Using Multiparametric MRI to Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed Prostate Cancer
- Conditions
- Prostate Cancer
- Interventions
- Registration Number
- NCT02430480
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background:
* There are several ways to treat prostate cancer. Researchers want to see how well a certain kind of imaging helps detect prostate cancer. They also want to see if a particular drug combination used before surgery will benefit people with prostate cancer that hasn't spread in the body (non-metastatic). The combination will be androgen deprivation therapy and enzalutamide.
* The combination of androgen deprivation therapy and enzalutamide has been shown to make patients with advanced (metastatic disease) live longer. The investigators want to see if using it earlier can increase cure rate of surgery and identify genetic or molecular characteristics that are associated with better outcomes.
Objectives:
- To develop better ways of detecting prostate cancer before and after pre-operative treatment.
Eligibility:
- Men at least 18 years old with non-metastatic prostate cancer. They must be candidates for a radical prostatectomy.
Design:
* Participants will be screened with medical history, physical exam, and blood tests. They will have scans and X-rays.
* Before starting the study drugs, participants will have:
* Vital signs taken, medical history, and blood tests.
* Electrocardiogram (ECG) heart test, with patches stuck on the skin.
* Small piece of tumor removed (biopsy) using image guidance from magnetic resonance imaging (MRI) and ultrasound.
* 3T multi-parametric magnetic resonance imaging (mpMRI). Participants will lie on a table that slides into a metal cylinder. A probe will be inserted in the rectum. They will be in the scanner for about 60 minutes, lying still. The scanner makes loud knocking sounds. Participants will get earplugs.
* Participants will take the 2 study drugs for 6 months.
* Enzalutamide is taken as 4 pills once a day.
* Androgen deprivation therapy is given by injection 2 times over 6 months.
* During these 6 months, participants will visit the clinic monthly. They will have physical exam, vital signs, and blood drawn.
* After finishing the study drugs, participants will have another 3T mpMRI. Then they will have prostate removal surgery.
- Detailed Description
Background:
* Most men diagnosed with prostate cancer will present with intermediate or high-risk disease
* Many develop castrate resistant prostate cancer (CRPC) as curative strategies are often unsuccessful
* Treatment options typically involve radical prostatectomy (RP) or radiation therapy (RT) in combination with androgen deprivation therapy (ADT)
* Even when cancers are initially sensitive to ADT, resistance ultimately emerges either through clonal selection or through a variety of adaptive mechanisms (secondary resistance).
* The recent introduction of novel androgen pathway inhibitors offers an opportunity to potentially improve the cure rate of men with intermediate and high risk localized prostate cancer
* There remains a great need for improved techniques to determine mechanisms of treatment response and resistance.
Objectives:
-To test the feasibility of multi parametric magnetic resonance imaging (mpMRI) for the localization and detection of focal prostate cancer both before and after pre-operative treatment with ADT and enzalutamide.
Eligibility:
* Patients with nonmetastatic castration sensitive prostate cancer with intermediate or high-risk features
* Patients with testosterone levels greater than or equal to 100 ng/dL.
* Eastern Cooperative Oncology Group (ECOG) 0-1.
Design:
* Patients will be treated with ADT and enzalutamide for 6 months
* Two 3T mpMRI endorectal examinations (One at screening and after 6 month of treatment)
* Screening biopsy (magnetic resonance (MR)/ultrasound (US) guided) samples
* Standard of care prostatectomy (RP) following post treatment mpMRI
* All tumor specimens will undergo genomic analysis
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Male
- Target Recruitment
- 39
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description 1/Arm 1- Enzalutamide and Goserelin mpMRI Patients will have an multi-parametric magnetic resonance imaging (mpMRI) guided biopsy, then receive enzalutamide and goserelin subcutaneous (SC) treatment for 6 months followed by a second mpMRI examination. 1/Arm 1- Enzalutamide and Goserelin Goserelin Patients will have an multi-parametric magnetic resonance imaging (mpMRI) guided biopsy, then receive enzalutamide and goserelin subcutaneous (SC) treatment for 6 months followed by a second mpMRI examination. 1/Arm 1- Enzalutamide and Goserelin Enzalutamide Patients will have an multi-parametric magnetic resonance imaging (mpMRI) guided biopsy, then receive enzalutamide and goserelin subcutaneous (SC) treatment for 6 months followed by a second mpMRI examination.
- Primary Outcome Measures
Name Time Method Median Tumor Volume Burden at Baseline Multi-parametric Magnetic Resonance Imaging (mpMRI) Before and After Surgery Baseline and 6 months The prostate lesion is contoured manually by an expert radiologist. Research software (mim-vista) calculates the volume. Greater tumor volumes may indicate higher prostate tumor growth.
