A Study of Mitomycin-c/ Capecitabine ChemoRadiotherapy Combined With Nivolumab Monotherapy or Ipilumimab and Nivolumab, as Bladder Sparing Curative Treatment for Muscle Invasive Bladder Cancer: the CRIMI Study

Inclusion Criteria:

• Be willing and able to provide written informed consent for the trial.
• Be ≥ 18 years of age on day of signing informed consent.
• Wish to preserve their bladder function or be ineligible for cystectomy.
• Must have undergone transurethral biopsy of the bladder tumor, within 35 days ofplanned treatment commencement. The patient should have a histologically-confirmeddiagnosis of muscle-invasive T2-T4a, N0-1M0 urothelial cell carcinoma of the bladder.
• Must have undergone maximal transurethral resection of the bladder tumour, to anextent that is judged as safe by the urologist performing the resection, within 35days of planned treatment commencement.
• Subjects with tumors of mixed urothelial/non-urothelial cell histology are allowed,but urothelial cell carcinoma must be the predominant histology (>50%). Subjects withpredominant or exclusively non-urothelial cell histology are not allowed.
• Have planned for chemoradiotherapy as definitive treatment.
• Have a performance status of 0 or 1 on the ECOG Performance Scale
• Have a bladder function that is accessible for cystoscopical follow up.
• Demonstrate adequate organ function. All screening labs should be performed within 28days of registering the patient on the trial.
• Female participants of childbearing potential should have a negative urine or serumpregnancy within 72 hours prior to registering the patient. If the urine test ispositive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female participants of childbearing potential should be willing to one highlyeffective method of birth control or be surgically sterile, or abstain fromheterosexual activity for the course of the study through 5 month after the last doseof study medication Participants of childbearing potential are those who have not beensurgically sterilized or have not been free from menses for > 1 year.
• Male participants should agree to use condoms starting with the first dose of studytherapy through 7 month after the last dose of study therapy.
• Willing to consent to the use of their collected tumor specimen, blood and urine asdetailed in the protocol for future scientific research including but not limited toDNA, RNA and protein based biomarker detection.

Exclusion Criteria:

• Has DPD deficiency.
• Has concurrent extra-vesical (i.e. urethra, ureter or renal pelvis) urothelial cellcarcinoma of the urothelium. Patients who have involvement of the prostatic urethrawith urothelial cell cancer may be included if the location can be safely incorporatedin the radiation field.
• Extensive or multifocal bladder carcinoma in situ (CIS) precluding curativechemoradiotherapy.
• Evidence of distant metastatic disease on a CT or FDG PET/CT chest/abdomen/pelvisperformed within 28 days prior to study entry. Up to 3 metastatic lymphnodes in thepelvis (below the common iliac arteries) are allowed, if these can be incorporated inthe radiotherapy field.
• Prior pelvic lymph-adenectomy
• Prior pelvic radiotherapy
• Has had prior intravenous chemotherapy, targeted small molecule therapy, or radiationtherapy for treatment of bladder cancer. Prior intravesical use of BCG and MMC ispermissible.
• Unsuitable for concurrent MMC / capecitabine based ChRT based on pre-existing medicalconditions.
• Is currently participating and receiving study therapy or has participated in a studyof an investigational agent and received study therapy or used an investigationaldevice within 4 weeks prior to the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy over 10mgdaily prednisone (or equivalent) or any other form of immunosuppressive therapy within 14 days prior to registering the patient. Patients with adrenal insufficiencyreceiving replacement dose steroids are allowed on the trial.
• Has a known history of active TB (Bacillus Tuberculosis)
• Hypersensitivity to nivolumab and/or ipilimumab or any of its excipients.
• Prior or concurrent known additional malignancy of any site unless disease free for 5years. Exceptions include basal cell carcinoma of the skin or squamous cell carcinomaof the skin that has undergone potentially curative therapy or in situ cervicalcancer, Stage T1a well differentiated prostatic carcinoma in men (Gleason = 3+3, PSA <5)
• Has any history of active autoimmune disease, Stevens-Johnson syndrome orGuillain-Barre. Exceptions to this are:

1. Patients with autoimmune-related hypothyroidism on a stable dose of thyroidreplacement hormone
2. Patients with controlled Type I diabetes mellitus on a stable dose of insulinregimen

• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the trial, interfere with the patient'sparticipation for the full duration of the trial, or is not in the best interest ofthe participant to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.
• Is pregnant or breastfeeding, or expecting to conceive or father children within theprojected duration of the trial, starting with the pre-screening or screening visitthrough 120 days after the last dose of trial treatment.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Has an Human Immunodeficiency Virus (HIV) infection with a PCR detectable viral load.
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Has received a live vaccine within 30 days of planned start of study therapy. Note:Seasonal influenza vaccines for injection are generally inactivated flu vaccines andare allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are liveattenuated vaccines, and are not allowed.