University of Kansas Medical Center

Eligibility

Eligible Ages

Over 18 Years

Eligible Genders

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- PRE-REGISTRATION: Histologically confirmed muscle-invasive urothelial carcinoma of
the bladder. Variant histology, including neuroendocrine differentiation, is allowed
if urothelial cancer is predominant histology (any amount of squamous
differentiation is allowed provided the tumor is not a pure squamous cell cancer)

- PRE-REGISTRATION: Patient must have had radical cystectomy and lymph node dissection
>= 3 weeks, but =< 12 weeks prior to pre-registration. Patients who have had a
partial cystectomy as definitive therapy are not eligible

- PRE-REGISTRATION: No gross cancer at the surgical margins. Microscopic invasive
urothelial carcinoma at the surgical margins (i.e., "positive margins") are allowed.
Carcinoma in situ (CIS) at margins is considered negative margins

- PRE-REGISTRATION: No evidence of residual cancer or metastasis after cystectomy
(imaging is not required prior to pre-registration but is required prior to
registration)

- PRE-REGISTRATION: Have undergone a radical cystectomy with pathological evidence of
urothelial carcinoma of the bladder at high risk of recurrence as described in one
of the two scenarios below (i or ii). The 7th edition of American Joint Committee on
Cancer (AJCC) staging will be utilized.:

- (i) Patients who have not received neoadjuvant cisplatin-based chemotherapy:
pT3-pT4* or pT0/x-pT4/N+ on cystectomy and are not eligible for adjuvant
cisplatin chemotherapy

- (i) Patients ineligible for cisplatin due to at least one of the following
criteria and reason for ineligibility should be documented:

- (i) Creatinine Clearance (using Cockcroft-Gault): < 60 mL/min

- (i) Common Terminology Criteria for Adverse Events (CTCAE) version 5,
grade >= 2 audiometric hearing loss

- (i) CTCAE version 5, grade >= 2 or above peripheral neuropathy

- New York Heart Association Class III heart failure

- (i) Eastern Cooperative Oncology Group (ECOG) performance status = 2

- (i) Patients who are eligible for cisplatin may be candidates if they
refuse available adjuvant chemotherapy, despite being informed by the
investigator about the treatment options. The patient's refusal must be
documented.

- (i) Patients with pT2N0 urothelial cancer on cystectomy (without
prior neoadjuvant chemotherapy) with ctDNA(+) Signatera results based
on an assay performed post-cystectomy as part of routine care outside
of the study may proceed with pre-registration but require
confirmation of ctDNA(+) Signatera testing on repeat "central
testing" in the context of A032103 testing. Patients with pT2N0 with
central testing not confirming ctDNA(+) will not be eligible for
A032103 (Note: this is distinct from patients with ypT2N0 who are
eligible based on ii).

- (ii) Patients who received cisplatin-based neoadjuvant chemotherapy: ypT2-ypT4
or ypT0/x-pT4/N+ on cystectomy

- PRE-REGISTRATION: Available tumor tissue for central Signatera testing to be
submitted after pre-registration. Central testing is defined as testing performed as
part of the A032103 study prior to registration and is provided by the study and not
routine standard commercial testing. Patients who have already had Signatera testing
performed as part of routine care will require repeat central testing as part of the
A032103 study to be eligible for registration/randomization. Tumor tissue from the
cystectomy is preferred over tissue from prior transurethral resection

- PRE-REGISTRATION: Age >= 18 years

- PRE-REGISTRATION: ECOG Performance Status 0-2

- PRE-REGISTRATION: Not pregnant and not nursing, because this study involves an agent
that has known genotoxic, mutagenic and teratogenic effects

- PRE-REGISTRATION: No postoperative/adjuvant systemic therapy after cystectomy

- PRE-REGISTRATION: No adjuvant radiation after cystectomy

- PRE-REGISTRATION: No treatment with any other type of investigational agent =< 4
weeks before pre-registration

- PRE-REGISTRATION: Not have ever received prior treatment with PD-1/PD-L1 blockade.

- PRE-REGISTRATION: Not have ever received prior treatment with LAG-3 blockade.

- PRE-REGISTRATION: 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

- PRE-REGISTRATION: Absolute Neutrophil Count (ANC) >= 1,200/mm^3

- PRE-REGISTRATION: Platelet count >= 100,000/mm^3

- PRE-REGISTRATION: Hemoglobin >= 8 g/dL

- PRE-REGISTRATION: Creatinine =< 1.5 x upper limit of normal (ULN) or calculated
(calc.) creatinine clearance > 30 mL/min (using either Cockcroft-Gault formula or
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation

- PRE-REGISTRATION: Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =<
3 x ULN

- PRE-REGISTRATION: Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in
patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

- PRE-REGISTRATION: For women of childbearing potential only: A negative urine or
serum pregnancy test done =< 14 days prior to pre-registration is required

- PRE-REGISTRATION: Not currently requiring hemodialysis

- PRE-REGISTRATION: No current or prior history of myocarditis

- PRE-REGISTRATION: No active autoimmune disease or history of autoimmune disease that
might recur, which may affect vital organ function or require immune suppressive
treatment including systemic corticosteroids. These include but are not limited to
patients with a history of immune related neurologic disease, multiple sclerosis,
autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis;
systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective
tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative
colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN),
Stevens- Johnson syndrome, or phospholipid syndrome because of the risk of
recurrence or exacerbation of disease.

