A Phase 2 interventional study of Laboratory Biomarker Analysis and Placebo in Hormone-Resistant Prostate Cancer, Prostate Adenocarcinoma and Recurrent Prostate Carcinoma, sponsored by National Cancer Institute (NCI). Completed at 20 sites in United States. Open to male participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-09-12.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
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.
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.
6,370 studies on the registry are indexed under Prostatic Neoplasms; 1,400 are open to participants now.
This study's enrollment of 78 is above the median of 58 across 4,822 interventional studies indexed under Prostatic Neoplasms.
Browse Prostatic Neoplasms studies →National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.
Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.
Counted across the registry records on this site, refreshed daily.
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):
Exclusion Criteria:
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 · Drug: Tivantinib
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 · Other: Placebo
Optional correlative studies
Given PO
Also known as: placebo therapy, PLCB, sham therapy
Given PO
Also known as: ARQ 197, ARQ-197, c-Met Inhibitor ARQ 197
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 frame: Time from study entry to the date of documented progression and/or death, assessed up to 6 months
Changes in PSA Levels
Evaluated and patterns graphically explored through waterfall plots.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Up to 1 year
Radiographic Response Rate Based on RECIST Criteria
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.
Time frame: Up to 12 weeks
Change in Bone Specific Alkaline Phosphatase (BSAP) in Serum
BSAP will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored.
Time frame: Baseline to up to 6 months
Change in Markers of Bone Turnover in Urine
NTx and CTX will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored.
Time frame: Baseline to up to 6 months
| Milestone | Arm I (Tivantinib) | Arm II (Placebo) | Crossover From Placebo to Tivantinib |
|---|---|---|---|
| Started | 52 | 26 | 0 |
| Completed | 52 | 26 | 0 |
| Not completed | 0 | 0 | 0 |
| Milestone | Arm I (Tivantinib) | Arm II (Placebo) | Crossover From Placebo to Tivantinib |
|---|---|---|---|
| Started | 52 | 14 | 12 |
| Completed | 52 | 14 | 12 |
| Not completed | 0 | 0 | 0 |
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.
| months | Arm I (Tivantinib) | Arm II (Placebo) |
|---|---|---|
| Progression-free Survival (PFS) Based on the RECIST Criteria | 5.5 (3.2 to 8.0) | 3.7 (2.7 to 5.4) |
Evaluated and patterns graphically explored through waterfall plots.
| percentage change from baseline | Arm I (Tivantinib) | Arm II (Placebo) |
|---|---|---|
| Changes in PSA Levels | 140.1 (-9.0 to 5768.1) | 301.5 (-3.3 to 3254.4) |
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.
| percentage of patients | Arm I (Tivantinib) | Arm II (Placebo) | Crossover From Placebo to Tivantinib |
|---|---|---|---|
| Proportion of Patients Who Respond | 1.9 (0.05 to 10.26) | 0 (0 to 0) | 8.3 (0.2 to 38.5) |
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.
| percentage of patients | Arm I (Tivantinib) | Arm II (Placebo) | Crossover From Placebo to Tivantinib |
|---|---|---|---|
| PSA Response Rate | 1.9 (0.05 to 10.26) | 0 (0 to 0) | 8.3 (0.2 to 38.5) |
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.
| patients | Arm I (Tivantinib) | Arm II (Placebo) | Crossover From Placebo to Tivantinib |
|---|---|---|---|
| Acute coronary syndrome | 1 | 0 | 0 |
| Alkaline phosphatase increased | 0 | 0 | 2 |
| Anemia | 3 | 0 | 2 |
| Back pain | 1 | 1 | 1 |
| Confusion | 0 | 2 | 0 |
| Cataract | 1 | 0 | 0 |
| Death NOS | 1 | 0 | 1 |
| Dehydration | 0 | 2 | 1 |
| Dizziness | 0 | 1 | 0 |
| Duodenal ulcer | 1 | 0 | 0 |
| Dyspnea | 0 | 1 | 0 |
| Enterocolitis infectious | 0 | 1 | 0 |
| Fall | 0 | 1 | 0 |
| Fatigue | 2 | 0 | 0 |
| Febrile neutropenia | 1 | 0 | 0 |
| Gait disturbance | 0 | 1 | 0 |
| Generalized muscle weakness | 0 | 1 | 0 |
| Hypertension | 1 | 0 | 0 |
| Hypokalemia | 0 | 1 | 0 |
| Hyponatremia | 1 | 0 | 0 |
| Hypotension | 0 | 1 | 0 |
| Hypoxia | 1 | 1 | 0 |
| Infections and infestations - Other, specify | 1 | 0 | 0 |
| Lymph gland infection | 1 | 0 | 0 |
| Lymphocyte count decreased | 2 | 2 | 2 |
| Musculoskeletal and connective tissue disorder - O | 0 | 1 | 0 |
| Neoplasms benign, malignant and unspecified (incl | 1 | 1 | 0 |
| Nervous system disorders - Other, specify | 0 | 1 | 0 |
| Neutrophil count decreased | 2 | 0 | 2 |
| Platelet count decreased | 1 | 0 | 0 |
| Pleural effusion | 0 | 0 | 1 |
| Productive cough | 0 | 0 | 1 |
| Sinus bradycardia | 3 | 0 | 0 |
| Sinus tachycardia | 0 | 1 | 0 |
| Syncope | 0 | 2 | 0 |
| Thromboembolic event | 0 | 1 | 0 |
| Tumor pain | 1 | 0 | 0 |
| Upper respiratory infection | 0 | 1 | 0 |
| Urinary tract obstruction | 0 | 0 | 1 |
| White blood cell decreased | 2 | 0 | 2 |
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.
