<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/NCT03258593</url>
  </required_header>
  <id_info>
    <org_study_id>170157</org_study_id>
    <secondary_id>17-C-0157</secondary_id>
    <nct_id>NCT03258593</nct_id>
  </id_info>
  <brief_title>Durvalumab and Vicineum in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)</brief_title>
  <official_title>A Phase I Single-Arm Study of the Combination of Durvalumab (MEDI4736) and Vicineum (Oportuzumab Monatox, VB4-845) in Subjects With High-Grade Non-Muscle-Invasive Bladder Cancer Previously Treated With Bacillus Calmette-Guerin (BCG)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <has_dmc>No</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>
      Background:&#xD;
&#xD;
      Non-muscle-invasive bladder cancer is in the early stages. But it usually comes back after&#xD;
      treatment. The drugs Vicineum and Durvalumab may help the immune system find and destroy&#xD;
      cancer cells.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To test if the drugs Durvalumab and Vicineum together are safe and effective to treat people&#xD;
      with bladder cancer that has not spread to the muscle in the bladder.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      People ages 18 and older who have bladder cancer that has not spread to the muscle in the&#xD;
      bladder and was treated unsuccessfully with Bacillus Calmette-Guerin&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with:&#xD;
&#xD;
      Medical history&#xD;
&#xD;
      Physical exam&#xD;
&#xD;
      Blood and urine tests&#xD;
&#xD;
      Tumor sample from previous surgery. If one is not available, they will have a biopsy: A small&#xD;
      piece of tumor is removed.&#xD;
&#xD;
      Cystoscopy to examine the inside of the bladder. This may include a biopsy or removing&#xD;
      tumors.&#xD;
&#xD;
      Computed tomography (CT) or magnetic resonance imaging (MRI): They lie in a machine that&#xD;
      takes pictures of the body.&#xD;
&#xD;
      Electrocardiogram to test heart function&#xD;
&#xD;
      Participants will receive Durvalumab and Vicineum in 2 phases:&#xD;
&#xD;
      First phase: Durvalumab every 4 weeks and Vicineum once a week for 3 months&#xD;
&#xD;
      Second phase: Durvalumab every 4 weeks and Vicineum once every other week&#xD;
&#xD;
      Participants will have tumor samples taken every 3 months. They will have blood and urine&#xD;
      tests throughout the study.&#xD;
&#xD;
      Participants will continue treatment for up to 2 years.&#xD;
&#xD;
      Participants will have a visit about 30 days after their last treatment. This includes blood&#xD;
      and urine tests. It may include a cytoscopy or additional biopsies.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In 2016, it is estimated that there will be 76,960 new cases of bladder cancer and 16,390&#xD;
      deaths associated with bladder cancer. Bladder cancer is associated with the highest costs&#xD;
      among all types of cancer, due to the need for lifelong routine monitoring and treatment.&#xD;
      Approximately 70% of cases are non-muscle invasive bladder cancer (NMIBC) at presentation and&#xD;
      are treated by transurethral resection of bladder tumor (TURBT) followed by intravesical&#xD;
      treatment with BCG (Bacillus Calmette-Guerin) or mitomycin C. However, in the setting of&#xD;
      high-grade disease, these therapies can become ineffective over time in up to two-thirds of&#xD;
      patients and disease progression to muscle invasive bladder cancer (MIBC) can occur. In&#xD;
      patients who present with CIS (carcinoma in situ) rates of progression are greater than 50%.&#xD;
      Progression to MIBC portends a poor outcome as only 50% of patients will survive five years&#xD;
      despite undergoing radical cystectomy. Clearly, there is a large unmet need in therapeutic&#xD;
      options for NMIBC that recurs or progresses.&#xD;
&#xD;
      Vicineum(TM) is a recombinant fusion protein, VB4-845, that contains a humanized single-chain&#xD;
      antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked&#xD;
      to ETA (252-608), a truncated form of Pseudomonas exotoxin A (ETA). EpCAM is overexpressed on&#xD;
      the surface of urothelial carcinoma cells and therefore represents a good target for&#xD;
      Vicineum(TM) to bind to. In a previous phase II study in BCG refractory or BCG intolerant&#xD;
      patients with high grade bladder cancer, 16% of patients treated with induction and&#xD;
      maintenance therapy with Vicineum(TM) remained disease-free at 1 year. As a result,&#xD;
      Vicineum(TM) is currently being evaluated as a single agent in a phase III trial.&#xD;
&#xD;
      Pre-clinical work with a drug called Proxinium, an earlier version of Vicineum(TM),&#xD;
      demonstrated an abscopal effect and synergy with the use of a checkpoint blockade inhibitor.&#xD;
      Although it was done in a non-small cell lung cancer (NSCLC) model, the results were&#xD;
      impressive in causing tumor shrinkage. Durvalumab is a human monoclonal antibody (MAb) that&#xD;
      inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], cluster of&#xD;
      differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). Durvalumab&#xD;
      has been demonstrated to have activity against advanced metastatic urothelial bladder cancer&#xD;
      whose tumor has progressed during or after one standard platinum-based regimen in a phase I&#xD;
      trial.&#xD;
&#xD;
      Therefore, this trial will take two agents with single agent activity against urothelial&#xD;
      cancer and combine them in a Phase I trial for patients with high-grade NMIBC Previously&#xD;
      Treated with BCG.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      Primary Objectives:&#xD;
&#xD;
      To evaluate the safety and tolerability of durvalumab and Vicineum when administered in&#xD;
      combination to subjects with BCG-refractory high-grade NMIBC&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      Subjects must have a histologically confirmed high-grade non-muscle invasive urothelial&#xD;
