Tivantinib in Treating Patients With Metastatic Prostate Cancer

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.

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