<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/NCT03234153</url>
  </required_header>
  <id_info>
    <org_study_id>NITIMIB-Trial</org_study_id>
    <nct_id>NCT03234153</nct_id>
  </id_info>
  <brief_title>Neoadjuvant Immunotherapy With Durvalumab and Tremelimumab for Bladder Cancer Patients Ineligible for Cisplatin</brief_title>
  <acronym>NITIMIB</acronym>
  <official_title>Neoadjuvant Immunotherapy With Durvalumab in Combination With Tremelimumab in Patients With Muscle-invasive Bladder Cancer Ineligible for Cisplatin-based Chemotherapy.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</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>
      The trial assess the safety and antitumor activity of the anti-PD-L1 antibody Durvalumab in&#xD;
      combination with the anti-CTLA4 antibody Tremelimumab.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background and Rationale:&#xD;
&#xD;
      The outcome for patients with muscle-invasive bladder cancer treated with surgery alone&#xD;
      remains dismal with a 5 year survival rate between 25% to 80% depending on the tumor stage&#xD;
      and lymph node status. Cisplatin-based chemotherapy regimens (Methotrexate, Vinblastine,&#xD;
      Doxorubicin, Cisplatin ; Cisplatin, Methotrexate, Vinblastine; Gemcitabine/Cisplatin) have&#xD;
      demonstrated a modest but absolute benefit in overall survival of 5-8% when administered in&#xD;
      the neoadjuvant setting. Therefore, neoadjuvant Cisplatin-based regimens are regarded as a&#xD;
      standard of care in treating patients with muscle-invasive bladder cancer. However, bladder&#xD;
      cancer is a disease of the elderly and due to age-associated factors (e.g. hearing impaired ≥&#xD;
      grade 2), peripheral neuropathy (≥ grade 2), disease associated impairment of renal function&#xD;
      (Glomerular filtration rate &lt; 60 mL/min) and performance status (ECOG ≥ 2) 30 to 50% are&#xD;
      ineligible for cisplatin-based chemotherapy regimens. Several combinations with Carboplatin&#xD;
      have been tested in single arm, phase II trials in patients ineligible for Cisplatin but no&#xD;
      standard regimen has been established for this patient population thus far. The Guidelines of&#xD;
      the European association of Urology (EAU) do not recommend any neoadjuvant treatment for&#xD;
      Cisplatin-ineligible patients.&#xD;
&#xD;
      The advent of immune checkpoint inhibitors like Durvalumab or Azetolizumab, both antibodies&#xD;
      blocking the PD1/PD-L1 interaction, have shown promising results as single agents in terms of&#xD;
      response (15-46%) and tolerability in the metastatic setting of bladder cancer.&#xD;
&#xD;
      A trial evaluating the safety, tolerability and antitumor activity of the combination of the&#xD;
      immune-checkpoint inhibitors Durvarlumab and the anti-CTLA4 antibody Tremelimumab in various&#xD;
      solid tumors, including urothelial carcinoma of the bladder is ongoing (protocol D4190C0010).&#xD;
      Blocking the PD1/PD-L1 pathway in combination with an anti-CTLA4 antibody has shown greater&#xD;
      antitumor activity than each antibody alone in malignant melanoma trials and showed a&#xD;
      promising antitumor activity (17% overall response rate, irrespective of the PD-L1 expression&#xD;
      status on tumor cells) in a phase Ib study of metastatic non-small-cell lung cancer. The&#xD;
      safety profile was acceptable (42% grade 3-4 treatment related adverse events across all&#xD;
      dosing cohorts, most common were diarrhea, colitis and increase lipase), however, the rate of&#xD;
      adverse events (e.g. autoimmune phenomena) and treatment interruptions was higher as compared&#xD;
      to single agent use.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      The Primary objective of the trial is to assess the safety and antitumor activity of the&#xD;
      anti-PD-L1 antibody Durvalumab in combination with the anti-CTLA4 antibody Tremelimumab.&#xD;
&#xD;
      Study Duration:&#xD;
&#xD;
      Trial study duration encompassed the time from when the participant signs the informed&#xD;
      consent until the last protocol-specific procedure has been completed (Cystectomy between&#xD;
      week 17 to 23). All patients will be followed up for up to 78 weeks after end of treatment.&#xD;
&#xD;
      This study will be conducted in compliance with the protocol, the current version of the&#xD;
      Declaration of Helsinki, the ICH-GCP as well as all national legal and regulatory&#xD;
      requirements.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    low accrual&#xD;
  </why_stopped>
  <start_date type="Actual">July 15, 2018</start_date>
  <completion_date type="Actual">May 18, 2020</completion_date>
  <primary_completion_date type="Actual">November 8, 2019</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>
    <intervention_model_description>Single Arm open-Label prospective Phase II</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective Response Rate</measure>
    <time_frame>16 weeks</time_frame>
    <description>Response rate (computer tomography or magnet resonance imaging) as measured per standard RECIST v1.1 after four cycles of combined treatment with Durvalumab (MEDI4736) and tremelimumab.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>26 weeks</time_frame>
    <description>Number of Patients experiencing Toxicity/Adverse Events (AE)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Recurrence-free Survival</measure>
    <time_frame>78 weeks</time_frame>
    <description>Number of Patients with Recurrence-free Survival at 78 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>78 weeks</time_frame>
    <description>Number of Patients alive at 78 weeks</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Muscle-invasive Bladder Cancer</condition>
  <arm_group>
    <arm_group_label>Durvalumab and Tremelimumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Durvalumab 1500 mg i.v. every 4 weeks in combination with Tremelimumab 75 mg i.v. every 4 weeks for a total of 4 cycles before surgery.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Durvalumab (Imfinzi)</intervention_name>
    <description>Durvalumab 1500 mg i.v. every 4 weeks in combination with Tremelimumab 75 mg i.v. every 4 weeks for a total of 4 cycles before surgery.</description>
    <arm_group_label>Durvalumab and Tremelimumab</arm_group_label>
    <other_name>Neoadjuvant Immunotherapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tremelimumab</intervention_name>
    <description>Tremelimumab 75 mg i.v. in combination with Durvalumab 1500 mg i.v. every 4 weeks every 4 weeks for a total of 4 cycles before surgery.</description>
    <arm_group_label>Durvalumab and Tremelimumab</arm_group_label>
    <other_name>Neoadjuvant Immunotherapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Signed Informed Consent Form&#xD;
&#xD;
          -  ECOG performance status of 0 or 1&#xD;
&#xD;
          -  Histologically confirmed muscle-invasive urothelial carcinoma of the bladder (T2-T4&#xD;