      carcinoma (transitional cell carcinoma) of the bladder as follows:&#xD;
&#xD;
      Carcinoma-in-situ (CIS) with or without papillary tumors&#xD;
&#xD;
      High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of the initial&#xD;
      dose of study treatment. If multiple bladder biopsies/TURBTs are required to confirm&#xD;
      eligibility, the timing of the last bladder biopsy to the initial dose of study treatment&#xD;
      must be within 12 weeks.&#xD;
&#xD;
      Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology and the&#xD;
      Food and Drug Administration (FDA): Subjects must have received at least two courses of&#xD;
      intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance&#xD;
      doses of BCG under a maintenance regimen or at least 2 doses of a repeat induction course).&#xD;
      See exception below for persistent T1 disease below. There is no upper limit on the amount of&#xD;
      prior BCG a subject may have received.&#xD;
&#xD;
      Patients with persistent T1 high grade disease on TURBT following a single induction course&#xD;
      of BCG (at least 5 of 6 doses) may also be eligible for this trial provided that the patient&#xD;
      is surgically unfit for cystectomy as deemed by the investigator or the patient declines&#xD;
      cystectomy&#xD;
&#xD;
      Design:&#xD;
&#xD;
      This is a Phase I, open-label study of the combination of durvalumab and Vicineum in subjects&#xD;
      with high-grade NMIBC previously treated with BCG.&#xD;
&#xD;
      All subjects will receive Vicineum intravesically and durvalumab systemically at the standard&#xD;
      doses for both drugs as determined by Phase II trials for each drug, as no synergy or&#xD;
      additive effect is expected for adverse events.&#xD;
&#xD;
      Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at&#xD;
      least one year with an option for a total of up to 2 years of treatment. During the Induction&#xD;
      Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase,&#xD;
      Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.&#xD;
&#xD;
      Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with&#xD;
      an option to continue therapy for an additional 12 months (total of 24 months) provided that&#xD;
      patient is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment&#xD;
      Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued&#xD;
      in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months&#xD;
      to provide an immune boost.&#xD;
&#xD;
      Vicineum will be given as monotherapy for 1 week followed by treatment with the combination&#xD;
      of Vicineum and durvalumab starting week 2.&#xD;
&#xD;
      In the initial six patients, three subjects at a time will enroll at these doses and&#xD;
      schedules. Dose-liming toxicity (DLT) for each subject will be determined during the initial&#xD;
      6-week period that the subject is on treatment (i.e., the DLT period). When all subjects in&#xD;
      the initial cohort have been on treatment through the DLT period, all available safety data&#xD;
      will be considered in decisions to enroll additional subjects at this dose level, or to&#xD;
      de-escalate the dose(s) of study drug(s), based on a standard &quot;3 + 3&quot; design. There will be&#xD;
      no dose-escalations in this study. The dose of durvalumab will remain at 1500 mg every 4&#xD;
      weeks, and the dose of each intravesical Vicineum treatment can be reduced to 20 mg if the&#xD;
      initial doses in combination induce DLTs.&#xD;
&#xD;
      After the first six patients, an additional 18 subjects will be enrolled at the initial doses&#xD;
      or at the reduced doses (if DLTs resulted in the first 6 patients) in order to obtain&#xD;
      additional safety data, biomarker data and preliminary anti-tumor activity.&#xD;
&#xD;
      Each subject's course will consist of the following periods:&#xD;
&#xD;
      Screening/Baseline Period: The subject is consented and undergoes screening assessments to&#xD;
      determine eligibility for the study.&#xD;
&#xD;
      Treatment Period: The subject is treated and monitored for safety. Biomarker data will be&#xD;
      obtained prior to treatment and at periodic intervals during treatment. Subjects who remain&#xD;
      free of high-grade NMIBC after 12 months of study treatment may continue to receive treatment&#xD;
      for an additional 12 months until they develop recurrent high-grade disease, disease&#xD;
      progression, or intolerable toxicity, or meet another withdrawal criterion (e.g., consent&#xD;
      withdrawal, pregnancy).&#xD;
&#xD;
      Post-Treatment. The subject will return to the study site monthly for up to 90 days after the&#xD;
      last dose of immunotherapy for end-of-treatment assessments. Subjects with ongoing clinically&#xD;
      significant related adverse events (AEs) or serious adverse events (SAEs) will have&#xD;
      additional follow-up after the initial post-treatment visit.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 7, 2018</start_date>
  <completion_date type="Actual">October 17, 2022</completion_date>
  <primary_completion_date type="Actual">August 1, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>safety and tolerability</measure>
    <time_frame>one year</time_frame>
    <description>List of adverse event frequency</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Urinary EpCAM</measure>
    <time_frame>Baseline, week 1, weeks 2-5, week 6, week 10, week 12</time_frame>
    <description>Urinary EpCAM will be measured and will be compared between patients who have a clinical response to therapy vs. those who do not respond. The results will be presented for both response categories using descriptive statistics such as mean, standard error, median, minimum, maximum and other descriptive measures. Although it is expected to have low power, a comparison of the EpCAM levels may be compared between the two response categories using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response rate</measure>
