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

Phase 2
18 Years
Open (Enrolling)
Epithelial Mesothelioma, Recurrent Malignant Mesothelioma, Sarcomatous Mesothelioma, Stage II Malignant Mesothelioma, Stage III Malignant Mesothelioma, Stage IV Malignant Mesothelioma

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Trial Information

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


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


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.


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

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.


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.

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 >= 80%)

- 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

Type of Study:


Study Design:

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

Outcome Measure:

Objective radiologic response rate (complete or partial response) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Outcome Time Frame:

Up to 1 year

Safety Issue:


Principal Investigator

Hedy Kindler

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

January 2013

Completion Date:

Related Keywords:

  • Epithelial Mesothelioma
  • Recurrent Malignant Mesothelioma
  • Sarcomatous Mesothelioma
  • Stage II Malignant Mesothelioma
  • Stage III Malignant Mesothelioma
  • Stage IV Malignant Mesothelioma
  • Mesothelioma



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