<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/NCT03816332</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2019-00239</org_study_id>
    <secondary_id>NCI-2019-00239</secondary_id>
    <secondary_id>ETCTN10214</secondary_id>
    <secondary_id>10214</secondary_id>
    <secondary_id>10214</secondary_id>
    <secondary_id>UM1CA186691</secondary_id>
    <nct_id>NCT03816332</nct_id>
  </id_info>
  <brief_title>Tacrolimus, Nivolumab, and Ipilimumab in Treating Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers</brief_title>
  <official_title>Immune Checkpoint Blockade for Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies how well tacrolimus, nivolumab, and ipilimumab work in treating&#xD;
      kidney transplant recipients with cancer that cannot be removed by surgery (unresectable) or&#xD;
      has spread to other places in the body (metastatic). Tacrolimus may stop the growth of tumor&#xD;
      cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal&#xD;
      antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the&#xD;
      cancer, and may interfere with the ability of tumor cells to grow and spread. Giving&#xD;
      tacrolimus, nivolumab, and ipilimumab may work better in treating kidney transplant&#xD;
      recipients with cancer compared to chemotherapy, surgery, radiation therapy, or targeted&#xD;
      therapies.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To estimate the percent of kidney transplant recipients with selected advanced cancers for&#xD;
      whom standard therapies would be insufficient who, 16 weeks after administration of&#xD;
      prednisone, tacrolimus, and nivolumab, experience complete response (CR), partial response&#xD;
      (PR), or stable disease (SD) without allograft loss.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To estimate the objective response rate (ORR), rate of allograft loss, and durations of&#xD;
      progression-free survival (PFS) and overall survival (OS) in the study population.&#xD;
&#xD;
      II. To estimate the ORR and rate of allograft loss in patients who experience progressive&#xD;
      disease (PD) after administration of nivolumab and 1) receive ipilimumab and nivolumab, or 2)&#xD;
      decrease or discontinue immunosuppression.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To characterize correlates of the host immune response, possibly including, but not&#xD;
      limited to:&#xD;
&#xD;
      Ia. Histopathological characteristics of allograft rejection/loss. Ib. Immunological changes&#xD;
      in the tumor microenvironment (e.g., changes in T-cell subset populations or expression of&#xD;
      immune checkpoint molecules) in paired biopsies obtained pre-treatment and on-treatment.&#xD;
&#xD;
      Ic. Changes in donor-derived cell-free deoxyribonucleic acid (DNA) (dd-cfDNA) as a marker for&#xD;
      allograft rejection.&#xD;
&#xD;
      Id. Characteristics of anti-programmed death-1 (PD-1)-associated immune-mediated adverse&#xD;
      reactions (IMAR) in this patient population treated with immunosuppression.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive tacrolimus orally (PO) twice daily (BID) and prednisone PO once daily (QD).&#xD;
      Within 28 days, patients then receive nivolumab intravenously (IV) over 30 minutes on day 1.&#xD;
      Cycles repeat every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease&#xD;
      progression or unacceptable toxicity.&#xD;
&#xD;
      Patients who experience progressive disease (PD) or patients who have experienced allograft&#xD;
      loss at 16 weeks receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on&#xD;
      day 1. Patients also receive tacrolimus PO BID and prednisone PO QD. Cycles repeat every 3&#xD;
      weeks for 4 cycles (12 weeks) in the absence of disease progression or unacceptable toxicity.&#xD;
      Starting 6 weeks later, patients receive nivolumab IV over 30 minutes every 4 weeks for up to&#xD;
      21 cycles (84 weeks) in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for 90 days, every 8 weeks for&#xD;
      year 1, every 12 weeks for year 2, every 16 weeks for year 3, then every 24 weeks for year 4.&#xD;
      Patients with PD are followed up every 12 weeks for up to 5 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 1, 2019</start_date>
  <completion_date type="Anticipated">March 27, 2024</completion_date>
  <primary_completion_date type="Actual">October 11, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number (and Percentage) of Outcome Responses After Receiving Nivolumab, Tacrolimus, and Prednisone</measure>
    <time_frame>At 16 weeks</time_frame>
    <description>Percentage of kidney transplant recipients who experienced complete response (CR), partial response (PR) or stable disease (SD) without allograft loss.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response (CR or PR) Rate (ORR) After Receiving Nivolumab, Tacrolimus, and Prednisone</measure>
    <time_frame>Up to 4 months</time_frame>
    <description>Number (and percentage) of patients with a complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria after receiving at least one dose of nivolumab.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Allograft Loss After Receiving Nivolumab, Tacrolimus, and Prednisone</measure>
    <time_frame>Up to 4 months</time_frame>
    <description>Number of subjects who experienced allograft loss after receiving at least one dose of nivolumab.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Progression-free Survival After Receiving Nivolumab, Tacrolimus, and Prednisone</measure>
    <time_frame>Up to 4 months</time_frame>
