<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/NCT03805594</url>
  </required_header>
  <id_info>
    <org_study_id>185511</org_study_id>
    <secondary_id>NCI-2018-02993</secondary_id>
    <secondary_id>R01CA229354</secondary_id>
    <nct_id>NCT03805594</nct_id>
  </id_info>
  <brief_title>177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Castration-Resistant Prostate Cancer</brief_title>
  <official_title>Immunogenic Priming With PSMA-Targeted Radioligand Therapy in Advanced Prostate Cancer: A Phase 1b Study of 177Lu-PSMA-617 in Combination With Pembrolizumab</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Prostate Cancer Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</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 Ib trial studies the dose and schedule of 177Lu-PSMA-617 and pembrolizumab in&#xD;
      treating patients with castration-resistant prostate cancer that has spread to other places&#xD;
      in the body. 177Lu-PSMA-617 carries a radioactive component which attached to the prostate&#xD;
      specific membrane antigen (PSMA) receptor found on tumor cells. Its radiation component&#xD;
      destroys the tumor cell. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may&#xD;
      help the body?s immune system attack the cancer, and may interfere with the ability of tumor&#xD;
      cells to grow and spread. Giving 177Lu-PSMA-617 and pembrolizumab may work better at treating&#xD;
      prostate cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
        1. To determine the recommended phase 2 dose and schedule of lutetium Lu 177-PSMA-617&#xD;
           (177Lu-PSMA-617) in combination with pembrolizumab in patients with metastatic&#xD;
           castration-resistant prostate carcinoma (mCRPC). (Part A)&#xD;
&#xD;
        2. To determine the objective response rate by Response Evaluation Criteria in Solid Tumors&#xD;
           (RECIST) 1.1 criteria. (Part B (Dose Expansion))&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
        1. To characterize the safety profile of the combination.&#xD;
&#xD;
        2. To determine the median duration of response by RECIST 1.1 criteria.&#xD;
&#xD;
        3. To determine the proportion of patients who experience &gt;= 50% decline from baseline in&#xD;
           serum prostate-specific antigen (PSA).&#xD;
&#xD;
        4. To determine the median PSA progression-free survival.&#xD;
&#xD;
        5. To determine the median time to symptomatic skeletal related event.&#xD;
&#xD;
        6. To determine the 6 month radiographic progression-free survival rate and median&#xD;
           radiographic progression-free survival.&#xD;
&#xD;
        7. To determine the median overall survival.&#xD;
&#xD;
      CORRELATIVE OBJECTIVES:&#xD;
&#xD;
        1. To assess the lesion-specific response rate by baseline PSMA avidity on gallium Ga&#xD;
           68-labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography (PET).&#xD;
&#xD;
        2. To quantify the change from baseline in T cell repertoire, circulating T cell subsets,&#xD;
           tumor infiltrating lymphocytes, and tumor programmed death-ligand 1 (PD-L1) expression&#xD;
           by immunohistochemistry after one priming dose of Lu-PSMA radioligand therapy (RLT).&#xD;
&#xD;
        3. To explore the relationship between timing of the 177Lu-PSMA-617 priming dose with&#xD;
           initiation of pembrolizumab with respect to immunologic, safety, and efficacy outcomes.&#xD;
&#xD;
        4. To descriptively characterize the patterns of uptake on 68Ga-PSMA-11 PET at the time of&#xD;
           disease progression.&#xD;
&#xD;
        5. To explore relationship between tumor genomic profile with clinical outcomes including&#xD;
           response rate and progression-free survival.&#xD;
&#xD;
        6. To explore the relationship between tumor dosimetry with objective response.&#xD;
&#xD;
      OUTLINE: Patients are assigned sequentially to 1 of 3 treatment schedules.&#xD;
&#xD;
      SCHEDULE 1: Patients receive lutetium Lu 177-PSMA-617 intravenously (IV) over 20-30 minutes&#xD;
      on day 1. Beginning in cycle 2, patients receive pembrolizumab IV over 30 minutes on day 1.&#xD;
&#xD;
      SCHEDULE 2: Patients receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes and pembrolizumab&#xD;
      IV over 30 minutes on day 1.&#xD;
&#xD;
      SCHEDULE 3: Starting day -21, patients receive pembrolizumab IV over 30 minutes. Patients&#xD;
      also receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1.&#xD;
&#xD;
      In all schedules, treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2&#xD;
      years) in the absence of disease progression or unacceptable toxicity. Patients who achieve&#xD;
      stable disease (SD) or better may receive 17 additional cycles (approximately 1 year) of&#xD;
      pembrolizumab.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 and 90 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">May 10, 2019</start_date>
  <completion_date type="Anticipated">April 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">April 30, 2024</primary_completion_date>
  <phase>Phase 1</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>Recommended phase 2 dose (Part A)</measure>
    <time_frame>Through study completion of Part A of study, estimated 1 year.</time_frame>
    <description>Will be determined from the aggregate of the safety and efficacy data observed graded by Common Terminology Criteria for Adverse Events (CTCAE).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (Part B)</measure>
