Clinical Trials /

Trimodality Therapy With/Out Durvalumab to Treat Patients With Muscle-Invasive Bladder Cancer



The purpose of this study is to find out what effects durvalumab has on bladder cancer, combined with treatment after completion of surgery, chemotherapy and radiotherapy.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:



Phase 2

Trial Eligibility



  • Brief Title: Trimodality Therapy With/Out Durvalumab to Treat Patients With Muscle-Invasive Bladder Cancer
  • Official Title: A Randomized Phase II Trial Assessing Trimodality Therapy With or Without Adjuvant Durvalumab to Treat Patients With Muscle-Invasive Bladder Cancer

Clinical Trial IDs

  • SECONDARY ID: 2019-001310-42
  • NCT ID: NCT03768570


  • Bladder Cancer




The purpose of this study is to find out what effects durvalumab has on bladder cancer, combined with treatment after completion of surgery, chemotherapy and radiotherapy.

Detailed Description

      This study is looking at whether a type of immunotherapy drug called durvalumab can be safely
      administered after initial treatment received by a patient. Durvalumab has been tested in
      many different types of cancers. Durvalumab works by allowing the immune system to detect
      cancer and reactivate the immune response. This may help to slow down the growth of cancer or
      may cause cancer cells to die. It is unclear if the addition of durvalumab is beneficial in
      patients with bladder cancer who have completed surgery, radiotherapy and chemotherapy.