             and/or N+). Patients with mixed histologies are required to have a dominant&#xD;
             transitional cell pattern.&#xD;
&#xD;
          -  Measurable disease according to RECIST v1.1 criteria&#xD;
&#xD;
          -  Representative fresh tumor specimen; TURB (transurethral resection of bladder )&#xD;
             specimens must contain a muscle invasive component (at least T2)&#xD;
&#xD;
          -  Ineligible to receive cisplatin-based neoadjuvant chemotherapy based on at least one&#xD;
             of the following criteria:&#xD;
&#xD;
               -  Creatinin clearance less than 60ml/min (24h urine)&#xD;
&#xD;
               -  CTCAE Gr ≥ 2 hearing loss&#xD;
&#xD;
               -  CTCAE Gr ≥ 2 neuropathy&#xD;
&#xD;
          -  Patient 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;
          -  Adequate hematologic and end-organ function, defined by the following laboratory&#xD;
             results obtained within 14 days prior the first study treatment:&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) ≥ 1500 cells/µl&#xD;
&#xD;
          -  WBC counts &gt; 2500/µl&#xD;
&#xD;
          -  Platelet count ≥ 100,000/µl&#xD;
&#xD;
          -  Hemoglobin ≥ 9.0 g/dL&#xD;
&#xD;
          -  AST, ALT and alkaline phosphatase ≤ 2.5 times the upper limit of normal (ULN)&#xD;
&#xD;
          -  Serum bilirubin ≤ 1.5 x ULN&#xD;
&#xD;
          -  INR and aPTT ≤ 1.5 x ULN&#xD;
&#xD;
          -  Serum creatinine clearance (CrCl) ≥ 40 mL/min using the Cockcroft-Gault equation&#xD;
&#xD;
          -  Evidence of post-menopausal status or negative urinary or serum pregnancy test for&#xD;
             premenopausal female. Women will be considered post-menopausal if they have been&#xD;
             amenorrheic for 12 months without an alternative medical cause.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known metastatic disease&#xD;
&#xD;
          -  Intravesical chemo- or biological/immune (BCG) therapy within 6 weeks of first&#xD;
             treatment dose&#xD;
&#xD;
          -  Prio treatment with immune checkpoint blockade therapies like anti-CTLA-4, anti-PD1&#xD;
             and anti-PD-L1 therapeutic antibodies, including durvalumab and tremelimumab&#xD;
&#xD;
          -  History of autoimmune disease, including but not limited to myasthenia gravis,&#xD;
             myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,&#xD;
             inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid&#xD;
             syndrome, Wegner's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome,&#xD;
             multiple sclerosis, vasculitis or glomerulonephritis Patients with a history of&#xD;
             autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are&#xD;
             eligible for this study. Patients with controlled Type I diabetes mellitus on a stable&#xD;
             dose of insulin regimen are eligible for this study&#xD;
&#xD;
          -  Major surgical procedure (as defined by the Investigator) within 28 days prior to the&#xD;
             first dose of investigational drug.&#xD;
&#xD;
          -  Female patients who are pregnant or breast feeding as well as male or female patients&#xD;
             of reproductive potential who are not willing to employ effective birth control from&#xD;
             screening to 180 days after the last dose of durvalumab + tremelimumab combination&#xD;
             therapy.&#xD;
&#xD;
          -  Known allergy or hypersensitivity to any of the investigational study drugs or any of&#xD;
             the study excipients.&#xD;
&#xD;
          -  Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical&#xD;
             study regardless of treatment arm assignment.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness, including but limited to, ongoing infection,&#xD;
             symptomatic congestive heart failure, uncontrolled hypertension, unstable angina&#xD;
             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 requirements, substantially increase&#xD;
             risk of incurring AEs or compromise the ability of the patient to give written&#xD;
             informed consent.&#xD;
&#xD;
          -  Significant cardiovascular disease, such as New York Heart Association cardiac disease&#xD;
             (Class II or greater), myocardial infarction within the previous 3 months, unstable&#xD;
             arrhythmias, or unstable angina.&#xD;
&#xD;
          -  Patients with prior allogeneic stem cell or solid organ transplantation&#xD;
&#xD;
          -  History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced&#xD;
             pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening&#xD;
             chest CT scan&#xD;
&#xD;
          -  Positive test for HIV&#xD;
&#xD;
          -  Patients with active hepatitis B (defined as having a positive hepatitis B surface&#xD;
             antigen test at screening) or hepatitis C.&#xD;
&#xD;
          -  Active tuberculosis&#xD;
&#xD;
          -  Administration of a living, attenuated vaccine within 4 weeks prior to treatment start&#xD;
&#xD;
          -  Severe infection within 4 weeks prior to cycle 1, day 1&#xD;
&#xD;
          -  Treatment with systemic corticosteroids or other systemic immunosuppressive&#xD;
             medications within 2 weeks prior treatment start or anticipated requirement for&#xD;
             systemic immunosuppressive medications during the trial. The use of inhaled&#xD;
             corticosteroids, physiologic replacement doses of glucocorticoids, and&#xD;
             mineralocorticoids is allowed&#xD;
&#xD;
          -  Known allergy or hypersensitivity to any of the study drugs or any of the study&#xD;
             excipients.&#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>Julian Schardt, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Departement of Medical Oncology, University Hospital Berne</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Departement of Medical Oncology, University Hospital Berne</name>
      <address>
        <city>Berne</city>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>July 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>June 16, 2020</last_update_submitted>
  <last_update_submitted_qc>June 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 17, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Muscle-invasive Bladder Cancer</keyword>
  <keyword>Ineligible for Cisplatin-based Chemotherapy</keyword>
  <keyword>Durvalumab</keyword>
  <keyword>Tremelimumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Urinary Bladder Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
    <mesh_term>Tremelimumab</mesh_term>
    <mesh_term>Immunomodulating Agents</mesh_term>
    <mesh_term>Immunologic Factors</mesh_term>
  </intervention_browse>
  <!-- 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/NCT03234153
org study id: NITIMIB-Trial
nct id: NCT03234153
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The trial assess the safety and antitumor activity of the anti-PD-L1 antibody Durvalumab in
      combination with the anti-CTLA4 antibody Tremelimumab.
Background and Rationale:

      The outcome for patients with muscle-invasive bladder cancer treated with surgery alone
      remains dismal with a 5 year survival rate between 25% to 80% depending on the tumor stage
      and lymph node status. Cisplatin-based chemotherapy regimens (Methotrexate, Vinblastine,
      Doxorubicin, Cisplatin ; Cisplatin, Methotrexate, Vinblastine; Gemcitabine/Cisplatin) have
      demonstrated a modest but absolute benefit in overall survival of 5-8% when administered in
      the neoadjuvant setting. Therefore, neoadjuvant Cisplatin-based regimens are regarded as a
      standard of care in treating patients with muscle-invasive bladder cancer. However, bladder
      cancer is a disease of the elderly and due to age-associated factors (e.g. hearing impaired ≥
      grade 2), peripheral neuropathy (≥ grade 2), disease associated impairment of renal function
      (Glomerular filtration rate < 60 mL/min) and performance status (ECOG ≥ 2) 30 to 50% are
      ineligible for cisplatin-based chemotherapy regimens. Several combinations with Carboplatin
      have been tested in single arm, phase II trials in patients ineligible for Cisplatin but no
      standard regimen has been established for this patient population thus far. The Guidelines of
      the European association of Urology (EAU) do not recommend any neoadjuvant treatment for
      Cisplatin-ineligible patients.