    <time_frame>Disease progression</time_frame>
    <description>The response to treatment will be determined for patients who receive treatment; the response rate for those patients who are evaluable for response, along with a 95% two-sided confidence interval will be reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters in urine</measure>
    <time_frame>Baseline, week 1, weeks 2-5</time_frame>
    <description>Evaluate the pharmacokinetic parameters of Vicineum obtained by urine samples. This will be a descriptive analysis and will report sample statistics such as mean, standard error, median, minimum, maximum and other descriptive measures only.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PD-L1 and PD-1 levels</measure>
    <time_frame>baseline and after treatment with both agents</time_frame>
    <description>PD-L1 and PD-1 levels will be obtained at baseline and after treatment with both agents. The change in levels will be determined between the two measurements, and these changes will be compared between responders and non-responders, as well as between those who respond or have SD (clinical benefit=CR+PR+SD) and those with PD. Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune parameters</measure>
    <time_frame>baseline, 3 months, and 6 months</time_frame>
    <description>All evaluable patients will have determinations of many immune parameters at baseline, 3 months, and 6 months. The changes in the parameters obtained from blood samples will be determined at baseline vs. 3 months, and baseline vs. 6 months. The changes in the parameters obtained from biopsies will be obtained from baseline vs. a single second biopsy at 6 months. Comparisons of the paired values will be performed using a Wilcoxon signed rank test, and a Hochberg adjustment may be used.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Free Survival (DFS) curve</measure>
    <time_frame>Disease progression</time_frame>
    <description>A DFS curve will be created using the Kaplan-Meier method based on all patients considered to be evaluable based on having received protocol treatment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Urinary Bladder Neoplasms</condition>
  <arm_group>
    <arm_group_label>1/ Run In</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 subjects</description>
  </arm_group>
  <arm_group>
    <arm_group_label>2/ Expansion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 subjects</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with an option to continue therapy for an additional 12 months (total of 24 months) provided that, participant is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost.</description>
    <arm_group_label>1/ Run In</arm_group_label>
    <arm_group_label>2/ Expansion</arm_group_label>
    <other_name>Imfinzi</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vicineum</intervention_name>
    <description>Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.</description>
    <arm_group_label>1/ Run In</arm_group_label>
    <arm_group_label>2/ Expansion</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed by National Cancer&#xD;
             Institute (NCI) Laboratory of Pathology as high-grade non-muscle invasive urothelial&#xD;
             (transitional cell carcinoma) of the bladder as follows:&#xD;
&#xD;
               -  Carcinoma-in-situ (CIS) with or without papillary tumors&#xD;
&#xD;
               -  High-grade Ta or T1 disease based on a biopsy/transurethral resection of bladder&#xD;
                  tumor (TURBT) performed within 12 weeks of the initial dose of study treatment.&#xD;
                  If multiple bladder biopsies/TURBTs are required to confirm eligibility, the&#xD;
                  timing of the last bladder biopsy to the initial dose of study treatment must be&#xD;
                  within 12 weeks.&#xD;
&#xD;
               -  Patients with persistent T1 high grade disease on TURBT following a single&#xD;
                  induction course of BCG (Bacillus Calmette-Guerin) (at least 5 of 6 doses) may&#xD;
                  also be eligible for this trial provided that the patient is surgically unfit for&#xD;
                  cystectomy as deemed by the investigator or the patient declines cystectomy.&#xD;
&#xD;
          -  Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology&#xD;
             and the Food and Drug Administration (FDA): Subjects must have received at least two&#xD;
             courses of intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of&#xD;
             3 maintenance doses of BCG under a maintenance regimen or at least 2 doses of a repeat&#xD;
             induction course). Please note exception above for persistent T1 disease. There is no&#xD;
             upper limit on the amount of prior BCG a subject may have received.&#xD;
&#xD;
          -  Patients who have met eligibility criterion above must have received last BCG dose&#xD;
             within a year of enrollment.&#xD;
&#xD;
          -  The investigator must document that he/she believes the subject would not benefit from&#xD;
             additional BCG treatment at the time of study entry.&#xD;
&#xD;
          -  Age &gt;= 18 years at time of signing the informed consent form (ICF). Because no dosing&#xD;
             or adverse event data are currently available on the use of Vicineum in combination&#xD;
             with durvalumab in patients &lt;18 years of age, children are excluded from this study,&#xD;
             but will be eligible for future pediatric trials. Furthermore, non-muscle invasive&#xD;
             bladder cancer (NMIBC) does not occur in children.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1&#xD;
&#xD;
          -  Adequate organ and marrow function as defined below:&#xD;
&#xD;
               -  Hemoglobin &gt;= 9.0 g/dL&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) &gt;= 1.5 x 10^9/L (&gt; 1500 per mm^3)&#xD;
&#xD;
               -  Platelet count &gt;= 75 x 10^9/L (&gt;75,000 per mm^3)&#xD;
