Hormone-Resistant Prostate Cancer, Prostate Adenocarcinoma, Recurrent Prostate Carcinoma, Stage IV Prostate Cancer
Conditions
Brief summary
This randomized phase II trial studies how well tivantinib works compared to placebo in treating patients with metastatic prostate cancer. 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 progression-free survival (PFS) in men with minimally symptomatic or asymptomatic metastatic, castrate-resistant, chemotherapy-naïve prostate cancer treated with ARQ 197 (tivantinib). SECONDARY OBJECTIVES: I. To determine the prostate-specific antigen (PSA) response rate at 12 weeks in men with metastatic, castrate-resistant, chemotherapy-naïve prostate cancer treated with ARQ 197. II. To determine the radiographic response rate at 12 weeks based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria on computed tomography (CT) scans and stability of bone lesions on bone scan in castrate-resistant, chemotherapy-naïve prostate cancer treated with ARQ 197. III. To determine the proportion of patients who are progression-free at 12 weeks. IV. To assess safety and tolerability in patients treated with ARQ 197 using the National Institute of Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grading of toxicities. TERTIARY OBJECTIVES: I. Evaluate markers of bone turnover. (Exploratory) OUTLINE: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive tivantinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive placebo PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Arm I. After completion of study treatment, patients are followed up every 3 months for 6 months.
Interventions
OTHERLaboratory Biomarker Analysis
Optional correlative studies
OTHERPlacebo
Given PO
DRUGTivantinib
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically documented adenocarcinoma of the prostate with progressive systemic disease (either rising PSA or progression of disease on CT scan or magnetic resonance imaging \[MRI\] or bone scan) despite castrate levels of testosterone due to orchiectomy or luteinizing hormone-releasing hormone (LHRH) agonist or antagonist; castrate levels of testosterone must be maintained throughout the study * Evidence of metastatic disease on CT or bone imaging * Patients must have demonstrated evidence of progressive disease since the most recent change in therapy; progressive disease is defined as any one of the following (measurable disease, bone scan, or PSA progression): * Measurable disease progression: objective evidence of increase \> 20% in the sum of the longest diameters (LD) of target lesions from the time of maximal regression or the appearance of one or more new lesions * Bone scan progression: appearance of two or more new lesions on bone scan attributable to prostate cancer will constitute progression * PSA progression: two successive rises from baseline PSA separated at least by one week with the last value \>= 2 ng/mL * Asymptomatic or minimally symptomatic from prostate cancer - no symptoms attributed to prostate cancer greater than grade I using NCI CTCAE version 4.0 grading of toxicities * Secondary hormonal therapies (e.g., abiraterone acetate, flutamide, estrogen) must be discontinued for at least 4 weeks prior to study enrollment unless the duration of the therapy was less than 8 weeks and there was no demonstrated decrease in PSA * Secondary hormonal therapies with bicalutamide or nilutamide must be discontinued for 6 weeks unless duration of therapy was less than 8 weeks and there was no demonstrated PSA decrease * Prior abiraterone (or investigational anti-androgen) use is allowed; these too will need to be discontinued at least 4 weeks prior to study enrollment * PSA prior to treatment must be \>= 2 ng/ml * Castrate testosterone level (\< 50 ng/dL) * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%) * No prior chemotherapy unless utilized in neoadjuvant/adjuvant setting and must have completed \> 6 months prior to enrollment * Four weeks since major surgery or radiation therapy * Absolute neutrophil count \>= 1,500/mcL * Platelets \>= 100,000/mcL * Total bilirubin within normal institutional limits * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.0 X institutional upper limit of normal * Creatinine within normal institutional limits OR creatinine clearance \>= 40 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal * Patients must have signed an informed consent document stating that they understand the investigational nature of the proposed treatment * Men and any female partners of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation and for additional 2 months after finishing therapy; should a patient's sexual partner become pregnant or suspect she is pregnant while patient is participating in this study, he should inform the treating physician immediately * Bisphosphonate or denosumab therapy is permitted provided patients began therapy prior to registration and that they continue them as per the manufacturer's guidelines and/or per institutional practice; patients not taking ongoing bisphosphonate or denosumab therapy will not be permitted to start such therapy until they have completed 12 weeks of study treatment * Patients must be able to swallow pills to participate in the study
Exclusion criteria
