Dex EXTends Enza Response (The DEXTER Trial) Dex EXTends Enza Response (The DEXTER Trial) Organization:

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    SKCCC Protocol #: J1548 ClinicalTrials.gov Identifier: NCT02491411

    TITLE: 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)

    Organization: Johns Hopkins Lead Site Principal Investigator: Samuel R. Denmeade, M.D.

    The Sidney Kimmel Comprehensive Cancer 1650 Orleans St, CRB-1, Room 1M45 Baltimore, MD 21231 Phone: 410-955-8875 Fax: 410-614-8397

    denmesa@jhmi.edu Co-Investigator: Benjamin A. Teply, M.D. Statistician: Hao Wang, PhD Lead Study Coordinator: Yan Tian Research Study Coordinator/Data Manager 550 North Broadway/ Suite 827 Baltimore, MD 21205 410-502-5101 Office 410-614-7287 Fax yantian@jhmi.edu Responsible Research Nurse: Irina Rifkind, RN Coordinating Center: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Samuel R. Denmeade, M.D. 1650 Orleans St, CRB-1, Room 1M45 Baltimore, MD 21231 Phone: 410-955-8875 Email: denmesa@jhmi.edu Participating Site: The Akron General Medical Center, Akron, OH Version # / Version Date: #1.0, Date 4/10/15 Version # / Version Date: #2.0, Date 09/17/2015 Version # / Version Date: #3.0, Date 08/24/2016

    mailto:yantian@jhmi.edu mailto:denmesa@jhmi.edu

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    SYNOPSIS Title: A Pilot Study of Dexamethasone Therapy Prior to Rechallenge with Enzalutamide in Men with Metastatic Castration-Resistant Prostate Cancer Phase of Study: Pilot Objectives: To determine if treatment with dexamethasone (Dex) followed by enzalutamide (Enza) provides PSA and objective response, in patients who have previously had disease progression after Enza. Prior treatment with docetaxel is allowed but not required. Study Design: The study is a single arm, open-label study wherein patients with metastatic castrate resistant prostate cancer (mCRPC) will be treated with Dex 2mg PO daily until PSA progression, then treated with Enza 160mg PO daily. Treatment Plan: Patients will be prescribed Dex 2mg tablets to take daily by mouth with food. All patients will receive a minimum of two months of Dex. Following PSA or radiographic progression of disease, patients will be prescribed Enza 160 mg (40 mg tablets x4) by mouth daily. Dex will be tapered and stopped over a one week period. Enza will be continued for three months, after which time patients will be assessed for response. All patients will come off study after 3 months of Enza. Patients without evidence of response to Enza will be offered other standard of care therapy or additional clinical trial. Patients demonstrating Enza response will come off trial and be allowed to continue Enza as standard of care therapy. Blood Samples for assessment of AR and AR-V expression will be taken at baseline and at time of initiation of Enza. Assessment of Response: Patients will have monthly PSA measurements. Disease will be assessed with bone scan and CT C/A/P at baseline, prior to initiation of Enza and at study conclusion. Progression will be defined by RECIST 1.1 and PCWG-2 criteria for soft tissue and bone metastasis, respectively. PSA response will be defined as 50% decrease in PSA from initiation of Enza. PSA progression will be defined by PCWG-2 criteria. Rationale: The treatment options are very limited for patients with metastatic prostate cancer whose disease has become resistant to hormonal therapy and chemotherapy. Initially, the disease responds to drugs such as Enza, which block the androgen receptor. However, prostate cancer becomes resistant to this therapy through several mechanisms, including changes in the cancer’s expression of the androgen receptor. Dex and other glucocorticoids are an established treatment for prostate cancer; they can provide pain control, relief of other cancer-related symptoms like anorexia and fatigue, as well as have a direct anti-cancer effect. The receptor for glucocorticoids is expressed on many advanced prostate cancers, and recent work has theorized that there is interaction between the glucocorticoid receptor and androgen receptor pathways. It is thought that using a drug to affect one of the receptors may change the expression patterns and signaling of the other receptor. Given that Dex has a known benefit, and that there is a likely interaction between the androgen

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    receptor and glucocorticoid receptor, this research aims to treat patients with medicines in sequence to attempt to achieve better responses to the therapies. By giving Dex and then transitioning to Enza at time of progression, patients may respond to Enza who may otherwise not have been responders to the therapy. In addition, the study will seek to identify whether there are characteristics of the cancer cells (specifically with regard to the androgen receptor expression and splicing) that predict response to the sequence of therapies. Study Population: Men with metastatic castration-resistant prostate cancer with progression after prior treatment with Enza. Prior treatment with docetaxel is allowed but not required. Number of Patients: 20 Treatment Sites: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; The Akron General Medical Center, Akron, OH Inclusion Criteria:

    1. Patients must have histologically or cytologically confirmed adenocarcinoma of the prostate

    2. Patients must have metastatic disease radiographically documented by CT/MRI or bone scan; measurable disease is not necessary for inclusion.

    3. Age ≥18 years. 4. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 5. Life expectancy of greater than 3 months in the opinion of the investigator 6. Patients must have acceptable organ and marrow function as defined below:

    • absolute neutrophil count ≥1,500/mcL • platelets ≥100,000/mcL • hemoglobin ≥ 8; transfusion is allowed • total bilirubin ≤1.5 × institutional upper limit of normal • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal • Creatinine clearance ≥30 by Cockcroft-Gault formula

    7. Patients must have progression after prior treatment with Enza at any point in the disease course (pre- or post-chemotherapy).

    8. Prior treatment with docetaxel is allowed but not required. 9. 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

    10. Prior treatment with Xofigo (223Radium), Provenge, mitoxantrone and cabazitaxel is allowed.

    11. Patients must have rising PSA on two successive measurements, at least 2 weeks apart. 12. 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 (

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    Exclusion Criteria: 1. 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) .

    2. Patients who are receiving any other investigational agents. 3. History of allergic reactions attributed to compounds of similar chemical or biologic

    composition to Dex or Enza. 4. Any use of systemic corticosteroids in the prior 4 weeks. 5. Uncontrolled diabetes mellitus 6. 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.

    7. Patients receiving any medications or substances that are inhibitors or inducers of CYP2C8 are ineligible (e.g. gemfibrozil, rifampin, trimethoprim, pioglitazone).

    8. 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.

    Study Endpoints: The primary endpoint:

    • Response rate to Enza after treatment with Dex therapy. Responses will be determined by PSA criteria as defined by Prostate Cancer Working Group (PCWG2) criteria. The baseline will be defined as the initiation of Enza. The percentage of patients with >50% PSA response on rechallenged with Enza will be the primary endpoint.

    The secondary endpoints/analysis:

    • Objective response rate to Enza in patients with measurable disease on CT scan using RECIST criteria.

    • Time to PSA progression (based upon PCWG2 criteria) for treatment with Dex. • Effect of each treatment on quality of life as assessed by patient completion of validated

    instruments. Quality of life assessments will be taken at study entry, periodically while on Dex and Enza, at time of progression on Dex, and at study completion.

    • PSA response rates to Dex for patients who are AR-V7 positive and AR-V7 negative, respectively, at study entry.

    • Response rates to Enza for patients who are AR-V7 positive and AR-V7 negative, respectively, at study entry.

    • Percentage of patients who are AR-V7 posi