    <time_frame>From the start of treatment until disease progression or recurrence, where the reference for progressive disease is the smallest measurements recorded from start of treatment, assessed up to 2 years</time_frame>
    <description>Defined as the best response (complete response or partial response). The proportion of patients with objective response will be descriptively reported with 95% confidence interval.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Frequency and severity of adverse events as defined by CTCAE version 4.0</measure>
    <time_frame>Up to 90 days</time_frame>
    <description>The incidence and severity of adverse events related to study treatment will be descriptively reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median duration of response by RECIST 1.1</measure>
    <time_frame>From date of first scan indicating response until loss of response or progression, or death, whichever occurs first, assessed up to 2 years</time_frame>
    <description>Will be estimated using Kaplan-Meier product limit method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prostate-specific antigen (PSA) response rate</measure>
    <time_frame>Baseline up to 2 years</time_frame>
    <description>The proportion of patients who achieve a greater than 50% decline from baseline PSA drawn on cycle 1 day 1 (C1D1), at any point in the treatment course, will be descriptively reported along with 95% confidence interval.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Radiographic progression-free survival (rPFS) rate</measure>
    <time_frame>6 months from date of first dose of study treatment</time_frame>
    <description>Will be defined by RECIST version 1.1 Prostate Cancer Working Group (PCWG)3 criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median PSA progression-free survival</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>Will be estimated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>From first date of study therapy to date of death from any cause, assessed up to 2 years</time_frame>
    <description>Median overall survival and 95% confidence interval will be estimated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Lesion-specific response rate by baseline PSMA avidity on gallium Ga 68-labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography (PET)</measure>
    <time_frame>Baseline up to 2 years</time_frame>
    <description>The median baseline uptake on Ga-PSMA-11 PET between responding versus non-responding lesions will be compared using Mann-Whitney test.</description>
  </other_outcome>
  <other_outcome>
    <measure>Percent change in T cell repertoire, circulating T cell subsets, tumor infiltrating lymphocytes (TILs), and tumor PD-L1 expression by immunohistochemistry</measure>
    <time_frame>Baseline up to 2 years</time_frame>
    <description>The percent change from baseline in these parameters will be reported using descriptive statistics (e.g. median, range, standard deviation).</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">43</enrollment>
  <condition>Castration Levels of Testosterone</condition>
  <condition>Castration-Resistant Prostate Carcinoma</condition>
  <condition>Metastatic Prostate Carcinoma</condition>
  <condition>Prostate Adenocarcinoma</condition>
  <condition>Stage IV Prostate Cancer</condition>
  <condition>Stage IVA Prostate Cancer</condition>
  <condition>Stage IVB Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1. Beginning in cycle 2, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Starting day -21, patients receive pembrolizumab IV over 30 minutes. Patients also receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lutetium Lu 177-PSMA-617</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)</arm_group_label>
    <arm_group_label>Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab)</arm_group_label>
    <arm_group_label>Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab)</arm_group_label>
    <other_name>177Lu-PSMA-617</other_name>
    <other_name>Lu177-PSMA-617</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)</arm_group_label>
    <arm_group_label>Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab)</arm_group_label>
    <arm_group_label>Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab)</arm_group_label>
    <other_name>Keytruda</other_name>
    <other_name>Lambrolizumab</other_name>
    <other_name>MK-3475</other_name>
    <other_name>SCH 900475</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  The subject is able and willing to comply with study procedures and provide signed and&#xD;
             dated informed consent&#xD;
&#xD;
          -  Histologically confirmed prostate adenocarcinoma. De novo small cell neuroendocrine&#xD;
             prostate cancer will not be allowed due to putative lower PSMA expression in this&#xD;
             tumor subtype. Treatment-emergent small cell neuroendocrine prostate cancer detected&#xD;
             in metastatic tumor biopsy is not an exclusion&#xD;
&#xD;
          -  A minimum of three PSMA-avid lesions on baseline 68Ga-PSMA-11 PET, with positive&#xD;
             lesions defined as those with maximum standardized uptake value (SUVmax) values&#xD;
             greater than liver.&#xD;
&#xD;
          -  Progressive metastatic castration-resistant prostate cancer by Prostate Cancer Working&#xD;
             Group (PCWG)3 criteria at the time of study entry&#xD;
&#xD;
          -  Castrate level of serum testosterone at study entry (&lt; 50 ng/dL). Patients without&#xD;
             prior bilateral orchiectomy are required to remain on luteinizing hormone-releasing&#xD;
