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NCI 1811   |   11-1169
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

Main Campus
Phase 2
ARQ 197 (Tivantinib)

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  1. Primary Objectives
    • To determine progression free survival (PFS) in men with minimally symptomatic or asymptomatic metastatic castrate resistant, chemotherapy-naive prostate cancer treated with ARQ 197.
  2. Secondary Objectives
    • To determine the PSA response rate at 12 weeks in men with metastatic castrate resistant chemotherapy-naive prostate cancer treated with ARQ 197
    • To determine the radiographic response rate at 12 weeks based on RECIST criteria on CT scans and stability of bone lesions on bone scan in castrate-resistant, chemotherapy-naive prostate cancer treated with ARQ 197
    • To determine the proportion of patients who are progression-free at 12 weeks
    • To assess safety and tolerability in patients treated with ARQ 197 using the NCI CTCAE Version 4.0 grading of toxicities
  3. Exploratory Objectives (Correlative Studies)
    • Evaluate markers of bone turnover

Inclusion Criteria
  1. Patients must have histologically documented adenocarcinoma of the prostate with progressive systemic disease (either rising PSA or progression of disease on CT scan or MRI or bone scan) despite castrate levels of testosterone due to orchiectomy or LHRH agonist or antagonist. Castrate levels of testosterone must be maintained throughout the study.
  2. Evidence of metastatic disease on CT or bone imaging
  3. 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.
  4. 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.
  5. 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 therapy was less than 8 weeks and there was no demonstrated decrease in PSA.
  6. 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.
  7. Prior abiraterone (or investigational anti-androgen) use is allowed. These too will need to be discontinued at least 4 weeks prior to study enrollment.
  8. PSA prior to treatment must be ≥ 2 ng/mL.
  9. Castrate testosterone level (< 50ng/dL).
  10. Minimum age requirement is ≥ 18 years old.
  11. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).
  12. No prior chemotherapy unless utilized in neoadjuvant/adjuvant setting and must have completed >6 months prior to enrollment.
  13. Four weeks since major surgery or radiation therapy
  14. Patients must have normal organ and marrow function as defined below:
    • absolute neutrophil count ≥1,500/mcL
    • platelets ≥100,000/mcL
    • total bilirubin within normal institutional limits
    • AST(SGOT)/ALT(SGPT) ≤2.5 X institutional upper limit of normal
    • creatinine within normal institutional limits OR creatinine clearance ≥40 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
  15. Patients must have signed an informed consent document stating that they understand the investigational nature of the proposed treatment.
  16. 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.
  17. 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.
  18. Patients must be able to swallow pills to participate in the study.

Exclusion Criteria
  1. 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.
  2. Previous C-MET inhibitor treatment (either monoclonal antibody to C-MET or HGF or small molecule inhibitory to C-MET)
  3. History of allergic reactions attributed to compounds of similar chemical or biologic composition ARQ 197.
  4. Caution should be used with patients receiving any inhibitors of CYP2C19 and strong inhibitors of CYP3A4. A list that includes medications and substances known or with the potential to interact with the CYP2C19 and CYP3A4 isoenzymes are provided in Appendix F. Additional hematologic testing will be advised if the medication cannot be substituted.
  5. 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.
  6. Known brain metastasis
  7. Current, recent (within 4 weeks of the first study drug administration), or concurrent planned participation in another investigational therapeutic study.
  8. 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).
  9. 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 Johns Wort, etc.) must be discontinued before registration.
  10. New York Heart Association (NYHA) Class III or greater congestive heart failure (See Appendix E)
  11. History of myocardial infarction or unstable angina within 6 months prior to initial treatment
  12. History of severely impaired lung function
  13. Baseline 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.
  14. Presence of non-healing wound, active ulcer, or untreated bone fracture
  15. Known diabetics that have poorly controlled diabetes mellitus (HbA1c ≥ 8.0%) or fasting glucose level ≥189 mg/dL (diabetic patient). Patients may be potentially eligible once anti-diabetic agent(s) is either added or titrated to control their diabetes mellitus.
  16. Active liver disease (AST or ALT ≥ 2.0x the upper limit of normal [ULN] or total bilirubin > institutional upper limit of normal) or gallbladder disease. Patients with known liver cirrhosis or severe hepatic impairment (Child-Pugh Class C) will also be excluded./li>
  17. A known history of HIV seropositivity
  18. 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)
  19. Patients with an active bleeding diathesis

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