&#xD;
               -  Serum bilirubin less than or equal to 1.5 x institutional upper limit of normal&#xD;
                  (ULN).&#xD;
&#xD;
               -  Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase&#xD;
                  (SGOT)/alanine aminotransferase (ALT) serum glutamate-pyruvate transaminase&#xD;
                  (SGPT) less than or equal to 2.5 x institutional ULN&#xD;
&#xD;
               -  Creatinine CL&gt;40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976)&#xD;
                  or by 24-hour urine collection for determination of creatinine clearance:&#xD;
&#xD;
                    -  Males: Creatinine CL (mL/min) = (Weight (kg) x (140 - Age))/72 x serum&#xD;
                       creatinine (mg/dL)&#xD;
&#xD;
                    -  Females: Creatinine CL (mL/min) = (Weight (kg) x (140 - Age) x 0.85)/72 x&#xD;
                       serum creatinine (mg/dL)&#xD;
&#xD;
          -  Female subjects must either be of non-reproductive potential (i.e., post-menopausal as&#xD;
             described below) OR history of surgical sterilization (hysterectomy, bilateral tubal&#xD;
             ligation, or bilateral oophorectomy) or must have a negative serum pregnancy test upon&#xD;
             study entry.&#xD;
&#xD;
               -  Women &lt;50 years of age would be considered post-menopausal if they have been&#xD;
                  amenorrheic for 12 months or more following cessation of exogenous hormonal&#xD;
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone&#xD;
                  levels in the post-menopausal range for the institution&#xD;
&#xD;
               -  Women &gt;= 50 years of age would be considered post-menopausal if they have been&#xD;
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal&#xD;
                  treatments, had radiation-induced menopause with last menses &gt;1 year ago, or had&#xD;
                  chemotherapy-induced menopause with last menses &gt;1 year ago&#xD;
&#xD;
          -  The effects of Vicineum and durvalumab on the developing human fetus are unknown. For&#xD;
             this reason, all sexually active subjects agree to use barrier contraception (i.e.,&#xD;
             condoms) while receiving study treatment and for 120 days following their last dose of&#xD;
             study treatment. Female subjects of child-bearing potential and male subjects whose&#xD;
             sexual partners are women of childbearing potential (WOCBP) agree to use barrier&#xD;
             contraception and a second form of contraception while receiving study treatment and&#xD;
             for 4 months following their last dose of study treatment. Should a woman become&#xD;
             pregnant or suspect she is pregnant while she or her partner is participating in this&#xD;
             study, she should inform her treating physician immediately.&#xD;
&#xD;
          -  Written informed consent obtained from the subject prior to performing any protocol-&#xD;
             related procedures&#xD;
&#xD;
          -  Subject is willing and able to comply with the protocol for the duration of the study&#xD;
             including undergoing treatment and scheduled visits and examinations including follow&#xD;
             up.&#xD;
&#xD;
          -  Body weight &gt; 30 kg&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients who are receiving any other investigational agents.&#xD;
&#xD;
          -  QT interval corrected for heart rate using Fridericia's formula the corrected QT&#xD;
             interval by Fridericia (QTcF) &gt;=470 ms. (Any clinically significant abnormalities&#xD;
             detected require triplicate ECG results and a mean QT interval corrected for heart&#xD;
             rate using Fridericia's formula (QTcF) &gt;=470 ms calculated from 3 ECGs.)&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to Vicineum or durvalumab or other agents used in the study.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements. Urinary tract infections (UTIs) are excluded from being an&#xD;
             exclusion criterion for treatment unless they are grade 3 or higher.&#xD;
&#xD;
          -  Pregnant women are excluded from this study because it is unknown whether Vicineum&#xD;
             and/or durvalumab have any teratogenic effects. In nursing mothers, breastfeeding&#xD;
             should be discontinued as these medications may have the potential risk for adverse&#xD;
             events in nursing infants secondary to treatment of the mother.&#xD;
&#xD;
          -  Any previous treatment with a programmed cell death 1 (PD-1) or programmed&#xD;
             death-ligand 1 (PD-L1) inhibitor, including durvalumab&#xD;
&#xD;
          -  Evidence of non-bladder urothelial (transitional cell) carcinoma by biopsy, cytology,&#xD;
             or radiological imaging within the past 2 years of treatment (e.g., upper tract&#xD;
             transitional cell carcinoma, urethral urothelial carcinoma).&#xD;
&#xD;
          -  Subjects with hydronephrosis, except for those subjects where hydronephrosis has been&#xD;
             longstanding (i.e., predates the diagnosis of the CIS (carcinoma in situ), Ta, or T1&#xD;
             by more than 2 years) and diagnostic evaluation at screening shows no evidence of&#xD;
             tumor causing the hydronephrosis.&#xD;
&#xD;
          -  Any other anticancer therapy (e.g., chemotherapy, biologic therapy, immunotherapy,&#xD;
             targeted therapy, endocrine therapy, radiation therapy, intravesical therapy,&#xD;
             investigational agent) within 28 days of the first dose of study therapy (and within 6&#xD;
             weeks for nitrosourea or mitomycin C) other than a single dose of intravesical&#xD;
             chemotherapy which is permitted between 28 days and 14 days prior to the first dose of&#xD;
             study treatment.&#xD;
&#xD;
          -  The subject has a diagnosis of another malignancy within 2 years before the first dose&#xD;