    <description>From the first dose of nivolumab to the date of the first documented tumor progression or death due to any cause, whichever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Overall Survival After Receiving Nivolumab, Tacrolimus, and Prednisone</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>The time from the participant's first dose of nivolumab to the date of death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR) in Patients After Receiving Ipilimumab, Nivolumab, Tacrolimus, and Prednisone</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>The number of participants with a CR or PR response after receiving ipilimumab, nivolumab, tacrolimus, and prednisone.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Allograft Loss After Receiving Ipilimumab, Nivolumab, Tacrolimus, and Prednisone</measure>
    <time_frame>Up to 3 years</time_frame>
    <description>Number of patients who experienced allograft loss after receiving nivolumab, ipilimumab, tacrolimus, and prednisone.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Clinical Stage III Cutaneous Melanoma AJCC v8</condition>
  <condition>Clinical Stage III Merkel Cell Carcinoma AJCC v8</condition>
  <condition>Clinical Stage IV Cutaneous Melanoma AJCC v8</condition>
  <condition>Clinical Stage IV Merkel Cell Carcinoma AJCC v8</condition>
  <condition>Metastatic Basal Cell Carcinoma</condition>
  <condition>Metastatic Melanoma</condition>
  <condition>Metastatic Merkel Cell Carcinoma</condition>
  <condition>Metastatic Skin Squamous Cell Carcinoma</condition>
  <condition>Pathologic Stage III Cutaneous Melanoma AJCC v8</condition>
  <condition>Pathologic Stage III Merkel Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIA Cutaneous Melanoma AJCC v8</condition>
  <condition>Pathologic Stage IIIA Merkel Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIB Cutaneous Melanoma AJCC v8</condition>
  <condition>Pathologic Stage IIIB Merkel Cell Carcinoma AJCC v8</condition>
  <condition>Pathologic Stage IIIC Cutaneous Melanoma AJCC v8</condition>
  <condition>Pathologic Stage IIID Cutaneous Melanoma AJCC v8</condition>
  <condition>Pathologic Stage IV Cutaneous Melanoma AJCC v8</condition>
  <condition>Pathologic Stage IV Merkel Cell Carcinoma AJCC v8</condition>
  <condition>Unresectable Basal Cell Carcinoma</condition>
  <condition>Unresectable Melanoma</condition>
  <condition>Unresectable Merkel Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive tacrolimus PO BID and prednisone PO QD. Within 28 days, patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease progression or unacceptable toxicity.&#xD;
Patients who experience PD or patients who have experienced allograft loss at 16 weeks receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Patients also receive tacrolimus PO BID and prednisone PO QD. Cycles repeat every 3 weeks for 4 cycles (12 weeks) in the absence of disease progression or unacceptable toxicity. Starting 6 weeks later, patients receive nivolumab IV over 30 minutes every 4 weeks for up to 21 cycles (84 weeks) in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)</arm_group_label>
    <other_name>Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody</other_name>
    <other_name>BMS-734016</other_name>
    <other_name>Ipilimumab Biosimilar CS1002</other_name>
    <other_name>MDX-010</other_name>
    <other_name>MDX-CTLA4</other_name>
    <other_name>Yervoy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)</arm_group_label>
    <other_name>BMS-936558</other_name>
    <other_name>CMAB819</other_name>
    <other_name>MDX-1106</other_name>
    <other_name>NIVO</other_name>
    <other_name>Nivolumab Biosimilar CMAB819</other_name>
    <other_name>ONO-4538</other_name>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisone</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)</arm_group_label>
    <other_name>.delta.1-Cortisone</other_name>
    <other_name>1, 2-Dehydrocortisone</other_name>
    <other_name>Adasone</other_name>
    <other_name>Cortancyl</other_name>
    <other_name>Dacortin</other_name>
    <other_name>DeCortin</other_name>
    <other_name>Decortisyl</other_name>
    <other_name>Decorton</other_name>
    <other_name>Delta 1-Cortisone</other_name>
    <other_name>Delta-Dome</other_name>
    <other_name>Deltacortene</other_name>
    <other_name>Deltacortisone</other_name>
    <other_name>Deltadehydrocortisone</other_name>
    <other_name>Deltasone</other_name>
    <other_name>Deltison</other_name>
    <other_name>Deltra</other_name>
    <other_name>Econosone</other_name>
    <other_name>Lisacort</other_name>
    <other_name>Meprosona-F</other_name>
    <other_name>Metacortandracin</other_name>
    <other_name>Meticorten</other_name>
    <other_name>Ofisolona</other_name>
    <other_name>Orasone</other_name>
    <other_name>Panafcort</other_name>
    <other_name>Panasol-S</other_name>
    <other_name>Paracort</other_name>
    <other_name>Perrigo Prednisone</other_name>
    <other_name>PRED</other_name>
    <other_name>Predicor</other_name>
    <other_name>Predicorten</other_name>
    <other_name>Prednicen-M</other_name>
    <other_name>Prednicort</other_name>
    <other_name>Prednidib</other_name>
    <other_name>Prednilonga</other_name>
    <other_name>Predniment</other_name>
    <other_name>Prednisone Intensol</other_name>
    <other_name>Prednisonum</other_name>
    <other_name>Prednitone</other_name>
    <other_name>Promifen</other_name>
    <other_name>Rayos</other_name>
    <other_name>Servisone</other_name>
    <other_name>SK-Prednisone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)</arm_group_label>
    <other_name>FK 506</other_name>
    <other_name>Fujimycin</other_name>
    <other_name>Hecoria</other_name>
    <other_name>Prograf</other_name>
    <other_name>Protopic</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must be kidney transplant recipients with a functioning allograft who do not&#xD;
             currently require dialysis&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed melanoma, basal cell&#xD;
             carcinoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma, or microsatellite&#xD;
             instability (MSI)-high cancers for which standard non-immunological medical, surgical,&#xD;
             or radiation therapy would be insufficient (i.e., patients who are not surgical&#xD;
             candidates). This trial is not intended to provide therapy as a neoadjuvant approach&#xD;
&#xD;
          -  Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)&#xD;
             1.1 criteria, i.e., at least one lesion that can be accurately measured in at least&#xD;
             one dimension (longest diameter to be recorded for non-nodal lesions and short axis&#xD;
             for nodal lesions) as &gt;= 20 mm by chest x-ray or as &gt;= 10 mm with computed tomography&#xD;
             (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam is&#xD;
             preferred, but not required. Patients with evaluable disease but no target lesions&#xD;
             (e.g., evaluable bone metastases) may be included after discussion with the principal&#xD;
             investigator (PI)&#xD;
&#xD;
          -  Patients must have documentation, in consultation with the PI, that they received,&#xD;
             refused, or were ineligible for the following non-immunologic therapies:&#xD;
&#xD;
               -  For patients with:&#xD;
&#xD;
                    -  BRAF-mutant melanoma: prior therapies include BRAF/MEK inhibitors&#xD;
&#xD;
                    -  Merkel cell carcinoma: prior therapies include platinum + VP-16&#xD;
&#xD;
                    -  Basal cell carcinoma: prior therapies include Hedgehog pathway inhibitors&#xD;
&#xD;
                    -  Cutaneous squamous cell carcinoma: prior therapies include cetuximab&#xD;
&#xD;
                    -  MSI colorectal carcinoma: prior therapies include: leucovorin calcium,&#xD;
                       5-fluorouracil and oxaliplatin (FOLFOX)&#xD;
&#xD;
          -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2&#xD;
             (Karnofsky &gt;= 60%)&#xD;
&#xD;
          -  Leukocytes &gt;= 2,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 2.5 x institutional ULN&#xD;
&#xD;
          -  Serum creatinine =&lt; 3 x ULN&#xD;
&#xD;
               -  Note: patients with creatinine levels above 3 x ULN may be eligible after&#xD;
                  consultation with the study PI&#xD;
&#xD;
          -  The effects of nivolumab and ipilimumab on the developing human fetus are unknown. For&#xD;
             this reason, and because other therapeutic agents used in this trial are known to be&#xD;
             teratogenic, women of child-bearing potential (WOCBP) and men must agree to use&#xD;
             adequate contraception (e.g., hormonal or barrier methods of birth control, or&#xD;
             abstinence) prior to study entry, for the duration of study participation, and for 31&#xD;
             weeks after the last dose of nivolumab or ipilimumab. Women who are not of&#xD;
             childbearing potential (i.e., who are postmenopausal or surgically sterile) as well as&#xD;
             azoospermic men do not require contraception. WOCBP must have a negative serum or&#xD;
             urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of beta-human&#xD;
             chorionic gonadotropin [B-HCG]) during the screening period. Follow-up evaluations&#xD;
             will include interval sexual/menstrual histories as needed. Men who receive nivolumab&#xD;
             or ipilimumab and are sexually active with WOCBP must use a contraceptive method with&#xD;
             a failure rate of &lt; 1% per year for the duration of the study and for a period of 7&#xD;
             months after the last dose of nivolumab or ipilimumab. Should a woman become pregnant&#xD;
             or suspect she is pregnant while she or her partner is participating in this study,&#xD;
             she (or the participating partner) should inform the treating physician immediately.&#xD;
             WOCBP is defined as any female who has experienced menarche and who has not undergone&#xD;
             surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not&#xD;
             postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman&#xD;
             over 45 in the absence of other biological or physiological causes. Women under the&#xD;
             age of 55 must have a documented serum follicle stimulating hormone (FSH) level less&#xD;
             than 40 mIU/mL to be considered postmenopausal&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-infected patients will be eligible for this trial&#xD;
             if they are on effective antiretroviral regimens utilizing non-CYP-interactive agents&#xD;
             and have an undetectable viral load. If there is evidence of chronic hepatitis B virus&#xD;
             (HBV) infection, HBV viral load must be undetectable on suppressive therapy, if&#xD;
             indicated. If there is history of hepatitis C virus (HCV) infection, the patient must&#xD;
             have been treated and have undetectable HCV viral load&#xD;
&#xD;
          -  Patients must be able to understand and be willing to sign a written informed consent&#xD;
             document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients must not have received a liver, lung, heart, or pancreas transplant; or&#xD;
             allogeneic stem cell transplant; or any kind of bone marrow transplant&#xD;
&#xD;
          -  Patients must not be unwilling or unable to undergo dialysis&#xD;
&#xD;
          -  Patients must not have prior evidence of human leukocyte antigen (HLA) or non-HLA&#xD;
             donor-specific antibodies (DSA). Patients with detectable DSA but negative dd-cfDNA&#xD;
             may be eligible after consultation with the study PI&#xD;
&#xD;