* Patients who have radiotherapy within 4 weeks or chemotherapy prior to entering the study or those who have not recovered (resolution to grade 1) from adverse events due to agents administered more than 4 weeks earlier; neoadjuvant/adjuvant chemotherapy for local disease is allowed if greater than 6 months have elapsed * Previous hepatocyte growth factor receptor (C-MET) inhibitor treatment (either monoclonal antibody to C-MET or human growth factor \[HGF\] or small molecule inhibitory to C-MET) * History of allergic reactions attributed to compounds of similar chemical or biologic composition ARQ 197 * Caution should be used with patients receiving inhibitors of cytochrome P450 family 2, subfamily C, polypeptide 19 (CYP2C19) and strong inhibitors of cytochrome P450 family 3, subfamily A, polypeptide4 (CYP3A4); additional hematologic testing will be advised if the medication cannot be substituted * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or known psychiatric illness/social situations that would limit compliance with study requirements * Known brain metastasis * Current, recent (within 4 weeks of the first study drug administration), or concurrent planned participation in another investigational therapeutic study * Patients with a currently active second malignancy other than non-melanoma skin cancers are not to be registered; patients are not considered to have a currently active malignancy if they have completed therapy and are now considered to be at less than 30% risk for relapse (by their physician) * Patients may continue on a daily multi-vitamin and calcium/vitamin D supplements; all other herbal, alternative, and food supplements (i.e., PC-SPES, Saw Palmetto, St. John wort, etc.) must be discontinued before registration * New York Heart Association (NYHA) class III or greater congestive heart failure * History of myocardial infarction or unstable angina within 6 months prior to initial treatment * History of severely impaired lung function * Baseline electrocardiogram (ECG) abnormalities including first degree (PR interval \> 210 ms), second degree, or third degree heart block (exception: patients with pacemakers may be enrolled); QRS prolongation or bundle branch block (QRS \>= 120 ms), or QT prolongation (per institutional standard of care: Fridericia corrected QT interval \[QTcF\] or Bazett corrected QT interval \[QTcB\] \>= 470 ms); other ECG abnormalities will need consideration by the treating investigator and enrollment is up to his/her discretion * Presence of non-healing wound, active ulcer, or untreated bone fracture * Known diabetics that have poorly controlled diabetes mellitus (glycated hemoglobin \[HbA1c\] \>= 8.0%) or fasting glucose level \>= 189 mg/dL (diabetic patient); patients may be potentially eligible once anti-diabetic agent(s) are either added or titrated to control their diabetes mellitus * Active liver disease (AST or ALT \>= 2.0 times the upper limit of normal \[ULN\] or total bilirubin \>= institutional ULN) or gallbladder disease; patients with known liver cirrhosis or severe hepatic impairment (Child-Pugh Class C) will also be excluded * A known history of human immunodeficiency virus (HIV) seropositivity * Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of ARQ 197 (e.g., uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or significant small bowel resection) * Patients with an active bleeding diathesis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Based on the RECIST Criteria | Time from study entry to the date of documented progression and/or death, assessed up to 6 months | The progression-free survival distributions between the two arms will be compared using log-rank tests. Progression-free survival curves will be constructed using the Kaplan-Meier product limit method, and additional analyses will be done using the Cox proportional hazards model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Who Respond | At 12 weeks | An assumed binomial distribution used. Summarized with their corresponding 95% binomial confidence intervals and compared in an exploratory manner between the two treatment arms. Dichotomized outcomes of response will be descriptively summarized and graphically evaluated using bar graphs. |
| Changes in PSA Levels | Baseline to 12 weeks | Evaluated and patterns graphically explored through waterfall plots. |
| PSA Response Rate | up to 12 weeks | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by 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. |
| Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Up to 1 year | Fisher's exact tests will be used to quantitatively compare the incidence of severe as well as specific toxicities of interest between the treatment arms and graphically assessed differences in maximum grades observed for toxicities between the arms. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Markers of Bone Turnover in Urine | Baseline to up to 6 months | NTx and CTX will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored. |
| Change in Bone Specific Alkaline Phosphatase (BSAP) in Serum | Baseline to up to 6 months | BSAP will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored. |
| Radiographic Response Rate Based on RECIST Criteria | Up to 12 weeks | Summarized with their corresponding 95% binomial confidence intervals and compared in an exploratory manner between the two treatment arms. Dichotomized outcomes of response will be descriptively summarized and graphically evaluated using bar graphs. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Tivantinib) Patients receive tivantinib 360 mg (3 \* 120 mg tablets) po BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | 52 |
| Arm II (Placebo) Patients receive matched placebo (3 tablets) po BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Arm I. | 26 |
| Total | 78 |
Baseline characteristics
| Characteristic | Arm II (Placebo) | Total | Arm I (Tivantinib) |
|---|---|---|---|
| Age, Continuous | 66.5 years | 67 years | 67 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 8 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 69 Participants | 49 Participants |
| Region of Enrollment United States | 26 patients | 78 patients | 52 patients |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 26 Participants | 78 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 52 | 4 / 26 | 0 / 12 |
| other Total, other adverse events | 52 / 52 | 26 / 26 | 12 / 12 |
| serious Total, serious adverse events | 19 / 52 | 22 / 26 | 5 / 12 |
Outcome results
Primary
Progression-free Survival (PFS) Based on the RECIST Criteria
The progression-free survival distributions between the two arms will be compared using log-rank tests. Progression-free survival curves will be constructed using the Kaplan-Meier product limit method, and additional analyses will be done using the Cox proportional hazards model.
