Tivantinib in Treating Patients With Previously Treated Malignant Mesothelioma

Recurrent Malignant Mesothelioma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01861301
• Other study ID #: NCI-2013-00937
• Secondary ID: NCI-2013-0093712
• Status: Terminated
• Phase: Phase 2
• First received: May 20, 2013
• Last updated: December 21, 2015
• Start date: January 2013
• Est. completion date: March 2015

Study information

• Verified date: November 2015
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 18
• Est. completion date: March 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Epithelioid Mesothelioma
• Lung Neoplasms
• Mesothelioma
• Recurrent Malignant Mesothelioma
• Sarcomatoid Mesothelioma
• Stage II Pleural Mesothelioma
• Stage III Pleural Mesothelioma
• Stage IV Pleural Mesothelioma

Intervention

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Tivantinib
Given PO

Locations

Country	Name	City	State
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana
United States	Ingalls Memorial Hospital	Harvey	Illinois
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	City of Hope South Pasadena	South Pasadena	California
United States	Southern Illinois University School of Medicine	Springfield	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Association between baseline HGF, MET gene amplification, MET IHC and PFS	Will be evaluated using the Cox regression model.	Baseline to 1 year	No
Other	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	No
Other	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	No
Primary	Objective radiologic response rate (complete or partial response) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1		Up to 1 year	No
Secondary	Incidence of adverse events, graded per NCI CTCAE version 4	Toxicity will be summarized by type and grade.	Up to 1 year	Yes
Secondary	Overall survival	Analyzed using the Kaplan-Meier method.	Up to 1 year	No
Secondary	Time to disease progression	Analyzed using the Kaplan-Meier method.	Up to 1 year	No