Avelumab in Combination With Fluorouracil and Mitomycin or Cisplatin and Radiation Therapy in Treating Participants With Muscle-Invasive Bladder Cancer
Condition: Bladder Carcinoma Infiltrating the Muscle of the Bladder Wall; Stage II Bladder Cancer AJCC v8; Stage II Renal Pelvis Cancer AJCC v8; Stage II Ureter Cancer AJCC v8; Stage II Urethral Cancer AJCC v8; Stage III Bladder Cancer AJCC v8; Stage III Renal Pelvis Cancer AJCC v8; Stage III Ureter Cancer AJCC v8; Stage III Urethral Cancer AJCC v8; Stage IIIA Bladder Cancer AJCC v8; Stage IIIB Bladder Cancer AJCC v8; Urethral Urothelial Carcinoma
MeSH terms: Carcinoma; Urinary Bladder Neoplasms; Urethral Neoplasms; Ureteral Neoplasms; Pelvic Neoplasms; Kidney Neoplasms
Intervention: Avelumab; Cisplatin; Fluorouracil; Mitomycin; Quality-of-Life Assessment; Radiation Therapy
Intervention description: Given IV; Given IV; Given IV; Given IV; Ancillary studies; Undergo RT
Intervention MeSH terms: Cisplatin; Fluorouracil; Mitomycins; Mitomycin; Avelumab; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies the side effects of avelumab and how well it works in combination
      with fluorouracil and mitomycin or cisplatin and radiation therapy in treating participants
      with muscle-invasive bladder cancer. Monoclonal antibodies, such as avelumab, may interfere
      with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as
      fluorouracil, mitomycin, and cisplatin, work in different ways to stop the growth of tumor
      cells, either by killing the cells, by stopping them from dividing, or by stopping them from
      spreading. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors.
      Giving avelumab with chemotherapy and radiotherapy may work better in treating participants
      with muscle-invasive bladder cancer.
    

Eligibility criteria:

        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).