Avelumab and Radiation in Muscle-Invasive Bladder Cancer

Subjects must meet all of the following applicable inclusion criteria to participate in the study.

Inclusion Criteria:

• Histologically confirmed transitional cell (urothelial) carcinoma of the bladderthat is invasive into the muscularis propria (≥T2 disease) within 6 months ofenrollment date. The presence of variant histologies (squamous, adenocarcinoma,micropapillary, etc.) is allowed. Note: A prior diagnosis of non-muscle-invasivebladder cancer (≤T1) managed with transurethral resection with or withoutintravesicular therapy (now with muscle invasion) is allowed.

• Inability to receive cisplatin-based chemotherapy, as defined by creatinineclearance <60 ml/min, ECOG PS ≤2, grade 2 or higher hearing loss, NYHA class 3 orhigher, neuropathy (grade 2 or higher), or patient refusal to receivecisplatin-based chemotherapy.

Additional Inclusion Criteria:

• Male or female subjects aged ≥18 years

• ECOG performance status ≤2 or Karnofsky score ≥60% (see Appendix A)

• Life expectancy of greater than 1 year

• Demonstrate normal organ and marrow function

• Estimated creatinine clearance > 30 mL/min according to the Cockcroft-Gault formula.

• Women of child-bearing age must have a negative serum pregnancy test at screening.

• Women of child-bearing potential and men must agree to use a highly effective methodof contraception (hormonal or barrier method of birth control, or abstinence)beginning prior to study entry, for the duration of study participation, and for atleast 30 days after last avelumab treatment administration if the risk of conceptionexists

• Ability to start study treatment (first cycle of Avelumab) within 1-8 weeks of themost recent pre-study TURBT.

• Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• Prior intravenous therapy for treatment of bladder cancer

• Prior pelvic radiation

• Any component of small cell histology in the bladder biopsy

• Any concurrent chemotherapy, biologic, or hormonal therapy for cancer treatment

• Current use of immunosuppressive medication, EXCEPT for the following: a.intranasal, inhaled, topical steroid, or local steroid injection (e.g.,intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10mg/day of prednisone or equivalent; c. Steroids as premedication forhypersensitivity reactions (e.g., CT scan premedication) are allowed.

• History of another malignancy within 5 years prior to randomization except for:non-muscle-invasive bladder cancer (i.e., ≤T1), completely resected basal cell orsquamous cell skin cancer, completed resected carcinoma-in-situ of any site, orlocalized prostate cancer managed definitively with a non-radiation based approach.

Additional Exclusion Criteria:

• Evidence of lymph node involvement or metastatic disease on CT of the chest,abdomen, and pelvis. To be considered positive, a lymph node must measure >15 mm inshort axis.

• Clinically significant (i.e. active) cardiovascular disease: symptomatic congestiveheart failure (≥ New York Heart Association Classification Class II), unstableangina pectoris, serious cardiac arrhythmia requiring medication, or CVA/stroke/MI (< 6 months prior to enrollment)

• Known prior severe hypersensitivity to investigational product or any component inits formulations, including known severe hypersensitivity reactions to monoclonalantibodies (NCI CTCAE v4.03 Grade ≥ 3)

• Breast feeding women who are unwilling to stop breastfeeding during treatment andfor at least one month after the duration of treatment

• Patients with known history of testing positive for HIV or known acquiredimmunodeficiency syndrome

• Active autoimmune disease that might deteriorate when receiving animmuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, orhypo- or hyperthyroid diseases not requiring immunosuppressive treatment areeligible.

• Active infection requiring intravenous antibiotic therapy

• Vaccination within 4 weeks of the first dose of avelumab and while on trial isprohibited except for administration of inactivated vaccines

• Major surgery within the last 30 days (with the exception of TURBT).

• Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positiveHBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)

• Prior organ transplantation including allogenic stem-cell transplantation

• Patient is unwilling to stop (or wishes to start) taking herbal and natural remediesthat may have immune-modulating effects during the study period

• Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however,alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safetyrisk based on investigator's judgment are acceptable

• Other severe acute or chronic medical conditions including immune colitis,inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatricconditions including recent (within the past year) or active suicidal ideation orbehavior; or laboratory abnormalities that may increase the risk associated withstudy participation or study treatment administration or may interfere with theinterpretation of study results and, in the judgment of the investigator, would makethe patient inappropriate for entry into this study.

• Pregnant women are excluded from this study.