      The advent of immune checkpoint inhibitors like Durvalumab or Azetolizumab, both antibodies
      blocking the PD1/PD-L1 interaction, have shown promising results as single agents in terms of
      response (15-46%) and tolerability in the metastatic setting of bladder cancer.

      A trial evaluating the safety, tolerability and antitumor activity of the combination of the
      immune-checkpoint inhibitors Durvarlumab and the anti-CTLA4 antibody Tremelimumab in various
      solid tumors, including urothelial carcinoma of the bladder is ongoing (protocol D4190C0010).
      Blocking the PD1/PD-L1 pathway in combination with an anti-CTLA4 antibody has shown greater
      antitumor activity than each antibody alone in malignant melanoma trials and showed a
      promising antitumor activity (17% overall response rate, irrespective of the PD-L1 expression
      status on tumor cells) in a phase Ib study of metastatic non-small-cell lung cancer. The
      safety profile was acceptable (42% grade 3-4 treatment related adverse events across all
      dosing cohorts, most common were diarrhea, colitis and increase lipase), however, the rate of
      adverse events (e.g. autoimmune phenomena) and treatment interruptions was higher as compared
      to single agent use.

      Objective:

      The Primary objective of the trial is to assess the safety and antitumor activity of the
      anti-PD-L1 antibody Durvalumab in combination with the anti-CTLA4 antibody Tremelimumab.

      Study Duration:

      Trial study duration encompassed the time from when the participant signs the informed
      consent until the last protocol-specific procedure has been completed (Cystectomy between
      week 17 to 23). All patients will be followed up for up to 78 weeks after end of treatment.

      This study will be conducted in compliance with the protocol, the current version of the
      Declaration of Helsinki, the ICH-GCP as well as all national legal and regulatory
      requirements.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Single Arm open-Label prospective Phase II
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Response Rate
time frame: 16 weeks
description: Response rate (computer tomography or magnet resonance imaging) as measured per standard RECIST v1.1 after four cycles of combined treatment with Durvalumab (MEDI4736) and tremelimumab.
measure: Adverse Events
time frame: 26 weeks
description: Number of Patients experiencing Toxicity/Adverse Events (AE)
measure: Recurrence-free Survival
time frame: 78 weeks
description: Number of Patients with Recurrence-free Survival at 78 weeks
measure: Overall Survival
time frame: 78 weeks
description: Number of Patients alive at 78 weeks
arm group label: Durvalumab and Tremelimumab
arm group type: Experimental
description: Durvalumab 1500 mg i.v. every 4 weeks in combination with Tremelimumab 75 mg i.v. every 4 weeks for a total of 4 cycles before surgery.
intervention type: Drug
intervention name: Durvalumab (Imfinzi)
description: Durvalumab 1500 mg i.v. every 4 weeks in combination with Tremelimumab 75 mg i.v. every 4 weeks for a total of 4 cycles before surgery.
arm group label: Durvalumab and Tremelimumab
other name: Neoadjuvant Immunotherapy
intervention type: Drug
intervention name: Tremelimumab
description: Tremelimumab 75 mg i.v. in combination with Durvalumab 1500 mg i.v. every 4 weeks every 4 weeks for a total of 4 cycles before surgery.
arm group label: Durvalumab and Tremelimumab
other name: Neoadjuvant Immunotherapy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Julian Schardt, MD
role: Study Chair
affiliation: Departement of Medical Oncology, University Hospital Berne
facility: 
country: Switzerland
responsible party type: Sponsor
mesh term: Urinary Bladder Neoplasms
mesh term: Durvalumab
mesh term: Tremelimumab
mesh term: Immunomodulating Agents
mesh term: Immunologic Factors