          -  Patients must not have a history of antibody- or cell-mediated allograft rejection&#xD;
             within 3 months of study entry&#xD;
&#xD;
          -  Patients must not have had chemotherapy or radiotherapy within 4 weeks of study entry&#xD;
             or those who have not recovered from adverse events (AEs) due to agents administered&#xD;
             more than 4 weeks earlier&#xD;
&#xD;
          -  Patients must not have had prior treatment for their current cancer with an anti-PD-1,&#xD;
             anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or any other antibody or drug&#xD;
             specifically targeting T-cell co-stimulation or immune checkpoint pathways&#xD;
&#xD;
          -  Patients must not be receiving any other investigational agents&#xD;
&#xD;
          -  Patients must not have known central nervous system (CNS) metastases or leptomeningeal&#xD;
             metastases because of poor prognosis and concerns regarding progressive neurologic&#xD;
             dysfunction that would confound the evaluation of neurologic and other AEs. Patients&#xD;
             with brain metastases are permitted to enroll if metastases have been treated and&#xD;
             there is no MRI evidence of progression for 4 weeks after treatment is complete and no&#xD;
             evidence of progression within 28 days prior to study entry&#xD;
&#xD;
          -  Patients must not have a history of severe hypersensitivity reaction to any monoclonal&#xD;
             antibody&#xD;
&#xD;
          -  Patients must not have a history of allergic reactions attributed to compounds of&#xD;
             similar chemical or biologic composition to other agents used in study&#xD;
&#xD;
          -  Patients must not have uncontrolled intercurrent illness including, but not limited&#xD;
             to, ongoing or active infection, symptomatic congestive heart failure, unstable angina&#xD;
             pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would&#xD;
             limit compliance with study requirements&#xD;
&#xD;
          -  Pregnant women are excluded from this study because nivolumab and ipilimumab have the&#xD;
             potential for teratogenic or abortifacient effects. Because there is an unknown but&#xD;
             potential risk for AEs in nursing infants secondary to treatment of the mother,&#xD;
             breastfeeding should be discontinued if the mother is treated with nivolumab or&#xD;
             ipilimumab. These potential risks may also apply to other agents used in this study&#xD;
&#xD;
          -  Patients must not have active autoimmune disease, or history of autoimmune disease&#xD;
             that might recur, which may affect vital organ function, and will only be eligible&#xD;
             after consultation with the study PI&#xD;
&#xD;
               -  This includes but is not limited to:&#xD;
&#xD;
                    -  Immune-related neurologic disease,&#xD;
&#xD;
                    -  Multiple sclerosis,&#xD;
&#xD;
                    -  Autoimmune (demyelinating) neuropathy,&#xD;
&#xD;
                    -  Guillain-Barre (GB) syndrome,&#xD;
&#xD;
                    -  Myasthenia gravis,&#xD;
&#xD;
                    -  Systemic autoimmune diseases such as systemic lupus erythematosus (SLE),&#xD;
&#xD;
                    -  Connective tissue diseases,&#xD;
&#xD;
                    -  Scleroderma,&#xD;
&#xD;
                    -  Inflammatory bowel disease (IBD; e.g., ulcerative colitis or Crohn's&#xD;
                       disease),&#xD;
&#xD;
                    -  Rheumatoid arthritis, and&#xD;
&#xD;
                    -  Sjogren's syndrome&#xD;
&#xD;
          -  Patients must not have had evidence of active or acute diverticulitis, intra-abdominal&#xD;
             abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are&#xD;
             known risk factors for bowel perforation should be evaluated for the potential need&#xD;
             for additional treatment before coming on study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Evan J Lipson</last_name>
    <role>Principal Investigator</role>
    <affiliation>JHU Sidney Kimmel Comprehensive Cancer Center LAO</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Moffitt Cancer Center - McKinley Campus</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moffitt Cancer Center</name>
      <address>
        <city>Tampa</city>
        <state>Florida</state>
        <zip>33612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Johns Hopkins University/Sidney Kimmel Cancer Center</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brigham and Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh Cancer Institute (UPCI)</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 24, 2019</study_first_submitted>
  <study_first_submitted_qc>January 24, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 25, 2019</study_first_posted>
  <results_first_submitted>June 8, 2023</results_first_submitted>
  <results_first_submitted_qc>June 8, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">June 27, 2023</results_first_posted>
  <last_update_submitted>June 30, 2023</last_update_submitted>
  <last_update_submitted_qc>June 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 3, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Merkel Cell</mesh_term>
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Melanoma</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Carcinoma, Basal Cell</mesh_term>
    <mesh_term>Skin Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisone</mesh_term>
    <mesh_term>Cortisone</mesh_term>
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page</ipd_description>
    <ipd_url>https://grants.nih.gov/policy/sharing.htm</ipd_url>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>January 28, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/32/NCT03816332/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Treatment</title>
