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.
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
ml/min.
- 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
acceptable.
- 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
trial.
- 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
to:
- 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
consent;
- 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
excipients.
- 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.
