Randomized Salvage Radiation Therapy Plus Enzalutamide Post Prostatectomy

Study Overview
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Brief Summary
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The primary hypothesis of this study is that outcomes for patients with biochemically recurrent prostate cancer following radical prostatectomy will be improved by the addition of enzalutamide for 6-months compared to standard-of-care salvage radiation therapy to allow for further study in the definitive phase III setting. This study builds on the prior success of high-dose bicalutamide (for 24 months) when combined with salvage external radiation therapy (XRT), while using a newer more potent anti-androgen for a shorter duration of time (6 months) in an effort to minimize adverse effects.

Detailed Description
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Enzalutamide is a second-generation androgen receptor signaling inhibitor that significantly prolongs survival in patients with metastatic castration-resistant prostate cancer who have received prior docetaxel chemotherapy 35,36. Enzalutamide has demonstrated activity in cells that overexpress the androgen receptor. Unlike previous androgen receptor blocker (ARB) agents, Enzalutamide does not display any agonist properties and blocks translocation of the ligand-receptor complex into the nucleus preventing DNA binding 33. Enzalutamide is an oral agent that is generally well tolerated and does not require concurrent steroid administration, which makes it an ideal candidate for combination with salvage radiation therapy (SRT). Finally, provocative preliminary Phase II data presented at the American Society of Clinical Oncology (ASCO) 2013 by M. Smith and colleagues assessed the efficacy and safety of 25-weeks ( 6-mos) of enzalutamide alone in prostate cancer of all stages who had never received hormone therapy; presenting with non-castrate testosterone levels ( 230 ng/dL). Enzalutamide alone for 6-mos achieved a high PSA response rate with efficacy similar to castration, but .in contrast to castration, bone mineral density (BMD) remained stable and metabolic variables were not substantially impacted. The trial described here differs from Radiation Therapy Oncology Group (RTOG) 96-01, RTOG 05-34 and RADICALS in several ways. First, the eligibility criteria are stricter; less favorable patients have been selected. Second, short-term ARB is being tested, while in RTOG 96-01 and RADICALS long-term ARB of 2-years was examined. Finally, and most importantly, we are testing the second generation ARB agent, enzalutamide, alone in combination with SRT as opposed to RTOG 05-34 and RADICALS which use androgen deprivation (AD). This trial is not intended to address the efficacy of SRT alone over observation. The complete response rate (a drop in PSA to undetectable levels) after SRT is 70%-80% and durable responses are observed in 30%-40% of patients. For these reasons, it is not feasible or appropriate to randomize men between observation and SRT. The more important issue is whether the proportion of durable responses is increased by altering the therapeutic approach, such as the use of enhanced ARB using enzalutamide.

Official Title
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Phase II Randomized Placebo-Controlled Double-Blind Study of Salvage Radiation Therapy (SRT) Plus Placebo Versus SRT Plus Enzalutamide in Men With High-Risk PSA-Recurrent Prostate Cancer After Radical Prostatectomy

Conditions
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Adenocarcinoma of the Prostate

