Enzalutamide + External Beam Rt For Prostate

Study Overview
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Brief Summary
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This research study is evaluating a drug called enzalutamide in combination with external beam radiation therapy as a possible treatment for prostate cancer. Presently, when participants receive hormonal therapy with radiation therapy for prostate cancer, medications are given to reduce testosterone levels in the blood stream. This leads to side effects such as loss of sex drive, erectile dysfunction (ED) and decrease in muscle strength. The purpose of this study is test another form of hormonal therapy with radiation therapy. The medication called enzalutamide will be used with radiation therapy. Instead of lowering testosterone, enzalutamide blocks testosterone in cells. This study will test if enzalutamide when used with radiation will lower the PSA without causing the side effects associated with medications that lower testosterone in the blood stream.

Detailed Description
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The participant will be given a study drug-dosing diary for each of 6 treatment cycles. Each treatment cycle lasts 28 days (4 weeks), during which time the participant will be taking the study drug enzalutamide by mouth (4 pills daily). The diary will also include special instructions for taking the enzalutamide. The participant will also be undergoing external beam radiation therapy during the study, for a duration of 8 ½-10 weeks. Treatment will be administered on an outpatient basis. This part of the study is considered standard of care. The participant will be required to have fiducial markers placed within the prostate as part of this study. These are very small gold markers that are placed in the prostate. This procedure is similar to the biopsy that the participant had to diagnose their cancer. This procedure is routinely performed to permit imaging and position corrections to improve the precision of the external beam (radiation) delivery (Image Guided Radiation Therapy). The placement of the three gold markers is performed by an Urologist. The fiducials are placed under ultrasound guidance. This is also considered standard of care and is not experimental. Planned Follow-up: Participants will be followed on study at a 3 month follow-up after treatment (cessation of enzalutamide). Additional follow-up to assess the status of the participant's cancer will be conducted at the discretion of the treating physicians as part of the participant's routine medical care.

Official Title
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Enzalutamide With External Beam Radiation for Intermediate Risk Prostate Cancer: A Phase II Study

Conditions
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Intermediate Risk Prostate Cancer