             hormone (LHRH) analogue treatment for duration of study&#xD;
&#xD;
          -  Prior progression on at least one second generation androgen signaling inhibitor&#xD;
             including abiraterone, apalutamide, darolutamide, and/or enzalutamide&#xD;
&#xD;
          -  Absolute neutrophil count &gt; 1.5 x 10^9/L&#xD;
&#xD;
          -  Hemoglobin &gt; 9.0 g/dL&#xD;
&#xD;
          -  Platelet count &gt; 100,000/microliter&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 x upper limit of normal (ULN) or estimated glomerular&#xD;
             filtration rate (GFR) &gt; 50 ml/min by Cockcroft-Gault or 24 hour urine collection&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x ULN. In patients with known or suspected Gilbert's disease,&#xD;
             direct bilirubin =&lt; ULN&#xD;
&#xD;
          -  Aspartate aminotransferase and alanine aminotransferase =&lt; 2.5 x ULN (&lt;= 5 x ULN in&#xD;
             patients with liver metastases)&#xD;
&#xD;
          -  No other systemic anti-cancer therapies administered other than LHRH analogue within&#xD;
             14 days, or 5 half-lives, whichever is shorter, prior to initiation of study&#xD;
             treatment. Adverse events related to prior anti-cancer treatment other than LHRH&#xD;
             analog treatment must have recovered to Grade &lt;= 1 with the exception of any grade&#xD;
             alopecia and grade &lt;= 2 neuropathy.&#xD;
&#xD;
          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of&#xD;
             0 or 1&#xD;
&#xD;
          -  Patients must use appropriate methods of contraception during study treatment and for&#xD;
             at least 60 days after last study treatment&#xD;
&#xD;
               -  Patients who are sexually active should consider their female partner to be of&#xD;
                  childbearing potential if she has experienced menarche and is not postmenopausal&#xD;
                  (defined as amenorrhea &gt; 24 consecutive months) or has not undergone successful&#xD;
                  surgical sterilization. Even women who use contraceptive hormones (oral,&#xD;
                  implanted, or injected), an intrauterine device, or barrier methods (diaphragms,&#xD;
                  condoms, spermicide) should be considered to be of childbearing potential&#xD;
&#xD;
               -  Patients who have undergone vasectomy themselves should also be considered to be&#xD;
                  of childbearing potential&#xD;
&#xD;
               -  Acceptable methods of contraception include continuous total abstinence, or&#xD;
                  double-barrier method of birth control (e.g. condoms used with spermicide, or&#xD;
                  condoms used with oral contraceptives). Periodic abstinence and withdrawal are&#xD;
                  not acceptable methods of contraception&#xD;
&#xD;
          -  Patients must provide consent to comply to recommended radioprotection precautions&#xD;
             during study&#xD;
&#xD;
          -  Patients willing to undergo tumor biopsy and have at least one lesion safely&#xD;
             accessible to tumor biopsy. Bone or soft tissue lesion is allowed&#xD;
&#xD;
          -  Measurable disease by RECIST 1.1 criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Untreated brain metastases at study entry. Patients with previously treated brain&#xD;
             metastases are eligible provided the following criteria are all met:&#xD;
&#xD;
               -  Last treatment was &gt; 28 days prior to cycle 1 day 1 (C1D1)&#xD;
&#xD;
               -  No evidence of new/progressive brain metastases is observed on magnetic resonance&#xD;
                  imaging (MRI) obtained during screening window&#xD;
&#xD;
               -  Patient is clinically stable without requirement of steroid treatment for at&#xD;
                  least 14 days prior to first dose of study treatment&#xD;
&#xD;
          -  Receipt of prior PSMA-directed treatment (e.g. radiotherapy, immunotherapy, or&#xD;
             antibody-drug conjugate)&#xD;
&#xD;
          -  Prior enrollment on clinical study investigating Lu-PSMA-based radioligand therapy&#xD;
&#xD;
          -  Prior treatment with radium-223 or other radioisotope for the treatment of prostate&#xD;
             cancer&#xD;
&#xD;
          -  Has received prior radiotherapy within 2 weeks of start of study treatment.&#xD;
             Participants must have recovered from all radiation-related toxicities, not require&#xD;
             corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted&#xD;
             for palliative radiation (=&lt; 2 weeks of radiotherapy) to non-central nervous system&#xD;
             (CNS) disease&#xD;
&#xD;
          -  Receipt of prior pembrolizumab or another immune checkpoint inhibitor (e.g. nivolumab,&#xD;
             ipilimumab)&#xD;
&#xD;
          -  Is currently participating in or has participated in a study of an investigational&#xD;
             agent or has used an investigational device within 4 weeks prior to the first dose of&#xD;
             study treatment&#xD;
&#xD;
               -  Note: Participants who have entered the follow-up phase of an investigational&#xD;
                  study may participate as long as it has been 4 weeks after the last dose of the&#xD;
                  previous investigational agent&#xD;
&#xD;
          -  Receipt of taxane chemotherapy applied in the castration-resistant setting. Prior&#xD;
             receipt of taxane chemotherapy in the hormone-sensitive setting is allowed&#xD;
