ARQ 197 for Participants With Relapsed or Refractory Germ Cell Tumors

Study Overview
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Brief Summary
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This is a multicenter, single-arm study for safety and efficacy.

Official Title
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Multicenter Phase 2 Trial of ARQ 197 for Subjects With Relapsed or Refractory Germ Cell Tumors

Conditions
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Non-CNS Germ Cell Tumors (Seminomas and Nonseminomas)

Intervention / Treatment
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* Drug: Tivantinib (ARQ 197)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed non-central nervous system germ cell tumor (non-CNS GCT), both seminomas and nonseminomas are allowed. Male subjects 16 years of age or older. Eastern Cooperative Oncology Group (ECOG) performance status of equal to or less than 1. Documented progression during or following equal to or greater than 1 prior platinum-containing chemotherapy regimen(s) (no limit to number of lines of prior treatment), and considered platinum-resistant by the Investigator. Subjects who have progressed or whose tumors have recurred after stem cell transplantation are also allowed. All subjects must have either declined or not be a candidate for curative therapy. In general, this means a subject would have to have progressive disease (PD) after receiving high-dose chemotherapy, have certain features making them ineligible for high-dose chemotherapy, or have refused high-dose chemotherapy despite being informed of its curative potential. Subjects must have radiographically measurable disease as defined by RECIST 1.1 and meet one of the following criteria: Documented germ cell tumor progression based on radiographic measurements; Elevated serum tumor markers in case of radiographically measured stable disease. Subjects should be able to provide written informed consent, comply with protocol visits and procedures, be able to take oral medication, and not have any active infection or chronic co-morbidity that would interfere with therapy. Subjects must agree to use double-barrier contraceptive measures or avoidance of intercourse during the study and for 90 days after the last dose of study drug. Adequate bone marrow, liver, and renal functions, defined as: Platelet count equal to or greater than 75 times 10^9/L; Hemoglobin equal to or greater than 9.0 g/dL; Absolute neutrophil count (ANC) equal to or greater than 1.5 times 10^9/L; Total bilirubin equal to or less than 2.5 mg/dL; Alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST) equal to or less than 2.5 times the upper limit of normal (ULN) (equal to or less than 5 times the ULN for subjects with liver metastases); Serum creatinine equal to or less than 1.5 times the ULN. Subjects must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an Independent Ethics Committee or Institutional Review Board approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study specific procedures or tests. Exclusion Criteria: Previous or concurrent cancer that is distinct from GCT in primary site or histology, EXCEPT treated basal cell carcinoma, superficial bladder tumors (Ta, Tis & T1). Any cancer curatively treated equal to or greater than 3 years prior to enrollment is permitted. History of cardiac disease: Congestive heart failure defined as Class II to IV per New York Heart Association classification. Active coronary artery disease. Previously diagnosed bradycardia or other cardiac arrhythmia defined as equal to or greater than Grade 2 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, or uncontrolled hypertension. Myocardial infarction that occurred within 6 months prior to study entry (myocardial infarction that occurred greater than 6 months prior to study entry is permitted). Active clinically serious infection(s) defined as equal to or greater than Grade 2 according to NCI CTCAE, version 4.0. Known metastatic brain or meningeal tumors, unless the subject is greater than 6 months from definitive therapy, has a negative imaging study within 4 weeks of first dose of study drug and is clinically stable (no concomitant therapy, including supportive therapy with steroids or anticonvulsant medications) with respect to the tumor at the time of first dose of study drug. Any primary CNS GCT. Concurrent treatment with anticancer therapies including cytotoxic chemotherapy, immunotherapy, radiotherapy, vaccines or investigational therapy during the study or within 3 weeks of first dose of study drug. Any major surgical procedure within 3 weeks prior to first dose of study drug. Prior therapy with c-MET inhibitors, including ARQ197. Substance abuse or medical, psychological or social conditions that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results. Any condition that is unstable or that could jeopardize the safety of the subject and the subject's protocol compliance, including known human immunodeficiency virus, hepatitis B virus or hepatitis C virus infection. Inability to swallow oral medications.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tivantinib (ARQ 197)<br>3 capsules of 120 mg each, administered twice a day (once in the morning and once in the evening - total daily dose of 720 mg) in continuous 4-week cycles | Drug: Tivantinib (ARQ 197)<br>* Capsule, 120 mg, BID (360 mg), approximately 112 days<br>* Other names: Tivantinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | The best overall response was the best response (in the order of confirmed complete response [CR], confirmed partial response [PR], unconfirmed CR, unconfirmed PR, stable disease [SD], and progressive disease [PD]) among all overall responses recorded from the start of treatment until the participant withdrew from the study. Objective response was defined as the number of participants with confirmed CR and confirmed PR after 4 cycles of therapy with ARQ 197. According to Response Evaluation Criteria in Solid Tumors v 1.1, CR was defined as a disappearance of all target lesions, PR was defined as at least a 30% decrease in the sum of diameters of target lesions, and SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, defined as at least a 20% increase in the sum of diameters of target lesions. | Baseline up to first objective response, up to 1 year 9 months postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Progression-free survival (PFS) is defined as the time from the date of the start of study treatment to the earlier of the dates of the first documentation of progressive disease (PD) or death due to any cause. According to Response Evaluation Criteria in Solid Tumors v 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. | Baseline up to progressive disease or death (whichever occurs first), up to 1 year 9 months postdose | 
| Overall Survival Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Overall survival (OS) was defined as the time from the date of the start of study treatment to the date of death due to any cause. | Baseline up to death (any cause), up to 1 year 9 months postdose | 
| Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Treatment-emergent adverse events (TEAEs) were defined as an adverse event (AE) that occurs, having been absent before the first dose of study drug, or has worsened in severity or seriousness after the first dose until 30 days after the last dose. | Baseline up to 30 days after last dose, up to 1 year 9 months postdose |