Durvalumab and Standard Chemotherapy Before Surgery in Treating Patients With Variant Histology Bladder Cancer

Inclusion Criteria:

   - Signed informed consent.

   - Eastern Collaborative Oncology Group (ECOG) performance status score of 0 or 1.

   - Body weight > 30 kg.

   - Absolute neutrophil count (ANC) >= 1500 mm^3 (within 28 days before the first study
   treatment).

   - Hemoglobin >= 9.0 g/dL (within 28 days before the first study treatment).

   - Platelet count >= 100,000 per mm^3 (within 28 days before the first study treatment).

   - Serum bilirubin =< 1.5 X upper limit of normal (ULN) (within 28 days before the first
   study treatment). Subjects with Gilbert's syndrome will be considered after
   consultation with the principal investigator (PI).

   - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X ULN
   (within 28 days before the first study treatment).

   - For subjects who will be treated with dose dense methotrexate, vinblastine,
   doxorubicin, and cisplatin (DD MVAC) or cisplatin and gemcitabine (CG), creatinine
   clearance >= 50 mL/min as measured based on Cockcroft-Gault glomerular filtration rate
   estimation (within 28 days before the first study treatment).

   - For subjects who will be treated with carboplatin and gemcitabine (Carbo Gem),
   creatinine clearance >= 30 mL/min as measured based on Cockcroft-Gault glomerular
   filtration rate estimation (within 28 days before the first study treatment).

   - Anticipated life expectancy of >= 12 weeks as assessed by the investigator.

   - Histologically proven carcinoma of the bladder of variant urothelial carcinoma
   histologies which include squamous, adenocarcinoma, nested, plasmacytoid,
   micropapillary, glandular differentiation, lipid cell, clear cell, undifferentiated,
   giant cell, trophoblastic, sarcomatoid, carcinosarcoma; subjects with mixed cell types
   are eligible.

   - Clinical T stage 2 (cT2) T4a, N0 N1, M0 disease. Clinical T stage is based on the
   transurethral resection of bladder tumor (TURBT) sample and imaging studies. Subjects
   must undergo cystoscopy and TURBT as part of screening within 30 days prior to
   registration.

   - Abdominal/pelvic imaging by computed tomography (CT) or magnetic resonance imaging
   (MRI) scan; chest imaging by CT scan or x-ray (CT/positron emission tomography (PET)
   within 30 days prior to registration.

   - Resting 12 lead electrocardiogram (ECG) documenting Fridericia's correction formula
   (QTcF) =< 470 ms.

   - Consent to provide a formalin fixed paraffin embedded (FFPE) tissue block and 1
   hematoxylin and eosin (H and E) slide (preferred) or one of the following:

      - 10 unstained slides and 1 H and E slide OR

      - Tissue block punches and 1 H and E slide, OR

      - 4 to 6 cores and 1 H and E slide.

   - Willing and able to comply with the protocol for the duration of the study including
   undergoing treatment, scheduled visits and examinations including follow up.

   - For female subjects:

      - Women < 50 years of age would be considered post-menopausal if they have been
      amenorrheic for 12 months or more following cessation of exogenous hormonal
      treatments and if they have luteinizing hormone and follicle stimulating hormone
      levels in the post-menopausal range for the institution or underwent surgical
      sterilization (bilateral oophorectomy or hysterectomy).

      - Women >= 50 years of age would be considered post-menopausal if they have been
      amenorrheic for 12 months or more following cessation of all exogenous hormonal
      treatments, had radiation induced menopause with last menses > 1 year ago, had
      chemotherapy induced menopause with last menses > 1 year ago, or underwent
      surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
      hysterectomy).

Exclusion Criteria:

   - Prior treatment with systemic cytotoxic chemotherapy for muscle invasive bladder
   cancer (MIBC).

   - Class III or IV heart failure, according to New York Heart Association
   Classifications. For patient on the dd MVAC or Cis-Gem arm, left ventricular ejection
   fraction of less than 50%

   - Administration of an investigational therapeutic agent within 28 days of protocol
   registration.

   - Current participation in a trial using an investigational agent. Subjects may
   participate in non-interventional, observational studies.

   - Prior treatment with an anti-programmed cell death 1(PD1) or anti--programmed cell
   death ligand 1(PDL1) inhibitor including durvalumab.

   - Receiving chronic systemic steroid therapy in dosing exceeding 10 mg daily of
   prednisone or equivalent per day within 7 days prior to the first dose of study
   treatment.

   - History of another malignancy within 5 years before the first dose of study drug, or
   any evidence of residual disease from a previously diagnosed malignancy. Subjects with
   the following are allowed on study:

      - Adequately treated non melanoma skin cancer or lentigo maligna without evidence
      of disease

      - Adequately treated carcinoma in situ without evidence of disease e.g., cervical
      cancer in situ.

   - Immunosuppressive medication within 28 days before the first dose of durvalumab, with
   the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids
   at physiological doses, which are not to exceed 10 mg/day of prednisone, or an
   equivalent corticosteroid. The following are exceptions to this criterion:

      - Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
      articular injection)

      - Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
      prednisone or its equivalent

      - Steroids as premedication for hypersensitivity reactions (e.g., CT scan
      premedication) or anti emetic during chemotherapy.

   - History of allogenic organ transplantation.

   - Active or prior documented autoimmune or inflammatory disorders (including
   inflammatory bowel disease [e.g., colitis or Crohn's disease]), diverticulitis (with
   the exception of diverticulosis), systemic lupus erythematosus, sarcoidosis syndrome,
   or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid
   arthritis, hypophysitis, uveitis, etc). The following are exceptions to this
   criterion:

      - Subjects with vitiligo or alopecia

      - Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on
      hormone replacement

      - Any chronic skin condition that does not require systemic therapy

      - Subjects with celiac disease controlled by diet alone.

   - Uncontrolled intercurrent illness, including but not limited to, ongoing or active
   infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
   angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
   gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
   situations that would limit compliance with study requirement, substantially increase
   risk of incurring adverse events (AEs) or compromise the ability of the subject to
   give written informed consent.

   - History of active primary immunodeficiency.

   - Active infection including:

      - Tuberculosis (clinical evaluation that includes clinical history, physical
      examination and radiographic findings, and tuberculosis (TB) testing in line with
      local practice)

      - Hepatitis B (known positive hepatitis B virus (HBV) surface antigen (HBsAg)
      result)

      - Hepatitis C

      - Human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies).

      - Subjects with a past or resolved HBV infection (defined as the presence of
      hepatitis B core antibody (anti HBc) and absence of HBsAg) are eligible. Subjects
      positive for hepatitis C (HCV) antibody are eligible only if polymerase chain
      reaction is negative for HCV ribonucleic acid (RNA).

   - Receipt of live attenuated vaccine within 30 days prior to the first dose of study
   medication. Note: subjects, if enrolled, should not receive live vaccine while
   receiving study medication and up to 30 days after the last dose of study medication.

   - Pregnant or lactating.

   - Male or female subject of reproductive potential who are not willing to employ
   effective birth control from screening to 90 days after the last dose of durvalumab
   monotherapy.

   - Known allergy or hypersensitivity to any of the study medications or any of the study
   medication excipients.

   - Judgment by the investigator that the subject is unsuitable to participate in the
   study and the subject is unlikely to comply with study procedures, restrictions and
   requirements.