Neoadjuvant Sasanlimab With Radiation as an in Situ Vaccine for Cisplatin-ineligible Muscle Invasive Bladder Cancer

Inclusion Criteria:

1. Capable of giving signed informed consent

2. Age ≥ 18 years

3. ECOG Eastern Cooperative Oncology Group performance status 0-2

4. Predominant (>50%) urothelial carcinoma histology

5. Muscle-invasive bladder cancer (cT2-4a, cN0, cM0)

6. Decline/refuse OR Ineligible to receive cisplatin-based Neoadjuvant Chemotherapy dueto at least one of the following criteria: a. Creatinine clearance less than 60 mL/min b. Eastern Cooperative Oncology Groupperformance status of ≥ 2 c. Grade ≥ 2 hearing loss d. Grade ≥ 2 neuropathy

7. Adequate Bone Marrow Function (without hematopoietic growth factor support within 14days prior to study screening), defined as: a. Absolute neutrophil count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L b. Platelets ≥100,000/mm3 or 100 x 109/L c. Hemoglobin ≥9 g/dL (≥5.6 mmol/L)

8. Adequate renal function defined by an estimated creatinine clearance ≥30 mL/minaccording to the Cockcroft Gault formula or by 24-hour urine collection forcreatinine clearance.

9. Adequate liver function, including: a. Aspartate and alanine aminotransferase (AST and ALT) ≤ 2.5 × the upper normallimit range (ULN) b. Total serum bilirubin ≤ 1.5 x ULN

10. Able to give informed consent and patient is willing and able to comply withscheduled study visits and treatment plan

11. Willing and able to comply with scheduled visits, treatment plan, laboratory tests,and other procedures.

12. Meeting the following criteria for sex specific considerations:

13. Males - for the duration of study and for at least 6 months after the last dose ofstudy drug (Sasanlimab):

14. Refrain from donating sperm and be abstinent from intercourse OR Agree to usemale condom and also consider the benefit for a female partner to use a highlyeffective method of contraception as a condom may break or leak when havingsexual intercourse with a woman of childbearing potential (WOCBP) who is notcurrently pregnant

15. Females: a) Eligible to participate if not pregnant or breast feeding AND Is not a woman ofchildbearing potential (WOCBP) OR Is a WOCBP and is using a contraceptive methodthat is highly effective (failure rate of < 1% per year), with low user dependencyduring the during the study treatment and for at least 6 months after the last doseof study drug (Sasanlimab) b) A WOCBP must have a negative, highly sensitive (atleast 25 IU/mL) pregnancy test by urine or serum testing within 24 hours before thefirst dose of study drug (Sasanlimab). In cases where the urine test cannot beconfirmed to be negative, a serum pregnancy test will be used.

Exclusion Criteria:

1. Lymphadenopathy (>1cm short-axis measurement on CT/MRI Imaging or biopsy proven)

2. Metastatic disease

3. Prior systemic chemotherapy for bladder cancer (however, may have had intra-vesicalchemotherapy such as gemcitabine, docetaxel or mitomycin-C)

4. Prior treatment with systemic anti-cancer investigational agent

5. Other malignancy within 2 years prior to study screening, or active malignancyexcept for adequately treated basal cell or squamous cell skin cancer, or carcinomain situ of the breast or of the cervix, or low-grade (Gleason 6 or below) prostatecancer on surveillance without any plans for treatment intervention (e.g., surgery,radiation, or castration) or other concurrent malignancy felt by the investigatorhas a very low likelihood to become metastatic

6. Previous radiation therapy to the bladder

7. Active or history of autoimmune disease which may deteriorate when receiving immunecheckpoint blockade.

8. These autoimmune conditions include but are not limited to limited to,myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease,antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome,Guillain-Barré syndrome, or multiple sclerosis

9. Participants with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroiddisease not requiring immunosuppressive treatment are eligible.

10. Severe active infections (e.g., pulmonary tuberculosis) requiring systemictherapeutic oral or IV antibiotics within 2 weeks prior to study entry.

11. Clinically significant, multiple or severe drug allergies, intolerance to topicalcorticosteroids

12. Current unstable liver or biliary disease, defined by the presence of ascites,encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices,persistent jaundice, or cirrhosis.

• NOTE: Stable chronic liver disease (including Gilbert's syndrome, asymptomaticgallstones, and chronic stable hepatitis B or C -e.g., presence of hepatitis Bsurface antigen [HBsAg] or positive hepatitis C antibody test result atscreening) is acceptable.

11. Active, uncontrolled HIV/AIDS infection (well-controlled HIV patients may beallowed).

12. Prior immunotherapy with anti PD-1, anti PD-L1, anti PD-L2, or anti cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody. Note: prior intra-vesical BCGtherapy is acceptable.

13. Prior treatment with immune-stimulatory agents including interleukin (IL)-2, IL-15,interferon (INF)- γ.

14. Vaccination within 4 weeks from study screening and while on study treatment unlessadministration of inactivated vaccines.

15. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenalreplacement doses >10 mg daily prednisone equivalents are permitted in the absenceof active autoimmune disease.

16. Clinically significant (active) cardiovascular disease including the following:cerebral vascular accident/stroke <6 months prior to screening; myocardialinfarction <6 months prior to screening; unstable angina; congestive heart failure (≥New York Heart Association Classification Class III); or serious cardiacarrhythmia (uncontrolled, clinically significant) requiring medication.

17. Q-T interval corrected for heart rate (QTc) >450 msec for male participants or QTc >470 msec for female participants or QTc >480 msec in participants with right bundlebranch block

18. Prior organ transplantation or allogenic stem cell transplantation.

19. Known history of: immune-mediated colitis, inflammatory bowel disease, pneumonitis,or pulmonary fibrosis.

20. Patients with intolerance to or who have had a severe (Grade ≥3) allergic oranaphylactic reaction to antibodies or infused therapeutic proteins

21. Pregnant female patients; breastfeeding female patients; male patients able tofather children and female patients of childbearing potential who are unwilling orunable to use a highly effective method(s) of contraception as outlined in thisprotocol for at least 6 months after the last dose of Sasanlimab (PF-06801591)