Focal Prostate Ablation With Androgen Deprivation and Novel Hormonal Therapy for Intermediate Risk Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine the proportion of men with residual/recurrent clinically significant prostate cancer (Grade Group ≥2 disease) in the ablated or unablated prostate tissue following the combination treatment of 6-months of androgen deprivation therapy, apalutamide, and partial ablation of the prostate in men with newly diagnosed non-metastatic intermediate risk prostate cancer; specifically, men with a histopathologic diagnosis of Grade Group 2 & 3, with prostate specific antigen level <20 ng/mL. And to assess the safety of the combination treatment of androgen deprivation therapy, apalutamide, and partial ablation of the prostate for the management of these patients.

Official Title
-----------------
Phase II Trial of Combination of Focal Prostate Ablation With Androgen Deprivation and Novel Hormonal Therapy for the Treatment of Intermediate Risk Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Apalutamide Oral Product
* Drug: Androgen Deprivation Therapy (ADT)
* Procedure: Focal Therapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects must have intermediate-risk PCa as defined by the below criteria: a. Favorable intermediate-risk PCa: i. ≤ clinical stage T2c, GG2, and PSA ≤ 10 ng/mL, and <50% positive biopsy cores with PCa b. Unfavorable intermediate-risk PCa: i. ≤ clinical stageT2c, GG2, and PSA 10-20 ng/mL, or ≥50% positive biopsy cores with PCa, or ii. ≤ clinical stage T2c, GG3, and PSA < 20 ng/mL Note: The PSA value for this inclusion criteria must be the value obtained just prior to the subject's MRI-TB that provided the initial histopathologic diagnosis. This is considered to be the subject's baseline PSA. If the MRI-TB which initially diagnosed the subject's PCa was obtained greater than 3-months from the time of study consent, then a repeat PSA should be completed for screening purposes to obtain a baseline PSA (unless one has been obtained for SOC at least 3-months after this initial biopsy in which case no repeat value is needed and this may be used for eligibility). This applies to all participants regardless of GG used for eligibility. Note: The histopathologic diagnosis must be obtained via MRI-TB, which for the purposes of the present study, is defined as both a systematic 12-core sextant random prostate biopsy and a targeted prostate biopsy. The targeted prostate biopsy can be performed via in-bore mpMRI prostate biopsy, cognitive mpMRI/ultrasound fusion prostate biopsy or software mpMRI/ultrasound fusion prostate biopsy. This MRI-TB must not be obtained greater than 1 year from the date of consent. No mpMRI evidence of extra-prostatic extension (EPE) or seminal vesicle invasion, and if seminal vesical invasion is suspected, it must be excluded by prostate biopsy. Subjects must have confirmed non-metastatic PCa following SOC screening for patients with unfavorable intermediate-risk PCa, a combination of computed tomography imaging of the abdomen and pelvis (CTAP) and technetium-99-mDP nuclear medicine bone scan (BS) and/or prostate-specific membrane antigen positron emission tomography (PSMA/PET) scan prior to enrollment. The imaging studies should be obtained within 6-months of enrollment. Additional imaging is not required for men with favorable intermediate-risk PCa. Subject must be male ≥ 18 years-old. Subjects must have a life expectancy of at least 10-years per the opinion of the treating investigator. Subjects must be designated as Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 or Karnofsky Performance Status Scale Score ≥ 60%, see Appendix A). Subjects must be fit to undergo general anesthesia and the FT surgical procedure, which includes adequate visualization of the prostate gland on transrectal ultrasound imaging, access to the urethra, perineum and rectum, as well as be tolerant of lithotomy positioning in the opinion of the treating investigator or the operating surgeon(s) if not the same as the treating investigator. Subjects must have adequate organ and marrow function as defined below: Hemoglobin ≥ 10 g/dL Leukocytes ≥ 3,000/mcL Absolute neutrophil count ≥ 1,500/mcL Platelets ≥ 100,000/mcL Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN Creatinine < 1.5 institutional ULN OR Calculated or measured creatinine clearance > 50 mL/min/1.73 m2 eGFR >30 mL/min using the MDRD (modification of diet and renal disease) formula Serum albumin ≥3.0 g/dL Serum potassium ≥3.5 mmol/L Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Subjects who are sexually active with a woman of childbearing potential must agree to use a condom with spermicidal foam/gel/film/cream/suppository and his partner must also be practicing a highly effective method of contraception (i.e., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system) during treatment and for 3-months following the last dose of apalutamide. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: 1. Subject has had prior or current PCa therapies, such as biologic, chemotherapy, hormone therapy, radiotherapy or surgery for PCa. Subjects may not have had undergone pelvic radiation, chemotherapy or immunotherapy treatment for a separate hematologic or visceral malignancy within 6-months of enrollment in the present study. 2. Subjects with locally advanced, nodal or metastatic prostate cancer. 3. Subjects who are unfit for pelvic mpMRI scanning (e.g., severe claustrophobia, permanent cardiac pacemaker, metallic implants that are likely to contribute to significant image artifacts, allergy or contraindication to gadolinium contrast agent. 4. History of allergy or intolerance to study drug components. 5. History of bilateral orchiectomy. 6. History of prior use of apalutamide. 