Non-CNS Germ Cell Tumors (Seminomas and Nonseminomas)
Conditions
Brief summary
This is a multicenter, single-arm study for safety and efficacy.
Interventions
DRUGTivantinib (ARQ 197)
Capsule, 120 mg, BID (360 mg), approximately 112 days
Sponsors
Daiichi Sankyo
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically-confirmed non-central nervous system germ cell tumor (non-CNS GCT), both seminomas and nonseminomas are allowed. 2. Male subjects 16 years of age or older. 3. Eastern Cooperative Oncology Group (ECOG) performance status of equal to or less than 1. 4. 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. 5. 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. 6. 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. 7. 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. 8. 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. 9. 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. 10. 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
1. 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. 2. 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). 3. Active clinically serious infection(s) defined as equal to or greater than Grade 2 according to NCI CTCAE, version 4.0. 4. 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. 5. Any primary CNS GCT. 6. 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. 7. Any major surgical procedure within 3 weeks prior to first dose of study drug. 8. Prior therapy with c-MET inhibitors, including ARQ197. 9. 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. 10. 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. 11. Inability to swallow oral medications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Baseline up to first objective response, up to 1 year 9 months postdose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Baseline up to progressive disease or death (whichever occurs first), up to 1 year 9 months postdose | 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. |
| Overall Survival Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Baseline up to death (any cause), up to 1 year 9 months postdose | 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. |
| Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Baseline up to 30 days after last dose, up to 1 year 9 months postdose | 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. |
Countries
France, United Kingdom, United States
Participant flow
Recruitment details
A total of 27 participants who met all inclusion and no exclusion criteria were enrolled and treated at 7 clinic sites in the United States, 2 in France, and 2 in the United Kingdom. Of the 27 enrolled, 21 were included in Stage 1 in which the interim futility analysis was performed per the Simon 2-stage design.
Pre-assignment details
Based on the Simon 2-stage design, 21 participants were enrolled (Stage 1). If \<2 had either a complete response (CR) or partial response (PR), then the study was terminated. If ≥2 had either CR or PR, then enrollment was extended to 41 participants. After Stage 2 with 41 participants, treatment was effective if ≥5 had CR or PR after 4 cycles.
Baseline characteristics
| Characteristic | Total |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Age, Continuous | 33.0 years STANDARD_DEVIATION 11.59 |
| Race/Ethnicity, Customized Caucasian | 23 Participants |
| Race/Ethnicity, Customized Other | 4 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 21 | 0 / 27 |
| other Total, other adverse events | 11 / 21 | 15 / 27 |
| serious Total, serious adverse events | 6 / 21 | 9 / 27 |
Outcome results
Primary
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.
Time frame: Baseline up to first objective response, up to 1 year 9 months postdose
Population: Objective response rate was assessed in the Full Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: ARQ 197 360 mg BID | Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Confirmed CR | 0 Participants |
| Stage 1: ARQ 197 360 mg BID | Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Progressive disease | 16 Participants |
| Stage 1: ARQ 197 360 mg BID | Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Confirmed PR | 0 Participants |
| Stage 1: ARQ 197 360 mg BID | Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Objective response rate | 0 Participants |
| Stage 1: ARQ 197 360 mg BID | Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Stable disease | 3 Participants |
| Total | Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Objective response rate | 0 Participants |
| Total | Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Confirmed CR | 0 Participants |
| Total | Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Stable disease | 5 Participants |
| Total | Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Progressive disease | 20 Participants |
| Total | Best Overall Response and Objective Response Rate Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Confirmed PR | 0 Participants |
Secondary
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.
Time frame: Baseline up to death (any cause), up to 1 year 9 months postdose
Population: Overall survival was assessed in the Full Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: ARQ 197 360 mg BID | Overall Survival Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | 6.2 months |
| Total | Overall Survival Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | 5.9 months |
Secondary
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.
Time frame: Baseline up to progressive disease or death (whichever occurs first), up to 1 year 9 months postdose
Population: Progression-free survival was assessed in the Full Analysis Set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stage 1: ARQ 197 360 mg BID | Progression-Free Survival Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | 4.3 weeks |
| Total | Progression-Free Survival Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | 4.3 weeks |
Secondary
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.
Time frame: Baseline up to 30 days after last dose, up to 1 year 9 months postdose
Population: Adverse events were assessed in the Safety Analysis Set.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Dyspnea | 4 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Any TEAEs | 19 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Gastrointestinal Disorders | 8 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Constipation | 2 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Nausea | 6 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Vomiting | 4 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | General Disorders & Administration Site Conditions | 12 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Fatigue | 7 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Edema peripheral | 3 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Metabolism and Nutrition Disorders | 3 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Decreased appetite | 3 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Musculoskeletal and Connective Tissue Disorders | 4 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Back pain | 2 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Nervous System Disorders | 7 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Neuropathy peripheral | 3 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Respiratory, Mediastinal, and Thoracic Disorders | 8 Participants |
| Stage 1: ARQ 197 360 mg BID | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Cough | 3 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Nervous System Disorders | 11 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Metabolism and Nutrition Disorders | 6 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Any TEAEs | 25 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Dyspnea | 6 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Gastrointestinal Disorders | 11 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Decreased appetite | 4 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Constipation | 3 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Neuropathy peripheral | 3 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Nausea | 7 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Musculoskeletal and Connective Tissue Disorders | 6 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Vomiting | 4 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Cough | 6 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | General Disorders & Administration Site Conditions | 15 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Back pain | 3 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Fatigue | 10 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Respiratory, Mediastinal, and Thoracic Disorders | 12 Participants |
| Total | Treatment-Emergent Adverse Events Reported in ≥ 10% of Participants Following Treatment With Tivantinib (ARQ 197) in Participants With Relapsed or Refractory Germ Cell Tumors | Edema peripheral | 4 Participants |