Primary Outcomes:

Primary Outcome 1 - Measure: Clinical complete response (CR)

Primary Outcome 1 - Time Frame: Up to 6 years

Condition:

• Bladder Urothelial Carcinoma
• Stage III Bladder Cancer AJCC v8
• Stage IIIA Bladder Cancer AJCC v8
• Stage IIIB Bladder Cancer AJCC v8

Eligibility

Criteria:
Inclusion Criteria:

- Step 1 (Registration) Inclusion

- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0-2 at the time of registration

- Patient must have histologically proven pure or mixed urothelial cancer of the bladder

- NOTE: Small cell carcinoma is excluded, however other variant histologies are
permitted provided a component of urothelial carcinoma is present

- Prior to receiving any induction chemotherapy, patient must have documented
node-positive and non-metastatic disease (any T, N1-2 M0). Patients with clinical N3
disease are ineligible.

- NOTE: Node positivity will be defined by the official interpretation of imaging
studies. Positive lymph nodes must be imaging read with suspicious lymph node
(LN) >= 1.0 cm in short axis to be eligible, with or without biopsy as documented
by a radiologist at the treating center. LN Biopsy is not mandatory but
encouraged if feasible and safe per physician discretion. Patients with a
negative biopsy of nodes determined to be suspicious on imaging are not eligible.
Please note that for non-muscle invasive disease on TURBT, node-positive disease
MUST be biopsy proven for patient to be eligible

- Induction Chemotherapy Requirements

- For patients registered to this protocol post-completion of induction systemic
chemotherapy:

- Patient must have received at least 3 cycles of induction chemotherapy
(cisplatin-based chemotherapy OR non-cisplatin based chemotherapy) with no
evidence of progressive disease (PD) on post-chemotherapy imaging. The end
of last cycle of induction chemotherapy must be within 12 weeks of
registration

- Patient who have received more than 3 cycles of induction systemic
chemotherapy are also eligible

- Patient must have had a CR, PR or SD to induction chemotherapy on standard
imaging

- NOTE: Patients who have only received 2 cycles of induction
chemotherapy and demonstrated clinical response (complete response [CR]
OR partial response [PR], OR stable disease [SD]) may be considered for
enrollment only after consultation and approval by the study chair
under exceptional circumstances where 3rd cycle cannot be delivered.
Documentation of correspondences with the study chair must be kept on
file. We encourage all patients to get 3 cycles of induction
chemotherapy

- For patients registered to this protocol prior to starting induction systemic
chemotherapy:

- Patient must agree to a planned treatment with 3 cycles of induction
chemotherapy (physician's choice)

- Patient will again be restaged after completion of induction chemotherapy
and prior to randomization to chemoRT +/- MEDI4736 (durvalumab)

- Patient must have a CR, PR or SD to induction chemotherapy on standard
imaging prior to randomization to chemoradiotherapy

- Patient must not have presence of concomitant active upper tract tumors or urethra
tumors. History of previously adequately treated non-muscle invasive bladder cancer
(NMIBC) are eligible; previously treated urothelial cancer or histological variant at
any site outside of the urinary bladder are allowed, provided they have been
Ta/T1/carcinoma in situ (CIS) and post treatment follow up imaging and endoscopic
evaluation shows no evidence of disease

- Patients with previous exposure to immune checkpoint inhibitor for non-muscle invasive
disease are eligible. If given for NMIBC, the last dose must have been completed > 12
months prior to registration

- For patients registered on the study

- Patient must not be pregnant or breast-feeding due to the potential harm to an
unborn fetus and possible risk for adverse events in nursing infants with the
treatment regimens being used

- All patients of childbearing potential must have a blood test or urine study
within 14 days prior to registration to rule out pregnancy

- A patient of childbearing potential is defined as any patient, regardless of
sexual orientation or whether they have undergone tubal ligation, who meets the
following criteria: 1) has achieved menarche at some point, 2) has not undergone
a hysterectomy or bilateral oophorectomy; or 3) has not been naturally
postmenopausal (amenorrhea following cancer therapy does not rule out
childbearing potential) for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months)

- For patients registered prior to induction chemotherapy only:

- Patients of childbearing potential and sexually active patients must not expect
to conceive or father children by using accepted and effected method(s) of
contraception or by abstaining from sexual intercourse from the time of
registration for the duration of their participation in the study and continue
for at least 3 months after the last dose of protocol treatment