          <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5mg by mouth once a day, and nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Patients who experienced disease progression by the 16-week time point, could receive tacrolimus, prednisone, nivolumab 3 mg/kg IV + ipilimumab 1 mg/kg by infusion every 3 weeks for 4 doses followed by maintenance nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Nivolumab, Tacrolimus, and Prednisone</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Did not receive Nivolumab</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Nivolumab, Ipilimumab, Tacrolimus, Pred</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Treatment (Tacrolimus, Prednisone, Nivolumab, Ipilimumab)</title>
          <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5mg by mouth once a day, and nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.&#xD;
Patients who experienced disease progression by the 16-week time point, could receive tacrolimus, prednisone, nivolumab 3 mg/kg IV + ipilimumab 1 mg/kg by infusion every 3 weeks for 4 doses followed by maintenance nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="12"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="69" lower_limit="44" upper_limit="84"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Height</title>
          <units>centimeter (cm)</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="168.4" lower_limit="145.5" upper_limit="189.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>kilogram (kg)</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="68.3" lower_limit="46.4" upper_limit="104.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>BSA</title>
          <units>meters squared (m^2)</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1.74" lower_limit="1.39" upper_limit="2.34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number (and Percentage) of Outcome Responses After Receiving Nivolumab, Tacrolimus, and Prednisone</title>
        <description>Percentage of kidney transplant recipients who experienced complete response (CR), partial response (PR) or stable disease (SD) without allograft loss.</description>
        <time_frame>At 16 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab, Tacrolimus, and Prednisone</title>
            <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5 mg by mouth once a day, and nivolumab 480 mg by infusion over 30 minutes on day 1. Cycles repeated every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Number (and Percentage) of Outcome Responses After Receiving Nivolumab, Tacrolimus, and Prednisone</title>
          <description>Percentage of kidney transplant recipients who experienced complete response (CR), partial response (PR) or stable disease (SD) without allograft loss.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete response (CR), partial response (PR) or stable disease (SD) without allograft loss</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Progressive Disease (PD) without allograft loss</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response (CR or PR) Rate (ORR) After Receiving Nivolumab, Tacrolimus, and Prednisone</title>
        <description>Number (and percentage) of patients with a complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria after receiving at least one dose of nivolumab.</description>
        <time_frame>Up to 4 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab, Tacrolimus, and Prednisone</title>
            <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5 mg by mouth once a day, and nivolumab 480 mg by infusion over 30 minutes on day 1. Cycles repeated every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response (CR or PR) Rate (ORR) After Receiving Nivolumab, Tacrolimus, and Prednisone</title>
          <description>Number (and percentage) of patients with a complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria after receiving at least one dose of nivolumab.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Complete response (CR) or Partial Response (PR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive Disease (PD)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Allograft Loss After Receiving Nivolumab, Tacrolimus, and Prednisone</title>
        <description>Number of subjects who experienced allograft loss after receiving at least one dose of nivolumab.</description>
        <time_frame>Up to 4 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab, Tacrolimus, and Prednisone</title>
            <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5 mg by mouth once a day, and nivolumab 480 mg by infusion over 30 minutes on day 1. Cycles repeated every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Allograft Loss After Receiving Nivolumab, Tacrolimus, and Prednisone</title>
          <description>Number of subjects who experienced allograft loss after receiving at least one dose of nivolumab.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Experienced allograft loss</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Did not experience allograft loss</title>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Progression-free Survival After Receiving Nivolumab, Tacrolimus, and Prednisone</title>
        <description>From the first dose of nivolumab to the date of the first documented tumor progression or death due to any cause, whichever occurs first.</description>
        <time_frame>Up to 4 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab, Tacrolimus, and Prednisone</title>
            <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5 mg by mouth once a day, and nivolumab 480 mg by infusion over 30 minutes on day 1. Cycles repeated every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Progression-free Survival After Receiving Nivolumab, Tacrolimus, and Prednisone</title>
