Tivantinib in Treating Patients With Previously Treated Malignant Mesothelioma

A Phase 2 Study of ARQ 197 in Patients With Previously-Treated Malignant Mesothelioma

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.

Study Overview

• Status: Terminated
• Conditions: Epithelioid Mesothelioma; Sarcomatoid Mesothelioma; Stage IV Pleural Mesothelioma; Recurrent Malignant Mesothelioma; Stage II Pleural Mesothelioma; Stage III Pleural Mesothelioma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Tivantinib

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • South Pasadena, California, United States, 91030
      • City of Hope South Pasadena
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem-Evanston Hospital
    • Harvey, Illinois, United States, 60426
      • Ingalls Memorial Hospital
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Springfield, Illinois, United States, 62702
      • Southern Illinois University School of Medicine
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Fort Wayne Medical Oncology and Hematology Inc-Parkview
    • Indianapolis, Indiana, United States, 46202
      • Indiana University/Melvin and Bren Simon Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Milton S Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (tivantinib); Patients receive tivantinib 360 PO BID. Treatment continues in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Tivantinib; Given PO; Other Names: ARQ 197; ARQ-197; c-Met Inhibitor ARQ 197

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Radiologic Response Rate (Complete or Partial Response) Assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Adverse Events, Graded Per NCI CTCAE Version 4	Grade 3 or higher AE of any type, regardless of attribution.	Up to 2 years
Overall Survival	Analyzed using the Kaplan-Meier method.	Up to 2 years
Progression-free Survival	Time to disease progression or death from any cause. Analyzed using the Kaplan-Meier method.	Up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Baseline Levels of Continuous or Ordinal Markers (e.g., Serum HGF/MET IHC) Between Responders and Non-responders	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.	Baseline to 1 year
Change in Serum HGF or MET IHC and Tumor Size Change (Percent Reduction in Sum of Longest Diameters)	Will be evaluated by Spearman's rank correlation coefficient.	Baseline to 1 year
Association Between Baseline HGF, MET Gene Amplification, MET IHC and PFS	Will be evaluated using the Cox regression model.	Baseline to 1 year

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: May 20, 2013
• First Submitted That Met QC Criteria: May 20, 2013
• First Posted (Estimate): May 23, 2013

Study Record Updates

• Last Update Posted (Estimate): October 24, 2016
• Last Update Submitted That Met QC Criteria: August 26, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant
• Other Study ID Numbers: NCI-2013-00937 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA014599 (U.S. NIH Grant/Contract); N01CM00071 (U.S. NIH Grant/Contract); 12-2158 (Other Identifier: University of Chicago Comprehensive Cancer Center); 9267 (Other Identifier: CTEP)