| percentage of patients | Arm I (Tivantinib) | Arm II (Placebo) | Crossover From Placebo to Tivantinib |
|---|---|---|---|
| Radiographic Response Rate Based on RECIST Criteria | 1.9 (0.05 to 10.26) | 0 (0 to 0) | 8.3 (0.2 to 38.5) |
BSAP will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored.
Results for this outcome have not been posted.
NTx and CTX will first be descriptively summarized by treatment group and also evaluated using graphical analyses to assess potential patterns over time and see if changes in bone resorption differ between those who are progression-free at 12 weeks vs. not after treatment with tivantinib. The potential impact of early changes in these markers on PFS using Cox regression models will be also explored.
Results for this outcome have not been posted.
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Arm I (Tivantinib) | 7/52 (13.5%) | 19/52 (36.5%) | 52/52 (100%) |
| Arm II (Placebo) | 4/26 (15.4%) | 22/26 (84.6%) | 26/26 (100%) |
| Crossover From Placebo to Tivantinib | 0/12 (0%) | 5/12 (41.7%) | 12/12 (100%) |
| Event | Arm I (Tivantinib) | Arm II (Placebo) | Crossover From Placebo to Tivantinib |
|---|---|---|---|
| Death NOSGeneral disorders | 1/52 | 0/26 | 1/12 |
| Edema limbsGeneral disorders | 1/52 | 0/26 | 1/12 |
| FatigueGeneral disorders | 1/52 | 0/26 | 1/12 |
| Urinary tract obstructionRenal and urinary disorders | 0/52 | 0/26 | 1/12 |
| Pleural effusionRespiratory, thoracic and mediastinal disorders | 0/52 | 0/26 | 1/12 |
| DehydrationMetabolism and nutrition disorders | 0/52 | 2/26 | 0/12 |
| ConfusionPsychiatric disorders | 0/52 | 2/26 | 0/12 |
| Thromboembolic eventVascular disorders | 1/52 | 2/26 | 0/12 |
| Sinus tachycardiaCardiac disorders | 0/52 | 1/26 | 0/12 |
| Abdominal painGastrointestinal disorders | 0/52 | 1/26 | 0/12 |
| Event | Arm I (Tivantinib) | Arm II (Placebo) | Crossover From Placebo to Tivantinib |
|---|---|---|---|
| FatigueGeneral disorders | 30/52 | 11/26 | 7/12 |
| AnemiaBlood and lymphatic system disorders | 23/52 | 12/26 | 6/12 |
| AnorexiaMetabolism and nutrition disorders | 17/52 | 5/26 | 6/12 |
| Back painMusculoskeletal and connective tissue disorders | 9/52 | 13/26 | 3/12 |
| Pain in extremityMusculoskeletal and connective tissue disorders | 13/52 | 11/26 | 2/12 |
| Neutrophil count decreasedInvestigations | 5/52 | 0/26 | 5/12 |
| White blood cell decreasedInvestigations | 12/52 | 1/26 | 5/12 |
| Lymphocyte count decreasedInvestigations | 11/52 | 6/26 | 4/12 |
| ConstipationGastrointestinal disorders | 14/52 | 7/26 | 3/12 |
| PainGeneral disorders | 5/52 | 7/26 | 2/12 |
| Age, Continuous(years) | Arm I (Tivantinib) | Arm II (Placebo) | Total |
|---|---|---|---|
| Median | 67 (43 to 84) | 66.5 (48 to 85) | 67 (43 to 85) |
| Sex: Female, Male(Participants) | Arm I (Tivantinib) | Arm II (Placebo) | Total |
|---|---|---|---|
| Female | 0 | 0 | 0 |
| Male | 52 | 26 | 78 |
| Race (NIH/OMB)(Participants) | Arm I (Tivantinib) | Arm II (Placebo) | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 1 | 0 | 1 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 2 | 6 | 8 |
| White | 49 | 20 | 69 |
| More than one race | 0 | 0 | 0 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(patients) | Arm I (Tivantinib) | Arm II (Placebo) | Total |
|---|---|---|---|
| United States | 52 | 26 | 78 |
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