University of Kansas Medical Center

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- PRE-REGISTRATION (STEP 0): Histologically confirmed muscle-invasive urothelial
carcinoma of the urethra, bladder, ureter or renal pelvis

- PRE-REGISTRATION (STEP 0): Variant histology, including neuroendocrine
differentiation, sarcomatoid, micropapillary, glandular, trophoblastic, Mullerian,
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 (STEP 0): Radical surgery (cystectomy with lymph node dissection or
nephroureterectomy or ureterectomy) must be ≥ 3 weeks and ≤ 12 weeks (central
Signatera pathway) or ≤ 16 weeks (commercial Signatera pathwary) prior to
pre-registration. Patients who have had a partial cystectomy as definitive therapy
are not eligible

- PRE-REGISTRATION (STEP 0): Patients who have had a partial cystectomy as definitive
therapy are not eligible

- PRE-REGISTRATION (STEP 0): 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 (STEP 0): No evidence of residual cancer or metastasis after
radical cystectomy or nephroureterectomy or ureterectomy (imaging is not required
prior to pre-registration but is required prior to registration)

- PRE-REGISTRATION (STEP 0): Have undergone a radical cystectomy nephroureterectomy,
or ureterectomy with pathological evidence of urothelial carcinoma 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 systemic therapy: pT4N0 or
pTanyN+ on radical surgery pathology specimen (i.e., cystectomy,
nephroureterectomy, or ureterectomy) 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 adjuvant cisplatin may be candidates if
they refuse adjuvant cisplatin-based 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 radical surgery specimen
(without prior neoadjuvant systemic therapy) with ctDNA(+) Signatera
results are eligible only if the result was obtained via commercial
testing (central testing is not permitted for this population) (Note:
this is distinct from patients with ypT2N0 who are eligible based on
ii).

- (ii) Patients who received neoadjuvant systemic therapy: ypT2-T4N0 or Nx or
ypTanyN+ on radical surgery (i.e., cystectomy. , nephroureterectomy, or
ureterectomy) pathology specimen. Neoadjuvant systemic therapy may have
included cisplatin-based chemotherapy, cisplatin-based chemotherapy plus
PD-1/PD-L1 blockade, or enfortumab vedotin plus PD-1/PD-L1 blockade

- PRE-REGISTRATION (STEP 0): Patients are required to meet criteria for one of two
criteria:

- 1) Commercial Signatera pathway:

- Available commercial Signatera testing result (i.e., ctDNA+ or ctDNA-)
from blood sample obtained ≥ 3 weeks and ≤ 16 weeks from time of radical
surgery performed as part of standard care

- Sites are required to verify that the commercial Signatera report
demonstrates a complete 16 target assay design and that the test was
designed on exome. This verification is conducted at the site level
during the eligibility review. OR

- Central Signatera pathway:

- Pre-registration samples are to be submitted after pre-registration, at ≥
3 weeks but ≤ 12 weeks from the time of radical surgery

- Ineligible patients for the commercial pathway must use the central
Signatera pathway and provide tumor tissue as part of the A032103
study

- For patients who have not had neoadjuvant chemotherapy, tumor tissue
is preferred from the radical surgery specimen

- For patients who have had neoadjuvant therapy, tissue is preferred
from the pre-chemotherapy specimen diagnosing muscle-invasive disease
(e.g., transurethral resection of bladder tumor specimen)

- PRE-REGISTRATION (STEP 0): Age >= 18 years

- PRE-REGISTRATION (STEP 0): ECOG performance status 0-2

- PRE-REGISTRATION (STEP 0): Not pregnant and not nursing, because this study involves
an agent that has known genotoxic, mutagenic and teratogenic effects

- PRE-REGISTRATION (STEP 0): No postoperative adjuvant systemic therapy after radical
surgery

- PRE-REGISTRATION (STEP 0): No adjuvant radiation after radical surgery

- PRE-REGISTRATION (STEP 0): No treatment with any other type of investigational agent
=< 4 weeks before pre-registration

- PRE-REGISTRATION (STEP 0): No previous treatment with LAG-3 blockade therapy

- PRE-REGISTRATION (STEP 0): 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 (STEP 0): Absolute neutrophil count (ANC) >= 1,200/mm^3

- PRE-REGISTRATION (STEP 0): Platelet count >= 100,000/mm^3

- PRE-REGISTRATION (STEP 0): Hemoglobin >= 8 g/dL

- PRE-REGISTRATION (STEP 0): 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 (STEP 0): Aspartate aminotransferase (AST)/alanine aminotransferase
(ALT) =< 3 x ULN

- PRE-REGISTRATION (STEP 0): 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 (STEP 0): For women of childbearing potential only: A negative
urine or serum pregnancy test done =< 14 days prior to pre-registration is required

- PRE-REGISTRATION (STEP 0): Not currently requiring hemodialysis

- PRE-REGISTRATION (STEP 0): No current or prior history of myocarditis

- PRE-REGISTRATION (STEP 0): No history of a grade ≥ 3 immune related adverse event
with prior PD-1/PD-L1 blockade in the neoadjuvant setting

- PRE-REGISTRATION (STEP 0): 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 (STEP 0): Patients with vitiligo, endocrine deficiencies including
type I diabetes mellitus, thyroiditis managed with replacement hormones including
physiologic corticosteroids are eligible.

- PRE-REGISTRATION (STEP 0): 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 (STEP 0): No current pneumonitis or prior history of non-infectious
pneumonitis that required steroids within the previous 5 years.

- PRE-REGISTRATION (STEP 0): 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 (STEP 0): 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 (STEP 0): Human immunodeficiency virus (HIV)-infected patients on
effective anti-retroviral therapy with undetectable viral load within 6 months are
eligible.

- PRE-REGISTRATION (STEP 0): No concurrent antineoplastic therapy including
anti-hormonal treatments used for cancer therapy (e.g., leuprolide, antiandrogens)

- PRE-REGISTRATION (STEP 0): No current immunosuppressive agents (except for
corticosteroids as described below).

- PRE-REGISTRATION (STEP 0): 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 (STEP 1): Patient must have had radical cystectomy and lymph node
dissection or nephroureterectomy or ureterectomy =< 18 weeks prior to registration.

- REGISTRATION (STEP 1): Must have evaluable ctDNA Signatera assay result (i.e.,
ctDNA+ or ctDNA-) based on either:

- Commercial Signatera result OR

- Central Signatera testing result (i.e. testing that was performed as part of
A032103.)

- REGISTRATION (STEP 1): 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 lymph 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 (STEP 1): No major surgery =< 3 weeks before registration.

- REGISTRATION (STEP 1): 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

- REGISTRATION (STEP 1): No change since Step 0 pre-registration in clinical condition
and/or laboratory tests that would impact the safety of nivolumab +/- relatlimab
administration in the opinion of the treating investigator

- REGISTRATION (STEP 1): No evidence of high grade urothelial cancer in the bladder
for patients with primary urothelial cancers of the upper urinary tract

- RE-REGISTRATION (STEP 2) 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 as part of A032103

- RE-REGISTRATION (STEP 2) 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[+]).

- RE-REGISTRATION (STEP 2) COHORT B, ARM 4 PATIENTS INITIATING NIVOLUMAB AFTER
CONVERSION OF ctDNA ASSAY FROM ctDNA(-) to ctDNA (+):

- In the opinion of the treating investigator, patient clinical condition and
laboratory tests would not impact the safety of nivolumab administration in the
opinion of the treating investigator