- Secondary Outcome Measures
Name Time Method Initial Multiparametric Magnetic Resonance Imaging (mpMRI) Percentage of Relative Tumor Volume Sensitivity 6 months The Youden index was used as a measure for evaluating biomarker effectiveness and was calculated to determine the cutoffs that gave the optimal combination of sensitivity and specificity for patient response to treatment. The index is: J=sensitivity + specificity -1. Its value ranges from 0 through 1 (inclusive). A value of 1 indicates that there are no false positives or false negatives, i.e. the test is perfect. The index gives equal weight to false positive and false negative values, so all tests with the same value of the index give the same proportion of total misclassified results. Sensitivity and specificity are the probability of truly identifying relative tumor burden on multiparametric magnetic resonance imaging (mpMRI) respectively at a statistically established cut point.
Number of Participants With Reduction in Phosphatase and Tensin Homolog (PTEN) Levels post treatment, approximately 1-3 months PTEN level reduction was evaluated using immunohistochemistry in post treatment specimens. For anti-PTEN immunohistochemistry, a case was considered PTEN-reduced (abnormal) if at least 5% of tumor cells demonstrated reduced PTEN intensity relative to PTEN in benign cells (lower than 5%, then abnormal).
Median Prostate Lesion Volume Before and After Treatment Baseline and 6 months Prostate lesion volumes on baseline and post-treatment multiparametric magnetic resonance imaging (mpMRI) were calculated from T2W-MRI sequences using software embedded in the PACS after manual contouring by the same radiologist. Lesion volume scores were categorized as low (2 or fewer positive sequences), moderate (3 positive sequences) and high (4 positive sequences). Lesion volume values are in cubic centimeters (cc's).
Median Nuclear Androgen Receptor (AR) Level in Biopsy Specimens Versus Residual Tumors 6 months The effect of intense androgen suppression and inhibition was measured on tumors using anti-AR immunostains of biopsy and surgical specimens. Detection of tumor nuclear AR was quantified on a per-nucleus basis using computer-aided image analysis with Definiens Developer XD 64, grouping nuclei into high, medium, low, and absent bins, a histology score was assigned to each sample.
Nucleus classification is low vs. med. at 0.7; med. vs. high at 0.95. Definiens reported the total # of positively stained nuclei or cells, along with the distribution of low-, med.-, and high-intensity stained nuclei/cells for ea. tumor focus. A %positive index score was calculated using a weighted avg. divided by the total # of objects, where index = \[ (1 × nuclei/cells stained low) + (2 × nuclei/cells stained med.) + (3 × nuclei/cells stained high) \](3 × total nuclei).Number of Participants With a Complete Response After neoadjuvant treatment with androgen deprivation therapy (ADT) and enzalutamide, approximately 6 months Complete response was evaluated after neoadjuvant treatment with androgen deprivation therapy (ADT) and enzalutamide and assessed by pathologic exam. Pathologic complete response: the absence of residual invasive cancer confirmed by immunohistochemistry (IHC).
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) Date treatment consent signed to date off study, approximately 51 months and 2 days. Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Number of Prostate Lesions Detected Within the Study Population at Baseline Multi-parametric Magnetic Resonance Imaging (mpMRI) and 6 Months After Enzalutamide Plus Androgen Deprivation Therapy (ADT) Baseline and 6 months Prostate lesion volumes on baseline and post-treatment mpMRI were calculated from T2W-MRI sequences using software embedded in the PACS after manual contouring by the same radiologist.
Number of Participants With Positive Erythroblast Transformation-specific (ETS)-Related Gene (ERG) Protein Overexpression Approximately one month-3 months post-treatment ERG protein overexpression was evaluated using immunohistochemistry in post treatment specimens. A positive ETS-related ERG overexpression is a bad outcome.
Initial Multiparametric Magnetic Resonance Imaging (mpMRI) Percentage of Relative Tumor Volume Specificity 6 months The Youden index was used as a measure for evaluating biomarker effectiveness and was calculated to determine the cutoffs that gave the optimal combination of sensitivity and specificity for patient response to treatment. The index is: J=sensitivity + specificity -1. Its value ranges from 0 through 1 (inclusive). A value of 1 indicates that there are no false positives or false negatives, i.e. the test is perfect. The index gives equal weight to false positive and false negative values, so all tests with the same value of the index give the same proportion of total misclassified results. Sensitivity and specificity are the probability of truly identifying relative tumor burden on multiparametric magnetic resonance imaging (mpMRI) respectively at a statistically established cut point.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States