- Leukocytes >= 3,000/mcL (obtained < 14 days prior to registration)

- Absolute neutrophil count >= 1,500/mcL (obtained < 14 days prior to registration)

- Hemoglobin >= 9 g/dL (obtained < 14 days prior to registration)

- Platelets >= 100,000/mcL (obtained < 14 days prior to registration)

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days
prior to registration)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN (obtained < 14 days prior to registration)

- Must have adequate renal function as evidenced by calculated (Cockcroft's formula)
creatinine clearance or 24 hours actual creatinine clearance >= 30mL/min. The
creatinine used to calculate the clearance result must have been obtained within 14
days prior to registration. Actual body weight, not ideal body weight, must be used in
the calculation

- Patients with human immunodeficiency virus (HIV) on effective anti-retroviral therapy
with undetectable viral load within 6 months of registration are eligible for this
trial

- Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial. Site is encouraged to discuss
with the study chair if needed prior to registration

- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association Functional Classification. To be
eligible for this trial, patients should be class IIB or better

- Step 2 (Randomization) Inclusion Criteria

- Patient must have an ECOG performance status of 0-2 at the time of randomization

- Patient must undergo selection of concurrent chemotherapy regimen

- Patient must agree to undergo CT simulation and treatment planning within two days of
randomization. If this is the first case registered at the site, then a pre-treatment
radiation therapy (RT) review will be required and will take up to 3 business days.
The patient cannot start radiation treatment prior to successful completion of this
pre-treatment review. Therefore, careful planning is necessary to meet the deadline of
starting radiation within 15 business days of randomization and within 12 weeks of the
end of induction chemotherapy

- NOTE: Chemoradiotherapy should be planned to start up to 12 weeks after the end
of induction chemotherapy, but after imaging and cystoscopic restaging,
randomization, and any pretreatment radiation quality assurance (QA) that is
required

- Patients must not be pregnant or breast-feeding due to the potential harm to an unborn
fetus and possible risk for adverse events in nursing infants with the treatment
regimens being used

- All patients of childbearing potential must have a blood test or urine study
within 14 days prior to registration to rule out pregnancy

- A patient of childbearing potential is defined as any patient, regardless of
sexual orientation or whether they have undergone tubal ligation, who meets the
following criteria: 1) has achieved menarche at some point, 2) has not undergone
a hysterectomy or bilateral oophorectomy; or 3) has not been naturally
postmenopausal (amenorrhea following cancer therapy does not rule out
childbearing potential) for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months)

- Patients of childbearing potential and/or sexually active patients must not expect to
conceive or father children by using accepted and effective method(s) of contraception
or by abstaining from sexual intercourse at least one week prior to the start of
treatment and continue for at least 3 months after the last dose of the protocol
treatment

- Leukocytes >= 3,000/mcL (obtained < 14 days prior to randomization)

- Absolute neutrophil count >= 1,500/mcL (obtained < 14 days prior to randomization)

- Hemoglobin >= 9 g/dL (obtained < 14 days prior to randomization)

- Platelets >= 100,000/mcL (obtained < 14 days prior to randomization)

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained < 14 days
prior to randomization)

- AST (SGOT)/ALT (SGPT) =< 2.5 x institutional ULN (obtained < 14 days prior to
randomization)

- Must have adequate renal function as evidenced by calculated (Cockcroft's formula)
creatinine clearance or 24 hours actual creatinine clearance >= 30 mL/min. The
creatinine used to calculate the clearance result must have been obtained within 14
days prior to randomization. Actual body weight, not ideal body weight, must be used
in the calculation

- Step 3 (Post chemoRT+/- MEDI4736 [durvalumab], prior to starting adjuvant MEDI4736
[durvalumab] versus [vs.] observation) Inclusion Criteria

- Patient must have evaluation to determine clinical outcome post chemoRT+/- MEDI4736
(durvalumab) with imaging and cystoscopy with biopsy confirmation to ensure no
progression and absence of >= T2 disease in the bladder

- Patient must have achieved either complete clinical response OR have demonstrated
clinical benefit prior to continuing onto adjuvant MEDI4736 (durvalumab)

