<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/NCT03040791</url>
  </required_header>
  <id_info>
    <org_study_id>64121317.4.1001.5330</org_study_id>
    <nct_id>NCT03040791</nct_id>
  </id_info>
  <brief_title>Nivolumab in Prostate Cancer With DNA Repair Defects (ImmunoProst Trial)</brief_title>
  <acronym>ImmunoProst</acronym>
  <official_title>Nivolumab in Prostate Cancer With DNA Repair Defects (ImmunoProst Trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital Moinhos de Vento</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Hospital Moinhos de Vento</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Prostate Cancer (PC) is the most frequent cancer in men, accounting for 21% of new cases of&#xD;
      cancer in men in the United States. Among the four most incident tumors (breast, lung and&#xD;
      colorectal cancer); prostate cancer is the only that does not have any predictive biomarker&#xD;
      to guide the treatment. Even though the molecular heterogeneity of PC is well-documented,&#xD;
      treatment has not been molecularly stratified and the need for genetic prognostic and&#xD;
      predictive markers is critical.&#xD;
&#xD;
      DNA repair defects (DRD), mainly in the Homologous Recombination (HR) pathway (such as BRCA1,&#xD;
      BRCA2, ATM and CHEK2) are emerging as potential biomarkers in prostate cancer. It is well&#xD;
      known BRCA1 and BRCA2 carriers have better Progression-Free Survival (PFS) and Overall&#xD;
      Survival (OS) than non-carriers in ovarian cancer. Differently than ovarian tumors that BRCA&#xD;
      mutations provides a good prognosis, PC patients who harbor HR defects have a higher Gleason&#xD;
      score 6, an increased risk of recurrence and poor prognosis. The predictive role of DRD in PC&#xD;
      was demonstrated in a recent trial using Olaparib, a PARP inhibitor, in DRD carriers. This&#xD;
      trial showed 88% of response rate with Olaparib, a PARP inhibitor that acts in HR pathway by&#xD;
      synthetic lethality.&#xD;
&#xD;
      Recent data demonstrated important association between HR deficient high-grade serous ovarian&#xD;
      cancer (HGSOC), high neoantigen load and high expression of PD-1/PD-L1 compared with HR&#xD;
      proficient HGSOCs 10. This study showed that BRCA1 and BRCA2 mutations increase the number of&#xD;
      tumor-infiltrating lymphocytes (TILs) and confer a better prognosis. The unprecedented&#xD;
      success of immunotherapy in malignant disorders has provided evidence that the patient's&#xD;
      immune system can be improved to attack established tumors, mainly melanoma, non-small cell&#xD;
      lung cancer and kidney cancer. A high mutational burden increases the likelihood of the&#xD;
      development of specific neoepitopes that would confer clinical benefit from CTLA-4 and PD-1&#xD;
      blockade.&#xD;
&#xD;
      These data showed that specific DNA repair defects increase the mutational burden, the&#xD;
      expression of PD-1/PD-L1 and TILs; and could improve the response to immunotherapy in cancer.&#xD;
      This rationale was already tested in a trial that evaluated the PD-1 checkpoint inhibitor&#xD;
      Pembrolizumab in mismatch-repair deficient patients, a kind of DNA repair defect by&#xD;
      definition. This important trial showed that this DRD predicted clinical benefit of immune&#xD;
      checkpoint blockade in many types of cancer, especially colorectal cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase II, two-stage, multi-center, single-arm, and open-label trial of Nivolumab&#xD;
      (BMS-936558) in patients with metastatic castration-resistant prostate cancer (mCRPC) who&#xD;
      have progressed to a taxane-based chemotherapy regimen previously. Eligible patients must&#xD;
      have ECOG 0-2 and material for biomarker analysis. Prior enzalutamide, abiraterone and&#xD;
      cabazitaxel are permitted but not necessary to enrollment. The germline and somatic DRD&#xD;
      (BRCA1, BRCA2, ATM, PTEN, CHEK2, RAD51C, RAD51D, PALB2, MLH1, MSH2, MSH6, PMS2.) will be&#xD;
      assessed by T-NGS of metastatic sites or by liquid biopsy. The primary endpoint is PSA 50&#xD;
      response rate (PSA50, following the Prostate Cancer Working Group 3 criteria). The trial will&#xD;
      meet its endpoint if ≥ 3/29 men achieve a PSA50 response. The secondary endpoints will&#xD;
      include progression-free survival (PFS), overall survival, radiologic PFS, PSA response rate&#xD;
      at 6 and 12 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">June 1, 2018</start_date>
  <completion_date type="Anticipated">March 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2022</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>
    <intervention_model_description>This is a Phase II, two-stage, multi-center, single-arm, and open-label trial of Nivolumab (BMS-936558) in patients with mCRPC who have progressed to a taxane-based chemotherapy regimen previously.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>PSA response rate</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>PSA partial response is defined as a ≥ 50% decline in PSA from cycle 1 day 1 (baseline) PSA value. This PSA decline must be confirmed as sustained by a second PSA value obtained ≥ 3 weeks later.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to PSA progression</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PSA Response Rate at 6 and 12 months</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiological progression-free survival (rPFS)</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Radiographic Progression</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">38</enrollment>
  <condition>Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All patients will receive Nivolumab 240 mg every 14 days until progression or unacceptable toxicity</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Nivolumab</description>
    <arm_group_label>Nivolumab</arm_group_label>
    <other_name>BMS-936558</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically confirmed adenocarcinoma of the prostate with tumor tissue available&#xD;
             for molecular analyses. If archival tissue for biomarker analysis is not available&#xD;
             then the patient must be willing to have a further biopsy to obtain tumor tissue for&#xD;
             histological diagnosis.&#xD;
&#xD;
          2. Metastatic Castrate-resistant prostate cancer (mCRPC), defined by:&#xD;
&#xD;
               -  Disease progression despite androgen deprivation therapy (ADT) and may present as&#xD;
                  either a continuous rise in serum prostate-specific antigen (PSA) levels, the&#xD;
                  progression of pre-existing disease, and/or the appearance of new metastases.&#xD;
&#xD;
               -  Surgically or medically castrated, with testosterone levels of &lt; 50 ng/dL (&lt; 2.0&#xD;
                  nM). If the patient is being treated with GnRH or LHRH agonists or antagonists&#xD;
                  (patient who have not undergone orchiectomy), this therapy should be maintained.&#xD;
&#xD;
          3. Documented prostate cancer progression, during treatment with Docetaxel, as assessed&#xD;
             by the investigator with one of the following:&#xD;
&#xD;
               -  PSA progression is defined according the PCWG3 criteria: PSA increase, that is ≥&#xD;
                  50% and ≥ 2 ng/mL above the nadir, and which is confirmed by a second value ≥ 3&#xD;
                  weeks later (confirmed the rising trend).&#xD;
&#xD;
               -  Radiographic progression of visceral lesions or soft tissue disease by modified&#xD;
                  RECIST 1.1 criteria.&#xD;
&#xD;
               -  Progression of bone metastasis is defined according the Appendix B: Prostate&#xD;
                  Cancer Clinical Trials Working Group 3 (Adapted) two or more documented new bone&#xD;
                  lesions on a bone scan with or without PSA progression. Confirmation of ambiguous&#xD;
                  results by other imaging modalities (eg, CT or MRI) is obligatory. If Docetaxel&#xD;
                  chemotherapy is used more than once, this will be considered as one regimen.&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 Appendix A:&#xD;
             Performance Status Criteria&#xD;
&#xD;
          5. Life expectancy &gt; 24 weeks.&#xD;
&#xD;
          6. Age ≥ 18 years&#xD;
&#xD;
          7. At least 28 days since the completion of any prior anti-cancer therapy (except for&#xD;
             LHRH agonists or antagonists), including chemotherapy (taxane-based). Additionally,&#xD;
             clinically relevant treatment toxicities should have resolved to grade 1 or less prior&#xD;
             to start study treatment.&#xD;
&#xD;
          8. For hormonal treatment must be followed the guideline below:&#xD;
&#xD;
               -  No antiandrogens are allowed during the study period. The use of antiandrogens&#xD;
                  before study entry is permitted, but at least 28 days since the completion of&#xD;
                  prior antiandrogen are required (washout period).&#xD;
&#xD;
               -  Corticosteroids dose &gt; Prednisolone 10 mg/day (or equivalent) are allowed only if&#xD;
                  clinically indicated for medical conditions. At least 28 days since the&#xD;
                  completion of prior corticotherapy are required (washout period).&#xD;
&#xD;
          9. Agreeable to have all the biomarker studies including the fresh tumor biopsies if&#xD;
             needed.&#xD;
&#xD;
         10. Patients must have adequate organ function within 1 weeks prior enrollment to and&#xD;
             evidenced by:&#xD;
&#xD;
               -  Hemoglobin ≥ 9.0 g/dL&#xD;
&#xD;
               -  WBC &gt; 2.000/mm3&#xD;
&#xD;
               -  Absolute neutrophil count ≥ 1.500/mm3&#xD;
&#xD;
               -  Platelet count ≥ 100.000/mm3&#xD;
&#xD;
               -  Creatinine Clearance ≥ 30 mL/min. Creatinine Clearance (CrCl) must be calculated&#xD;
                  at screening using the Cockcroft-Gault formula:&#xD;
&#xD;
               -  Bilirubin &lt; 3 x upper limit of normal (ULN) except for patients with known&#xD;
                  Gilbert's syndrome.&#xD;
&#xD;
               -  Aspartate transaminase (AST) (SGOT) &lt; 3.0 x ULN.&#xD;
&#xD;
               -  Alanine transaminase (ALT) (SGPT) &lt; 3.0 x ULN.&#xD;
&#xD;
               -  No cardiac disease defined by as active angina, symptomatic congestive heart&#xD;
                  failure, or myocardial infarction within previous six months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with any active known or suspected autoimmune disease. Patients with&#xD;
             vitiligo, type I diabetes mellitus, controlled autoimmune hypothyroidism, psoriasis&#xD;
             not requiring systemic treatment, or other conditions under control are permitted to&#xD;
             enroll.&#xD;
&#xD;
          -  Patients with conditions that needs systemic corticosteroids dose &gt; Prednisolone 10&#xD;
             mg/day (or equivalent) or other immunosuppressive medications within 28 days prior to&#xD;
             the first dose of study drug. Inhaled steroids are permitted if necessary.&#xD;
&#xD;
          -  Patients with any known active chronic liver disease.&#xD;
&#xD;
          -  Patients who have prior history of malignancy treated with curative intention in the&#xD;
             past 2 years with the exception of basal cell carcinoma and squamous cell carcinoma of&#xD;
             the skin, which were allowed in any case. Patients with other malignancies that do not&#xD;
             fulfill the prior criteria could be considered for recruitment if they do not&#xD;
             represent a competitive cause of death and have a low potential to progress to&#xD;
             metastatic progression. Patients in this condition may be enrolled in the trial if&#xD;
             approved after review by principal investigator.&#xD;
&#xD;
          -  Known history of testing positive for human immunodeficiency virus (HIV), known&#xD;
             acquired immunodeficiency syndrome (AIDS), or any positive test for hepatitis B or&#xD;
             hepatitis C virus representing acute or chronic disease.&#xD;
&#xD;
          -  Preceding treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody, or any&#xD;
             other antibody or drug specifically targeting T-cell co-stimulation or checkpoint&#xD;
             pathways.&#xD;
&#xD;
          -  Major surgery less than 28 days prior to the first dose of study drug.&#xD;
&#xD;
          -  Radiation therapy less than 14 days prior to the first dose of study drug.&#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>Pedro Isaacsson, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital Moinhos de Vento</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Moinhos de Vento</name>
      <address>
        <city>Porto Alegre</city>
        <state>Rio Grande Do Sul</state>
        <zip>90035000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto do Câncer do Estado de São Paulo</name>
      <address>
        <city>Sao Paulo</city>
        <state>São Paulo</state>
        <zip>01246000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>January 27, 2017</study_first_submitted>
  <study_first_submitted_qc>January 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 2, 2017</study_first_posted>
  <last_update_submitted>August 24, 2021</last_update_submitted>
  <last_update_submitted_qc>August 24, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 26, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>prostate cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>At the end of study For 1 year</ipd_time_frame>
    <ipd_access_criteria>RedCap / Excel</ipd_access_criteria>
  </patient_data>
  <!-- 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/NCT03040791
org study id: 64121317.4.1001.5330
nct id: NCT03040791
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Prostate Cancer (PC) is the most frequent cancer in men, accounting for 21% of new cases of
      cancer in men in the United States. Among the four most incident tumors (breast, lung and
      colorectal cancer); prostate cancer is the only that does not have any predictive biomarker
      to guide the treatment. Even though the molecular heterogeneity of PC is well-documented,
      treatment has not been molecularly stratified and the need for genetic prognostic and
      predictive markers is critical.

      DNA repair defects (DRD), mainly in the Homologous Recombination (HR) pathway (such as BRCA1,
      BRCA2, ATM and CHEK2) are emerging as potential biomarkers in prostate cancer. It is well
      known BRCA1 and BRCA2 carriers have better Progression-Free Survival (PFS) and Overall
      Survival (OS) than non-carriers in ovarian cancer. Differently than ovarian tumors that BRCA
      mutations provides a good prognosis, PC patients who harbor HR defects have a higher Gleason
      score 6, an increased risk of recurrence and poor prognosis. The predictive role of DRD in PC
      was demonstrated in a recent trial using Olaparib, a PARP inhibitor, in DRD carriers. This
      trial showed 88% of response rate with Olaparib, a PARP inhibitor that acts in HR pathway by
      synthetic lethality.

      Recent data demonstrated important association between HR deficient high-grade serous ovarian
      cancer (HGSOC), high neoantigen load and high expression of PD-1/PD-L1 compared with HR
      proficient HGSOCs 10. This study showed that BRCA1 and BRCA2 mutations increase the number of
      tumor-infiltrating lymphocytes (TILs) and confer a better prognosis. The unprecedented
      success of immunotherapy in malignant disorders has provided evidence that the patient's
      immune system can be improved to attack established tumors, mainly melanoma, non-small cell
      lung cancer and kidney cancer. A high mutational burden increases the likelihood of the
      development of specific neoepitopes that would confer clinical benefit from CTLA-4 and PD-1
      blockade.

      These data showed that specific DNA repair defects increase the mutational burden, the
      expression of PD-1/PD-L1 and TILs; and could improve the response to immunotherapy in cancer.
      This rationale was already tested in a trial that evaluated the PD-1 checkpoint inhibitor
      Pembrolizumab in mismatch-repair deficient patients, a kind of DNA repair defect by
      definition. This important trial showed that this DRD predicted clinical benefit of immune
      checkpoint blockade in many types of cancer, especially colorectal cancer.
This is a Phase II, two-stage, multi-center, single-arm, and open-label trial of Nivolumab
      (BMS-936558) in patients with metastatic castration-resistant prostate cancer (mCRPC) who
      have progressed to a taxane-based chemotherapy regimen previously. Eligible patients must
      have ECOG 0-2 and material for biomarker analysis. Prior enzalutamide, abiraterone and
      cabazitaxel are permitted but not necessary to enrollment. The germline and somatic DRD
      (BRCA1, BRCA2, ATM, PTEN, CHEK2, RAD51C, RAD51D, PALB2, MLH1, MSH2, MSH6, PMS2.) will be
      assessed by T-NGS of metastatic sites or by liquid biopsy. The primary endpoint is PSA 50
      response rate (PSA50, following the Prostate Cancer Working Group 3 criteria). The trial will
      meet its endpoint if ≥ 3/29 men achieve a PSA50 response. The secondary endpoints will
      include progression-free survival (PFS), overall survival, radiologic PFS, PSA response rate
      at 6 and 12 months.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is a Phase II, two-stage, multi-center, single-arm, and open-label trial of Nivolumab (BMS-936558) in patients with mCRPC who have progressed to a taxane-based chemotherapy regimen previously.
primary purpose: Treatment
masking: None (Open Label)
measure: PSA response rate
time frame: through study completion, an average of 1 year
description: PSA partial response is defined as a ≥ 50% decline in PSA from cycle 1 day 1 (baseline) PSA value. This PSA decline must be confirmed as sustained by a second PSA value obtained ≥ 3 weeks later.
measure: Time to PSA progression
time frame: through study completion, an average of 1 year
measure: PSA Response Rate at 6 and 12 months
time frame: through study completion, an average of 1 year
measure: Radiological progression-free survival (rPFS)
time frame: through study completion, an average of 1 year
measure: Time to Radiographic Progression
time frame: through study completion, an average of 1 year
measure: Progression free survival (PFS)
time frame: through study completion, an average of 1 year
measure: Overall survival
time frame: through study completion, an average of 1 year
arm group label: Nivolumab
arm group type: Experimental
description: All patients will receive Nivolumab 240 mg every 14 days until progression or unacceptable toxicity
intervention type: Drug
intervention name: Nivolumab
description: Nivolumab
arm group label: Nivolumab
other name: BMS-936558
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Pedro Isaacsson, MD
role: Principal Investigator
affiliation: Hospital Moinhos de Vento
facility: 
facility: 
country: Brazil
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
mesh term: Nivolumab
sharing ipd: Yes
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: At the end of study For 1 year
ipd access criteria: RedCap / Excel