<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02966587</url>
  </required_header>
  <id_info>
    <org_study_id>9768</org_study_id>
    <secondary_id>NCI-2016-01618</secondary_id>
    <secondary_id>9768</secondary_id>
    <secondary_id>P30CA015704</secondary_id>
    <nct_id>NCT02966587</nct_id>
  </id_info>
  <brief_title>Durvalumab in Treating Patients With Metastatic Hormone-Resistant Prostate Cancer</brief_title>
  <official_title>Durvalumab (MEDI4736) in Hypermutated Metastatic Castration-Resistant Prostate Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Washington</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well durvalumab works in treating patients with prostate&#xD;
      cancer that is resistant to hormones and has spread to other places in the body. Monoclonal&#xD;
      antibodies, such as durvalumab, may interfere with the ability of tumor cells to grow and&#xD;
      spread.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. Determine the response rate to durvalumab in metastatic castration-resistant prostate&#xD;
      cancer (mCRPC) patients with microsatellite instability (MSI), where response rate is defined&#xD;
      either according to modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1&#xD;
      criteria or a reduction in prostate specific antigen (PSA) level of &gt;= 50%.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Determine the percent of mCRPC patients with MSI achieving a radiographic response per&#xD;
      modified RECIST 1.1 criteria following treatment with durvalumab.&#xD;
&#xD;
      II. Determine the percent of mCRPC patients with MSI achieving a reduction in PSA level of &gt;=&#xD;
      50% following treatment with durvalumab.&#xD;
&#xD;
      III. Determine the radiographic progression free survival (PFS) in hypermutated mCRPC&#xD;
      patients with MSI treated with durvalumab using modified RECIST 1.1 criteria for soft tissue&#xD;
      metastases and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases.&#xD;
&#xD;
      IV. Determine the PSA PFS rate according to PCWG3 criteria in hypermutated mCRPC patients&#xD;
      with MSI treated with durvalumab.&#xD;
&#xD;
      V. Determine the time to response in hypermutated mCRPC patients with MSI treated with&#xD;
      durvalumab using modified RECIST 1.1 criteria.&#xD;
&#xD;
      VI. Determine the overall survival in hypermutated mCRPC patients with MSI treated with&#xD;
      durvalumab.&#xD;
&#xD;
      VII. Determine the change in PSA doubling time 12-weeks after the initiation of durvalumab.&#xD;
&#xD;
      VIII. Track pain as assessed by the Brief Pain Inventory during the course of treatment with&#xD;
      durvalumab.&#xD;
&#xD;
      IX. Assess the incidence and severity of adverse events according to the National Cancer&#xD;
      Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.&#xD;
&#xD;
      TERTIARY OBJECTIVES:&#xD;
&#xD;
      I. Determine mismatch repair gene mutational status and mutational load (by UWOncoPlex).&#xD;
&#xD;
      II. Determine mismatch repair gene mutational status, mutational load and microsatellite&#xD;
      stability from circulating tumor cells (CTCs) and/or cell-free tumor DNA (ctDNA).&#xD;
&#xD;
      III. PD-L1 expression by immunohistochemistry (IHC) and transcript profiling (e.g.&#xD;
      quantitative real-time polymerase chain reaction [qRT-PCR]).&#xD;
&#xD;
      IV. Determine the relative location of T-cells within the tumor microenvironment (i.e. stroma&#xD;
      vs. tumor edge) using CD3/CD8 IHC.&#xD;
&#xD;
      V. Evaluate for tumor specific T-cell responses in blood and within the tumor&#xD;
      microenvironment using next generation sequencing assays.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive durvalumab intravenously (IV) over 60 minutes on day 1. Courses repeat every&#xD;
      4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days, at 2, 3, 4, 6, 8,&#xD;
      and 10 months, and then every 6 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Withdrawn prior to opening to enrollment&#xD;
  </why_stopped>
  <start_date type="Anticipated">May 15, 2018</start_date>
  <completion_date type="Anticipated">May 15, 2023</completion_date>
  <primary_completion_date type="Anticipated">May 15, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Response rate to durvalumab defined according to modified RECIST 1.1 criteria or a reduction in PSA level &gt;= 50%</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be calculated as the percentage with 95% confidence interval (CI) of the total number of subjects that achieved a response.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events according to NCI-CTCAE version 4.0</measure>
    <time_frame>Up to 3 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>From the start of treatment until death from any cause, assessed up to 3 years</time_frame>
    <description>Will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PSA PFS</measure>
    <time_frame>From the start of treatment until PSA progression, assessed up to 3 years</time_frame>
    <description>Will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PSA response rate as defined per the PCWG3 criteria</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be reported as percentages with 95% CI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiographic PFS</measure>
    <time_frame>From the start of treatment until disease progression, clinical progression, or death, whichever occurs first, assessed up to 3 years</time_frame>
    <description>Will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiographic response rate defined as CR or PR using RECIST 1.1</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be reported as percentages with 95% CI.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Mismatch repair gene mutational status and mutational load determined by UW-OncoPlex</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be conducted on matched metastatic biopsies and ctDNA and/or CTCs. Baseline exploratory biomarker levels/values, as well as changes in these levels/values pre-/post-treatment will be correlated with the primary endpoint and secondary endpoints using chi-square tests and logistic regression, or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods and log-rank tests.</description>
  </other_outcome>
  <other_outcome>