&#xD;
          -  Grade &gt; 2 peripheral neuropathy at the time of study entry&#xD;
&#xD;
          -  Has severe hypersensitivity (&gt;= grade 3) to pembrolizumab and/or any of its excipients&#xD;
&#xD;
          -  Has an active autoimmune disease that has required systemic treatment in the past 2&#xD;
             years (i.e., with use of disease modifying agents, corticosteroids or&#xD;
             immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or&#xD;
             physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)&#xD;
             or treatment with drugs (e.g. neomercazole, carbimazole, etc.) that function to&#xD;
             decrease the generation of thyroid hormone by a hyperfunctioning thyroid gland (e.g.&#xD;
             in Graves? disease) is not considered a form of systemic treatment of an autoimmune&#xD;
             disease&#xD;
&#xD;
          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a&#xD;
             prednisone equivalent dose of &gt; 10 mg daily or other form of immunosuppressive therapy&#xD;
             within 7 days prior to first dose of study drug&#xD;
&#xD;
          -  Has a history of (non-infectious) ≥ grade 2 pneumonitis/interstitial lung disease that&#xD;
             required steroids within past 2 years or has current ≥ grade 1&#xD;
             pneumonitis/interstitial lung disease at the time of study enrollment..&#xD;
&#xD;
          -  Has received a live vaccine or live-attenuated vaccine within 30 days prior to the&#xD;
             first dose of study drug. Administration of killed vaccines is allowed.&#xD;
&#xD;
          -  Patients who because of age, general medical or psychiatric condition, or physiologic&#xD;
             status cannot give valid informed consent&#xD;
&#xD;
          -  Has clinically significant cardiovascular disease including, but not limited to:&#xD;
&#xD;
               -  Uncontrolled or any New York Heart Association class 3 or 4 congestive heart&#xD;
                  failure&#xD;
&#xD;
               -  Uncontrolled angina, history of myocardial infarction, unstable angina or stroke&#xD;
                  within 6 months before study entry&#xD;
&#xD;
               -  Clinically significant arrhythmias not controlled by medication. Chronic rate&#xD;
                  controlled or paroxysmal atrial fibrillation/flutter is not an exclusion to study&#xD;
                  participation&#xD;
&#xD;
          -  Prior external beam radiation involving &gt;= 25% of bone marrow or within 14 days of&#xD;
             start of protocol therapy&#xD;
&#xD;
          -  Major surgery within 28 days of study treatment&#xD;
&#xD;
             *Note: If participant received major surgery, they must have recovered adequately from&#xD;
             the toxicity and/or complications from the intervention prior to starting study&#xD;
             treatment.&#xD;
&#xD;
          -  Has an active infection requiring systemic therapy&#xD;
&#xD;
          -  Has a known history of human immunodeficiency virus (HIV) (screening not required)&#xD;
&#xD;
          -  Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]&#xD;
             reactive) or known active hepatitis C virus (HCV) (defined as HCV ribonucleic acid&#xD;
             [RNA] [qualitative] is detected) infection (screening not required)&#xD;
&#xD;
          -  Has a known history of active Bacillus tuberculosis (TB)&#xD;
&#xD;
          -  Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial&#xD;
&#xD;
          -  Any condition that, in the opinion of the principal investigator, would impair the&#xD;
             patient's ability to comply with study procedures&#xD;
&#xD;
          -  History of bleeding diathesis and not currently on anti-coagulation therapy that&#xD;
             cannot be safely discontinued for the tumor biopsy procedure&#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>Rahul Aggarwal, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>January 9, 2019</study_first_submitted>
  <study_first_submitted_qc>January 14, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 15, 2019</study_first_posted>
  <last_update_submitted>April 12, 2023</last_update_submitted>
  <last_update_submitted_qc>April 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of California, San Francisco</investigator_affiliation>
    <investigator_full_name>Rahul Aggarwal</investigator_full_name>
    <investigator_title>Associate Clinical Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
    <mesh_term>177Lu-PSMA-617</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>November 5, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT03805594/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03805594
org study id: 185511
secondary id: NCI-2018-02993
secondary id: R01CA229354
nct id: NCT03805594
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This phase Ib trial studies the dose and schedule of 177Lu-PSMA-617 and pembrolizumab in
      treating patients with castration-resistant prostate cancer that has spread to other places
      in the body. 177Lu-PSMA-617 carries a radioactive component which attached to the prostate
      specific membrane antigen (PSMA) receptor found on tumor cells. Its radiation component
      destroys the tumor cell. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may
      help the body?s immune system attack the cancer, and may interfere with the ability of tumor
      cells to grow and spread. Giving 177Lu-PSMA-617 and pembrolizumab may work better at treating
      prostate cancer.
PRIMARY OBJECTIVES:

        1. To determine the recommended phase 2 dose and schedule of lutetium Lu 177-PSMA-617
           (177Lu-PSMA-617) in combination with pembrolizumab in patients with metastatic
           castration-resistant prostate carcinoma (mCRPC). (Part A)

        2. To determine the objective response rate by Response Evaluation Criteria in Solid Tumors
           (RECIST) 1.1 criteria. (Part B (Dose Expansion))

      SECONDARY OBJECTIVES:

        1. To characterize the safety profile of the combination.

        2. To determine the median duration of response by RECIST 1.1 criteria.

        3. To determine the proportion of patients who experience >= 50% decline from baseline in
           serum prostate-specific antigen (PSA).

        4. To determine the median PSA progression-free survival.

        5. To determine the median time to symptomatic skeletal related event.

        6. To determine the 6 month radiographic progression-free survival rate and median
           radiographic progression-free survival.

        7. To determine the median overall survival.

      CORRELATIVE OBJECTIVES:

        1. To assess the lesion-specific response rate by baseline PSMA avidity on gallium Ga
           68-labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography (PET).

        2. To quantify the change from baseline in T cell repertoire, circulating T cell subsets,
           tumor infiltrating lymphocytes, and tumor programmed death-ligand 1 (PD-L1) expression
           by immunohistochemistry after one priming dose of Lu-PSMA radioligand therapy (RLT).

        3. To explore the relationship between timing of the 177Lu-PSMA-617 priming dose with
           initiation of pembrolizumab with respect to immunologic, safety, and efficacy outcomes.

        4. To descriptively characterize the patterns of uptake on 68Ga-PSMA-11 PET at the time of
           disease progression.

        5. To explore relationship between tumor genomic profile with clinical outcomes including
           response rate and progression-free survival.

        6. To explore the relationship between tumor dosimetry with objective response.

      OUTLINE: Patients are assigned sequentially to 1 of 3 treatment schedules.

      SCHEDULE 1: Patients receive lutetium Lu 177-PSMA-617 intravenously (IV) over 20-30 minutes
      on day 1. Beginning in cycle 2, patients receive pembrolizumab IV over 30 minutes on day 1.

      SCHEDULE 2: Patients receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes and pembrolizumab
      IV over 30 minutes on day 1.