Time frame: Time from study entry to the date of documented progression and/or death, assessed up to 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Tivantinib) | Progression-free Survival (PFS) Based on the RECIST Criteria | 5.5 months |
| Arm II (Placebo) | Progression-free Survival (PFS) Based on the RECIST Criteria | 3.7 months |
p-value: 0.02Log Rank
Secondary
Changes in PSA Levels
Evaluated and patterns graphically explored through waterfall plots.
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Tivantinib) | Changes in PSA Levels | 140.1 percentage change from baseline |
| Arm II (Placebo) | Changes in PSA Levels | 301.5 percentage change from baseline |
Secondary
Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0
Fisher's exact tests will be used to quantitatively compare the incidence of severe as well as specific toxicities of interest between the treatment arms and graphically assessed differences in maximum grades observed for toxicities between the arms.
Time frame: Up to 1 year
Population: Adverse events graded as 3, 4 or 5 per NCI CTCAE version 4 (regardless of attribution)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Neoplasms benign, malignant and unspecified (incl | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Fatigue | 2 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Tumor pain | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Musculoskeletal and connective tissue disorder - O | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Febrile neutropenia | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Confusion | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Lymphocyte count decreased | 2 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Gait disturbance | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Alkaline phosphatase increased | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Lymph gland infection | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Generalized muscle weakness | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Thromboembolic event | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Infections and infestations - Other, specify | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypertension | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Cataract | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Acute coronary syndrome | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypoxia | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hyponatremia | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Sinus tachycardia | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypotension | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Death NOS | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Urinary tract obstruction | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Sinus bradycardia | 3 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Dehydration | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Anemia | 3 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Productive cough | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Dizziness | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypokalemia | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Pleural effusion | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Duodenal ulcer | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Platelet count decreased | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Neutrophil count decreased | 2 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Dyspnea | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Upper respiratory infection | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Syncope | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Enterocolitis infectious | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Back pain | 1 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Nervous system disorders - Other, specify | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Fall | 0 patients |
| Arm I (Tivantinib) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | White blood cell decreased | 2 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Duodenal ulcer | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Acute coronary syndrome | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Alkaline phosphatase increased | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Anemia | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Back pain | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Confusion | 2 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Cataract | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Death NOS | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Dehydration | 2 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Dizziness | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Dyspnea | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Enterocolitis infectious | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Fall | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Fatigue | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Febrile neutropenia | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Gait disturbance | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Generalized muscle weakness | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypertension | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypokalemia | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hyponatremia | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypotension | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypoxia | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Infections and infestations - Other, specify | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Lymph gland infection | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Lymphocyte count decreased | 2 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Musculoskeletal and connective tissue disorder - O | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Neoplasms benign, malignant and unspecified (incl | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Nervous system disorders - Other, specify | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Neutrophil count decreased | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Platelet count decreased | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Pleural effusion | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Productive cough | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Sinus bradycardia | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Sinus tachycardia | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Syncope | 2 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Thromboembolic event | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Tumor pain | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Upper respiratory infection | 1 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Urinary tract obstruction | 0 patients |