          <description>From the first dose of nivolumab to the date of the first documented tumor progression or death due to any cause, whichever occurs first.</description>
          <units>days</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59" lower_limit="54" upper_limit="70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Overall Survival After Receiving Nivolumab, Tacrolimus, and Prednisone</title>
        <description>The time from the participant's first dose of nivolumab to the date of death from any cause.</description>
        <time_frame>Up to 3 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab, Tacrolimus, and Prednisone</title>
            <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5 mg by mouth once a day, and nivolumab 480 mg by infusion over 30 minutes on day 1. Cycles repeated every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Overall Survival After Receiving Nivolumab, Tacrolimus, and Prednisone</title>
          <description>The time from the participant's first dose of nivolumab to the date of death from any cause.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.1" lower_limit="1.9" upper_limit="37.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate (ORR) in Patients After Receiving Ipilimumab, Nivolumab, Tacrolimus, and Prednisone</title>
        <description>The number of participants with a CR or PR response after receiving ipilimumab, nivolumab, tacrolimus, and prednisone.</description>
        <time_frame>Up to 3 years</time_frame>
        <population>Two participants who completed the initial treatment period did not start the second, optional treatment period due to disease progression or death.</population>
        <group_list>
          <group group_id="O1">
            <title>Ipilimumab, Nivolumab, Tacrolimus, and Prednisone</title>
            <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5 mg every day, nivolumab 3 mg/kg by infusion and ipilimumab 1 mg/kg by infusion every 3 weeks for 4 doses followed by maintenance nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate (ORR) in Patients After Receiving Ipilimumab, Nivolumab, Tacrolimus, and Prednisone</title>
          <description>The number of participants with a CR or PR response after receiving ipilimumab, nivolumab, tacrolimus, and prednisone.</description>
          <population>Two participants who completed the initial treatment period did not start the second, optional treatment period due to disease progression or death.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Complete or Partial Response (CR or PR)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Progressive Disease (PD)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Allograft Loss After Receiving Ipilimumab, Nivolumab, Tacrolimus, and Prednisone</title>
        <description>Number of patients who experienced allograft loss after receiving nivolumab, ipilimumab, tacrolimus, and prednisone.</description>
        <time_frame>Up to 3 years</time_frame>
        <population>Two participants who completed the initial treatment period did not start the second, optional treatment period due to disease progression or death.</population>
        <group_list>
          <group group_id="O1">
            <title>Ipilimumab, Nivolumab, Tacrolimus, and Prednisone</title>
            <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5 mg every day, nivolumab 3 mg/kg by infusion and ipilimumab 1 mg/kg by infusion every 3 weeks for 4 doses followed by maintenance nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Allograft Loss After Receiving Ipilimumab, Nivolumab, Tacrolimus, and Prednisone</title>
          <description>Number of patients who experienced allograft loss after receiving nivolumab, ipilimumab, tacrolimus, and prednisone.</description>
          <population>Two participants who completed the initial treatment period did not start the second, optional treatment period due to disease progression or death.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Experienced allograft loss</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Did not experience allograft loss</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 3 years</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Nivolumab, Tacrolimus, and Prednisone</title>
          <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5mg by mouth once a day, and nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="E2">
          <title>Ipilimumab, Nivolumab, Tacrolimus, and Prednisone</title>
          <description>Patients received low-dose tacrolimus (serum trough goal 2-5 ng/mL), prednisone 5mg by mouth once a day, nivolumab 3 mg/kg by infusion and ipilimumab 1 mg/kg by infusion every 3 weeks for 4 doses followed by maintenance nivolumab 480mg by infusion every 4 weeks for up to 96 weeks in the absence of disease progression or unacceptable toxicity.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE v5.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial flutter</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Inferior vena cava stenosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lactic acidosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Small bowel obstruction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Viral gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Cardiac troponin</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Stroke</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Suspected allograft rejection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Urinary hesitancy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Aspiration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Pseudoaneurysm</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE v5.