<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/NCT03759496</url>
  </required_header>
  <id_info>
    <org_study_id>ESR-16-12611</org_study_id>
    <secondary_id>2018-002100-13</secondary_id>
    <nct_id>NCT03759496</nct_id>
  </id_info>
  <brief_title>Efficacy of Durvalumab in Non-muscle-invasive Bladder Cancer</brief_title>
  <official_title>Intravesical Administration of Durvalumab (MEDI4736) to Patients With High-risk, Non-muscle-invasive Bladder Cancer (NMIBC). A Phase II Study With Correlative</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hellenic GenitoUrinary Cancer Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hellenic GenitoUrinary Cancer Group</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Research Hypothesis Approximately 75% of patients with bladder cancer (BC) present with a&#xD;
      disease confined to the mucosa (stage Ta, CIS) or submucosa (stage T1) (non-muscle invasive&#xD;
      BC [NMIBC]). For high grade NMIBC, i.e. TaG3, T1G3 and CIS, intravesical bacillus&#xD;
      Calmette-Guérin (BCG) immunotherapy is the treatment of choice, given that it prevents&#xD;
      recurrence and reduces the odds of progression to MIBC. However, since initial BCG therapy&#xD;
      fails in approximately 40% of patients over a 2-year period, new treatment options for these&#xD;
      patients are of utmost importance.&#xD;
&#xD;
      In that field of research durvalumab, a human monoclonal antibody that binds programmed cell&#xD;
      death ligand-1 (PD-L1), demonstrated meaningful clinical activity as well as manageable&#xD;
      safety profile in PD-L1-positive patients with BC, many of whom were heavily pretreated.&#xD;
      Certain studies using systemic administration of anti-PD1 agents for BCG refractory NMIBC are&#xD;
      ongoing. Nevertheless, intravesical administration may be advantageous, since selective&#xD;
      bladder tumor uptake of monoclonal antibodies following intravesical administration, while&#xD;
      this method results in negligible absorption in the circulation and, therefore, minimal risk&#xD;
      of systemic toxicity. This notion is supported by the findings of a recent study of&#xD;
      intravesical administration of recombinant adenovirus-mediated interferon-α2b gene therapy&#xD;
      (rAd-IFNα), No rAd-IFNα DNA was detected in the blood. Furthermore, no systemic toxicity was&#xD;
      reported in a phase II study using the same agent.&#xD;
&#xD;
      The investigators, therefore, propose a phase II study of intravesical administration of&#xD;
      durvalumab in patients with BCG refractory NMIBC. Since no safety or efficacy data&#xD;
      specifically on intravesical administration of durvalumab exist, a run-in part will precede&#xD;
      the main phase II, in order to confirm safety of the procedure and to reject a futility&#xD;
      hypothesis, as described in the following sections of the protocol. Correlative studies of&#xD;
      potential biomarkers in tumor tissue before and after durvalumab instillation are also&#xD;
      proposed.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 15, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The maximum tolerated dose (MTD) of Durvalumab among 500mg, 750mg and 1000mg that will be given intravesically to patients with BCG-refractory NMIBC</measure>
    <time_frame>6 months after trial initiation</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>The possibility of a rate of high-grade relapse free (HGFR) that it is defined as the development of TaG3, T1G3, CIS or muscle-invasive disease after the initiation of durvalumab therapy.</measure>
    <time_frame>6 months after trial initiation</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Efficacy of intravesical administration of Durvalumab at MTD in patients with BCG-refractory NMIBC assessed by 1-year high-grade-relapse-free (HGRF)-rate</measure>
    <time_frame>1 year after patient enrollment</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Toxicity of the MTD of intravesical Durvalumab administration assessed according to the NCI CTC version 4.03 except from local irritation.</measure>
    <time_frame>6 months after trial initiation</time_frame>
    <description>Local irritation will be assessed according to the following criteria: Grade 1: Microscopic hematuria Grade 2: Moderate frequency. Intermittent macroscopic hematuria. Grade 3: Severe frequency and dysuria. Frequent hematuria. Reduction in bladder capacity (&lt;150 cc) Grade 4: Necrosis/ Contracted bladder (capacity &lt;100 cc). Severe hemorrhagic cystitis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy assessed by the high-grade progression-free rate at 30 days after the last durvalumab instillation and 6 months following durvalumab therapy.</measure>
    <time_frame>30 days and 6 month after last durvalumab instillation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PD-L1 and VEGF expression assessed in tumor tissue obtained before and after durvalumab instillation</measure>
    <time_frame>33 months after FPFV</time_frame>
    <description>Immunohistochemistry will be used for the evaluation of PD-L1 and VEGF expression levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of PD-L1 and VEGF protein levels in urine samples obtained before and after durvalumab instillation</measure>
    <time_frame>33 months after FPFV</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">39</enrollment>
