A032103: MODERN: An Integrated Phase 2/3 and Phase 3 Trial of MRD-Based Optimization of ADjuvant ThErapy in URothelial CaNcer

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.