             of study treatment, except for superficial skin cancer, localized prostate cancer on&#xD;
             active surveillance, or localized solid tumors deemed cured by surgery and not treated&#xD;
             with systemic anticancer therapy and not expected to require anticancer therapy in the&#xD;
             next 2 years i.e., while the subject may be taking study treatment.&#xD;
&#xD;
          -  Current or prior use of immunosuppressive medication within 28 days before the first&#xD;
             dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or&#xD;
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of&#xD;
             prednisone, or an equivalent corticosteroid.&#xD;
&#xD;
          -  Active or prior documented autoimmune or inflammatory disorders (including&#xD;
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with&#xD;
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,&#xD;
             or Wegener syndrome [granulomatosis with polyangiitis, Grave's disease, rheumatoid&#xD;
             arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this&#xD;
             criterion:&#xD;
&#xD;
               -  Subjects with vitiligo or alopecia&#xD;
&#xD;
               -  Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on&#xD;
                  hormonal replacement&#xD;
&#xD;
               -  Any chronic skin condition that does not require systemic therapy&#xD;
&#xD;
               -  Subjects without active disease in the last 5 years may be included but only&#xD;
                  after consultation with the Principal Investigator&#xD;
&#xD;
               -  Subjects with celiac disease controlled by diet alone&#xD;
&#xD;
          -  History of primary immunodeficiency.&#xD;
&#xD;
          -  History of allogeneic organ transplant.&#xD;
&#xD;
          -  History of hypersensitivity to durvalumab or any excipient&#xD;
&#xD;
          -  History of hypersensitivity to Vicineum or its components&#xD;
&#xD;
          -  Active infection with tuberculosis (clinical evaluation that includes clinical&#xD;
             history, physical examination, and radiographic findings, and purified protein&#xD;
             derivative (PPD) testing if indicated), hepatitis B (known positive HBV surface&#xD;
             antigen (HBsAg) result, hepatitis C, or human immunodeficiency virus (positive HIV 1/2&#xD;
             antibodies). Patients with HIV are excluded from participating on this clinical trial&#xD;
             because their immunodeficiency would confound the evaluation of adverse events which&#xD;
             would hinder meeting the primary objective. Subjects with a past or resolved HBV&#xD;
             infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence&#xD;
             of HBsAg) are eligible. Subjects positive for hepatitis C (HCV) antibody are eligible&#xD;
             only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).&#xD;
&#xD;
          -  History of leptomeningeal carcinomatosis&#xD;
&#xD;
          -  Receipt of live attenuated vaccination within 30 days prior to the first dose of&#xD;
             Vicineum or durvalumab&#xD;
&#xD;
          -  Any condition that, in the opinion of the investigator, would interfere with&#xD;
             evaluation of study treatment or interpretation of patient safety or study results&#xD;
&#xD;
          -  Subjects with uncontrolled seizures&#xD;
&#xD;
          -  Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria&#xD;
             for Adverse Events (CTCAE) Grade &gt;=2 from previous anticancer therapy with the&#xD;
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion&#xD;
             criteria&#xD;
&#xD;
               -  Subjects with Grade &gt;=2 neuropathy will be evaluated on a case-by-case basis&#xD;
                  after consultation with the Principal Investigator.&#xD;
&#xD;
               -  Subjects with irreversible toxicity not reasonably expected to be exacerbated by&#xD;
                  treatment with durvalumab may be included only after consultation with the&#xD;
                  Principal Investigator.&#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>Vladimir A Valera Romero, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2017-C-0157.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>August 22, 2017</study_first_submitted>
  <study_first_submitted_qc>August 22, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 23, 2017</study_first_posted>
  <disposition_first_submitted>August 1, 2023</disposition_first_submitted>
  <disposition_first_submitted_qc>August 1, 2023</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">August 22, 2023</disposition_first_posted>
  <last_update_submitted>August 1, 2023</last_update_submitted>
  <last_update_submitted_qc>August 1, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Cancer Institute (NCI)</investigator_affiliation>
    <investigator_full_name>Vladimir Valera Romero, M.D. Ph.D</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Carcinoma-in-situ</keyword>
  <keyword>High-grade Ta or T1 disease</keyword>
  <keyword>Papillary Tumors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Urinary Bladder Neoplasms</mesh_term>
    <mesh_term>Non-Muscle Invasive Bladder Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol genomic data sharing (GDS) plan for as long as database is active.</ipd_time_frame>
    <ipd_access_criteria>Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.</ipd_access_criteria>
  </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 10, 2023</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/93/NCT03258593/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>February 21, 2023</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/93/NCT03258593/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <pending_results>
    <submitted>August 29, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</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/NCT03258593
org study id: 170157
secondary id: 17-C-0157
nct id: NCT03258593
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Background:

      Non-muscle-invasive bladder cancer is in the early stages. But it usually comes back after
      treatment. The drugs Vicineum and Durvalumab may help the immune system find and destroy
      cancer cells.

      Objective:

      To test if the drugs Durvalumab and Vicineum together are safe and effective to treat people
      with bladder cancer that has not spread to the muscle in the bladder.

      Eligibility:

      People ages 18 and older who have bladder cancer that has not spread to the muscle in the
      bladder and was treated unsuccessfully with Bacillus Calmette-Guerin

      Design:

      Participants will be screened with:

      Medical history

      Physical exam

      Blood and urine tests

      Tumor sample from previous surgery. If one is not available, they will have a biopsy: A small
      piece of tumor is removed.

      Cystoscopy to examine the inside of the bladder. This may include a biopsy or removing
      tumors.

      Computed tomography (CT) or magnetic resonance imaging (MRI): They lie in a machine that
      takes pictures of the body.

      Electrocardiogram to test heart function

      Participants will receive Durvalumab and Vicineum in 2 phases:

      First phase: Durvalumab every 4 weeks and Vicineum once a week for 3 months

      Second phase: Durvalumab every 4 weeks and Vicineum once every other week

      Participants will have tumor samples taken every 3 months. They will have blood and urine
      tests throughout the study.

      Participants will continue treatment for up to 2 years.

      Participants will have a visit about 30 days after their last treatment. This includes blood
      and urine tests. It may include a cytoscopy or additional biopsies.
In 2016, it is estimated that there will be 76,960 new cases of bladder cancer and 16,390
      deaths associated with bladder cancer. Bladder cancer is associated with the highest costs
      among all types of cancer, due to the need for lifelong routine monitoring and treatment.
      Approximately 70% of cases are non-muscle invasive bladder cancer (NMIBC) at presentation and
      are treated by transurethral resection of bladder tumor (TURBT) followed by intravesical
      treatment with BCG (Bacillus Calmette-Guerin) or mitomycin C. However, in the setting of
      high-grade disease, these therapies can become ineffective over time in up to two-thirds of
      patients and disease progression to muscle invasive bladder cancer (MIBC) can occur. In
      patients who present with CIS (carcinoma in situ) rates of progression are greater than 50%.
      Progression to MIBC portends a poor outcome as only 50% of patients will survive five years
      despite undergoing radical cystectomy. Clearly, there is a large unmet need in therapeutic
      options for NMIBC that recurs or progresses.