  <condition>Bladder Cancer</condition>
  <arm_group>
    <arm_group_label>Durvalumab treated patients</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive up to 1000mg durvalumab (MEDI4736) via weekly intravesical administration, for up to a maximum of 6 weeks or until confirmed progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass</description>
    <arm_group_label>Durvalumab treated patients</arm_group_label>
    <other_name>MEDI4736</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent and any locally-required authorization (eg, HIPAA in the USA,&#xD;
             EU Data Privacy Directive in the EU) obtained from the subject prior to performing any&#xD;
             protocol-related procedures, including screening evaluations&#xD;
&#xD;
          2. Age &gt; 18 years at time of study entry&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          4. Body weight &gt;30kg&#xD;
&#xD;
          5. Diagnosis of high grade, non-muscle invasive urothelial carcinoma. High-grade&#xD;
             carcinoma includes the following types&#xD;
&#xD;
               1. TaG3&#xD;
&#xD;
               2. T1G3&#xD;
&#xD;
               3. CIS&#xD;
&#xD;
          6. Tumors with combinations of the above types or containing low grade components in&#xD;
             addition to the high-grade component are acceptable. Disease refractory to Bacillus&#xD;
             Calmette Guerin (BCG) therapy to adequate BCG exposure. BCG refractory disease is&#xD;
             defined as&#xD;
&#xD;
               1. If high-grade tumor appears during BCG therapy&#xD;
&#xD;
               2. If high-grade, non-muscle-invasive papillary tumor is present at three months&#xD;
&#xD;
               3. If CIS (with or without concomitant papillary tumor) is present at three and six&#xD;
                  months Adequate exposure is defined as a minimum of 5 out of 6 BCG induction&#xD;
                  doses. Μaintenance or re-induction can be used according to local practice but&#xD;
                  are not mandatory for the definition of adequate exposure.&#xD;
&#xD;
          7. High grade recurrence after an initial response to BCG therapy.&#xD;
&#xD;
          8. Patients intolerant to adequate BCG exposure, defined as&#xD;
&#xD;
               1. fewer than 5 instillations of BCG induction therapy&#xD;
&#xD;
               2. No more than one cycle of maintenance BCG therapy&#xD;
&#xD;
          9. Subjects may have received other intravesical or systemic therapies XML File&#xD;
             Identifier: goagJWHcccRmyt+fBE00IC1ok+0= Page 12/26 for NMIBC or CIS before or after&#xD;
             receiving BCG, as long as they meet the aforementioned criteria for BCG refractory&#xD;
             disease.&#xD;
&#xD;
         10. Subjects are not candidates for immediate cystectomy or have elected not to undergo&#xD;
             the procedure.&#xD;
&#xD;
         11. Adequate normal organ and marrow function as defined below:&#xD;
&#xD;
               1. Haemoglobin ≥ 9.0 g/dL&#xD;
&#xD;
               2. Absolute neutrophil count (ANC) &gt; 1500 per mm3&#xD;
&#xD;
               3. Platelet count &gt;100,000 per mm3&#xD;
&#xD;
               4. Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not&#xD;
                  apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent&#xD;
                  hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis&#xD;
                  or hepatic pathology), who will be allowed only in consultation with their&#xD;
                  physician.&#xD;
&#xD;
               5. AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of normal unless liver&#xD;
                  metastases are present, in which case it must be ≤ 5x ULN&#xD;
&#xD;
               6. Serum creatinine Cl&gt;40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault&#xD;
                  1976) or by 24-hour urine collection for determination of creatinine clearance&#xD;
&#xD;
         12. Evidence of post-menopausal status or negative urinary or serum pregnancy test for&#xD;
             female pre-menopausal subjects. Women will be considered post-menopausal if they have&#xD;
             been amenorrheic for 12 months without an alternative medical cause. The following&#xD;
             age-specific requirements apply:&#xD;
&#xD;
               1. 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 or underwent surgical&#xD;
                  sterilization (bilateral oophorectomy or hysterectomy).&#xD;
&#xD;
               2. Women ≥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, had&#xD;
                  chemotherapy-induced menopause with last menses &gt;1 year ago, or underwent&#xD;
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or&#xD;
                  hysterectomy).&#xD;
&#xD;
         13. 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;
        Exclusion Criteria:&#xD;
&#xD;
          1. Disease of the upper urinary tract or prostatic urethra&#xD;
&#xD;
          2. ECG with QTcF value &gt;470 ms&#xD;
&#xD;
          3. Participation in another clinical study with an investigational product during the&#xD;
             last 4 weeks&#xD;
&#xD;
          4. Concurrent enrolment in another clinical study, unless it is an observational (non&#xD;
             interventional) clinical study or during the follow-up period of an interventional&#xD;
             study&#xD;
&#xD;
          5. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,&#xD;
