Nivolumab and Radiation Therapy in Treating Patients With Localized/Locally Advanced Urothelial Bladder Cancer Ineligible for Chemotherapy

PRIMARY OBJECTIVES:

I. To compare the 12-month rate of progression-free survival (PFS) achieved with the
combination of nivolumab, a programmed death (PD-1) inhibitor, and radiation therapy in
localized/locally advanced urothelial cancer patients, who are chemotherapy ineligible, to a
historical control reference 12-month PFS rate.

SECONDARY OBJECTIVES:

I. To assess the toxicity of concurrent nivolumab and radiation therapy in urothelial cancer.

II. To determine overall response rate (ORR). III. To determine metastasis-free survival
(MFS). IV. To determine overall survival (OS). V. To evaluate the quality of life and bladder
functioning during and after the therapy.

VI. To explore the relationships of PD-1 expression, PDL-1 expression, and the Th1/Th2
cytokine ratio to clinical outcomes (response, PFS, MFS, and OS).

OUTLINE:

Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Treatment repeats
every 14 days (2 weeks) for up to 14 courses (6 months) in the absence of disease progression
or unacceptable toxicity. Beginning 3 days of course 1, patients undergo radiation therapy
over 32-35 on weeks 1, 3, 5, 7 and 9.

After completion of study treatment, patients are followed up every 3 months for 12 months.

Inclusion Criteria:

- Localized urothelial cancer of bladder with presence of transitional cell carcinoma (TCC)
component; mixed histologies are allowed Clinical or pathologic stage T2 -T4 disease
including T4a and 4b if feasible to treat with radiation therapy Locoregional lymph node
metastases are permitted but patients with distant metastases are ineligible; imaging to
evaluate for distant metastases should consist of a minimum of computed tomography
(CT)/magnetic resonance imaging (MRI) of abdomen/pelvis or CT urogram and a chest x-ray
(CXR) or CT chest; patients for which there is clinical suspicion or symptoms of bone
metastasis should have a bone scan completed to rule out metastatic disease prior to
enrollment on study Agreeable to consider radiation therapy (RT) for the urothelial cancer:
patients have to be evaluated by a radiation oncologist and deemed to be candidates for RT

The patients must not be candidates for chemotherapy due to at least one of the following
reasons:

- Performance status of 2

- Creatinine clearance =< 60 ml/min as calculated by the Cockcroft-Gault formula

- Cardiac disease such as New York Heart Association (NYHA) class III or IV heart
failure or cardiac ischemia within the last 12 months, grade 2 or greater neuropathy,
or other comorbidities based on which patient is not considered a candidate for
chemotherapy Alkaline phosphatase =< 3 x upper limit of normal Aspartate
aminotransferase (AST) =< 3 x upper limit of normal Alanine aminotransferase (ALT) =<
3 x upper limit of normal Bilirubin < 1.5 x upper limit of normal (ULN) Absolute
neutrophil count >= 1500/mm^3 Hemoglobin >= 9 g/dL Platelets >= 100 K/mm^3 Performance
score (PS) of 0-2 by Zubrod score Life expectancy of 12 months Willingness to sign
informed consent Patients cannot have active autoimmune disease or immunosuppressive
conditions Serum creatinine =< 1.5 X institutional ULN or creatinine clearance > 40
ml/min as calculated by the Cockcroft-Gault formula In females with childbearing
potential, or men with partners of child bearing potential, willingness to use
adequate contraception for a minimum duration of 155 days in females and 215 days in
males, after last dose of nivolumab Maximal tumor resection has been performed as
feasible

Exclusion Criteria:

- The subject has received cytotoxic chemotherapy (including investigational cytotoxic
chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 4 weeks, or
intravesical Bacillus Calmette-Guerin (BCG) within 6 weeks of the first dose of study
treatment Prior treatment with any PD-1 or PDL-1 inhibitor

The subject has received therapeutic radiation:

- To the bladder/prostate/rectum pelvis

- To any other site(s) within 28 days of the first dose of study treatment Obstructive
renal failure that is not relieved with stents or nephrostomy tube/s The subject has
received any other type of investigational agent within 28 days before the first dose
of study treatment Steroid doses greater than an equivalent of prednisone 10 mg daily
The subject has prothrombin time (PT)/international normalized ratio (INR) or partial
thromboplastin time (PTT) test results at screening >= 2 x the laboratory ULN
Uncontrolled hematuria

The subject has uncontrolled, significant intercurrent or recent illness including, but not
limited to, the following conditions:

- Cardiovascular disorders such as uncontrolled arrhythmias or uncontrolled congestive
heart failure

- Gastrointestinal disorders particularly those associated with a high risk of
perforation or fistula formation including:

- Any of the following at the time of screening

- Active peptic ulcer disease,

- Active inflammatory bowel disease (including ulcerative colitis and Crohn's
disease), diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis

- Any of the following within 6 months before the first dose of study treatment:

- History of abdominal fistula

- Bowel perforation The subject has a previously identified allergy or
hypersensitivity to components of the study treatment formulation The
subject is unable or unwilling to abide by the study protocol or cooperate
fully with the investigator or designee Presence of another invasive
malignancy, which required systemic therapy within 12 months of protocol
enrollment, except for resected skin cancers or prostate cancer that is in
remission Pregnant or nursing women Patient is a candidate for radical
cystectomy as a potentially curative option Patients with inherited
syndromes associated with hypersensitivity to ionizing radiation (e.g.,
ataxia-telangiectasia, Nijmegen breakage syndrome)