      Vicineum(TM) is a recombinant fusion protein, VB4-845, that contains a humanized single-chain
      antibody fragment specific for the epithelial cell adhesion molecule (EpCAM) antigen linked
      to ETA (252-608), a truncated form of Pseudomonas exotoxin A (ETA). EpCAM is overexpressed on
      the surface of urothelial carcinoma cells and therefore represents a good target for
      Vicineum(TM) to bind to. In a previous phase II study in BCG refractory or BCG intolerant
      patients with high grade bladder cancer, 16% of patients treated with induction and
      maintenance therapy with Vicineum(TM) remained disease-free at 1 year. As a result,
      Vicineum(TM) is currently being evaluated as a single agent in a phase III trial.

      Pre-clinical work with a drug called Proxinium, an earlier version of Vicineum(TM),
      demonstrated an abscopal effect and synergy with the use of a checkpoint blockade inhibitor.
      Although it was done in a non-small cell lung cancer (NSCLC) model, the results were
      impressive in causing tumor shrinkage. Durvalumab is a human monoclonal antibody (MAb) that
      inhibits binding of programmed cell death ligand 1 (PD-L1) (B7 homolog 1 [B7-H1], cluster of
      differentiation [CD]274) to programmed cell death 1 (PD-1; CD279) and CD80 (B7-1). Durvalumab
      has been demonstrated to have activity against advanced metastatic urothelial bladder cancer
      whose tumor has progressed during or after one standard platinum-based regimen in a phase I
      trial.

      Therefore, this trial will take two agents with single agent activity against urothelial
      cancer and combine them in a Phase I trial for patients with high-grade NMIBC Previously
      Treated with BCG.

      Objectives:

      Primary Objectives:

      To evaluate the safety and tolerability of durvalumab and Vicineum when administered in
      combination to subjects with BCG-refractory high-grade NMIBC

      Eligibility:

      Subjects must have a histologically confirmed high-grade non-muscle invasive urothelial
      carcinoma (transitional cell carcinoma) of the bladder as follows:

      Carcinoma-in-situ (CIS) with or without papillary tumors

      High-grade Ta or T1 disease based on a biopsy/TURBT performed within 12 weeks of the initial
      dose of study treatment. If multiple bladder biopsies/TURBTs are required to confirm
      eligibility, the timing of the last bladder biopsy to the initial dose of study treatment
      must be within 12 weeks.

      Subjects with BCG unresponsive disease as defined by the Society of Urologic Oncology and the
      Food and Drug Administration (FDA): Subjects must have received at least two courses of
      intravesical BCG (at least 5 of 6 induction doses of BCG and at least 2 of 3 maintenance
      doses of BCG under a maintenance regimen or at least 2 doses of a repeat induction course).
      See exception below for persistent T1 disease below. There is no upper limit on the amount of
      prior BCG a subject may have received.

      Patients with persistent T1 high grade disease on TURBT following a single induction course
      of BCG (at least 5 of 6 doses) may also be eligible for this trial provided that the patient
      is surgically unfit for cystectomy as deemed by the investigator or the patient declines
      cystectomy

      Design:

      This is a Phase I, open-label study of the combination of durvalumab and Vicineum in subjects
      with high-grade NMIBC previously treated with BCG.

      All subjects will receive Vicineum intravesically and durvalumab systemically at the standard
      doses for both drugs as determined by Phase II trials for each drug, as no synergy or
      additive effect is expected for adverse events.

      Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at
      least one year with an option for a total of up to 2 years of treatment. During the Induction
      Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase,
      Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.

      Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with
      an option to continue therapy for an additional 12 months (total of 24 months) provided that
      patient is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment
      Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued
      in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months
      to provide an immune boost.

      Vicineum will be given as monotherapy for 1 week followed by treatment with the combination
      of Vicineum and durvalumab starting week 2.

      In the initial six patients, three subjects at a time will enroll at these doses and
      schedules. Dose-liming toxicity (DLT) for each subject will be determined during the initial
      6-week period that the subject is on treatment (i.e., the DLT period). When all subjects in
      the initial cohort have been on treatment through the DLT period, all available safety data
      will be considered in decisions to enroll additional subjects at this dose level, or to
      de-escalate the dose(s) of study drug(s), based on a standard "3 + 3" design. There will be
      no dose-escalations in this study. The dose of durvalumab will remain at 1500 mg every 4
      weeks, and the dose of each intravesical Vicineum treatment can be reduced to 20 mg if the
      initial doses in combination induce DLTs.

      After the first six patients, an additional 18 subjects will be enrolled at the initial doses
      or at the reduced doses (if DLTs resulted in the first 6 patients) in order to obtain
      additional safety data, biomarker data and preliminary anti-tumor activity.

      Each subject's course will consist of the following periods:

      Screening/Baseline Period: The subject is consented and undergoes screening assessments to
      determine eligibility for the study.