             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal&#xD;
             antibodies, other investigational agent) within 14 days prior to the first dose of&#xD;
             study drug. Immediate postoperative intravesical instillation of epirubicin or&#xD;
             mitomycin C is allowed if occurred more than 14 days prior to the first dose of the&#xD;
             study drug.&#xD;
&#xD;
          6. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the&#xD;
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion&#xD;
             criteria Subjects with Grade ≥2 neuropathy will be evaluated on a case-by-case basis&#xD;
             after consultation with the Study Physician. Subjects with irreversible toxicity not&#xD;
             reasonably expected to be exacerbated by treatment with durvalumab may be included&#xD;
             only after consultation with the Study Physician.&#xD;
&#xD;
          7. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.&#xD;
             Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone&#xD;
             replacement therapy) is acceptable.&#xD;
&#xD;
          8. Major surgical procedure (as defined by the Investigator) within 28 days prior to the&#xD;
             first dose of IP. Note: Local surgery of isolated lesions for palliative intent is&#xD;
             acceptable.&#xD;
&#xD;
          9. History of allogenic organ transplantation.&#xD;
&#xD;
         10. Active or prior documented autoimmune or inflammatory disorders (including&#xD;
             inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the&#xD;
             exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or&#xD;
             Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid&#xD;
             arthritis, hypophysitis, uveitis, etc]) - more details in protocol.&#xD;
&#xD;
         11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable&#xD;
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic&#xD;
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social&#xD;
             situations that would limit compliance with study requirement, substantially increase&#xD;
             risk of incurring AEs or compromise the ability of the patient to give written&#xD;
             informed consent&#xD;
&#xD;
         12. History of another primary malignancy with exceptions described in protocol&#xD;
&#xD;
         13. History of leptomeningeal carcinomatosis&#xD;
&#xD;
         14. History of active primary immunodeficiency&#xD;
&#xD;
         15. Active infection including tuberculosis, hepatitis B, hepatitis C, or human&#xD;
             immunodeficiency virus. Subjects with a past or resolved HBV infection are eligible.&#xD;
             Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain&#xD;
             reaction is negative for HCV RNA (see details in protocol)&#xD;
&#xD;
         16. Current or prior use of immunosuppressive medication within 14 days before the first&#xD;
             dose of durvalumab with exceptions described in protocol&#xD;
&#xD;
         17. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:&#xD;
             Subjects, if enrolled, should not receive live vaccine whilst receiving IP and up to&#xD;
             30 days after the last dose of IP.&#xD;
&#xD;
         18. Female subjects who are pregnant or breastfeeding or male or female subjects of&#xD;
             reproductive potential who are not willing to employ effective birth control from&#xD;
             screening to 90 days after the last dose of durvalumab monotherapy.&#xD;
&#xD;
         19. Known allergy or hypersensitivity to any of the study drugs or any of the study drug&#xD;
             excipients.&#xD;
&#xD;
         20. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical&#xD;
             study regardless of treatment arm assignment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Hellenic GenitoUrinary Cancer Group</name>
      <address>
        <city>Athens</city>
        <state>Attica</state>
        <zip>11527</zip>
        <country>Greece</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Greece</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>November 26, 2018</study_first_submitted>
  <study_first_submitted_qc>November 28, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 30, 2018</study_first_posted>
  <last_update_submitted>March 22, 2022</last_update_submitted>
  <last_update_submitted_qc>March 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>bladder</keyword>
  <keyword>durvalumab</keyword>
  <keyword>cancer</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>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03759496
org study id: ESR-16-12611
secondary id: 2018-002100-13
nct id: NCT03759496
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Research Hypothesis Approximately 75% of patients with bladder cancer (BC) present with a
      disease confined to the mucosa (stage Ta, CIS) or submucosa (stage T1) (non-muscle invasive
      BC [NMIBC]). For high grade NMIBC, i.e. TaG3, T1G3 and CIS, intravesical bacillus
      Calmette-Guérin (BCG) immunotherapy is the treatment of choice, given that it prevents
      recurrence and reduces the odds of progression to MIBC. However, since initial BCG therapy
      fails in approximately 40% of patients over a 2-year period, new treatment options for these
      patients are of utmost importance.

