), as well as changes in serum HGF during treatment at pre-defined early time points, correlate with treatment efficacy and clinical outcome, as measured by response rate and progression-free survival.

IV. To identify mutations by sequencing of specific areas of the MET gene in tumor samples (semaphorin [SEMA], jumonji [JM] and tyrosine kinase domains).

V. To perform immunohistochemistry (IHC) of mesothelioma tumors for HGF, MET and phosphorylated (p)-MET (pY1003 and pY1230/34/35).

VI. To assess serum HGF and serum soluble MET levels by enzyme linked immunosorbent assay (ELISA) (R&D systems) pre-treatment, after 2 cycles and at disease progression.

OUTLINE:

Patients receive tivantinib orally (PO) twice daily (BID). Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed malignant pleural or peritoneal mesothelioma, epithelial, sarcomatoid, or mixed subtype; the patient's disease must be metastatic, recurrent, or unresectable
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam; pleural effusions and ascites are not considered measurable lesions
  • No more than two prior cytotoxic chemotherapy regimens; prior chemotherapy with pemetrexed is required; prior intrapleural cytotoxic agents (including bleomycin) are allowed, and are not counted as a cytotoxic chemotherapy; chemotherapy must have been completed at least 4 weeks prior; patients who have previously received radiation therapy are eligible provided that the only site of measurable disease is not located within the radiation therapy port; at least 4 weeks must have elapsed from completion of the radiation therapy and all signs of toxicity must have resolved
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Life expectancy of greater than 3 months
  • Hemoglobin >= 9.0 g/dL
  • White blood cells (WBC) >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 X institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
  • Serum creatinine =< 1.5 X institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • The effects of ARQ 197 on the developing human fetus are unknown; for this reason and because tyrosine kinase inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, 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 and for the duration of study participation; 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; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ARQ 197 administration
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (to grade =< 1) due to agents administered more than 4 weeks earlier
  • Patients who are receiving any other investigational agents
  • Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ARQ 197
  • ARQ 197 is metabolized by cytochrome P450 (CYP)2C19, and to a lesser extent CYP3A4; the metabolism and consequently overall pharmacokinetics of ARQ 197 could be altered by inhibitors and/or inducers or other substrates of CYP2C19 and CYP3A4; while inhibitors/inducers of these cytochrome P450 isoenzymes are not specifically excluded, investigators should be aware that ARQ 197 exposure may be altered by the concomitant administration of these drugs; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
  • History of congestive heart failure defined as Class II to IV per New York Heart Association (NYHA) classification; active coronary artery disease (CAD); clinically significant bradycardia or other uncontrolled, cardiac arrhythmia defined as >= grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, or uncontrolled hypertension; myocardial infarction occurring within 6 months prior to study entry (myocardial infarction occurring > 6 months prior to study entry is permitted)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because ARQ 197 is a tyrosine kinase inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ARQ 197, breastfeeding should be discontinued if the mother is treated with ARQ 197
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with ARQ197; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • No prior treatment with a c-MET inhibitor
  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: NCT01861301

Locations
United States, California
City of Hope
Duarte, California, United States, 91010
University of Southern California/Norris Cancer Center
Los Angeles, California, United States, 90033
University of California at Davis Cancer Center
Sacramento, California, United States, 95817
City of Hope South Pasadena
South Pasadena, California, United States, 91030
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
University of Chicago
Chicago, Illinois, United States, 60637
Decatur Memorial Hospital
Decatur, Illinois, United States, 62526
NorthShore University HealthSystem-Evanston Hospital
Evanston, Illinois, United States, 60201
Ingalls Memorial Hospital
Harvey, Illinois, United States, 60426
Illinois CancerCare-Peoria
Peoria, Illinois, United States, 61615
Southern Illinois University
Springfield, Illinois, United States, 62702
United States, Indiana
Fort Wayne Medical Oncology and Hematology Inc-Parkview
Fort Wayne, Indiana, United States, 46845
Indiana University Medical Center
Indianapolis, Indiana, United States, 46202
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Wayne State University/Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Missouri
Saint John's Mercy Medical Center
Saint Louis, Missouri, United States, 63141
United States, Pennsylvania
Penn State Milton S Hershey Medical Center
Hershey, Pennsylvania, United States, 17033-0850
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
Investigators
Principal Investigator: Hedy Kindler University of Chicago
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01861301     History of Changes
Other Study ID Numbers: NCI-2013-00937, NCI-2013-00937, 12-2158, 9267, N01CM00071, P30CA014599
Study First Received: May 20, 2013
Last Updated: October 2, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Mesothelioma
Lung Neoplasms
Neoplasms, Mesothelial
Adenoma
Lung Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms

ClinicalTrials.gov processed this record on October 23, 2014