      SCHEDULE 3: Starting day -21, patients receive pembrolizumab IV over 30 minutes. Patients
      also receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1.

      In all schedules, treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2
      years) in the absence of disease progression or unacceptable toxicity. Patients who achieve
      stable disease (SD) or better may receive 17 additional cycles (approximately 1 year) of
      pembrolizumab.

      After completion of study treatment, patients are followed up at 30 and 90 days.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Recommended phase 2 dose (Part A)
time frame: Through study completion of Part A of study, estimated 1 year.
description: Will be determined from the aggregate of the safety and efficacy data observed graded by Common Terminology Criteria for Adverse Events (CTCAE).
measure: Objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria (Part B)
time frame: From the start of treatment until disease progression or recurrence, where the reference for progressive disease is the smallest measurements recorded from start of treatment, assessed up to 2 years
description: Defined as the best response (complete response or partial response). The proportion of patients with objective response will be descriptively reported with 95% confidence interval.
measure: Frequency and severity of adverse events as defined by CTCAE version 4.0
time frame: Up to 90 days
description: The incidence and severity of adverse events related to study treatment will be descriptively reported.
measure: Median duration of response by RECIST 1.1
time frame: From date of first scan indicating response until loss of response or progression, or death, whichever occurs first, assessed up to 2 years
description: Will be estimated using Kaplan-Meier product limit method.
measure: Prostate-specific antigen (PSA) response rate
time frame: Baseline up to 2 years
description: The proportion of patients who achieve a greater than 50% decline from baseline PSA drawn on cycle 1 day 1 (C1D1), at any point in the treatment course, will be descriptively reported along with 95% confidence interval.
measure: Radiographic progression-free survival (rPFS) rate
time frame: 6 months from date of first dose of study treatment
description: Will be defined by RECIST version 1.1 Prostate Cancer Working Group (PCWG)3 criteria.
measure: Median PSA progression-free survival
time frame: Up to 2 years
description: Will be estimated using the Kaplan-Meier method.
measure: Overall survival
time frame: From first date of study therapy to date of death from any cause, assessed up to 2 years
description: Median overall survival and 95% confidence interval will be estimated using the Kaplan-Meier method.
measure: Lesion-specific response rate by baseline PSMA avidity on gallium Ga 68-labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography (PET)
time frame: Baseline up to 2 years
description: The median baseline uptake on Ga-PSMA-11 PET between responding versus non-responding lesions will be compared using Mann-Whitney test.
measure: Percent change in T cell repertoire, circulating T cell subsets, tumor infiltrating lymphocytes (TILs), and tumor PD-L1 expression by immunohistochemistry
time frame: Baseline up to 2 years
description: The percent change from baseline in these parameters will be reported using descriptive statistics (e.g. median, range, standard deviation).
arm group label: Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)
arm group type: Experimental
description: Patients receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1. Beginning in cycle 2, patients receive pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.
arm group label: Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab)
arm group type: Experimental
description: Patients receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes and pembrolizumab IV over 30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.
arm group label: Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab)
arm group type: Experimental
description: Starting day -21, patients receive pembrolizumab IV over 30 minutes. Patients also receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1. Treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients who achieve SD or better may receive 17 additional cycles (approximately 1 year) of pembrolizumab.
intervention type: Drug
intervention name: Lutetium Lu 177-PSMA-617
description: Given IV
arm group label: Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)
arm group label: Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab)
arm group label: Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab)
other name: 177Lu-PSMA-617
other name: Lu177-PSMA-617
intervention type: Biological
intervention name: Pembrolizumab
description: Given IV
arm group label: Schedule 1 (lutetium Lu 177-PSMA-617, pembrolizumab)
arm group label: Schedule 2 (lutetium Lu 177-PSMA-617, pembrolizumab)
arm group label: Schedule 3 (lutetium Lu 177-PSMA-617, pembrolizumab)
other name: Keytruda
other name: Lambrolizumab
other name: MK-3475
other name: SCH 900475
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rahul Aggarwal, MD
role: Principal Investigator
affiliation: University of California, San Francisco
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of California, San Francisco
investigator full name: Rahul Aggarwal
investigator title: Associate Clinical Professor
mesh term: Carcinoma
mesh term: Prostatic Neoplasms
mesh term: Pembrolizumab
mesh term: 177Lu-PSMA-617
sharing ipd: No
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