      In that field of research durvalumab, a human monoclonal antibody that binds programmed cell
      death ligand-1 (PD-L1), demonstrated meaningful clinical activity as well as manageable
      safety profile in PD-L1-positive patients with BC, many of whom were heavily pretreated.
      Certain studies using systemic administration of anti-PD1 agents for BCG refractory NMIBC are
      ongoing. Nevertheless, intravesical administration may be advantageous, since selective
      bladder tumor uptake of monoclonal antibodies following intravesical administration, while
      this method results in negligible absorption in the circulation and, therefore, minimal risk
      of systemic toxicity. This notion is supported by the findings of a recent study of
      intravesical administration of recombinant adenovirus-mediated interferon-α2b gene therapy
      (rAd-IFNα), No rAd-IFNα DNA was detected in the blood. Furthermore, no systemic toxicity was
      reported in a phase II study using the same agent.

      The investigators, therefore, propose a phase II study of intravesical administration of
      durvalumab in patients with BCG refractory NMIBC. Since no safety or efficacy data
      specifically on intravesical administration of durvalumab exist, a run-in part will precede
      the main phase II, in order to confirm safety of the procedure and to reject a futility
      hypothesis, as described in the following sections of the protocol. Correlative studies of
      potential biomarkers in tumor tissue before and after durvalumab instillation are also
      proposed.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The maximum tolerated dose (MTD) of Durvalumab among 500mg, 750mg and 1000mg that will be given intravesically to patients with BCG-refractory NMIBC
time frame: 6 months after trial initiation
measure: The possibility of a rate of high-grade relapse free (HGFR) that it is defined as the development of TaG3, T1G3, CIS or muscle-invasive disease after the initiation of durvalumab therapy.
time frame: 6 months after trial initiation
measure: Efficacy of intravesical administration of Durvalumab at MTD in patients with BCG-refractory NMIBC assessed by 1-year high-grade-relapse-free (HGRF)-rate
time frame: 1 year after patient enrollment
measure: Toxicity of the MTD of intravesical Durvalumab administration assessed according to the NCI CTC version 4.03 except from local irritation.
time frame: 6 months after trial initiation
description: Local irritation will be assessed according to the following criteria: Grade 1: Microscopic hematuria Grade 2: Moderate frequency. Intermittent macroscopic hematuria. Grade 3: Severe frequency and dysuria. Frequent hematuria. Reduction in bladder capacity (<150 cc) Grade 4: Necrosis/ Contracted bladder (capacity <100 cc). Severe hemorrhagic cystitis
measure: Efficacy assessed by the high-grade progression-free rate at 30 days after the last durvalumab instillation and 6 months following durvalumab therapy.
time frame: 30 days and 6 month after last durvalumab instillation
measure: PD-L1 and VEGF expression assessed in tumor tissue obtained before and after durvalumab instillation
time frame: 33 months after FPFV
description: Immunohistochemistry will be used for the evaluation of PD-L1 and VEGF expression levels
measure: Assessment of PD-L1 and VEGF protein levels in urine samples obtained before and after durvalumab instillation
time frame: 33 months after FPFV
arm group label: Durvalumab treated patients
arm group type: Experimental
description: Subjects will receive up to 1000mg durvalumab (MEDI4736) via weekly intravesical administration, for up to a maximum of 6 weeks or until confirmed progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.
intervention type: Biological
intervention name: Durvalumab
description: Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass
arm group label: Durvalumab treated patients
other name: MEDI4736
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Greece
responsible party type: Sponsor
mesh term: Urinary Bladder Neoplasms
mesh term: Non-Muscle Invasive Bladder Neoplasms
mesh term: Durvalumab
sharing ipd: Undecided