Avelumab in Combination With Fluorouracil and Mitomycin or Cisplatin and Radiation Therapy in Treating Participants With Muscle-Invasive Bladder Cancer

PRIMARY OBJECTIVES:

I. To evaluate the complete response rate of concurrent chemotherapy radiation treatment
combined with avelumab for patients with muscle invasive bladder cancer.

SECONDARY OBJECTIVES:

I. To evaluate the safety and toxicity (adverse event profile) of concurrent chemotherapy
radiation treatment combined with avelumab.

II. To evaluate quality of life (QoL) at 1 year of concurrent chemotherapy radiation
treatment combined with avelumab.

III. To evaluate progression-free survival and relapse-free survival at 1 year with
concurrent chemotherapy radiation treatment combined with avelumab.

CORRELATIVE OBJECTIVES:

I. To explore biomarkers that may predict response to avelumab in the muscle invasive
population.

II. To evaluate the association of tumor mutational burden with response to concurrent chemo-
radiation and immunotherapy.

III. To evaluate whether concurrent chemoradiation and immunotherapy after maximal
transurethral resection of bladder tumor (TURBT) is associated with a decrease in circulating
Bim+CD11a^high PD-1+CD8+ T-cells and myeloid-derived suppressor cells (MDSCs).

OUTLINE:

Participants receive avelumab intravenously (IV) over 60 minutes every 14 days for a total of
10 courses in the absence of disease progression or unacceptable toxicity. Beginning 29 days
after the first dose of avelumab, participants receive either fluorouracil IV on days 1-5 and
16-20 during radiation therapy (RT) and mitomycin IV on day 1 of course 3, or cisplatin IV
starting on day 1 of courses 3-5 for up to 6 weeks in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, participants are followed up at 30 days, 6, 9, and 12
months.

Inclusion Criteria:

- Histologic proof of T2-T4a N0M0 (American Joint Committee on Cancer [AJCC] 8th
edition) with predominant urothelial carcinoma. Mixed histologies are acceptable
provided urothelial carcinoma is the predominant histology. Small cell urothelial
carcinoma is excluded.

- Cystoscopy with maximal TURBT performed =< 70 days of study registration. NOTE: Both
completely resectable or partially resectable tumors are eligible as long as the
treating urologist attempted complete resection. Exam under anesthesia needs to be
performed and documented.

- Absolute neutrophil count (ANC) >= 1500/mm^3 =< 28 days prior to registration.

- Platelets (PLT) 100,000/mm^3 =< 28 days prior to registration.

- Total bilirubin =< 1.5 upper limit of normal (ULN) =< 28 days prior to registration.

- Aspartate transaminase (AST) =< 2.5 x ULN (=< 5 x ULN for patients with liver
involvement) =< 28 days prior to registration.

- Alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN for patients with liver
involvement) =< 28 days prior to registration.

- Hemoglobin (Hgb) >= 9 gm/dl =< 28 days prior to registration.

- Calculated creatinine clearance must be >= 30 ml/min using the Cockcroft-Gault formula
=< 28 days prior to registration.

- Eastern Cooperative Oncology Group (ECOG) performance status (PS 0, 1, 2).

- Ability to provide informed written consent.

- Willing to return to enrolling institution for follow-up (during the active monitoring
phase of the study).

- Life expectancy >= 6 months.

- Negative serum pregnancy test done =< 14 days prior to registration, for women of
childbearing potential only.

Exclusion Criteria:

- Patients with locally advanced unresectable (T4b) or metastatic urothelial carcinoma
(N1M0-1) as assessed on baseline radiographic imaging obtained =< 70 days prior to
study registration. The required radiographic imaging includes:

- Abdomen/pelvis computed tomography (CT) or magnetic resonance imaging (MRI) scan

- Chest x-ray or CT scan.

- Patients with concurrent urothelial carcinoma and/or related variants anywhere outside
bladder

- NOTE: Patients with history of non-invasive (Ta, Tis) upper tract urothelial
carcinoma that has been definitively treated with at least one post-treatment
disease assessment (i.e. cytology, biopsy, imaging) that demonstrates no evidence
of residual disease are eligible.

- A prior or concurrent malignancy of any other site or histology unless the patient has
been disease-free for > 2 years prior to registration except for:

- Non-melanoma skin cancer and/or localized prostate cancer (T2 a or b , Gleason <
3+4) or carcinoma in situ of the uterine cervix which has been adequately treated
=< 2 years prior to registration

- Or undergoing active surveillance per standard-of-care management (e.g., chronic
lymphocytic leukemia Rai stage 0, prostate cancer with Gleason score =< 3+4, and
prostate-specific antigen [PSA] =< 10 mg/mL, etc.).

- Patients who have received the last administration of an anti-cancer therapy including
chemotherapy, immunotherapy, and monoclonal antibodies =< 4 weeks prior to
registration, or who have not recovered from the side effects of such therapy.

- EXCEPTION: Except single dose intravesical chemotherapy administered after TURBT.

- Patients who have received prior therapy with immune checkpoint inhibitors (e.g.
anti-PD-1, anti-PD-L1, anti-LAG3, anti-CTLA-4, anti-TIM3) or immune co-stimulatory
molecules (e.g. anti-CD137, anti-OX40, anti-GITR) directed agents.

- Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or
intra-pelvic), open biopsy or significant traumatic injury =< 4 weeks prior to
registration, or who have not recovered from side effects of such procedure or injury
prior to registration.

- NOTE: Patients who have had minor procedures (i.e. TURBT) or percutaneous
biopsies prior to registration are eligible.

- Patients with history of cirrhosis, alcoholic or non-alcoholic steatohepatitis (NASH),
auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis.

- Patient with history of prior solid organ or allogeneic bone marrow transplant.

- Clinically significant cardiac diseases, including any of the following:

- History or presence of serious uncontrolled ventricular arrhythmias.

- Clinically significant resting bradycardia.

- Any of the following =< 3 months prior to registration: myocardial infarction
(MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive
heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack
(TIA), pulmonary embolism (PE).

- Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg
and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without
anti-hypertensive medication(s).

- History of untreated human immunodeficiency virus (HIV)

- NOTE: There is no requirement to screen patients for HIV. Patients with history
of HIV infection are allowed if on effective highly active antiretroviral therapy
(HAART) therapy and CD4 count more than 250.

- History of active hepatitis B infection

- NOTE: There is no requirement to screen patients for hepatitis B.

- Known diagnosis of any condition (i.e. post-hematopoietic or organ transplant,
rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, etc.)
that requires chronic immunosuppressive therapy.

- NOTE: Usage of non-steroidal anti-inflammatory medications (NSAIDS) for the
treatment of osteoarthritis and uric acid synthesis inhibitors for the treatment
of gout are permitted. For questions, please consult the study chair.

- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.
active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable
safety risks or compromise compliance with the protocol.

- Pregnant or breast-feeding women.

- Women of child-bearing potential, who are biologically able to conceive, and not
employing two forms of highly effective contraception. Highly effective contraception
must be used throughout the trial and up to 8 weeks after the last dose of study drug
(e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device).
Women of child-bearing potential, defined as sexually mature women who have not
undergone a hysterectomy or who have not been naturally postmenopausal for at least 12
consecutive months (i.e., who has had menses any time in the preceding 12 consecutive
months), must have a negative serum pregnancy test =< 14 days prior to registration.

- Fertile males not willing to use contraception, as stated above.

- Patients unwilling or unable to comply with the protocol.

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm.

- Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (National Cancer Institute [NCI] Common Terminology Criteria for Adverse
Events [CTCAE] version [v] 5.0 grade >= 3).