    <measure>PD-L1 expression assessed by IHC and transcript profiling (e.g. qRT-PCR)</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be conducted on matched metastatic biopsies and ctDNA and/or CTCs. Baseline exploratory biomarker levels/values, as well as changes in these levels/values pre-/post-treatment will be correlated with the primary endpoint and secondary endpoints using chi-square tests and logistic regression, or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods and log-rank tests.</description>
  </other_outcome>
  <other_outcome>
    <measure>Relative location of T-cells using CD3/CD8 IHC</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be conducted on matched metastatic biopsies and ctDNA and/or CTCs. Baseline exploratory biomarker levels/values, as well as changes in these levels/values pre-/post-treatment will be correlated with the primary endpoint and secondary endpoints using chi-square tests and logistic regression, or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods and log-rank tests.</description>
  </other_outcome>
  <other_outcome>
    <measure>Tumor specific T-cell responses using next generation sequencing assays</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Will be conducted on matched metastatic biopsies and ctDNA and/or CTCs. Baseline exploratory biomarker levels/values, as well as changes in these levels/values pre-/post-treatment will be correlated with the primary endpoint and secondary endpoints using chi-square tests and logistic regression, or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods and log-rank tests.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Castration Levels of Testosterone</condition>
  <condition>Hormone-Resistant Prostate Cancer</condition>
  <condition>Microsatellite Instability</condition>
  <arm_group>
    <arm_group_label>Treatment (durvalumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive durvalumab IV over 60 minutes on day 1. Courses repeat every 4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (durvalumab)</arm_group_label>
    <other_name>Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer</other_name>
    <other_name>MEDI-4736</other_name>
    <other_name>MEDI4736</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Laboratory Biomarker Analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (durvalumab)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient must have evidence of castration resistant prostate cancer as evidenced by a&#xD;
             confirmed rising PSA (per Prostate Cancer Working Group 3 [PCWG3] criteria) and a&#xD;
             castrate serum testosterone level (i.e. =&lt; 50 mg/dL); if a subject also received an&#xD;
             anti-androgen, he must first progress through antiandrogen withdrawal prior to being&#xD;
             eligible; the minimum timeframe to document failure of anti-androgen withdrawal will&#xD;
             be four weeks&#xD;
&#xD;
          -  Patients must have received at least one of the approved products known to improve the&#xD;
             overall survival of patients with metastatic castration resistant prostate cancer&#xD;
             (i.e. abiraterone, enzalutamide, sipuleucel-t, radium-223, docetaxel or cabazitaxel)&#xD;
&#xD;
          -  Microsatellite instability as determined by MSI-plus assay&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent&#xD;
&#xD;
          -  Written informed consent and any locally-required authorization (e.g., Health&#xD;
             Insurance Portability and Accountability Act [HIPAA] authorization) obtained from the&#xD;
             subject prior to performing any protocol-related procedures, including screening&#xD;
             evaluations&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2&#xD;
&#xD;
          -  Life expectancy of &gt;= 4 months&#xD;
&#xD;
          -  Hemoglobin &gt;= 9.0 g/dL Note: patient may receive blood transfusion to achieve a&#xD;
             hemoglobin &gt;= 9.1 g/dL; however, hemoglobin must be stable at or above 9 g/dL two&#xD;
             weeks prior to dosing&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1.5 x 10^9 /L (&gt;= 1500 per mm^3)&#xD;
&#xD;
          -  Platelet count &gt;= 100 x 10^9/L (&gt;= 100,000 per mm^3)&#xD;
&#xD;
          -  Serum bilirubin =&lt; 1.5 x institutional upper limit of normal (ULN); this will not&#xD;
             apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent&#xD;
             hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or&#xD;
             hepatic pathology), who will be allowed only in consultation with their physician and&#xD;
             the study principal investigator (PI)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 2.5 x institutional upper limit of normal unless liver metastases are present, in&#xD;
             which case it must be =&lt; 5 x ULN&#xD;
&#xD;
          -  Serum creatinine clearance (CL) &gt; 40 mL/min by the Cockcroft-Gault formula or by&#xD;
             24-hour urine collection for determination of creatinine clearance&#xD;
&#xD;
          -  Subject is willing and able to comply with the protocol for the duration of the study&#xD;
             including undergoing treatment and scheduled visits and examinations including follow&#xD;
             up&#xD;
&#xD;
          -  Body weight &gt; 30 kg&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca&#xD;
             staff and/or staff at the study site)&#xD;
&#xD;
          -  Previous enrollment in the present study&#xD;
&#xD;
          -  Participation in another clinical study with an investigational product during the&#xD;
             last 14 days&#xD;
&#xD;
          -  Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab&#xD;
&#xD;
          -  History of another primary malignancy except for:&#xD;
&#xD;
               -  Malignancy treated with curative intent and with no known active disease &gt;= 5&#xD;
                  years before the first dose of study drug and of low potential risk for&#xD;
                  recurrence&#xD;
&#xD;
               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence&#xD;
                  of disease&#xD;
&#xD;
               -  Adequately treated carcinoma in situ without evidence of disease (e.g., cervical&#xD;
                  cancer in situ)&#xD;
&#xD;
          -  Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,&#xD;
             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal&#xD;
             antibodies, other investigational agent) =&lt; 28 days prior to the first dose of study&#xD;
             drug (if sufficient wash-out time has not occurred due to the schedule or&#xD;
             pharmacokinetics [PK] properties of an agent, a longer wash-out period may be&#xD;
             required)&#xD;
&#xD;
          -  Major surgical procedure (as defined by the local/lead site PI) within 28 days prior&#xD;