Intervention / Treatment
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* Drug: Enzalutamide
* Radiation: External Beam Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study population: Participants must have histologically confirmed malignancy and are candidates for external beam radiation therapy. Patients eligible for this study must have intermediate risk disease defined as PSA values between 10-20 ng/ml and/or T2b-c and/or Gleason grade 7. If all three are present, less than 50% of the core biopsies can be positive. Patients previously diagnosed with low risk (Gleason score < 6, clinical stage < T2a, and PSA< 10) prostate cancer undergoing active surveillance who are re-biopsied and found to have intermediate risk disease according to the protocol criteria are eligible for enrollment within 180 days of the repeat biopsy procedure. Age 18 years or more. Life expectancy of greater than 1 year. ECOG performance status ≤ 2 (see Appendix D). Participants must have normal organ and marrow function as defined below: Leukocytes ≥3,000/mcL Platelets ≥80,000/mcL Total bilirubin < 2X institutional upper limit AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal Creatinine < 2x institutional limits . The effects of enzalutamide on the developing human fetus are unknown. For this reason and because enzalutamide may be teratogenic, men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Ability to understand and the willingness to sign a written informed consent Exclusion Criteria: Patients must NOT meet any of the following exclusion criteria Received an investigational agent within 4 weeks prior to enrollment Stage T4 prostate cancer by clinical examination or radiologic evaluation. Hypogonadism or severe androgen deficiency as defined by screening serum testosterone less than 50 ng/dL below the normal range for the institution. Prior androgen deprivation, chemotherapy, surgery, or radiation for prostate cancer. Receiving concurrent androgens, anti-androgens, estrogens, or progestational agents, or received any of these agents within the 6 months prior to enrollment or having taken finasteride or dutasteride within 30 days of registration. History of another active malignancy within the previous 5 years other than curatively treated nonmelanomatous skin cancer and superficial bladder cancer. Participants treated for malignancy with no relapse within two years are eligible to participate in the study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment. Unwilling to use contraceptives while on study if relevant to patient. History of seizure or any condition or concurrent medication that may predispose to seizure. History of loss of consciousness or transient ischemic attack within 12 months prior to enrollment. Clinically significant cardiovascular disease, including: Myocardial infarction within 3 months of enrollment; Uncontrolled angina within 3 months of enrollment; Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction ≥ 45%; History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes); History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place; Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 consecutive measurements at the Screening visit; Bradycardia as indicated by a heart rate < 50 beats per minute at the Screening visit; Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the screening visit; EKG demonstrating equal to or greater than grade III toxicity according the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 History of gastrointestinal disorders (medical disorders or extensive surgery) that may interfere with the absorption of oral study drug(s) within 3 months of enrollment. Major surgery within 4 weeks of registration. Previous use, or participation in a clinical trial, of an investigational agent that blocks androgen synthesis (e.g., abiraterone acetate, TAK-700, TAK-683, TAK-448) or targets the androgen receptor (e.g., enzalutamide, BMS 641988); ketoconazole. Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, places the patient at undue risk, or complicates the interpretation of safety data. Need for any of the medications on the list of drugs to be used with caution or to be avoided (see APPENDIX F). Use of herbal or alternative remedies that may affect hormonal status such as Prostasol or PC-SPES.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzalutamide with External Beam Radiation<br>Enzalutamide 40 mg orally 4x daily for 6 (28 day +/-3 days) cycles. External Beam Radiation Therapy (EBRT) - 7-10 weeks after beginning Enzalutamide 75.6 to 79.2 Gy in 1.8 Gy fractions for up to 11 weeks. *Patients that are unable to complete enzalutamide therapy will still be treated with EBRT | Drug: Enzalutamide<br> <br> * Other names: Xtandi;Radiation: External Beam Radiation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With PSA at or Below 0.2 ng/ml | Percentage of participants with PSA level of less than or equal to 0.2 ng/ml at the end of six cycles of enzalutamide and EBRT treatment. Post-treatment PSA nadir level has been shown to be a validated intermediate cancer endpoint in similar settings. The chosen cut-off of 0.2 ng/ml was informed by D'Amico et al Lancet Oncology 2012. PSA levels determined through established methods (blood draw and serum analysis). | End of treatment, up to 27 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median DHEA-S | Median DHEA-S, collected and assessed using established methods. Reference range is 28-640 ug/dL for adult males. | Assessed cycle 1, cycle 5, and end of treatment, up to 27 weeks | 