7. If the subject has an uncontrolled or major debilitating inter-current illness that would contraindicate or implicate significant morbidity of the proposed combination treatment, which includes but is not limited to poorly-controlled diabetes mellitus, medical conditions requiring chronic continuous oxygen therapy, active urinary tract infection (i.e., the subject must have discontinued all antibiotic(s) for at least one week prior to first dose of study drug), seizure disorder, or psychiatric illness/social situation that would limit compliance with study requirements. 8. Subjects who are receiving any other investigational agents, or who have received other investigational agents in the past and who are no longer receiving these investigational agents may be eligible at the discretion of the principal investigator (PI). 9. Subjects with history of seizure or known condition that may pre-dispose to seizure, uncontrolled hypertension, unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within 12-months of consent to participate in the study. 10. Subjects who are unable to stop taking the following prohibited medications prior at least 4-weeks prior to initiating apalutamide treatment and throughout treatment with apalutamide will be excluded due to the risk of seizure: a. Aminophylline/theophylline b. Atypical antipsychotics (e.g., clozapine, olanzapine, risperidone, ziprasidone) c. Bupropion d. Lithium e. Meperidine and pethidine f. Phenothiazine antipsychotics (e.g., chlorpromazine, mesoridazine, thioridazine) g. Tricyclic and tetracyclic antidepressants (e.g., amitriptyline, desipramine, doxepin, imipramine, maprotiline, mirtazapine) 11. Judgment by the treating investigator or PI that the subject is unsuitable to participate in the study and the subject is unlikely to comply with study procedures, restrictions and requirements.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Focal Prostate Ablation + Androgen Deprivation + Novel Hormonal Therapy<br>A. Apalutamide 240 mg by mouth daily for a total of 6-months B. ADT therapy will consist of any generic luteinizing hormone-releasing hormone agonist which will provide either 6-months of treatment or two injections every 3-months. (e.g., one injection with a treatment period of 6 months or two injections, one at drug start and one 3-months later). C. Focal therapy to be completed within 8- to 12-weeks of the initiation of apalutamide but after the completion of the 8-week mpMRI to allow for it to be used in FT planning | Drug: Apalutamide Oral Product<br>* Apalutamide 240 mg by mouth daily for a total of 6-months.<br>Drug: Androgen Deprivation Therapy (ADT)<br>* ADT therapy will consist of any generic luteinizing hormone-releasing hormone agonist which will provide either 6-months of treatment or two injections every 3-months. (e.g., one injection with a treatment period of 6 months or two injections, one at drug start and one 3-months later).<br>Procedure: Focal Therapy<br>* Focal therapy to be completed within 8- to 12-weeks of the initiation of apalutamide but after the completion of the 8-week mpMRI to allow for it to be used in FT planning.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically significant prostate cancer (GG ≥2) Proportion in ablated tissue measured by mpMRI and MRI-TB. | Proportion of men with clinically significant prostate cancer (GG ≥2) in the ablated prostate tissue by performing a surveillance mpMRI and MRI-TB. GG stands for grade group, which is a way to describe prostate cancer. GG of ≥2 means intermediate (GG = 2 or 3) or high (GG = 4 or 5). | 6-months following FT | 
| Clinically significant prostate cancer (GG ≥2) Proportion in unablated tissue measured by mpMRI and MRI-TB. GG stands for grade group, which is a way to describe prostate cancer. GG of ≥2 means intermediate (GG = 2 or 3) or high (GG = 4 or 5). | Proportion of men with clinically significant prostate cancer (GG ≥2) in the unablated prostate tissue by performing a surveillance mpMRI and MRI-TB. GG stands for grade group, which is a way to describe prostate cancer. GG of ≥2 means intermediate (GG = 2 or 3) or high (GG = 4 or 5). | 6-months following FT | 
| Incidence of Adverse Events to measure Safety of combination treatment (measured by CTCAE v5) | Demonstrate the safety of combining ADT, apalutamide, and FT for the treatment of men with histopathologic diagnosis of GG 2 & 3 PCa, with PSA level < 20 ng/mL utilizing the NCI's CTCAE v.5 classification to quantify and characterize the incidence of AEs. | 12 months following FT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measuring change in genitourinary and sexual function and health-related quality of life (measured by HRQoL) | Define change in genitourinary and sexual function from baseline following ADT, apalutamide, and FT by measuring the subject's HRQoL | 6-and 12-months after FT | 
| PSA response to the combination treatment | Determine the PSA response to the combination treatment by measuring the subject's PSA at baseline (PSA at time of initial diagnosis) 3-months, 6-months, and 1-year from FT | Baseline, 3-months, 6-months, and 1-year from FT | 
| Proportion of men converting therapy or dying of prostate cancer during study | Determine the proportion of men converting to whole gland therapy (radical prostatectomy or radiation therapy) and/or requiring systemic therapy and/or developing metastases and/or dying of PCa during the course of study. | 12 months after FT | 
| Post Treatment biopsy with no prostate cancer | Determine the proportion of men without any prostate cancer on any post treatment prostate biopsy. | 6 months after FT | 
| Proportion of men with normal baseline serum | Determine the proportion of men with normal baseline serum testosterone who had testosterone recovery (defined as testosterone levels >300 ng/dL) at 6-, 9- and 12-months after FT. Testosterone recovery: Number of men who have recovered normal serum testosterone levels will be expressed as proportions of total number of eugonadal patients and the 95% confidence interval of the proportion will be presented. | 6-, 9- and 12-months after FT. |