             to the first dose of investigational product (IP); Note: local surgery of isolated&#xD;
             lesions for palliative intent is acceptable&#xD;
&#xD;
          -  Ongoing systemic therapy (other than a luteinizing hormone-releasing hormone agonists&#xD;
             [LHRH] agonist/antagonist) for prostate cancer including, but not limited to:&#xD;
&#xD;
               -  CYP-17 inhibitors (e.g. ketoconazole, abiraterone)&#xD;
&#xD;
               -  Antiandrogens (e.g. bicalutamide, nilutamide)&#xD;
&#xD;
               -  Second generation antiandrogens (e.g. ARN-509)&#xD;
&#xD;
               -  Immunotherapy (e.g. sipuleucel-T)&#xD;
&#xD;
               -  Chemotherapy (e.g. docetaxel, cabazitaxel)&#xD;
&#xD;
               -  Radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium- 153)&#xD;
&#xD;
          -  QT interval corrected for heart rate using Fridericia's formula (QTcF) &gt;= 70 ms; any&#xD;
             clinically significant abnormalities detected, require triplicate electrocardiography&#xD;
             (ECG) results and a mean QT interval corrected for heart rate using Fridericia's&#xD;
             formula (QTcF) &gt;= 470 ms calculated from 3 ECGs&#xD;
&#xD;
          -  Current or prior use of immunosuppressive medication within 28 days before the first&#xD;
             dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or&#xD;
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of&#xD;
             prednisone, or an equivalent corticosteroid (steroids as pre-med for hypersensitivity&#xD;
             reactions eg. computed tomography (CT) scan premedication is acceptable)&#xD;
&#xD;
          -  Any unresolved toxicity (&gt; CTCAE grade 2) from previous anti-cancer therapy; subjects&#xD;
             with irreversible toxicity that is not reasonably expected to be exacerbated by the&#xD;
             investigational product may be included (e.g., hearing loss, peripherally neuropathy)&#xD;
&#xD;
          -  Any prior grade &gt;= 3 immune-related adverse event (irAE) while receiving any previous&#xD;
             immunotherapy agent, or any unresolved irAE &gt; grade 1&#xD;
&#xD;
          -  Active or prior documented autoimmune or inflammatory disorders (including&#xD;
             inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the&#xD;
             exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or&#xD;
             Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid&#xD;
             arthritis, hypophysitis, uveitis, etc]); the following are exceptions to this&#xD;
             criterion:&#xD;
&#xD;
               -  Patients with vitiligo or alopecia&#xD;
&#xD;
               -  Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone&#xD;
                  replacement&#xD;
&#xD;
               -  Any chronic skin condition that does not require systemic therapy&#xD;
&#xD;
               -  Patients without active disease in the last 5 years may be included but only&#xD;
                  after consultation with the study physician&#xD;
&#xD;
               -  Patients with celiac disease controlled by diet alone&#xD;
&#xD;
          -  History of primary immunodeficiency&#xD;
&#xD;
          -  History of allogeneic organ transplant&#xD;
&#xD;
          -  History of hypersensitivity to durvalumab or any excipient&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, symptomatic&#xD;
             congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac&#xD;
             arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, or&#xD;
             psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements or compromise the ability of the subject to give written informed consent&#xD;
&#xD;
          -  Active infection including tuberculosis (TB), hepatitis B, hepatitis C, or human&#xD;
             immunodeficiency virus. Note: TB testing will be at the discretion of the treating&#xD;
             physician and should be in line with local practice&#xD;
&#xD;
          -  History of leptomeningeal carcinomatosis&#xD;
&#xD;
          -  Receipt of live attenuated vaccination within 30 days prior to study entry or within&#xD;
             30 days of receiving durvalumab&#xD;
&#xD;
          -  Patients of reproductive potential who are not employing an effective method of birth&#xD;
             control; male patients of reproductive potential who are not willing to employ&#xD;
             effective birth control from screening to 90 days after the last dose of durvalumab&#xD;
             monotherapy, whichever is the longer time period&#xD;
&#xD;
          -  Any condition that, in the opinion of the local/lead site PI, would interfere with&#xD;
             evaluation of study treatment or interpretation of patient safety or study results&#xD;
&#xD;
          -  Brain metastases or spinal cord compression unless asymptomatic or treated and stable&#xD;
             off steroids and anti-convulsants for at least 14 days prior to study treatment start;&#xD;
             patients with suspected brain metastases at screening should have a CT/magnetic&#xD;
             resonance imaging (MRI) of the brain prior to study entry&#xD;
&#xD;
          -  Subjects with uncontrolled seizure&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael Schweizer</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fred Hutch/University of Washington Cancer Consortium</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Fred Hutch/University of Washington Cancer Consortium</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>November 15, 2016</study_first_submitted>
  <study_first_submitted_qc>November 15, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 17, 2016</study_first_posted>
  <last_update_submitted>January 12, 2018</last_update_submitted>
  <last_update_submitted_qc>January 12, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 17, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
    <mesh_term>Microsatellite Instability</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
    <mesh_term>Immunoglobulin G</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02966587
org study id: 9768
secondary id: NCI-2016-01618
secondary id: 9768
secondary id: P30CA015704
nct id: NCT02966587
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies how well durvalumab works in treating patients with prostate
      cancer that is resistant to hormones and has spread to other places in the body. Monoclonal
      antibodies, such as durvalumab, may interfere with the ability of tumor cells to grow and
      spread.
PRIMARY OBJECTIVES:

      I. Determine the response rate to durvalumab in metastatic castration-resistant prostate
      cancer (mCRPC) patients with microsatellite instability (MSI), where response rate is defined
      either according to modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
      criteria or a reduction in prostate specific antigen (PSA) level of >= 50%.

      SECONDARY OBJECTIVES:

      I. Determine the percent of mCRPC patients with MSI achieving a radiographic response per
      modified RECIST 1.1 criteria following treatment with durvalumab.

      II. Determine the percent of mCRPC patients with MSI achieving a reduction in PSA level of >=
      50% following treatment with durvalumab.

      III. Determine the radiographic progression free survival (PFS) in hypermutated mCRPC
      patients with MSI treated with durvalumab using modified RECIST 1.1 criteria for soft tissue
      metastases and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases.

      IV. Determine the PSA PFS rate according to PCWG3 criteria in hypermutated mCRPC patients
      with MSI treated with durvalumab.

      V. Determine the time to response in hypermutated mCRPC patients with MSI treated with
      durvalumab using modified RECIST 1.1 criteria.

      VI. Determine the overall survival in hypermutated mCRPC patients with MSI treated with
      durvalumab.

      VII. Determine the change in PSA doubling time 12-weeks after the initiation of durvalumab.

      VIII. Track pain as assessed by the Brief Pain Inventory during the course of treatment with
      durvalumab.

      IX. Assess the incidence and severity of adverse events according to the National Cancer
      Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

      TERTIARY OBJECTIVES:

      I. Determine mismatch repair gene mutational status and mutational load (by UWOncoPlex).

      II. Determine mismatch repair gene mutational status, mutational load and microsatellite
      stability from circulating tumor cells (CTCs) and/or cell-free tumor DNA (ctDNA).

      III. PD-L1 expression by immunohistochemistry (IHC) and transcript profiling (e.g.
      quantitative real-time polymerase chain reaction [qRT-PCR]).

      IV. Determine the relative location of T-cells within the tumor microenvironment (i.e. stroma
      vs. tumor edge) using CD3/CD8 IHC.

      V. Evaluate for tumor specific T-cell responses in blood and within the tumor
      microenvironment using next generation sequencing assays.

      OUTLINE:

      Patients receive durvalumab intravenously (IV) over 60 minutes on day 1. Courses repeat every
      4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, at 2, 3, 4, 6, 8,
      and 10 months, and then every 6 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Response rate to durvalumab defined according to modified RECIST 1.1 criteria or a reduction in PSA level >= 50%
time frame: Up to 3 years
description: Will be calculated as the percentage with 95% confidence interval (CI) of the total number of subjects that achieved a response.
measure: Incidence of adverse events according to NCI-CTCAE version 4.0
time frame: Up to 3 years
measure: Overall survival
time frame: From the start of treatment until death from any cause, assessed up to 3 years
description: Will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI.
measure: PSA PFS
time frame: From the start of treatment until PSA progression, assessed up to 3 years
description: Will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI.
measure: PSA response rate as defined per the PCWG3 criteria
time frame: Up to 3 years
description: Will be reported as percentages with 95% CI.
measure: Radiographic PFS
time frame: From the start of treatment until disease progression, clinical progression, or death, whichever occurs first, assessed up to 3 years
description: Will be presented with Kaplan-Meier curves, and the median survival with 95% CI will be calculated. Rates will be reported as percentages with 95% CI.
measure: Radiographic response rate defined as CR or PR using RECIST 1.1
time frame: Up to 3 years
description: Will be reported as percentages with 95% CI.
measure: Mismatch repair gene mutational status and mutational load determined by UW-OncoPlex
time frame: Up to 3 years
description: Will be conducted on matched metastatic biopsies and ctDNA and/or CTCs. Baseline exploratory biomarker levels/values, as well as changes in these levels/values pre-/post-treatment will be correlated with the primary endpoint and secondary endpoints using chi-square tests and logistic regression, or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods and log-rank tests.
measure: PD-L1 expression assessed by IHC and transcript profiling (e.g. qRT-PCR)
time frame: Up to 3 years
description: Will be conducted on matched metastatic biopsies and ctDNA and/or CTCs. Baseline exploratory biomarker levels/values, as well as changes in these levels/values pre-/post-treatment will be correlated with the primary endpoint and secondary endpoints using chi-square tests and logistic regression, or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods and log-rank tests.
measure: Relative location of T-cells using CD3/CD8 IHC
time frame: Up to 3 years
description: Will be conducted on matched metastatic biopsies and ctDNA and/or CTCs. Baseline exploratory biomarker levels/values, as well as changes in these levels/values pre-/post-treatment will be correlated with the primary endpoint and secondary endpoints using chi-square tests and logistic regression, or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods and log-rank tests.
measure: Tumor specific T-cell responses using next generation sequencing assays
time frame: Up to 3 years
description: Will be conducted on matched metastatic biopsies and ctDNA and/or CTCs. Baseline exploratory biomarker levels/values, as well as changes in these levels/values pre-/post-treatment will be correlated with the primary endpoint and secondary endpoints using chi-square tests and logistic regression, or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods and log-rank tests.
arm group label: Treatment (durvalumab)
arm group type: Experimental
description: Patients receive durvalumab IV over 60 minutes on day 1. Courses repeat every 4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.
intervention type: Biological
intervention name: Durvalumab
description: Given IV
arm group label: Treatment (durvalumab)
other name: Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
other name: MEDI-4736
other name: MEDI4736
intervention type: Other
intervention name: Laboratory Biomarker Analysis
description: Correlative studies
arm group label: Treatment (durvalumab)
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael Schweizer
role: Principal Investigator
affiliation: Fred Hutch/University of Washington Cancer Consortium
facility: 
country: United States
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
mesh term: Microsatellite Instability
mesh term: Durvalumab
mesh term: Immunoglobulins
mesh term: Antibodies, Monoclonal
mesh term: Immunoglobulin G