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A Randomized, Double-Blind, Placebo-Controlled Phase II Study of ARQ197 (Tivantinib) in Men With Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer

Phase 2
18 Years
Open (Enrolling)
Adenocarcinoma of the Prostate, Hormone-resistant Prostate Cancer, Recurrent Prostate Cancer, Stage IV Prostate Cancer

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Trial Information

A Randomized, Double-Blind, Placebo-Controlled Phase II Study of ARQ197 (Tivantinib) in Men With Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer


I. To determine progression-free survival (PFS) of men with minimally symptomatic or
asymptomatic metastatic, castrate-resistant, chemotherapy-naïve prostate cancer treated with
tivantinib (ARQ 197).


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.


I. Evaluate markers of bone turnover. (Exploratory)

OUTLINE: This is a multicenter study. Patients are stratified according to prior abiraterone
or sipuleucel-T therapy (yes vs no). 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.

Patients may undergo serum and urine sample collection at baseline and periodically during
treatment for biomarker studies.

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

- 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

- 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 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 CYP2C19 and strong
inhibitors of 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

- 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: QTcF or 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 >= 1.5 times 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

PFS based on the RECIST criteria

Outcome Description:

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.

Outcome Time Frame:

Time from study entry to the date of documented progression and/or death, assessed up to 6 months

Safety Issue:


Principal Investigator

J. Paul Monk

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University


United States: Food and Drug Administration

Study ID:




Start Date:

January 2012

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Prostate
  • Hormone-resistant Prostate Cancer
  • Recurrent Prostate Cancer
  • Stage IV Prostate Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Prostatic Neoplasms



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