Tivantinib in Treating Patients With Previously Treated Malignant Mesothelioma

• ClinicalTrials.gov Identifier: NCT01861301
• Recruitment Status: Terminated
• First Posted: May 23, 2013
• Results First Posted: October 24, 2016
• Last Update Posted: October 24, 2016
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: May 20, 2013
• First Posted Date: May 23, 2013
• Results First Submitted Date: August 26, 2016
• Results First Posted Date: October 24, 2016
• Last Update Posted Date: October 24, 2016
• Study Start Date: January 2013
• Actual Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 26, 2016)

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 ]

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.

• Original Primary Outcome Measures (submitted: May 20, 2013): 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 ]

Current Secondary Outcome Measures (submitted: August 26, 2016)

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

Original Secondary Outcome Measures (submitted: May 20, 2013)

• Time to disease progression [ Time Frame: Up to 1 year ]
  Analyzed using the Kaplan-Meier method.
• Overall survival [ Time Frame: Up to 1 year ]
  Analyzed using the Kaplan-Meier method.
• Changes in levels between responders and non-responders [ Time Frame: Baseline to disease progression, assessed up to 1 year ]
  Paired t-tests or Wilcoxon rank-sum tests will be used to compare 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). In addition, the association between 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.
• Presence/absence of MET gene amplification, assessed by MET expression scores (0, 1+, 2+, 3+) between MET gene amplification positive and negative patients [ Time Frame: Up to 1 year ]
  Spearman's rank correlation will be utilized to measure the association between MET IHC and baseline serum HGF. The association between baseline HGF, MET gene amplification, MET IHC and PFS will be evaluated using the Cox regression model, incorporating these variables as covariates. Remaining correlative data will be summarized descriptively.
• Adverse events, graded according to the NCI CTCAE v4.0 [ Time Frame: Up to 1 year ]
  Summarized by type and grade.

Current Other Pre-specified Outcome Measures (submitted: August 26, 2016)

• 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 ]
  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 ]
  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 ]
  Will be evaluated using the Cox regression model.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Tivantinib in Treating Patients With Previously Treated Malignant Mesothelioma
• Official Title: A Phase 2 Study of ARQ 197 in Patients With Previously-Treated Malignant Mesothelioma
• Brief 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.

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
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Epithelioid 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
  Other Names:

  • ARQ 197
  • ARQ-197
  • c-Met Inhibitor ARQ 197

Study Arms

Experimental: Treatment (tivantinib)

Patients receive tivantinib 360 PO BID. Treatment continues in the absence of disease progression or unacceptable toxicity.

Interventions:

• Other: Laboratory Biomarker Analysis
• Drug: Tivantinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: November 23, 2015): 18
• Original Estimated Enrollment (submitted: May 20, 2013): 49
• Actual Study Completion Date: March 2015
• Actual Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01861301
• Other Study ID Numbers: NCI-2013-00937; NCI-2013-00937 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 12-2158; 12-2158 ( Other Identifier: University of Chicago Comprehensive Cancer Center ); 9267 ( Other Identifier: CTEP ); N01CM00071 ( U.S. NIH Grant/Contract ); P30CA014599 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: National Cancer Institute (NCI)
• Original Responsible Party: Same as current
• Current Study Sponsor: National Cancer Institute (NCI)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Hedy Kindler; University of Chicago Comprehensive Cancer Center

• PRS Account: National Cancer Institute (NCI)
• Verification Date: August 2016