Clinical trial NCT02430480: Using Multiparametric MRI to Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed Prostate Cancer
Official title: Neoadjuvant Androgen Deprivation and Enzalutamide: Using Multiparametric MRI to Evaluate Intraprostatic Tumor Responses and Androgen Resistance Patterns in Newly Diagnosed Prostate Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Prostate Cancer
Keywords: Multiparametric MRI
Prostatectomy
Focal Prostate Cancer
Normal Testosterone
Non-Metastatic
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2015-04-30
Enrollment: 39
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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

Eligibility criteria: * INCLUSION CRITERIA:
* Patients must have histologically or cytologically confirmed prostate cancer confirmed by the Laboratory of Pathology, National Cancer Institute (NCI) or Pathology Department at Walter Reed Bethesda
* Must have previously untreated (with definitive therapy) prostate cancer with intermediate or high risk features defined as:

  * Intermediate risk:

    * Prostate-specific antigen, (PSA) level is between 10 and 20 ng/ml or
    * Gleason score is 7 or
    * Stage T2b or T2c
  * High Risk:

    * Gleason 8 and higher OR
    * PSA greater than 20 at the time of diagnosis OR
    * Seminal vesicle involvement OR
    * Possible (on magnetic resonance imaging (MRI) Extra-capsular extension (T3 disease)
* Patients must be eligible for and must be planning to undergo radical prostatectomy
* Patients must have testosterone levels greater than or equal to 100 ng/dL
* Men age greater than or equal to 18 years.

  * Children are excluded because prostate cancer is not common in pediatric populations.
  * Women are not eligible because this disease occurs only in men.
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1
* Patients must have normal organ and marrow function as defined below:
* Hemoglobin greater than or equal to 9 g/dL
* leukocytes greater than or equal to 3,000/mcL
* absolute neutrophil count greater than or equal to 1,500/mcL
* platelets greater than or equal to 150,000/mcL
* total bilirubin within normal institutional limits
* Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase(SGOT)/Alanine aminotransferase (ALT) Serum glutamic pyruvic transaminase (SGPT) less than or equal to 3 X institutional upper limit of normal
* creatinine within normal institutional limits

OR

* creatinine clearance greater than or equal to 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal.
* The effects of enzalutamide on the developing human fetus are unknown. For this reason and because androgen receptor antagonists as well as other therapeutic agents used in this trial are known to be teratogenic, male participants and their female partners of child bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence). Male participants should use a condom if having intercourse with a pregnant woman. Additionally, a condom plus another effective method of birth control is recommended during therapy and for 3 months after treatment for male participants having intercourse with a woman of reproductive potential. Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately.
* Ability of subject to understand and the willingness to sign a written informed consent document.
* Willingness to undergo biopsy.
* Ability to detect lesions within prostate on magnetic resonance imaging (MRI) for biopsy
* Willingness to travel to National Institutes of Health (NIH) for follow-up visits.

EXCLUSION CRITERIA:

* Patients who are receiving any other investigational agents (in the past 28 days) or herbal medications (within 1 day).
* Patients with distant metastatic disease beyond N1(regional) lymph nodes on conventional imaging studies (Computed tomography (CT), MRI or Bone Scan).
* Patients who have received any prior therapy for prostate cancer with surgery, radiation, and/or chemotherapy
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to enzalutamide or other agents used in study.
* Clinically significant cardiac disease, e.g. New York Heart Association (NYHA) classes III-IV; uncontrolled angina, uncontrolled arrhythmia or uncontrolled hypertension, myocardial infarction in the previous 6 months as confirmed by an electrocardiogram (ECG).
* Contraindication to biopsy:

  * Bleeding disorders
  * Prothrombin Time (PT)/Partial Thromboplastin Time (PTT) greater than or equal to 1.5 times the upper limit of normal
  * Artificial heart valve
* Contraindication to MRI:

  * Patients weighing more than weight limit for the scanner tables
  * Allergy to MR contrast agent
  * Patients with pacemakers, cerebral aneurysm clips, shrapnel injury or implantable electronic device
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Patients with known human immunodeficiency virus (HIV) are eligible. These patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. In addition, if patients are receiving combination antiretroviral therapy, there is potential for pharmacokinetic interactions with enzalutamide. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
* Patients with known active treatment for Hepatitis B and C infections.
* Patients who are taking medications that are strong inhibitors of Cytochrome P450 3A4 (CYP3A4) or P-glycoprotein (PgP) and need to remain on these medications. For a current table of Substrates, Inhibitors and Inducers please access the following website:

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm

* History of seizure, including any febrile seizure, loss of consciousness, or transient ischemic attack, or any condition that may pre-dispose to seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss of consciousness requiring hospitalization).
* Other medications used for urinary symptoms including 5-alpha reductase inhibitors (finasteride and dutasteride) and alternative medications known to alter prostate specific antigen (PSA) (eg phytoestrogens and saw palmetto) cannot be taken while patients are receiving enzalutamide
* Patients with a malignancy within the past 3 years for which study drugs or a prostatectomy is a contraindication.

Primary outcomes:
measure: Median Tumor Volume Burden at Baseline Multi-parametric Magnetic Resonance Imaging (mpMRI) Before and After Surgery
timeFrame: Baseline and 6 months
Secondary outcomes:
measure: Median Nuclear Androgen Receptor (AR) Level in Biopsy Specimens Versus Residual Tumors
timeFrame: 6 months
measure: Median Prostate Lesion Volume Before and After Treatment
timeFrame: Baseline and 6 months
measure: Number of Participants With a Complete Response
timeFrame: After neoadjuvant treatment with androgen deprivation therapy (ADT) and enzalutamide, approximately 6 months
measure: Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
timeFrame: Date treatment consent signed to date off study, approximately 51 months and 2 days.
measure: 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)
timeFrame: Baseline and 6 months
measure: Initial Multiparametric Magnetic Resonance Imaging (mpMRI) Percentage of Relative Tumor Volume Sensitivity
timeFrame: 6 months
measure: Number of Participants With Reduction in Phosphatase and Tensin Homolog (PTEN) Levels
timeFrame: post treatment, approximately 1-3 months
measure: Number of Participants With Positive Erythroblast Transformation-specific (ETS)-Related Gene (ERG) Protein Overexpression
timeFrame: Approximately one month-3 months post-treatment
measure: Initial Multiparametric Magnetic Resonance Imaging (mpMRI) Percentage of Relative Tumor Volume Specificity
timeFrame: 6 months
Other outcomes:
measure: Any Grade 1 Adverse Events in More Than One Patient and Grades 2 -3 Attributable to Research
timeFrame: Date treatment consent signed to date off study, approximately 51 months and 2 days.
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Fatima Karzai, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Karzai F, Walker SM, Wilkinson S, Madan RA, Shih JH, Merino MJ, Harmon SA, VanderWeele DJ, Cordes LM, Carrabba NV, Bright JR, Terrigino NT, Chun G, Bilusic M, Couvillon A, Hankin A, Williams MN, Lis RT, Ye H, Choyke PL, Gulley JL, Sowalsky AG, Turkbey B, Pinto PA, Dahut WL. Sequential Prostate Magnetic Resonance Imaging in Newly Diagnosed High-risk Prostate Cancer Treated with Neoadjuvant Enzalutamide is Predictive of Therapeutic Response. Clin Cancer Res. 2021 Jan 15;27(2):429-437. doi: 10.1158/1078-0432.CCR-20-2344. Epub 2020 Oct 6.
citation: Gold SA, VanderWeele DJ, Harmon S, Bloom JB, Karzai F, Hale GR, Marhamati S, Rayn KN, Mehralivand S, Merino MJ, Gulley JL, Bilusic M, Madan RA, Choyke PL, Turkbey B, Dahut W, Pinto PA. mpMRI preoperative staging in men treated with antiandrogen and androgen deprivation therapy before robotic prostatectomy. Urol Oncol. 2019 Jun;37(6):352.e25-352.e30. doi: 10.1016/j.urolonc.2019.01.012. Epub 2019 Apr 15.