| Arm II (Placebo) | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | White blood cell decreased | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Neoplasms benign, malignant and unspecified (incl | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Enterocolitis infectious | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Thromboembolic event | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Dyspnea | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Nervous system disorders - Other, specify | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Duodenal ulcer | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Back pain | 1 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Neutrophil count decreased | 2 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypertension | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Urinary tract obstruction | 1 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Platelet count decreased | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Dizziness | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Tumor pain | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Pleural effusion | 1 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Dehydration | 1 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Anemia | 2 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Productive cough | 1 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Death NOS | 1 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Acute coronary syndrome | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Sinus bradycardia | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hyponatremia | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Cataract | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypotension | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypokalemia | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Upper respiratory infection | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Hypoxia | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Generalized muscle weakness | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Sinus tachycardia | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Infections and infestations - Other, specify | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Gait disturbance | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Alkaline phosphatase increased | 2 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Lymph gland infection | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Febrile neutropenia | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Syncope | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Lymphocyte count decreased | 2 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Fatigue | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Confusion | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Musculoskeletal and connective tissue disorder - O | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | Fall | 0 patients |
| Crossover From Placebo to Tivantinib | Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0 | White blood cell decreased | 2 patients |
Secondary
Proportion of Patients Who Respond
An assumed binomial distribution used. Summarized with their corresponding 95% binomial confidence intervals and compared in an exploratory manner between the two treatment arms. Dichotomized outcomes of response will be descriptively summarized and graphically evaluated using bar graphs.
Time frame: At 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Tivantinib) | Proportion of Patients Who Respond | 1.9 percentage of patients |
| Arm II (Placebo) | Proportion of Patients Who Respond | 0 percentage of patients |
| Crossover From Placebo to Tivantinib | Proportion of Patients Who Respond | 8.3 percentage of patients |
Secondary
PSA Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by 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.
Time frame: up to 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Tivantinib) | PSA Response Rate | 1.9 percentage of patients |
| Arm II (Placebo) | PSA Response Rate | 0 percentage of patients |
| Crossover From Placebo to Tivantinib | PSA Response Rate | 8.3 percentage of patients |
Other Pre-specified
Change in Bone Specific Alkaline Phosphatase (BSAP) in Serum
BSAP will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored.
Time frame: Baseline to up to 6 months
Other Pre-specified
Change in Markers of Bone Turnover in Urine
NTx and CTX will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored.
Time frame: Baseline to up to 6 months
Other Pre-specified
Radiographic Response Rate Based on RECIST Criteria
Summarized with their corresponding 95% binomial confidence intervals and compared in an exploratory manner between the two treatment arms. Dichotomized outcomes of response will be descriptively summarized and graphically evaluated using bar graphs.
Time frame: Up to 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Tivantinib) | Radiographic Response Rate Based on RECIST Criteria | 1.9 percentage of patients |
| Arm II (Placebo) | Radiographic Response Rate Based on RECIST Criteria | 0 percentage of patients |
| Crossover From Placebo to Tivantinib | Radiographic Response Rate Based on RECIST Criteria | 8.3 percentage of patients |