Trial Arms

SurveillanceNo Intervention
    DurvalumabActive Comparator
    • Durvalumab

    Eligibility Criteria

            Inclusion Criteria:
              -  Histologic diagnosis of urothelial carcinoma of the bladder. Patients with mixed
                 histology (including small cell) and urothelial carcinoma are eligible. Patients with
                 pure small cell carcinoma will be excluded.
              -  Stage T2-T4a N0M0 at time of diagnosis based on trans-urethral resection of bladder
                 tumour, imaging, and/or bimanual examination under anesthesia.
              -  CT scan of the chest/abdomen/pelvis within 8 weeks from enrollment, showing no
                 evidence of metastatic disease.
              -  Patients must be ≥ 18 years of age.
              -  Patients must have a life expectancy greater than 6 months.
              -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
                 0-2 and a body weight of > 30kg.
              -  Patients must have adequate hematologic reserve: Platelet count ≥ 75 x 10^9/L,
                 Absolute neutrophils ≥ 1.0 x 10^9/L. Anemia will be corrected to minimum hemoglobin of
                 90 g/L with red cell transfusions, if necessary.
              -  Patients must have an estimated creatinine clearance (Cockcroft-Gault Equation) ≥ 30
              -  Patients must have adequate liver function with a bilirubin ≤ 1.5 ULN (if confirmed
                 Gilbert's, eligible providing bilirubin ≤ 3 x UNL) and AST/ALT (SGOT/SGPT) < 2.5 x the
                 upper normal limit.
              -  All patients must have a tumour block from their primary tumour available and consent
                 to release the block/cores/cut slides for correlative analyses ( and the
                 centre/pathologist must have agreed to the submission of the specimen(s).
              -  Patients have completed prior trimodality therapy (TMT) consisting of surgery,
                 chemotherapy and radiation therapy treatment prior to enrollment. Patient should start
                 treatment within 42 days after completion of TMT.
              -  Patients must have undergone a transurethral resection prior to study enrollment.
              -  Patient may have completed up to 4 cycles of cisplatin-based neo-adjuvant
                 chemotherapy. Adjuvant chemotherapy is not permitted. Patients will have received
                 cisplatin, given intravenously during the radiation therapy. OR Patients may have
                 received fluorouracil and mitomycin given intravenously once weekly or gemcitabine as
                 an alternative to cisplatin during radiotherapy.
              -  The following are radiotherapy guidelines for patients treated on study. Patients will
                 be treated to radical treatment doses using IMRT, VMAT or 4 field conformal
                 techniques. Planning will be based on CT planning. IGRT is recommended during the
                 radiotherapy treatment. Recognizing differences in usual radiotherapy doses used in
                 the various participating countries and centres the following would be acceptable
                 doses in this study. The bladder CTV will include the whole empty bladder and any
                 extravesical extension. PTV expansion will be a minimum of 0.75 cm right, left and
                 inferiorly, 1.5 cm Anteriorly and superiorly and 1 cm posteriorly. These minimum
                 expansions are with Cone beam verification. For patients undergoing RT without
                 image-guided verification 1.5 cm expansion in all directions is recommended.
                 Acceptable doses for this study include:
                   -  Bladder only: 64-66 Gy in 32-33 fractions over 6.5 weeks; 50-55 Gy in 20
                      fractions over 4 weeks
                   -  Pelvis and bladder: 45-46 Gy to pelvic nodes + 17-20 Gy bladder boost in 33-35
                      fractions over 6.5-7 wks [Note: minimal nodal dose (if used) is 44 Gy in 32f or
                      40 Gy in 20f]
              -  Patients receiving concurrent bladder boost: pelvis dose 40 Gy and bladder dose 50 Gy
                 given in 20 fractions over 4 weeks. Adaptive radiotherapy techniques would be
              -  Patient is able (i.e. sufficiently fluent) and willing to complete the quality of life
                 questionnaires in either English, French or Spanish.
              -  Patient consent must be appropriately obtained in accordance with applicable local and
                 regulatory requirements. Each patient must sign a consent form prior to enrollment in
                 the trial to document their willingness to participate.
              -  Patients must be accessible for treatment and follow up. Patients registered on this
                 trial must be treated and followed at the participating centre. This implies there
                 must be reasonable geographical limits placed on patients being considered for this
              -  In accordance with CCTG policy, protocol treatment is to begin within 2 working days
                 of patient enrollment.
              -  Women/men of childbearing potential must have agreed to use a highly effective
                 contraceptive method during and for 3 months following treatment.
              -  Patients with a prior or concurrent malignancy whose natural history or treatment does
                 not have the potential to interfere with the safety or efficacy assessment of the
                 investigational regimen are eligible for this trial.
            Exclusion Criteria:
              -  Pre-existing medical conditions precluding treatment.
              -  Pregnancy or lactating mothers.
              -  Received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1),
                 anti-PD-L1, including durvalumab anti-programmed cell death-ligand 2 (anti-PD-L2),
                 anti-CD137 (4-1BB ligand, a member of the Tumour Necrosis Factor Receptor [TNFR]
                 family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody
                 (including ipilimumab or any other antibody or drug specifically targeting T-cell
                 co-stimulation or checkpoint pathways).
              -  Active or prior documented autoimmune or inflammatory disorders (including
                 inflammatory bowel disease (e.g. colitis or Crohn's disease: not due to radiation
                 reaction), diverticulitis with the exception of diverticulosis, celiac disease
                 (controlled by diet alone) or other serious gastrointestinal chronic conditions
                 associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, or
                 Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis,
                 hypophysitis, uveitis, etc., within the past 3 years prior to the start of treatment.
                 The following are exceptions to this criterion:
                   -  Patients with alopecia;
                   -  Patients with Grave's disease, vitiligo or psoriasis not requiring systemic
                      treatment (within the last 2 years);
                   -  Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on
                      hormone replacement;
                   -  Any chronic skin condition that does not require systemic therapy.
              -  Patients with active or uncontrolled intercurrent illness including, but not limited
                   -  cardiac dysfunction (symptomatic congestive heart failure, uncontrolled
                      hypertension, unstable angina pectoris, cardiac arrhythmia);
                   -  active peptic ulcer disease or gastritis;
                   -  active bleeding diatheses;
                   -  psychiatric illness/social situations that would limit compliance with study
                      requirements or compromise the ability of the subject to give written informed
                   -  known history of previous clinical diagnosis of tuberculosis;
                   -  known active human immunodeficiency virus infection (positive HIV 1/2
                      antibodies). HIV-infected patients on effective anti-retroviral therapy with
                      undetectable viral load within 6 months are eligible;
                   -  known active hepatitis B infection (positive HBV surface antigen (HBsAg).
                      Patients with a past or resolved HBV infection (defined as presence of hepatitis
                      B core antibody (anti-HBc) and absence of HBsAg) are eligible;
                   -  known active hepatitis C infection. Patients positive for hepatitis C (HCV)
                      antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
              -  History of primary immunodeficiency, history of allogenic organ transplant that
                 requires therapeutic immunosuppression and the use of immunosuppressive agents within
                 28 days of randomization or a prior history of severe (grade 3 or 4) immune mediated
                 toxicity from other immune therapy or grade ≥ 3 infusion reaction.
              -  Current or prior use of immunosuppressive medication within 28 days of study entry,
                 with the exceptions of intranasal and inhaled corticosteroids or systemic chronic
                 corticosteroids at physiological doses, which are not to exceed 10 mg/day of
                 prednisone, or an equivalent corticosteroid. Corticosteroids used on study for
                 anti-emetic purpose are allowed. Corticosteroids as premedication for hypersensitivity
                 reactions (e.g. computed tomography [CT] scan premedication) are allowed.
              -  Peripheral neuropathy ≥ grade 2 (CTCAE v5.0).
              -  History of allergic or hypersensitivity reactions to any study drug or their
              -  Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 msec
                 in screening ECG measured using standard institutional method or history of familial
                 long QT syndrome.
              -  History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or
                 evidence of interstitial lung disease on baseline CT scan.
              -  Any active disease condition which would render the protocol treatment dangerous or
                 impair the ability of the patient to receive protocol therapy.
              -  Any condition (e.g. psychological, geographical, etc.) that does not permit compliance
                 with the protocol.
              -  Live attenuated vaccination administered within 30 days prior to randomization.
              -  Any prior carboplatin based therapy.
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Disease-free survival
    Time Frame:5 years
    Safety Issue:
    Description:defined as the time from the randomization to the time of the first event that is either recurrent (local or distant) bladder cancer, a new primary bladder cancer or death from any cause