| Median Androstenedione | Median androstenedione, collected and assessed using established methods. Reference range is 40-150 ng/dL for adult males. | Assessed cycle 1, cycle 5, and end of treatment, up to 27 weeks | 
| Median Testosterone | Median testosterone, collected and assessed using established methods. Reference range is 300-1050 ng/dL for adult males. | Assessed cycle 1, cycle 5, and end of treatment, up to 27 weeks | 
| Median Free Testosterone | Median free testosterone, collected and assessed using established methods. Reference range is 350-1200 ng/dL for adult males. | Assessed cycle 1, cycle 5, and end of treatment, up to 27 weeks | 
| Median Estrone | Median estrone, collected and assessed using established methods. Reference range is 12-72 pg/mL for adult males. | Assessed cycle 1, cycle 5, and end of treatment, up to 27 weeks | 
| Median Estradiol | Median estradiol, collected and assessed using established methods. The reference range is 13-42 pg/mL for adult males. | Assessed cycle 1, cycle 5, and end of treatment, up to 27 weeks | 
| Median Bicep Fat Fold Measurement | Median bicep fat fold measurement taken at baseline and end of treatment. | At baseline and end of treatment, up to 27 weeks | 
| Median Tricep Fat Fold Measurement | Median tricep fat fold measurement taken at baseline and end of treatment. | At baseline and end of treatment, up to 27 weeks | 
| Median Shoulder Blade Fat Fold Measurement | Median shoulder blade fat fold measurement taken at baseline and end of treatment. | At baseline and end of treatment, up to 27 weeks | 
| Median Waist Fat Fold Measurement | Median waist fat fold measurement taken at baseline and end of treatment. | At baseline and end of treatment, up to 27 weeks | 
| Median Waist Circumference | Median waist circumference taken at baseline and end of treatment. | At baseline and end of treatment, up to 27 weeks | 
| Median Weight | Median weight taken at baseline and end of treatment. | At baseline and end of treatment, up to 27 weeks | 
| Number of Participants With a Sleep Quality Score of 0 or 1 | Sleep quality measure of the Pittsburgh Sleep Quality Index (PSQI) is scored from 0-3 [0=Very bad, 1=Fairly bad, 2=Fairly good, 3=Very good]. The higher the score, the better the sleep quality. | Measured at cycles 1, 3, and 5. | 
| Urinary Incontinence Median Score | Urinary incontinence evaluated using the Expanded-Prostate Index Composite - 26 (EPIC 26) EPIC-26 evaluates patient's urinary incontinence (4 items). The 4 items are reported on a scale of 0 - 100. A higher score indicates better urinary function. | Measured at cycles 1, 3, and 5. | 
| Urinary Irritation Median Score | Urinary irritation evaluated using the Expanded-Prostate Index Composite - 26 (EPIC 26). EPIC-26 evaluates urinary irritation/obstruction (4 items). The final score from the 4 items is reported on a scale of 0 - 100. A higher score indicates better urinary function. | Measured at cycles 1, 3, and 5. | 
| Bowel Function Median Score | Bowel function measure through the Expanded-Prostate Index Composite - 26 (EPIC 26). EPIC-26 evaluates patient's bowel (6 items). The 6 items are reported on a scale of 0 - 100. A higher score indicates better urinary function. | Measured at cycles 1, 3, and 5. | 
| Sexual Function Median Score | Sexual function measure through The Expanded-Prostate Index Composite - 26 (EPIC 26). EPIC-26 evaluates patient's sexual function (5 items). The 5 items are reported on a scale of 0 - 100.A higher score indicates better urinary function. | Measured at cycles 1, 3, and 5. | 
| Hormone Function Median Score | Hormone function evaluated by the Expanded-Prostate Index Composite - 26 (EPIC 26). EPIC-26 evaluates patient's hormonal function (5 items). The 5 items are reported on a scale of 0 - 100. A higher score indicates better urinary function. | Measured at cycles 1, 3, and 5. | 
| Number of Participants With a Fatigue Score of 3 or 4 | Feeling fatigue measure of the Patient-Reported Outcome Measurement Information System (PROMIS)-Fatigue Short Form is scored from 0-4 [0=Not at all, 1=A little bit, 2=Somewhat, 3=Quite a bit, 4=Very much]. The higher the score, the more fatigued the patient is. | Cycles 1, 3, and 5 | 
| Median Collagen Type 1 C-Telopeptide | Median Collagen Type 1 C-Telopeptide is a biomarker for bone metabolism measured and analyzed using established methods. Reference range for adult males is 60-1200 pg/mL | Measured at baseline, end of treatment, and at 3 month follow-up, up to 40 weeks | 
| Median Bone-Specific Alkaline Phosphatase | Median Bone-Specific Alkaline Phosphatase is a biomarker for bone metabolism measured and analyzed using established methods. Reference range for adult males is 7.5-69.8 ug/L | Measured at baseline, end of treatment, and at 3 month follow-up, up to 40 weeks | 
| Median Procollagen Type II Intact N Terminal Propeptide | Median Procollagen Type II Intact N Terminal Propeptide is a biomarker for bone metabolism measured and analyzed using established methods. Reference range for adult males is 22-87 ug/L | Measured at baseline, end of treatment, and at 3 month follow-up, up to 40 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intermediate Risk Prostate Cancer