Table 1 Inclusion and exclusion criteria

Inclusion

- Histologically confirmed, locally advanced bladder cancer (cT3/4 cN0/N+ cM0) with ≥10% urothelial differentiation

- Ineligibility for neoadjuvant cisplatin-based chemotherapy due to any of the following criteria:

 • Creatinine Clearance (using the Cockcroft-Gault formula) < 60 mL/min

 • Hearing loss ≥ grade 2 (CTCAE version 4)

 • Peripheral neuropathy ≥ grade 2 (CTCAE version 4)

 • ECOG performance score 2

- Subjects that are eligible for cisplatin may be candidates if they refuse available neoadjuvant cisplatin-based chemotherapy, despite being informed by the investigator about the treatment options. The subject’s refusal must be thoroughly documented.

- ECOG 0–2

- Life expectancy > 6 months

- Adequate function of bone marrow, liver and coagulation as determined by blood tests

- Able to give informed consent

- Body weight 35 kg - 160 kg

Exclusion

- Metastatic disease defined as distant metastasis or suspicious lymph nodes outside the pelvis (above aortic bifurcation) using RECIST 1.1 criteria

- Prior chemotherapy before treatment (not including intravesical chemotherapy)

- Prior radiation therapy of the pelvis

- Active, known or suspected autoimmune disease (not including: vitiligo, allergic rhinitis/asthma, type 1 diabetes mellitus, residual hypothyroidism due to an autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger)

- Immunosuppressive treatment with corticosteroids or other drugs within 14 days of study drug administration (not including: inhaled or topical steroids and adrenal replacement doses are permitted in the absence of active autoimmune disease)

- Experimental therapy or clinical trial at time of inclusion or the previous 4 weeks before inclusion

- Previous treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways (not including BCG therapy)

- Any uncontrolled or severe cardiovascular or pulmonary disease determined by the investigator, including i) NYHA functional classification III or IV, congestive heart failure, unstable or poorly controlled angina, uncontrolled hypertension, serious arrhythmia or myocardial infarction in the past 12 months before inclusion; ii) Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity.

- End-stage kidney disease defined as GFR < 15 mL/min or need for dialysis

- Thromboembolic events like pulmonary embolism or stroke in previous 3 months before inclusion

- Other active tumor disease (not including basal cell carcinoma of the skin and carcinoma in situ of the cervix). Tumor is regarded non-active after curative therapy and 5 years of follow up without pathological findings.

- Medium to extended surgery or trauma in the previous 4 weeks before inclusion (not including transurethral bladder resection, nephrostomy or ureteral stent or biopsy)

- Uncontrolled and serious somatic or mental illness

- Pregnant or lactating women

- Age < 18 years

- Prior organ transplantation

- Positive test result for hepatitis B or C indicating acute or chronic infection

- Positive HIV test or acquired immunodeficiency syndrome (AIDS)

- Gastrointestinal disorders, particularly those with high risk of perforation or fistula formation including i) active peptic ulcer disease or active inflammatory bowel disease (incl. Ulcerative colitis and Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis) during screening and/or ii) history of abdominal fistula or bowel perforation within 6 months prior to first dose of study treatment.