    Secondary Outcome Measures

    Measure:Non-muscle invasive bladder cancer recurrence rate
    Time Frame:5 years
    Safety Issue:
    Measure:Loco-regional control rate between study arms at the 12 week visit
    Time Frame:5 years
    Safety Issue:
    Description:defined as proportion of patients with a confirmed locoregional complete response at 3 months post randomization
    Measure:Patterns of disease recurrence between study arms
    Time Frame:5 years
    Safety Issue:
    Description:The two treatment arms will be compared using the log-rank test stratified by ECOG Performance Status (0, 1 vs. 2+), Neoadjuvant chemotherapy (Yes/No), whole bladder versus partial bladder versus bladder plus regional lymph nodes RT field, and disease stage (T2 vs T3/4). A table will be presented summarizing the patterns of disease recurrence by treatment arms
    Measure:Compare overall and bladder intact disease-free survival between study arms
    Time Frame:5 years
    Safety Issue:
    Measure:Metastasis-free survival between study arms
    Time Frame:5 years
    Safety Issue:
    Measure:Number and severity of adverse events between study arms
    Time Frame:5 years
    Safety Issue:
    Measure:Quality of Life between treatment arms using Functional Assessment of Cancer Therapy-Bladder Cancer (FACT-BL) questionnaire
    Time Frame:5 years
    Safety Issue:
    Description:It consists of 39 questions, of which 12 are specific to bladder cancer. The questionnaire consists of 5 subscales: physical well-being (PWB), social/family well-being (SWB), emotional well-being (EWB), functional well-being (FWB), and a final subscale focusing specifically on bladder cancer.
    Measure:Cost-effectiveness between study arms
    Time Frame:5 years
    Safety Issue:
    Description:Estimate an incremental cost-effectiveness ratio reported as a difference in cost per Disease free survival-year gained of durvalumab vs. surveillance. analyses will focus on the incremental cost-effectiveness of durvalumab from a government payer perspective, over a disease-free survival time horizon by prospectively collecting economic and resource utilization information during the clinical trial.
    Measure:Cost-utility between study arms
    Time Frame:5 years
    Safety Issue:
    Description:A partitioned-survival model (Markov model) will be developed using data obtained from the trial. Different parametric models will be evaluated to fit data from the trial in order to evaluate the incremental cost-utility over a 3-, 5- and 10-y horizon.


    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Canadian Cancer Trials Group

    Last Updated

    April 13, 2021