      Treatment Period: The subject is treated and monitored for safety. Biomarker data will be
      obtained prior to treatment and at periodic intervals during treatment. Subjects who remain
      free of high-grade NMIBC after 12 months of study treatment may continue to receive treatment
      for an additional 12 months until they develop recurrent high-grade disease, disease
      progression, or intolerable toxicity, or meet another withdrawal criterion (e.g., consent
      withdrawal, pregnancy).

      Post-Treatment. The subject will return to the study site monthly for up to 90 days after the
      last dose of immunotherapy for end-of-treatment assessments. Subjects with ongoing clinically
      significant related adverse events (AEs) or serious adverse events (SAEs) will have
      additional follow-up after the initial post-treatment visit.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: safety and tolerability
time frame: one year
description: List of adverse event frequency
measure: Urinary EpCAM
time frame: Baseline, week 1, weeks 2-5, week 6, week 10, week 12
description: Urinary EpCAM will be measured and will be compared between patients who have a clinical response to therapy vs. those who do not respond. The results will be presented for both response categories using descriptive statistics such as mean, standard error, median, minimum, maximum and other descriptive measures. Although it is expected to have low power, a comparison of the EpCAM levels may be compared between the two response categories using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.
measure: Response rate
time frame: Disease progression
description: The response to treatment will be determined for patients who receive treatment; the response rate for those patients who are evaluable for response, along with a 95% two-sided confidence interval will be reported.
measure: Pharmacokinetic parameters in urine
time frame: Baseline, week 1, weeks 2-5
description: Evaluate the pharmacokinetic parameters of Vicineum obtained by urine samples. This will be a descriptive analysis and will report sample statistics such as mean, standard error, median, minimum, maximum and other descriptive measures only.
measure: PD-L1 and PD-1 levels
time frame: baseline and after treatment with both agents
description: PD-L1 and PD-1 levels will be obtained at baseline and after treatment with both agents. The change in levels will be determined between the two measurements, and these changes will be compared between responders and non-responders, as well as between those who respond or have SD (clinical benefit=CR+PR+SD) and those with PD. Although it is expected to have low power, in each case the comparisons between the two response categories will be made using a Wilcoxon rank sum test, with the resulting p-value intended to help describe the differences noted.
measure: Immune parameters
time frame: baseline, 3 months, and 6 months
description: All evaluable patients will have determinations of many immune parameters at baseline, 3 months, and 6 months. The changes in the parameters obtained from blood samples will be determined at baseline vs. 3 months, and baseline vs. 6 months. The changes in the parameters obtained from biopsies will be obtained from baseline vs. a single second biopsy at 6 months. Comparisons of the paired values will be performed using a Wilcoxon signed rank test, and a Hochberg adjustment may be used.
measure: Disease Free Survival (DFS) curve
time frame: Disease progression
description: A DFS curve will be created using the Kaplan-Meier method based on all patients considered to be evaluable based on having received protocol treatment.
arm group label: 1/ Run In
arm group type: Experimental
description: Durvalumab + Vicineum, escalating doses. Up to 2 dose levels will be evaluated in the first 6 - 12 subjects
arm group label: 2/ Expansion
arm group type: Experimental
description: Durvalumab + Vicineum, at the maximum tolerated dose (MTD). Up to 24 subjects
intervention type: Drug
intervention name: Durvalumab
description: Durvalumab 1500 mg is administered intravenously (IV) once every 4 weeks for 12 months with an option to continue therapy for an additional 12 months (total of 24 months) provided that, participant is tolerating therapy and remains free of recurrent high grade NMIBC (see Treatment Period below). The dose of durvalumab is 1500 mg. If optional maintenance therapy continued in the second year, durvalumab 1500 mg will be administered intravenously once every 3 months to provide an immune boost.
arm group label: 1/ Run In
arm group label: 2/ Expansion
other name: Imfinzi
intervention type: Drug
intervention name: Vicineum
description: Vicineum is administered in a 12-week Induction Phase followed by a Maintenance Phase for at least one year with an option for a total of up to 2 years of treatment. During the Induction Phase, Vicineum is administered once weekly for 12 weeks. During the Maintenance Phase, Vicineum is administered every other week. The dose of Vicineum is 30 mg in 50 mL of saline.
arm group label: 1/ Run In
arm group label: 2/ Expansion
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Vladimir A Valera Romero, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2017-C-0157.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Principal Investigator
investigator affiliation: National Cancer Institute (NCI)
investigator full name: Vladimir Valera Romero, M.D. Ph.D
investigator title: Principal Investigator
mesh term: Urinary Bladder Neoplasms
mesh term: Non-Muscle Invasive Bladder Neoplasms
mesh term: Durvalumab
sharing ipd: Yes
ipd description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol genomic data sharing (GDS) plan for as long as database is active.
ipd access criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
provided document: 
provided document: 
submitted: August 29, 2023