Tivantinib in Treating Patients With Metastatic Prostate Cancer

Study Overview
=================
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.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled Phase II Study of ARQ 197 (Tivantinib) in Men With Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer

Conditions
-----------------
Hormone-Resistant Prostate Cancer, Prostate Adenocarcinoma, Recurrent Prostate Carcinoma, Stage IV Prostate Cancer

Intervention / Treatment
-----------------
* Other: Laboratory Biomarker Analysis
* Other: Placebo
* Drug: Tivantinib


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (tivantinib)<br>Patients receive tivantinib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Drug: Tivantinib<br>* Given PO<br>* Other names: c-Met Inhibitor ARQ 197;|
| Placebo Comparator: Arm II (placebo)<br>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. | Other: Laboratory Biomarker Analysis<br>* Optional correlative studies<br>Other: Placebo<br>* Given PO<br>* Other names: sham therapy;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 from study entry to the date of documented progression and/or death, assessed up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in PSA Levels | Evaluated and patterns graphically explored through waterfall plots. | Baseline to 12 weeks | 
| 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. | At 12 weeks | 
| 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. | up to 12 weeks | 
| 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. | Up to 1 year |