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Bleeding at VasCath Site</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neutrophil Count Increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>White Blood cell Count Increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Corneal dellan, right eye</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Eye conjunctival tumor</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Eye redness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cheilitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Loose Stools</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Infusion site extravasation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Tumor Odor</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatocellular Liver Injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Vascular access complication</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Blood lactate dehydrogenase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cardiac troponin I increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>CPK increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Thyroid stimulating hormone increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyperphosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Neck stiffness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Tumor hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Tumor pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Delirium</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Blood Urea Nitrogen Increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Cystitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Urinary hesitancy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Laryngeal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Porocarcinoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Tumor Malodor</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>The second treatment period where participants received ipilimumab, nivolumab, tacrolimus, and prednisone was optional.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Grants Administrative Manager</name_or_title>
      <organization>Johns Hopkins University/SKCCC</organization>
      <phone>4439273568</phone>
      <email>jmurra33@jhmi.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03816332
org study id: NCI-2019-00239
secondary id: NCI-2019-00239
secondary id: ETCTN10214
secondary id: 10214
secondary id: 10214
secondary id: UM1CA186691
nct id: NCT03816332
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies how well tacrolimus, nivolumab, and ipilimumab work in treating
      kidney transplant recipients with cancer that cannot be removed by surgery (unresectable) or
      has spread to other places in the body (metastatic). Tacrolimus may stop the growth of tumor
      cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal
      antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the
      cancer, and may interfere with the ability of tumor cells to grow and spread. Giving
      tacrolimus, nivolumab, and ipilimumab may work better in treating kidney transplant
      recipients with cancer compared to chemotherapy, surgery, radiation therapy, or targeted
      therapies.
PRIMARY OBJECTIVE:

      I. To estimate the percent of kidney transplant recipients with selected advanced cancers for
      whom standard therapies would be insufficient who, 16 weeks after administration of
      prednisone, tacrolimus, and nivolumab, experience complete response (CR), partial response
      (PR), or stable disease (SD) without allograft loss.

      SECONDARY OBJECTIVES:

      I. To estimate the objective response rate (ORR), rate of allograft loss, and durations of
      progression-free survival (PFS) and overall survival (OS) in the study population.

      II. To estimate the ORR and rate of allograft loss in patients who experience progressive
      disease (PD) after administration of nivolumab and 1) receive ipilimumab and nivolumab, or 2)
      decrease or discontinue immunosuppression.

      EXPLORATORY OBJECTIVES:

      I. To characterize correlates of the host immune response, possibly including, but not
      limited to:

      Ia. Histopathological characteristics of allograft rejection/loss. Ib. Immunological changes
      in the tumor microenvironment (e.g., changes in T-cell subset populations or expression of
      immune checkpoint molecules) in paired biopsies obtained pre-treatment and on-treatment.

      Ic. Changes in donor-derived cell-free deoxyribonucleic acid (DNA) (dd-cfDNA) as a marker for
      allograft rejection.

      Id. Characteristics of anti-programmed death-1 (PD-1)-associated immune-mediated adverse
      reactions (IMAR) in this patient population treated with immunosuppression.

      OUTLINE:

      Patients receive tacrolimus orally (PO) twice daily (BID) and prednisone PO once daily (QD).
      Within 28 days, patients then receive nivolumab intravenously (IV) over 30 minutes on day 1.
      Cycles repeat every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease
      progression or unacceptable toxicity.

      Patients who experience progressive disease (PD) or patients who have experienced allograft
      loss at 16 weeks receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on
      day 1. Patients also receive tacrolimus PO BID and prednisone PO QD. Cycles repeat every 3
      weeks for 4 cycles (12 weeks) in the absence of disease progression or unacceptable toxicity.
      Starting 6 weeks later, patients receive nivolumab IV over 30 minutes every 4 weeks for up to
      21 cycles (84 weeks) in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 90 days, every 8 weeks for
      year 1, every 12 weeks for year 2, every 16 weeks for year 3, then every 24 weeks for year 4.