- Patients who are to go on the adjuvant MEDI4736 (durvalumab) arm must have recovered
to at least grade 2 or less immune related adverse events (AE) prior to starting
treatment except for immune related alopecia, clinically asymptomatic
endocrinopathies. For patients who may have gotten immune related AEs during chemoRT+
MEDI4736 (durvalumab), registration could be delayed up to additional 4 weeks to
ensure recovery to at least grade 2 or lower prior to starting adjuvant therapy.
However patients with MEDI4736 (durvalumab) related AEs that require permanent
discontinuation of MEDI4736 (durvalumab) will not continue on the adjuvant treatment
regardless of the response

- ANC >= 1,000 mcL (within 4 weeks of start of day 1 [D1] of adjuvant treatment)

- Hemoglobin >= 8 g/dL (within 4 weeks of start of D1 of adjuvant treatment)

- Platelets >= 70,000 mcL (within 4 weeks of start of D1 of adjuvant treatment)

- Patient on the chemoRT arm must have achieved either complete clinical response OR
have demonstrated clinical benefit prior to be placed on the observation alone arm

Exclusion Criteria:

- Step 1 (Registration) Exclusion

- Patient must not have received any previous radiation therapy to the pelvic area

- For patients with autoimmune conditions, patient must not have history of prior
documented autoimmune disease within the past 2 years

- NOTE: Patient with vitiligo, Grave's disease, eczema or psoriasis (not requiring
systemic treatment within the past 2 years) are not excluded. Patients with
history of completely resolved childhood asthma or atopy are not excluded.
Patients with asthma not requiring more than 10 mg/d or equivalent of prednisone
are not excluded. Patients with well-controlled hypothyroidism on thyroxine
replacement will be eligible as well. Patients with known history of
hypoadrenalism on maintenance steroids will be eligible. Patients with type I
diabetes mellitus will be eligible, provided their disease is well controlled.
History of autoimmune related alopecia is also not an exclusion criteria

- Patient with active or prior documented inflammatory bowel disease (e.g., Crohn's
disease, ulcerative colitis) are not eligible

- Patient with a history of and/or confirmed pneumonitis will not be eligible

- Patient with a history of primary immunodeficiency will not be eligible

- Patient with history of allogeneic organ transplant are not eligible

- Patient must not have clinically significant liver disease that precludes patient from
treatment regimens prescribed on the study (including, but not limited to, active
viral, alcoholic or other autoimmune hepatitis, cirrhosis or inherited liver disease)

- Patient must not have any unresolved toxicity (National Cancer Institute [NCI] CTCAE
grade >= 2) from previous anti-cancer therapy with the exception of alopecia,
vitiligo, and the laboratory values

- NOTE: Patients with grade >= 2 neuropathy will be evaluated on a case-by-case
basis after consultation with the study chair

- NOTE: Patients with irreversible toxicity not reasonably expected to be
exacerbated by treatment with MEDI4736 (durvalumab) may be included only after
consultation with the study chair. Documentation of correspondences with the
study chair must be kept on file

- Step 2 (Randomization) Exclusion Criteria

- Patient must have no signs of progression (CR/PR or SD) based on restaging imaging and
cystoscopy after completion of induction chemotherapy, which consists of:

- Computed tomography (CT) chest, abdomen, or pelvis. Magnetic resonance imaging
(MRI) pelvis can be used instead of CT per treating physician discretion. The
imaging must be done within 4 weeks prior to randomization

- Cystoscopic evaluation and attempt to perform maximal transurethral resection of
bladder tumor (TURBT) performed by the participating urologist ideally within 8
weeks but up to 10 weeks is allowed prior to randomization. If maximal TURBT is
not possible for medical reasons, the enrollment must be discussed and approved
with the study chair. Documentation of correspondences with the study chair must
be kept on file

- For patients with autoimmune conditions: Patient must not have a history of active or
prior documented autoimmune disease within the past 2 years

- NOTE: Patient with vitiligo, Grave's disease, eczema or psoriasis (not requiring
systemic treatment within the past 2 years) are not excluded. Patients with
history of completely resolved childhood asthma or atopy are not excluded.
Patients with asthma not requiring more than 10mg/d or equivalent of prednisone
are not excluded. Patient with well-controlled hypothyroidism on thyroxine
replacement will be eligible as well. Patients with known history of
hypoadrenalism on maintenance steroids will be e
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No