Dexamethasone Prior to Re-treatment With Enzalutamide in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer Previously Treated With Enzalutamide and Docetaxel

Study Overview
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Brief Summary
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This pilot trial studies how well dexamethasone and re-treatment with enzalutamide work in treating patients with prostate cancer that has spread to other places in the body (metastatic), does not respond to hormone therapy (hormone-resistant), and was previously treated with enzalutamide and docetaxel. Dexamethasone treatment may be able to reverse one resistance mechanism to enzalutamide therapy (overabundance of receptors for dexamethasone and other glucocorticoids inside cancer cells) and allow for renewed therapeutic sensitivity to enzalutamide. Androgens (a type of male hormone) can bind to androgen receptors found inside prostate cancer cells, which may cause the cancer cells to grow. Enzalutamide may stop the growth of prostate cancer cells by blocking the activity of the cancer cell androgen receptors. Giving dexamethasone prior to re-treatment with enzalutamide may be a treatment for prostate cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the prostate-specific antigen (PSA) response rate to enzalutamide (Enza) after treatment with dexamethasone (Dex) therapy. SECONDARY OBJECTIVES: I. Objective response rate to Enza in patients with measurable disease on computed tomography (CT) scan using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. II. Time to PSA progression (based upon Prostate Cancer Working Group 2 [PCWG2] criteria) for treatment with Dex. III. Effect of each treatment on quality of life as assessed by patient completion of validated instruments (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue Scale, RAND Short Form-36 [RANDSF-36]). IV. PSA response rates to Dex for patients who are androgen receptor splice variant 7 (AR-V7) positive and AR-V7 negative, respectively, at study entry. V. Response rates to Enza for patients who are AR-V7 positive and AR-V7 negative, respectively, at study entry. VI. Percentage of patients who are AR-V7 positive at study entry who are AR-V7 negative at time of initiation of Enza, or vice-versa. OUTLINE: Patients receive dexamethasone orally (PO) once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity until there is evidence of PSA progression, clinical disease progression, or radiographic disease progression. At time of progression, dexamethasone will be stopped via a rapid taper over one week if patients were treated for over 30 days. Patients then receive enzalutamide PO once daily on days 1-28. Treatment repeats every 28 days for up to 3 courses in the absence of clinical disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.

Official Title
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A Pilot Study of Dexamethasone Therapy Prior to Rechallenge With Enzalutamide in Men With Metastatic Castration-Resistant Prostate Cancer Dex EXTends Enza Response (The DEXTER Trial)

Conditions
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Hormone-Resistant Prostate Cancer, Metastatic Prostate Carcinoma, Prostate Adenocarcinoma, Stage IV Prostate Cancer

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Enzalutamide
* Other: Laboratory Biomarker Analysis
* Other: Quality-of-Life Assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed adenocarcinoma of the prostate Patients must have metastatic disease radiographically documented by CT/magnetic resonance imaging (MRI) or bone scan; measurable disease is not necessary for inclusion Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) Life expectancy of greater than 3 months in the opinion of the investigator Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Hemoglobin >= 8; transfusion is allowed Total bilirubin =< 1.5 x institutional upper limit of normal Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal Creatinine clearance >= 30 by Cockcroft-Gault formula Patients must have progression after prior treatment with Enza at any point in the disease course (pre- or post-chemotherapy) Patients must have progressed after prior treatment with docetaxel; docetaxel must have specifically been given for castration-resistant metastatic disease Prior treatment with other second line hormone therapy is allowed (e.g. flutamide, bicalutamide, nilutamide, ketoconazole, abiraterone, ARN-509); patients must be off these therapies for at least 4 weeks prior to starting treatment Prior treatment with Xofigo (223Radium), Provenge, mitoxantrone and cabazitaxel is allowed Patients must have rising PSA on two successive measurements, at least 2 weeks apart Patient must be treated with continuous androgen ablative therapy (e.g. goserelin, leuprolide, triptorelin, or degarelix, if he has not had prior surgical castration) and have castrate levels of testosterone (< 50 ng/dL or 1.7 nmol/L) Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier (persistent toxicity >= grade 1) Patients who have received any other investigational agents within the last 4 weeks History of allergic reactions attributed to compounds of similar chemical or biologic composition to Dex or Enza Any use of systemic corticosteroids in the prior 4 weeks Uncontrolled diabetes mellitus History of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, and brain arteriovenous malformations Patients receiving any medications or substances that are inhibitors or inducers of cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible (e.g. gemfibrozil, rifampin, trimethoprim, pioglitazone) 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 or geographical condition that would limit compliance with study requirements

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: Treatment (dexamethasone and enzalutamide)<br>Patients receive dexamethasone PO once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity until there is evidence of PSA progression, clinical disease progression, or radiographic disease progression. At time of progression, dexamethasone will be stopped via a rapid taper over one week if patients were treated for over 30 days. Patients then receive enzalutamide PO once daily on days 1-28. Treatment repeats every 28 days for up to 3 courses in the absence of clinical disease progression or unacceptable toxicity. | Drug: Dexamethasone<br>* Given PO<br>* Other names: Visumetazone;Drug: Enzalutamide<br>* Given PO<br>* Other names: Xtandi;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA Response Rate | PSA response rate is defined as the proportion of subjects with a >= 50% PSA decline from baseline level when starting enzalutamide and maintained for >= 4 weeks at any time-point after receiving enzalutamide. Will determine its corresponding 95% confidence interval. | Up to 4 weeks post-treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Quality of Life Assessment Scores, Assessed Using FACIT-Fatigue Scale and RANDSF-36 Surveys | Summary statistics of the scores will be reported at baseline before starting dexamethasone and each follow-up time during the treatment of dexamethasone and enzalutamide. Changes in quality of life scores over the course of the study will be computed and their significance will be evaluated by paired-sample t-tests. | Baseline to up to 4 weeks post-treatment | 
| Objective Response Rate to Enzalutamide in Patients With Measurable Disease on CT Scan | Will estimate 95% confidence interval. | Up to 4 weeks post-treatment | 
| Response Rate With Dexamethasone by AR-V7 Status at Study Entry |  | Baseline | 
| Response Rate With Enzalutamide by AR-V7 Status at Study Entry |  | Baseline | 
| Time to PSA Progression, Based Upon PCWG2 Criteria, for Treatment With Dexamethasone | Will be summarized using Kaplan-Meier approach. | Up to 4 weeks post-treatment | 
| Time to Radiographic Progression for Treatment With Dexamethasone | Will be summarized using Kaplan-Meier approach. | Up to 4 weeks post-treatment |