Clinical trial NCT01519414: Tivantinib in Treating Patients With Metastatic Prostate Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hormone-Resistant Prostate Cancer
Prostate Adenocarcinoma
Recurrent Prostate Carcinoma
Stage IV Prostate Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2012-01-27
Enrollment: 78
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Progression-free Survival (PFS) Based on the RECIST Criteria
timeFrame: Time from study entry to the date of documented progression and/or death, assessed up to 6 months
Secondary outcomes:
measure: Changes in PSA Levels
timeFrame: Baseline to 12 weeks
measure: Proportion of Patients Who Respond
timeFrame: At 12 weeks
measure: PSA Response Rate
timeFrame: up to 12 weeks
measure: Incidence of Adverse Events Graded as 3, 4, or 5 Per NCI CTCAE Version 4.0
timeFrame: Up to 1 year
Other outcomes:
measure: Radiographic Response Rate Based on RECIST Criteria
timeFrame: Up to 12 weeks
measure: Change in Bone Specific Alkaline Phosphatase (BSAP) in Serum
timeFrame: Baseline to up to 6 months
measure: Change in Markers of Bone Turnover in Urine
timeFrame: Baseline to up to 6 months
Locations:
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Michael Reese Hospital
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem-Evanston Hospital
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Peoria
country: United States
facility: Illinois CancerCare-Peoria
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University School of Medicine
state: Illinois
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology Inc - Jefferson Boulevard
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University/Melvin and Bren Simon Cancer Center
state: Indiana
city: Baltimore
country: United States
facility: University of Maryland/Greenebaum Cancer Center
state: Maryland
city: Towson
country: United States
facility: University of Maryland Saint Joseph Medical Center
state: Maryland
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Comprehensive Cancer Center
state: Ohio
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: Ohio State University Comprehensive Cancer Center
name: J. Monk
role: PRINCIPAL_INVESTIGATOR
References: