<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/NCT03821246</url>
  </required_header>
  <id_info>
    <org_study_id>18702</org_study_id>
    <secondary_id>NCI-2018-02805</secondary_id>
    <nct_id>NCT03821246</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Atezolizumab-Based Combination Therapy in Men With Localized Prostate Cancer Prior to Radical Prostatectomy</brief_title>
  <official_title>An Open-Label Multi-Center Phase II Study of Neoadjuvant Atezolizumab-Based Combination Therapy in Men With Localized Prostate Cancer Prior to Radical Prostatectomy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawrence Fong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Genentech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Francisco</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>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well atezolizumab works alone or in combination with&#xD;
      etrumadenant or tocilizumab in treating men with localized prostate cancer before radical&#xD;
      prostatectomy. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the&#xD;
      body's immune system attack the cancer, and may interfere with the ability of tumor cells to&#xD;
      grow and spread. Androgens can cause the growth of prostate cancer cells. IL-6 is expressed&#xD;
      by prostate cancer and within the tumor microenvironment and shown to enhance prostate cancer&#xD;
      and disease progression. Treatment with an anti-IL-6 antibody such as tocilizumab may inhibit&#xD;
      cancer progression. Giving atezolizumab in combination with etrumadenant or tocilizumab may&#xD;
      work better in treating prostate cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the impact of atezolizumab-based combination therapy on the composition and&#xD;
      function of tumor-infiltrating immune cells (TIICS).&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the safety and tolerability of atezolizumab-based combination therapy in&#xD;
      localized prostate cancer (PC).&#xD;
&#xD;
      II. To determine the clinical efficacy of atezolizumab-based combination therapy in localized&#xD;
      PC.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To characterize changes in the frequency and number of circulating immune cells following&#xD;
      atezolizumab-based combination therapy in localized PC.&#xD;
&#xD;
      II. To determine the impact of atezolizumab-based combination therapy on the composition and&#xD;
      phenotype of the tumor microenvironment.&#xD;
&#xD;
      III. To determine the impact of atezolizumab-based combination therapy on the circulating and&#xD;
      intratumoral T cell repertoire.&#xD;
&#xD;
      IV. To explore the role of novel imaging modalities to understand the immunologic and&#xD;
      clinical impact to immunotherapeutic approaches in localized PC.&#xD;
&#xD;
      V. To characterize changes in the gut microbiome associated with each therapeutic&#xD;
      combination.&#xD;
&#xD;
      OUTLINE: Patients are assigned sequentially to 1 of 2 groups.&#xD;
&#xD;
      COHORT A: Patients receive one cycle of atezolizumab intravenously (IV) over 30-60 minutes on&#xD;
      day 1 of a 14 day cycle prior to radical prostatectomy (RP).&#xD;
&#xD;
      COHORT B: Patients will receive 1 cycle of neoadjuvant atezolizumab and etrumadenant (AB928)&#xD;
      prior to RP; atezolizumab will be administered in an identical fashion as Cohort A.&#xD;
      Etrumadenant will be administered at a dose of 150 mg once daily, until 48 hours prior to RP.&#xD;
&#xD;
      COHORT C: Patients will receive 1 cycle of neoadjuvant atezolizumab and tocilizumab prior to&#xD;
      RP; atezolizumab will be administered in an identical fashion as Cohort A. Etrumadenant will&#xD;
      be administered at a dose of 6mg/kg.&#xD;
&#xD;
      Two more groups consisting of treatment with atezolizumab in combination with other drugs may&#xD;
      be added in the future.&#xD;
&#xD;
      RP will occur 21 days (+/- 7 days) following treatments on Cycle 1 Day 1. No further study&#xD;
      therapy will be administered following RP&#xD;
&#xD;
      Following RP, subjects will be followed at 6 weeks, 3 months, 6 months, and 12 months (from&#xD;
      date of RP), or until disease progression, whichever occurs sooner&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 30, 2019</start_date>
  <completion_date type="Anticipated">October 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">October 31, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of subjects who demonstrate a positive response to neoadjuvant atezolizumab and atezolizumab-based combination therapy for each Cohort of the study</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>A positive response is defined as a ≥40% increase in the number of infiltrating cluster of differentiation 3 (CD3) + T cells between the pre-treatment biopsy at baseline and the post-treatment RP specimen. Thus, a negative response is a &lt;40% increase. The primary endpoint will include all enrolled subjects who receive at least 1 dose of study treatment and undergo RP. Analysis of the primary endpoint will be performed for each cohort independently</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of treatment-related of adverse events</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>The number of treatment-related adverse events will be reported and classified per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sum of Pathologic complete response (pCR) and Minimal residual disease (MRD) rate</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Defined as defined as the absence of tumor on the gross specimen.Will be reported following standard pathologic review of the radical prostatectomy (RP) specimen. These will be reported in sum [pCR+ MRD) rate] and independently.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Pathologic complete response (pCR) rate</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Defined as defined as the absence of tumor on the gross specimen.Will be reported following standard pathologic review of the radical prostatectomy (RP) specimen. These will be reported in sum [pCR+ minimal residual disease (MRD) rate] and independently.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Minimal residual disease (MRD)</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Defined as the sum of the cross-sectional diameter of residual tumors =&lt; 0.5 cm. Will be reported following standard pathologic review of the RP specimen. These will be reported in sum (pCR+MRD rate) and independently.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prostate specific antigen (PSA) response</measure>
    <time_frame>Up to 12 months</time_frame>
    <description>Defined as &gt;= 50% decline in PSA. The PSA response proportion will be reported for each cohort.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">68</enrollment>
  <condition>Prostate Adenocarcinoma</condition>
  <condition>Prostate Cancer</condition>
  <condition>Localized Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>Cohort A (atezolizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive one (1) cycle of atezolizumab, 1200mg intravenously (IV) over 30-60 minutes on day 1 of a 14 day cycle. Radical Prostatectomy (RP) will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort B (atezolizumab, etrumadenant)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive one (1) cycle of atezolizumab, 1200mg intravenously (IV) over 30-60 minutes on day 1 of a 14 day cycle and etrumadenant will be taken at a dose of 150mg PO, once daily, until 48 hours prior to RP, for at least 12 days. Radical Prostatectomy (RP) will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort C (atezolizumab, tocilizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive one (1) cycle of neoadjuvant atezolizumab and one (1) cycle of tocilizumab, 6mg/kg will be administered IV on day 1 of a 14 day IV prior to RP; atezolizumab will be administered in an identical fashion as Cohort A. RP will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atezolizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Cohort A (atezolizumab)</arm_group_label>
    <arm_group_label>Cohort B (atezolizumab, etrumadenant)</arm_group_label>
    <arm_group_label>Cohort C (atezolizumab, tocilizumab)</arm_group_label>
    <other_name>MPDL 3280A</other_name>
    <other_name>MPDL 328OA</other_name>
    <other_name>MPDL-3280A</other_name>
    <other_name>MPDL3280A</other_name>
    <other_name>MPDL328OA</other_name>
    <other_name>RG7446</other_name>
    <other_name>RO5541267</other_name>
    <other_name>Tecentriq</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tocilizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Cohort C (atezolizumab, tocilizumab)</arm_group_label>
    <other_name>Actemra</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Etrumadenant</intervention_name>
    <description>Given Orally</description>
    <arm_group_label>Cohort B (atezolizumab, etrumadenant)</arm_group_label>
    <other_name>AB928</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically confirmed adenocarcinoma of the prostate.&#xD;
&#xD;
             a. Subjects with small cell or neuroendocrine PC are not eligible.&#xD;
&#xD;
          2. Eligible for radical prostatectomy as determined by urologic oncology surgeon, and&#xD;
             subject consents to proceeding with radical prostatectomy.&#xD;
&#xD;
             a. Deemed by urologic oncology surgeon to be appropriate for a&#xD;
             &quot;window-of-opportunity&quot;study.&#xD;
&#xD;
          3. Only patients with high-risk disease are eligible for the safety lead-in for each&#xD;
             cohort. Patients with intermediate-risk disease will be included after interim&#xD;
             analyses is complete for the corresponding cohort and the PI has determined that it is&#xD;
             safe to do so.&#xD;
&#xD;
          4. Availability of a representative tumor specimen that is suitable for the planned study&#xD;
             analyses, as determined by the Principal Investigator.&#xD;
&#xD;
               1. A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block&#xD;
                  (preferred) or at least 15 slides containing unstained, freshly cut, serial&#xD;
                  sections should be submitted along with an associated pathology report prior to&#xD;
                  study treatment. If only 10-14 slides are available, the patient may still be&#xD;
                  eligible for the study, after Principal Investigator approval has been obtained.&#xD;
&#xD;
               2. If archival tumor tissue is unavailable or is determined to be unsuitable for&#xD;
                  required testing, tumor tissue must be obtained from a biopsy performed at&#xD;
                  screening. Refer to Section 6.3 for additional information on tumor specimens&#xD;
                  collected at screening.&#xD;
&#xD;
          5. Subjects have not received any prior systemic or locally directed therapy for PC (see&#xD;
             exclusion criteria).&#xD;
&#xD;
          6. Age &gt;= 18 years&#xD;
&#xD;
          7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          8. Requirements for organ and marrow function:&#xD;
&#xD;
               -  Hemoglobin &gt;= 9 g/dL&#xD;
&#xD;
               -  - Participants must not have been transfused within 2 weeks prior to screening to&#xD;
                  meet this criterion&#xD;
&#xD;
               -  Absolute neutrophil count &gt;= 1,500/microliter (uL) without granulocyte&#xD;
                  colonystimulating factor support&#xD;
&#xD;
               -  Absolute lymphocyte count &gt;= 500/uL&#xD;
&#xD;
               -  Platelets &gt;= 100,000/uL without transfusion&#xD;
&#xD;
               -  Total bilirubin &lt; 1.5 x institutional upper limit of normal (ULN) (known Gilbert&#xD;
                  disease: &lt; 3 x ULN)&#xD;
&#xD;
               -  Alkaline phosphatase &lt; 2 x institutional ULN&#xD;
&#xD;
               -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT))&#xD;
                  =&lt; 2 x institutional ULN&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =&lt;&#xD;
                  2 x institutional ULN&#xD;
&#xD;
               -  International normalized ratio (INR) or activated partial thromboplastin time&#xD;
                  (aPTT) &lt; 1.5 x institutional ULN for subjects not receiving therapeutic&#xD;
                  anticoagulation&#xD;
&#xD;
               -  Creatinine clearance &gt;= 30 mL/min (calculated using the Cockcroft-Gault formula)&#xD;
&#xD;
               -  Serum creatinine &lt;=1.6 mg/dL (141 μmol/L) in female patients and ≤1.9 mg/dL (168&#xD;
                  μmol/L) in male patients . Patients with serum creatinine values exceeding limits&#xD;
                  may be eligible for the study if their estimated glomerular filtration rates&#xD;
                  (GFR) are &gt;30&#xD;
&#xD;
          9. Testosterone level &gt; 150 ng/dL.&#xD;
&#xD;
         10. Contraception: agreement to remain abstinent or use contraceptive measures, and&#xD;
             agreement to refrain from donating sperm as defined below:&#xD;
&#xD;
               1. With female partners of childbearing potential: men must remain abstinent or use&#xD;
                  a condom plus an additional contraceptive method that together result in a&#xD;
                  failure rate of &lt; 1% per year during the treatment period and for 4 months after&#xD;
                  the last dose of study treatment. Men must refrain from donating sperm during the&#xD;
                  same period&#xD;
&#xD;
               2. With pregnant female partners: men must remain abstinent or use a condom during&#xD;
                  the treatment period and for 4 months after the last dose of study treatment to&#xD;
                  avoid exposing the embryo&#xD;
&#xD;
               3. Abstinence: the reliability of sexual abstinence should be evaluated in relation&#xD;
                  to the duration of the clinical trial and the preferred and usual lifestyle of&#xD;
                  the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or&#xD;
                  postovulation methods) and withdrawal are not acceptable methods of contraception&#xD;
&#xD;
         11. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen &gt; 3&#xD;
             months.&#xD;
&#xD;
         12. Ability to understand a written informed consent document, and the willingness to sign&#xD;
             it.&#xD;
&#xD;
         13. Ability to comply with the study protocol, in the investigator's judgment.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Evidence of metastatic disease as determined by standard staging scans.&#xD;
&#xD;
             a. Staging scans should be performed per urologic standard of care for patients&#xD;
             undergoing radical prostatectomy [per American Urological Association (AUA)/National&#xD;
             Comprehensive Cancer Network (NCCN) guidelines].&#xD;
&#xD;
          2. Not a candidate for radical prostatectomy as determined by treating urologic oncology&#xD;
             surgeon&#xD;
&#xD;
          3. Any prior systemic therapy for PC, including antiandrogens, androgen deprivation&#xD;
             therapy [gonadotropin-releasing hormone (GnRH) agonist or antagonist], chemotherapy,&#xD;
             targeted therapy, immunotherapy, OR radiopharmaceuticals.&#xD;
&#xD;
             a. Subjects who are on finasteride or dutasteride must discontinue therapy and undergo&#xD;
             a washout period of 6 weeks to become eligible for the study. Screening procedures&#xD;
             should begin following the washout period&#xD;
&#xD;
          4. Prior radiotherapy for PC.&#xD;
&#xD;
          5. Any history of prior malignancy, except:&#xD;
&#xD;
               1. Non-melanoma skin cancer treated with curative intent&#xD;
&#xD;
               2. Carcinoma-in-situ (CIS) treated with curative intent, without evidence of&#xD;
                  recurrence or disease progression for 3 years&#xD;
&#xD;
               3. Appropriately treated Stage I uterine cancer&#xD;
&#xD;
               4. All other cancer: treated with curative intent and without evidence of disease on&#xD;
                  standard of care follow-up for 5 years&#xD;
&#xD;
          6. Active or history of autoimmune disease or immune deficiency, including, but not&#xD;
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus&#xD;
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid&#xD;
             antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre&#xD;
             syndrome, or multiple sclerosis, with the following exceptions:&#xD;
&#xD;
               1. Subjects with a history of autoimmune-related hypothyroidism who are on&#xD;
                  thyroid-replacement therapy, with a stable dose &gt; 3 months, are eligible for the&#xD;
                  study&#xD;
&#xD;
               2. Subjects with controlled type 1 diabetes mellitus who are on an insulin regimen,&#xD;
                  with a Glycated hemoglobin (hemoglobin A1C) &lt; 7.0 are eligible for the study. All&#xD;
                  subjects with controlled type 2 diabetes mellitus are eligible for the study&#xD;
&#xD;
               3. Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with&#xD;
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis are&#xD;
                  excluded from the study) are eligible for the study provided all of the following&#xD;
                  conditions are met:&#xD;
&#xD;
                    -  Rash covers &lt; 10% of body surface area&#xD;
&#xD;
                    -  Disease is well controlled at baseline and requires only low-potency topical&#xD;
                       steroids&#xD;
&#xD;
                    -  No occurrence of acute exacerbations of the underlying condition requiring&#xD;
                       psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic&#xD;
                       agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids&#xD;
                       within the previous 12 months&#xD;
&#xD;
          7. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis&#xD;
             obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or any evidence of&#xD;
             active, non-infectious pneumonitis requiring corticosteroids.&#xD;
&#xD;
          8. History of prior positive human immunodeficiency virus (HIV) test.&#xD;
&#xD;
          9. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (chronic or&#xD;
             acute).&#xD;
&#xD;
               1. Subjects with a past or resolved HBV infection are eligible for this study.&#xD;
&#xD;
               2. HCV positivity is defined as having a positive HCV antibody test followed by a&#xD;
                  positive HCV ribonucleic acid (RNA) test at screening; the HCV RNA test will only&#xD;
                  be performed for subjects who have a positive HCV antibody test.&#xD;
&#xD;
         10. Significant cardiovascular disease, such as New York Heart Association class III or&#xD;
             greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3&#xD;
             months prior to initiation of study treatment, unstable arrhythmia, or unstable&#xD;
             angina.&#xD;
&#xD;
         11. Active chronic obstructive pulmonary disease (COPD) requiring use of home oxygen (O2)&#xD;
             or systemic steroid therapy &gt; 10 mg prednisone (or equivalent) daily.&#xD;
&#xD;
         12. Asthma requiring systemic corticosteroids &gt; 10 mg prednisone (or equivalent) daily.&#xD;
             Inhaled corticosteroids for the treatment of asthma are permitted.&#xD;
&#xD;
         13. Major surgical procedure (including joint surgery) other than for diagnosis within 4&#xD;
             weeks prior to initiation of study treatment, or anticipation of need for a major&#xD;
             surgical procedure during the course of the study&#xD;
&#xD;
             a. Placement of central venous access catheter (e.g., port or similar) is not&#xD;
             considered a major surgical procedure and is therefore permitted.&#xD;
&#xD;
         14. Severe infection within 4 weeks prior to initiation of study treatment, including, but&#xD;
             not limited to, hospitalization for complications of infection, bacteremia, or severe&#xD;
             pneumonia.&#xD;
&#xD;
         15. Any other disease, metabolic dysfunction, physical examination finding, or clinical&#xD;
             laboratory finding that contraindicates the use of an investigational drug, may affect&#xD;
             the interpretation of the results, or may render the patient at high risk from&#xD;
             treatment complications.&#xD;
&#xD;
         16. Prior allogeneic stem cell or solid organ transplantation.&#xD;
&#xD;
         17. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study&#xD;
             treatment, or anticipation of need for such a vaccine during the course of the study&#xD;
             or within 5 months after the last dose of atezolizumab. Note: Because IL-6 inhibition&#xD;
             may interfere with the normal immune response to new antigen, patients should be&#xD;
             brought up to date on all recommended vaccinations, except for live vaccines, prior to&#xD;
             initiation of therapy with tocilizumab to maximize vaccine response.&#xD;
&#xD;
         18. Treatment with investigational therapy within 28 days prior to initiation of study&#xD;
             treatment.&#xD;
&#xD;
         19. Prior treatment with adenosine-axis inhibitors, cluster of differentiation 137 (CD137)&#xD;
             agonists or immune checkpoint blockade therapies, including anti-cytotoxic&#xD;
             T-lymphocyte-associated protein 4 (CTLA-4), ant-PD-1, and anti-PD-L1 therapeutic&#xD;
             antibodies.&#xD;
&#xD;
         20. Treatment with systemic immunostimulatory agents [including, but not limited to,&#xD;
             interferon and interleukin 2 (IL-2)] within 4 weeks or five half-lives of the drug&#xD;
             (whichever is longer) prior to initiation of study treatment.&#xD;
&#xD;
         21. Treatment with systemic immunosuppressive medication (including, but not limited to,&#xD;
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and&#xD;
             anti-tumor necrosis factor (TNF)- agents) within 2 weeks prior to initiation of study&#xD;
             treatment, or anticipation of need for systemic immunosuppressive medication during&#xD;
             the course of the study, with the following exceptions:&#xD;
&#xD;
               1. Patients who receive acute, low-dose systemic immunosuppressant medication or a&#xD;
                  one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of&#xD;
                  corticosteroids for a contrast allergy) are eligible for the study&#xD;
&#xD;
               2. Patients who receive mineralocorticoids (e.g., fludrocortisone), corticosteroids&#xD;
                  for chronic obstructive pulmonary disease (COPD) or asthma (=&lt; 10 mg prednisone&#xD;
                  or equivalent), or low-dose corticosteroids for orthostatic hypotension or&#xD;
                  adrenal insufficiency (=&lt; 10 mg prednisone or equivalent) are eligible for the&#xD;
                  study.&#xD;
&#xD;
         22. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies&#xD;
             or fusion proteins.&#xD;
&#xD;
         23. Known hypersensitivity to Chinese hamster ovary cell products or to any component of&#xD;
             the atezolizumab formulation.&#xD;
&#xD;
         24. Known allergy or hypersensitivity to any of the study drugs of their excipients.&#xD;
&#xD;
         25. Previous treatment with any cell-depleting therapies, including investigational agents&#xD;
             or approved therapies, some examples include: CAMPATH, anti-cluster of differentiation&#xD;
             4 (CD4), anti-cluster of differentiation 5 (CD5), anti-cluster of differentiation 3&#xD;
             (CD3), anti-Cluster of Differentiation 19 (CD19) and anti-Cluster of Differentiation&#xD;
             20 (CD20).&#xD;
&#xD;
         26. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6&#xD;
             months of baseline.&#xD;
&#xD;
         27. Previous treatment with tocilizumab (an exception to this criterion may be granted for&#xD;
             single dose exposure upon application to the Sponsor-Investigator on a case-by-case&#xD;
             basis).&#xD;
&#xD;
         28. Any previous treatment with alkylating agents such as chlorambucil, or with total&#xD;
             lymphoid irradiation.&#xD;
&#xD;
         29. History of severe allergic or anaphylactic reactions to human, humanized or murine&#xD;
             monoclonal antibodies.&#xD;
&#xD;
         30. Evidence of serious uncontrolled concomitant, nervous system, pulmonary, renal,&#xD;
             hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal&#xD;
             disease (including complicated diverticulitis, ulcerative colitis, or Crohn's&#xD;
             disease).&#xD;
&#xD;
         31. Any history of recent serious bacterial, viral, fungal, or other opportunistic&#xD;
             infections.&#xD;
&#xD;
         32. Primary or secondary immunodeficiency (history of or currently active) unless related&#xD;
             to primary disease under investigation.&#xD;
&#xD;
         33. Any medical or psychological condition that in the opinion of the principal&#xD;
             investigator would interfere with safe completion of the trial.&#xD;
&#xD;
         34. Pregnant women or nursing (breast feeding) mothers.&#xD;
&#xD;
         35. Neuropathies or other conditions that might interfere with pain evaluation unless&#xD;
             related to primary disease under investigation.&#xD;
&#xD;
         36. Patients with lack of peripheral venous access&#xD;
&#xD;
             Additional Exclusion Criteria for Cohort B (atezolizumab + etrumadenant):&#xD;
&#xD;
         37. Treatment with known P-glycoprotein (P-gp) substrates with a narrow therapeutic&#xD;
             window, administered orally (e.g., digoxin) within 4 weeks or 5 half-lives of the drug&#xD;
             (whichever is longer) prior to initiation of study treatment.&#xD;
&#xD;
         38. Treatment with known strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine,&#xD;
             phenobarbital, and St. John's Wort) and strong CYP3A4 inhibitors (eg,clarithromycin,&#xD;
             grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin,and&#xD;
             voriconazole) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior&#xD;
             to initiation of study treatment.&#xD;
&#xD;
         39. Treatment with known breast cancer resistance protein (BCRP) substrates with a narrow&#xD;
             therapeutic window, administered orally (e.g., prazosin, rosuvastatin) within 4 weeks&#xD;
             or 5 half-lives of the drug (whichever is longer) prior to initiation of study&#xD;
             treatment.&#xD;
&#xD;
             Additional Exclusion Criteria for Cohort C (atezolizumab + tocilizumab):&#xD;
&#xD;
         40. Known active infection or history of recurrent bacterial, viral, fungal, mycobacterial&#xD;
             or other infections, including, but not limited to, TB (i.e., has signs and symptoms&#xD;
             of TB) and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but&#xD;
             excluding fungal infections of nail beds.&#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>Lawrence Fong, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>UCSF HDFCCC Cancer Immunotherapy Program (CIP)</last_name>
    <phone>877-827-3222</phone>
    <email>HDFCCC.CIP@ucsf.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>UCSF HDFCCC Cancer Immunotherapy Program (CIP)</last_name>
      <phone>877-827-3222</phone>
      <email>HDFCCC.CIP@ucsf.edu</email>
    </contact>
    <investigator>
      <last_name>Lawrence Fong, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Alvin J. Siteman Cancer Center at Washington University</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Russell K. Pachynski</last_name>
      <phone>314-286-2341</phone>
      <email>rkpachynski@wustl.edu</email>
    </contact>
    <investigator>
      <last_name>Russell K. Pachynski</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>January 10, 2019</study_first_submitted>
  <study_first_submitted_qc>January 28, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 29, 2019</study_first_posted>
  <last_update_submitted>October 8, 2022</last_update_submitted>
  <last_update_submitted_qc>October 8, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 12, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of California, San Francisco</investigator_affiliation>
    <investigator_full_name>Lawrence Fong</investigator_full_name>
    <investigator_title>Professor in Residence</investigator_title>
  </responsible_party>
  <keyword>Neoadjuvant therapy</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>Atezolizumab</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT03821246
org study id: 18702
secondary id: NCI-2018-02805
nct id: NCT03821246
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This phase II trial studies how well atezolizumab works alone or in combination with
      etrumadenant or tocilizumab in treating men with localized prostate cancer before radical
      prostatectomy. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the
      body's immune system attack the cancer, and may interfere with the ability of tumor cells to
      grow and spread. Androgens can cause the growth of prostate cancer cells. IL-6 is expressed
      by prostate cancer and within the tumor microenvironment and shown to enhance prostate cancer
      and disease progression. Treatment with an anti-IL-6 antibody such as tocilizumab may inhibit
      cancer progression. Giving atezolizumab in combination with etrumadenant or tocilizumab may
      work better in treating prostate cancer.
PRIMARY OBJECTIVES:

      I. To determine the impact of atezolizumab-based combination therapy on the composition and
      function of tumor-infiltrating immune cells (TIICS).

      SECONDARY OBJECTIVES:

      I. To determine the safety and tolerability of atezolizumab-based combination therapy in
      localized prostate cancer (PC).

      II. To determine the clinical efficacy of atezolizumab-based combination therapy in localized
      PC.

      EXPLORATORY OBJECTIVES:

      I. To characterize changes in the frequency and number of circulating immune cells following
      atezolizumab-based combination therapy in localized PC.

      II. To determine the impact of atezolizumab-based combination therapy on the composition and
      phenotype of the tumor microenvironment.

      III. To determine the impact of atezolizumab-based combination therapy on the circulating and
      intratumoral T cell repertoire.

      IV. To explore the role of novel imaging modalities to understand the immunologic and
      clinical impact to immunotherapeutic approaches in localized PC.

      V. To characterize changes in the gut microbiome associated with each therapeutic
      combination.

      OUTLINE: Patients are assigned sequentially to 1 of 2 groups.

      COHORT A: Patients receive one cycle of atezolizumab intravenously (IV) over 30-60 minutes on
      day 1 of a 14 day cycle prior to radical prostatectomy (RP).

      COHORT B: Patients will receive 1 cycle of neoadjuvant atezolizumab and etrumadenant (AB928)
      prior to RP; atezolizumab will be administered in an identical fashion as Cohort A.
      Etrumadenant will be administered at a dose of 150 mg once daily, until 48 hours prior to RP.

      COHORT C: Patients will receive 1 cycle of neoadjuvant atezolizumab and tocilizumab prior to
      RP; atezolizumab will be administered in an identical fashion as Cohort A. Etrumadenant will
      be administered at a dose of 6mg/kg.

      Two more groups consisting of treatment with atezolizumab in combination with other drugs may
      be added in the future.

      RP will occur 21 days (+/- 7 days) following treatments on Cycle 1 Day 1. No further study
      therapy will be administered following RP

      Following RP, subjects will be followed at 6 weeks, 3 months, 6 months, and 12 months (from
      date of RP), or until disease progression, whichever occurs sooner
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of subjects who demonstrate a positive response to neoadjuvant atezolizumab and atezolizumab-based combination therapy for each Cohort of the study
time frame: Up to 12 months
description: A positive response is defined as a ≥40% increase in the number of infiltrating cluster of differentiation 3 (CD3) + T cells between the pre-treatment biopsy at baseline and the post-treatment RP specimen. Thus, a negative response is a <40% increase. The primary endpoint will include all enrolled subjects who receive at least 1 dose of study treatment and undergo RP. Analysis of the primary endpoint will be performed for each cohort independently
measure: Number of treatment-related of adverse events
time frame: Up to 12 months
description: The number of treatment-related adverse events will be reported and classified per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
measure: Sum of Pathologic complete response (pCR) and Minimal residual disease (MRD) rate
time frame: Up to 12 months
description: Defined as defined as the absence of tumor on the gross specimen.Will be reported following standard pathologic review of the radical prostatectomy (RP) specimen. These will be reported in sum [pCR+ MRD) rate] and independently.
measure: Rate of Pathologic complete response (pCR) rate
time frame: Up to 12 months
description: Defined as defined as the absence of tumor on the gross specimen.Will be reported following standard pathologic review of the radical prostatectomy (RP) specimen. These will be reported in sum [pCR+ minimal residual disease (MRD) rate] and independently.
measure: Rate of Minimal residual disease (MRD)
time frame: Up to 12 months
description: Defined as the sum of the cross-sectional diameter of residual tumors =< 0.5 cm. Will be reported following standard pathologic review of the RP specimen. These will be reported in sum (pCR+MRD rate) and independently.
measure: Prostate specific antigen (PSA) response
time frame: Up to 12 months
description: Defined as >= 50% decline in PSA. The PSA response proportion will be reported for each cohort.
arm group label: Cohort A (atezolizumab)
arm group type: Experimental
description: Patients receive one (1) cycle of atezolizumab, 1200mg intravenously (IV) over 30-60 minutes on day 1 of a 14 day cycle. Radical Prostatectomy (RP) will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.
arm group label: Cohort B (atezolizumab, etrumadenant)
arm group type: Experimental
description: Patients will receive one (1) cycle of atezolizumab, 1200mg intravenously (IV) over 30-60 minutes on day 1 of a 14 day cycle and etrumadenant will be taken at a dose of 150mg PO, once daily, until 48 hours prior to RP, for at least 12 days. Radical Prostatectomy (RP) will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.
arm group label: Cohort C (atezolizumab, tocilizumab)
arm group type: Experimental
description: Patients will receive one (1) cycle of neoadjuvant atezolizumab and one (1) cycle of tocilizumab, 6mg/kg will be administered IV on day 1 of a 14 day IV prior to RP; atezolizumab will be administered in an identical fashion as Cohort A. RP will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.
intervention type: Drug
intervention name: Atezolizumab
description: Given IV
arm group label: Cohort A (atezolizumab)
arm group label: Cohort B (atezolizumab, etrumadenant)
arm group label: Cohort C (atezolizumab, tocilizumab)
other name: MPDL 3280A
other name: MPDL 328OA
other name: MPDL-3280A
other name: MPDL3280A
other name: MPDL328OA
other name: RG7446
other name: RO5541267
other name: Tecentriq
intervention type: Drug
intervention name: Tocilizumab
description: Given IV
arm group label: Cohort C (atezolizumab, tocilizumab)
other name: Actemra
intervention type: Drug
intervention name: Etrumadenant
description: Given Orally
arm group label: Cohort B (atezolizumab, etrumadenant)
other name: AB928
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lawrence Fong, MD
role: Principal Investigator
affiliation: University of California, San Francisco
last name: UCSF HDFCCC Cancer Immunotherapy Program (CIP)
phone: 877-827-3222
email: HDFCCC.CIP@ucsf.edu
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of California, San Francisco
investigator full name: Lawrence Fong
investigator title: Professor in Residence
mesh term: Prostatic Neoplasms
mesh term: Atezolizumab
mesh term: Antibodies, Monoclonal
sharing ipd: No