Intervention / Treatment
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* Drug: Enzalutamide
* Radiation: SRT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide written informed consent and Health Insurance Portability and Accountability Act (HIPPA) authorization for the release of personal health information. Males aged 18 years of age and above Patients must have adenocarcinoma of the prostate gland Patients must have received primary treatment with radical prostatectomy. Patients must have evidence of biochemical (PSA) relapse after prostatectomy Patients must have PSA within study range Patients must have non-metastatic (M0) disease, as defined by a lack of metastases seen on CT scan of the chest/abdomen/pelvis and whole-body radionuclide 99Technetium (Tc) bone scan, (or sodium fluoride PET scan) taken within 3 months of study entry. Patients must have had node negative (pN0) disease found at the time of surgery. Patients must have non-castrate levels of serum testosterone levels within study range. Patients must not have previously received hormonal therapy (LHRH agonist, antiandrogen, or both), with the exception of neoadjuvant or adjuvant hormones given in conjunction with prostatectomy. Patients must have Eastern Cooperative Oncology Group (ECOG)performance status of 0-1, and life expectancy greater 3 years. Patients must have laboratory test results within the certain ranges Patients must be disease-free from prior malignancies for greater than 3 years, with the exception of non-melanoma skin cancers and superficial urothelial cancers. Patients must have the ability to swallow the study drug whole as a tablet or capsule. Throughout study, male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration or per local guidelines where these require additional description of contraceptive methods. Throughout the study, patients must use a condom if having sex with a pregnant woman. Exclusion Criteria: Currently active second malignancy Primary treatment with radiation therapy. Radiographic or clinical evidence of local-regional tumor recurrence, Concurrent use of other antiandrogens, estrogen-like agents, or 5a-reductase inhibitors. Use of systemic corticosteroids equivalent to prednisone (inhaled corticosteroids are permitted). Concurrent use of other anti-cancer agents or treatments. Serious concurrent medical illnesses (including uncontrolled major cardiac, pulmonary, Child-Pugh C liver or psychiatric diseases) or active major infections (including HIV, Hepatitis A-C). Clinically significant cardiovascular disease including: Myocardial infarction within 6 months of Screening visit. Uncontrolled angina within 3 months of Screening visit. Congestive heart failure (within certain ranges) History of clinically significant ventricular arrhythmias Prolonged corrected QT interval History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place. Hypotension within certain ranges Uncontrolled hypertension within certain ranges Medications which lowers seizure threshold. History of seizure or any condition that may predispose to seizure including, but not limited to underlying brain injury, stroke, primary brain tumors, brain metastases, or alcoholism. Also, history of loss of consciousness or transient ischemic attack within 12months of enrollment (Day 1 visit). Patients taking medications that may have adverse interactions with enzalutamide

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SRT plus Enzalutamide<br>Arm 2 (experimental): (SRT) Salvage radiation therapy (Three dimensional conformal radiation therapy (3D-CRT)/IMRT [Intensity-modulated radiation therapy]) 66.6-70.2 Gy as 1.8 Gy M-F for 37-39 fx PLUS Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT) | Drug: Enzalutamide<br>* Enzalutamide (MDV3100) 160 mg PO once daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT)<br>* Other names: XTANDI;|
| Placebo Comparator: SRT plus placebo<br>Arm 1 (control): Salvage radiation therapy (3D-CRT (Three dimensional conformal radiation therapy)/IMRT (Intensity-modulated radiation therapy)) 66.6-70.2 Gy given 1.8 Gy M-F for 37 -39 fx PLUS Placebo PO daily for 6 months (2 months prior to SRT, 2 months during SRT and 2 months following SRT) | Radiation: SRT<br>* Salvage radiation therapy (3D-CRT (Three dimensional conformal radiation therapy)/IMRT) 66.6-70.2 Gy given 1.8 Gy M-F for 37 -39 fx<br>* Other names: Salvage Radiation Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom of PSA (Prostate Specific Antigen) progression | The primary efficacy endpoint is the rate of Freedom-from-PSA-progression (FFPP) at 2-years. FFPP is defined as the time from randomization to the date of PSA progression. A subject who does not have PSA progression at the time of the analysis will be censored at the last date of PSA measurement. | 2 years from end of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local recurrence | Local recurrence within the radiation field (confirmed pathologically) at 2-years | 2 years from end of therapy | 
| Metastatic free survival rate | Metastasis-free survival (MFS) rates at 2 years. Metastasis-free survival will be defined as the time from the date of registration to date of evidence of systemic disease on bone scan or cross sectional imaging or death, which occurs first. | 2 years from the time of registration | 
| Adverse Events Encountered | Safety as assessed by NCI Common Toxicity Scales (v4.0) | At the end of therapy at months 2, 3, 4, 5, 6 and then every 3 months for 24 months | 
| How well participants tolerate treatment | Quality of life (QoL) tools to be used to determine participant tolerability of treatment will include FACT-P, European Organization for the Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ) -C30/QLQ-PR25, and SHIM. | During active treatment phase of study, at the end of therapy at months 2, 3, 4, 5, 6 and then every 3 months for 24 months | 
| Feasibility of achieving stated accrual | Compare anticipated accrual versus actual. | During active treatment phase of study, at the end of therapy at months 2, 3, 4, 5, 6 and then every 3 months for 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Salvage Radiation Therapy (SRT), Enzalutamide