      Patients with PD are followed up every 12 weeks for up to 5 years.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number (and Percentage) of Outcome Responses After Receiving Nivolumab, Tacrolimus, and Prednisone
time frame: At 16 weeks
description: Percentage of kidney transplant recipients who experienced complete response (CR), partial response (PR) or stable disease (SD) without allograft loss.
measure: Objective Response (CR or PR) Rate (ORR) After Receiving Nivolumab, Tacrolimus, and Prednisone
time frame: Up to 4 months
description: Number (and percentage) of patients with a complete response (CR) or partial response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria after receiving at least one dose of nivolumab.
measure: Rate of Allograft Loss After Receiving Nivolumab, Tacrolimus, and Prednisone
time frame: Up to 4 months
description: Number of subjects who experienced allograft loss after receiving at least one dose of nivolumab.
measure: Duration of Progression-free Survival After Receiving Nivolumab, Tacrolimus, and Prednisone
time frame: Up to 4 months
description: From the first dose of nivolumab to the date of the first documented tumor progression or death due to any cause, whichever occurs first.
measure: Duration of Overall Survival After Receiving Nivolumab, Tacrolimus, and Prednisone
time frame: Up to 3 years
description: The time from the participant's first dose of nivolumab to the date of death from any cause.
measure: Overall Response Rate (ORR) in Patients After Receiving Ipilimumab, Nivolumab, Tacrolimus, and Prednisone
time frame: Up to 3 years
description: The number of participants with a CR or PR response after receiving ipilimumab, nivolumab, tacrolimus, and prednisone.
measure: Rate of Allograft Loss After Receiving Ipilimumab, Nivolumab, Tacrolimus, and Prednisone
time frame: Up to 3 years
description: Number of patients who experienced allograft loss after receiving nivolumab, ipilimumab, tacrolimus, and prednisone.
arm group label: Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)
arm group type: Experimental
description: Patients receive tacrolimus PO BID and prednisone PO QD. Within 28 days, patients then receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 4 weeks for up to 24 cycles (96 weeks) in the absence of disease progression or unacceptable toxicity.
Patients who experience PD or patients who have experienced allograft loss at 16 weeks receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Patients also receive tacrolimus PO BID and prednisone PO QD. Cycles repeat every 3 weeks for 4 cycles (12 weeks) in the absence of disease progression or unacceptable toxicity. Starting 6 weeks later, patients receive nivolumab IV over 30 minutes every 4 weeks for up to 21 cycles (84 weeks) in the absence of disease progression or unacceptable toxicity.
intervention type: Biological
intervention name: Ipilimumab
description: Given IV
arm group label: Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)
other name: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
other name: BMS-734016
other name: Ipilimumab Biosimilar CS1002
other name: MDX-010
other name: MDX-CTLA4
other name: Yervoy
intervention type: Biological
intervention name: Nivolumab
description: Given IV
arm group label: Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)
other name: BMS-936558
other name: CMAB819
other name: MDX-1106
other name: NIVO
other name: Nivolumab Biosimilar CMAB819
other name: ONO-4538
other name: Opdivo
intervention type: Drug
intervention name: Prednisone
description: Given PO
arm group label: Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)
other name: .delta.1-Cortisone
other name: 1, 2-Dehydrocortisone
other name: Adasone
other name: Cortancyl
other name: Dacortin
other name: DeCortin
other name: Decortisyl
other name: Decorton
other name: Delta 1-Cortisone
other name: Delta-Dome
other name: Deltacortene
other name: Deltacortisone
other name: Deltadehydrocortisone
other name: Deltasone
other name: Deltison
other name: Deltra
other name: Econosone
other name: Lisacort
other name: Meprosona-F
other name: Metacortandracin
other name: Meticorten
other name: Ofisolona
other name: Orasone
other name: Panafcort
other name: Panasol-S
other name: Paracort
other name: Perrigo Prednisone
other name: PRED
other name: Predicor
other name: Predicorten
other name: Prednicen-M
other name: Prednicort
other name: Prednidib
other name: Prednilonga
other name: Predniment
other name: Prednisone Intensol
other name: Prednisonum
other name: Prednitone
other name: Promifen
other name: Rayos
other name: Servisone
other name: SK-Prednisone
intervention type: Drug
intervention name: Tacrolimus
description: Given PO
arm group label: Treatment (tacrolimus, prednisone, nivolumab, ipilimumab)
other name: FK 506
other name: Fujimycin
other name: Hecoria
other name: Prograf
other name: Protopic
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Evan J Lipson
role: Principal Investigator
affiliation: JHU Sidney Kimmel Comprehensive Cancer Center LAO
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Carcinoma, Merkel Cell
mesh term: Carcinoma
mesh term: Melanoma
mesh term: Neoplasm Metastasis
mesh term: Carcinoma, Basal Cell
mesh term: Skin Neoplasms
mesh term: Prednisone
mesh term: Cortisone
mesh term: Nivolumab
mesh term: Ipilimumab
mesh term: Tacrolimus
sharing ipd: Yes
ipd description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
ipd url: https://grants.nih.gov/policy/sharing.htm
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: The second treatment period where participants received ipilimumab, nivolumab, tacrolimus, and prednisone was optional.
point of contact: 