- PRE-REGISTRATION: Patients with vitiligo, endocrine deficiencies including type I
diabetes mellitus, thyroiditis managed with replacement hormones including
physiologic corticosteroids are eligible.

- PRE-REGISTRATION: Patients with rheumatoid arthritis and other arthropathies,
Sjögren's syndrome and psoriasis controlled with topical medication and patients
with positive serology, such as antinuclear antibodies (ANA), anti-thyroid
antibodies should be evaluated for the presence of target organ involvement and
potential need for systemic treatment but should otherwise be eligible.

- PRE-REGISTRATION: No current pneumonitis or prior history of non-infectious
pneumonitis that required steroids within the previous 5 years.

- PRE-REGISTRATION: No known active hepatitis B (e.g., hepatitis B surface antigen
[HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid
[RNA] [qualitative] is detected).

- PRE-REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV)
infection, the HBV viral load must be undetectable on suppressive therapy, if
indicated. Patients with a history of hepatitis C virus (HCV) infection must have
been treated and cured. For patients with HCV infection who are currently on
treatment, they are eligible if they have an undetectable HCV viral load.

- PRE-REGISTRATION: Human immunodeficiency virus (HIV)-infected patients on effective
anti-retroviral therapy with undetectable viral load within 6 months are eligible.

- PRE-REGISTRATION: No concurrent antineoplastic therapy.

- PRE-REGISTRATION: No current immunosuppressive agents (with the exception of
corticosteroids as described below).

- PRE-REGISTRATION: No condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
medications within 14 days of pre-registration (with the exception of steroid
pre-medications for contrast allergies). Inhaled or topical steroids and adrenal
replacement doses < 10 mg daily prednisone equivalents are permitted in the absence
of active autoimmune disease.

- REGISTRATION: Patient must have had radical cystectomy and lymph node dissection =<
18 weeks prior to registration.

- REGISTRATION: Must have evaluable ctDNA Signatera assay result (i.e., ctDNA[+]or
ctDNA[-]) based on test performed as part of central testing after pre-registration
to A032103. Central testing is defined as testing performed as part of the A032103.
Local/commercial testing results may not be used for registration to A032103

- Cisplatin-ineligible (or cisplatin-declining) patients with a pT2N0 urothelial
cancer on cystectomy who were pre-registered based on routine standard care
ctDNA(+) Signatera testing must have confirmed ctDNA(+) Signatera testing on
central testing. If central Signatera testing yields a ctDNA(-) result, these
patients are ineligible. NOTE: This is a distinct consideration from patients
with ypT2-4 and/or ypN+ urothelial cancer (i.e., patients who had received
neoadjuvant cisplatin-based chemotherapy) who are eligible with either ctDNA(+)
or ctDNA(-) central Signatera testing

- REGISTRATION: All patients must have confirmed disease-free status defined as no
measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or
definitive non-measurable radiographic metastatic disease, within 60 days prior to
registration. Patients with equivocal nodes less than 15 mm in short axis, or < 10
mm in long axis for non-lymph node lesions, not considered by the investigator to
represent malignant disease will be eligible. Attempts should be made to resolve the
etiology of equivocal lesions with complementary imaging (e.g., PET scan) or biopsy.

- REGISTRATION: No major surgery =< 3 weeks before registration.

- REGISTRATION: No live vaccine within 30 days prior to registration. Examples of live
vaccines include, but are not limited to, the following: measles, mumps, rubella,
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette- Guerin
(BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally
killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g.,
FluMist [registered trademark]) are live attenuated vaccines and are not allowed.
Coronavirus disease 2019 (COVID-19) vaccines are not live vaccines and are allowed

- COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM
ctDNA(-) to ctDNA (+):

- Patient must have converted to ctDNA(+) during serial monitoring performed
centrally in the setting of the A032103 study

- COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM
ctDNA(-) to ctDNA (+):

- No evidence of metastatic disease on the most recent scheduled imaging
assessment as outlined in the study calendar (no repeat imaging is necessary
specifically at the time of the conversion from ctDNA[-] to ctDNA[+]).

- COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM
ctDNA(-) to ctDNA (+):

- No change in clinical condition and/or laboratory tests that would impact the
safety of nivolumab in the opinion of the treating investigator

- COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER CONVERSION OF ctDNA ASSAY FROM
ctDNA(-) to ctDNA (+):

- =< 6 weeks from reporting of ctDNA(+) result by Natera.